Innate Immunity: Barriers, Complement, and Cytokines

Overview

Immune system Immune system The body’s defense mechanism against foreign organisms or substances and deviant native cells. It includes the humoral immune response and the cell-mediated response and consists of a complex of interrelated cellular, molecular, and genetic components. Primary Lymphatic Organs

The immune system Immune system The body’s defense mechanism against foreign organisms or substances and deviant native cells. It includes the humoral immune response and the cell-mediated response and consists of a complex of interrelated cellular, molecular, and genetic components. Primary Lymphatic Organs provides defense (immunity) against invading pathogens ranging from viruses Viruses Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells. Virology to parasites; components are interconnected by blood and lymphatic circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment.

Two lines of overlapping defense:

• Innate immunity Innate immunity The capacity of a normal organism to remain unaffected by microorganisms and their toxins. It results from the presence of naturally occurring anti-infective agents, constitutional factors such as body temperature and immediate acting immune cells such as natural killer cells. Innate Immunity: Phagocytes and Antigen Presentation (nonspecific) 
• Adaptive immunity (based on specific antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination recognition):
  • Cell-mediated immunity Cell-mediated immunity Manifestations of the immune response which are mediated by antigen-sensitized T-lymphocytes via lymphokines or direct cytotoxicity. This takes place in the absence of circulating antibody or where antibody plays a subordinate role. Squamous Cell Carcinoma (SCC): adaptive response in cells/tissues involving the T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions
  • Humoral immunity: adaptive response in fluids (“humoral”) involving B cells B cells Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions and immunoglobulins Immunoglobulins Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions

Innate versus adaptive immunity

Components of the Innate Immune System

Innate immune response

• Barriers:
  • 1st line of defense (mechanical, chemical, and biological)
  • Define and line surfaces of the body
  • Secrete substances to remove and reduce pathogens
• Microbe detection: The 1st step is pathogen recognition:
  • Pattern recognition receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (PRRs): proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis distinguishing self from foreign material and recognizing components specific to microbes:
    • Pathogen-associated molecular patterns Pathogen-Associated Molecular Patterns Sepsis and Septic Shock ( PAMPs PAMPs Sepsis and Septic Shock): structures conserved among microbial species
    • Damage-associated molecular patterns Damage-Associated Molecular Patterns Sepsis and Septic Shock (DAMPs) (also known as alarmins): endogenous molecules released from damaged cells
  • According to the location of PRR and PAMP interaction, PRRs can be associated with cells as transmembrane or intracellular receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors:
    • Toll-like receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (TLRs)
    • Retinoic acid-inducible gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics I (RIG-I)-like receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (RLRs)  
    • NOD-like receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (NLRs)
    • C-type lectin receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (CLRs) 
  • Secreted and circulating PRRs are involved when the interaction occurs in body fluids (bloodstream and interstitial fluids):
    • Antimicrobial peptides (AMPs)
    • Collectins
    • Lectins
    • Pentraxins
    • Antimicrobial oligosaccharides Oligosaccharides Carbohydrates consisting of between two (disaccharides) and ten monosaccharides connected by either an alpha- or beta-glycosidic link. They are found throughout nature in both the free and bound form. Basics of Carbohydrates
• Several processes trigger Trigger The type of signal that initiates the inspiratory phase by the ventilator Invasive Mechanical Ventilation a breach in barriers → inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation:
  • Occurs in response to infection or injury
  • Results in the cardinal signs ( swelling Swelling Inflammation, redness Redness Inflammation, heat Heat Inflammation, and pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways) 
  • Once the pathogen is identified via PRRs, proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis are secreted:
    • Cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response (functions include recruitment Recruitment Skeletal Muscle Contraction, cell-to-cell communication Communication The exchange or transmission of ideas, attitudes, or beliefs between individuals or groups. Decision-making Capacity and Legal Competence, and antiviral Antiviral Antivirals for Hepatitis B, antibacterial Antibacterial Penicillins, and antifungal Antifungal Azoles actions)
    • Chemokines Chemokines Class of pro-inflammatory cytokines that have the ability to attract and activate leukocytes. They can be divided into at least three structural branches: c; cc; and cxc; according to variations in a shared cysteine motif. Adaptive Cell-mediated Immunity (cell migration)
    • Complement system (“complements” or assists in eliminating microbes)
    • Some PRRs (e.g., AMPs) are also involved in pathogen elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy.
• Cellular response: Various cells (e.g., phagocytes) are recruited and participate in the microbial killing.
• The immune response is terminated when a need no longer exists ( homeostasis Homeostasis The processes whereby the internal environment of an organism tends to remain balanced and stable. Cell Injury and Death).

Cells of the innate immune system Immune system The body’s defense mechanism against foreign organisms or substances and deviant native cells. It includes the humoral immune response and the cell-mediated response and consists of a complex of interrelated cellular, molecular, and genetic components. Primary Lymphatic Organs

• Many subsets of cells involved in the innate response develop from hematopoietic stem cells Hematopoietic stem cells Progenitor cells from which all blood cells derived. They are found primarily in the bone marrow and also in small numbers in the peripheral blood. Bone Marrow: Composition and Hematopoiesis (HSCs) in the bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis (a primary lymphoid organ):
  • HSCs → common myeloid progenitor → gives rise to:
    • Granulocytes Granulocytes Leukocytes with abundant granules in the cytoplasm. They are divided into three groups according to the staining properties of the granules: neutrophilic, eosinophilic, and basophilic. Mature granulocytes are the neutrophils; eosinophils; and basophils. White Myeloid Cells: Histology: professional phagocytes ( neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation, monocytes Monocytes Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. Innate Immunity: Phagocytes and Antigen Presentation, macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation), eosinophils Eosinophils Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. Innate Immunity: Phagocytes and Antigen Presentation, basophils Basophils Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. Innate Immunity: Phagocytes and Antigen Presentation, and mast cells Mast cells Granulated cells that are found in almost all tissues, most abundantly in the skin and the gastrointestinal tract. Like the basophils, mast cells contain large amounts of histamine and heparin. Unlike basophils, mast cells normally remain in the tissues and do not circulate in the blood. Mast cells, derived from the bone marrow stem cells, are regulated by the stem cell factor. Innate Immunity: Phagocytes and Antigen Presentation
    • Megakaryocytes → platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets: Histology
  • HSCs → common lymphoid progenitor → lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes: Histology (generally undergo activation and proliferation in secondary lymphoid organs Lymphoid organs A system of organs and tissues that process and transport immune cells and lymph. Primary Lymphatic Organs):
    • B cells B cells Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions and T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions: adaptive immunity
    • Natural killer (NK) cells: mostly innate immune response
    • Natural killer T (NKT) cells: bridge innate and adaptive immunity
• Individually, the cells have varying functions and targets in the immune response.
• Crucial roles:
  • Phagocytosis Phagocytosis The engulfing and degradation of microorganisms; other cells that are dead, dying, or pathogenic; and foreign particles by phagocytic cells (phagocytes). Innate Immunity: Phagocytes and Antigen Presentation: Microbes or damaged particles are engulfed and digested.
  • Antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination presentation: performed by dendritic cells Dendritic cells Specialized cells of the hematopoietic system that have branch-like extensions. They are found throughout the lymphatic system, and in non-lymphoid tissues such as skin and the epithelia of the intestinal, respiratory, and reproductive tracts. They trap and process antigens, and present them to T-cells, thereby stimulating cell-mediated immunity. They are different from the non-hematopoietic follicular dendritic cells, which have a similar morphology and immune system function, but with respect to humoral immunity (antibody production). Skin: Structure and Functions, macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation, and B cells B cells Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions, which facilitate antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination recognition by adaptive immunity

Barriers

Mechanical barrier

Epithelial cells line body surfaces and are heavily exposed to antigens.

• Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions keratinocytes Keratinocytes Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. Skin: Structure and Functions:
  • Express mannose-binding receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors: mediate the killing of Candida Candida Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis
  • Regular Regular Insulin shedding and sweat secretion Secretion Coagulation Studies: limits the adhesion Adhesion The process whereby platelets adhere to something other than platelets, e.g., collagen; basement membrane; microfibrils; or other ‘foreign’ surfaces. Coagulation Studies and invasion of microorganisms
• Respiratory, GI, and genitourinary tracts:
  • Mucus, a ciliated layer, and sloughing: reduce the adherence of microbes in the respiratory tract
  • GI tract peristalsis Peristalsis A movement, caused by sequential muscle contraction, that pushes the contents of the intestines or other tubular organs in one direction. Gastrointestinal Motility and urine flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure: limits pathogen attachment

Chemical barrier

• Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions and stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach: Anatomy: produce hydrochloric acid Hydrochloric acid A strong corrosive acid that is commonly used as a laboratory reagent. It is formed by dissolving hydrogen chloride in water. Gastric acid is the hydrochloric acid component of gastric juice. Caustic Ingestion (Cleaning Products) to kill bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology
• Saliva Saliva The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptyalin. Salivary Glands: Anatomy and tears produce lysozyme: breaks up bacterial peptidoglycan Peptidoglycan Penicillins in the cell wall Cell wall The outermost layer of a cell in most plants; bacteria; fungi; and algae. The cell wall is usually a rigid structure that lies external to the cell membrane, and provides a protective barrier against physical or chemical agents. Cell Types: Eukaryotic versus Prokaryotic
• The respiratory and GI tracts produce defensins: positively charged peptides creating holes/ channels Channels The Cell: Cell Membrane in the walls of bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology, fungi Fungi A kingdom of eukaryotic, heterotrophic organisms that live parasitically as saprobes, including mushrooms; yeasts; smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi, commonly known as molds, refer to those that grow as multicellular colonies. Mycology, and viruses Viruses Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells. Virology
• Paneth cells (base of intestinal crypts Intestinal crypts Colon, Cecum, and Appendix: Anatomy): secrete AMPs, defensin, and lysozyme
• Surfactant Surfactant Substances and drugs that lower the surface tension of the mucoid layer lining the pulmonary alveoli. Acute Respiratory Distress Syndrome (ARDS) in the alveoli Alveoli Small polyhedral outpouchings along the walls of the alveolar sacs, alveolar ducts and terminal bronchioles through the walls of which gas exchange between alveolar air and pulmonary capillary blood takes place. Acute Respiratory Distress Syndrome (ARDS): binds to the microbe surface and facilitates phagocytosis Phagocytosis The engulfing and degradation of microorganisms; other cells that are dead, dying, or pathogenic; and foreign particles by phagocytic cells (phagocytes). Innate Immunity: Phagocytes and Antigen Presentation

Biological barrier

Includes:

• Microbiome (commensal organisms living in and on the body):
  • Nonpathogenic, coagulase-negative Staphylococci Coagulase-negative staphylococci Staphylococcus: inhibit the growth of Staphylococcus aureus Staphylococcus aureus Potentially pathogenic bacteria found in nasal membranes, skin, hair follicles, and perineum of warm-blooded animals. They may cause a wide range of infections and intoxications. Brain Abscess by secreting antimicrobial peptides
  • Dysbiosis: a change in the microbiome composition of the GI tract (seen with antibiotic use), which can lead to Clostridioides difficile infection
• IgA IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions and IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis

Cell-associated PRRs

Cell-associated PRRs are expressed in various immune cells and can be intracellular (endolysosomal/cytoplasmic) or transmembrane.

TLRs

• Detect a range of human pathogens
• 10 well-defined TLRs in humans
• TLRs recognize a particular microbial building block (e.g., an amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids sequence of endotoxin Endotoxin Toxins closely associated with the living cytoplasm or cell wall of certain microorganisms, which do not readily diffuse into the culture medium, but are released upon lysis of the cells. Proteus or peptidoglycan Peptidoglycan Penicillins):
  • Transcription factors Transcription Factors Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. Stages of Transcription are activated.
  • The process leads to the synthesis Synthesis Polymerase Chain Reaction (PCR) of proinflammatory cytokines Proinflammatory Cytokines Metabolic Syndrome and cell surface molecules, ultimately resulting in a rapid innate immune response.
• TLR1, TLR2, TLR4, TLR5, and TLR6 recognize microbial cell wall Cell wall The outermost layer of a cell in most plants; bacteria; fungi; and algae. The cell wall is usually a rigid structure that lies external to the cell membrane, and provides a protective barrier against physical or chemical agents. Cell Types: Eukaryotic versus Prokaryotic components:
  • TLR4 identifies lipopolysaccharide Lipopolysaccharide Lipid-containing polysaccharides which are endotoxins and important group-specific antigens. They are often derived from the cell wall of gram-negative bacteria and induce immunoglobulin secretion. The lipopolysaccharide molecule consists of three parts: lipid a, core polysaccharide, and o-specific chains (o antigens). When derived from Escherichia coli, lipopolysaccharides serve as polyclonal b-cell mitogens commonly used in laboratory immunology. Klebsiella (LPS) in the outer membrane of gram-negative bacteria gram-negative bacteria Bacteria which lose crystal violet stain but are stained pink when treated by gram’s method. Bacteriology (involved in septic shock Septic shock Sepsis associated with hypotension or hypoperfusion despite adequate fluid resuscitation. Perfusion abnormalities may include, but are not limited to lactic acidosis; oliguria; or acute alteration in mental status. Sepsis and Septic Shock).
  • TLR4 binds to viral envelope Envelope Bilayer lipid membrane acquired by viral particles during viral morphogenesis. Although the lipids of the viral envelope are host derived, various virus-encoded integral membrane proteins, i.e. Viral envelope proteins are incorporated there. Virology proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis.
  • TLR5 recognizes flagellin from flagellated bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology.
  • TLR1, TLR2, and TLR6 recognize lipoproteins Lipoproteins Lipid-protein complexes involved in the transportation and metabolism of lipids in the body. They are spherical particles consisting of a hydrophobic core of triglycerides and cholesterol esters surrounded by a layer of hydrophilic free cholesterol; phospholipids; and apolipoproteins. Lipoproteins are classified by their varying buoyant density and sizes. Lipid Metabolism.
• TLR3, TLR7, TLR8, TLR9, and TLR10 are cytoplasmic:
  • Recognize nucleic acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance derived from organisms
  • Endogenous nucleic acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance → implicated in autoimmunity Autoimmunity Autoimmunity is a pathologic immune response toward self-antigens, resulting from a combination of factors: immunologic, genetic, and environmental. The immune system is equipped with self-tolerance, allowing immune cells such as T cells and B cells to recognize self-antigens and to not mount a reaction against them. Defects in this mechanism, along with environmental triggers (such as infections) and genetic susceptibility factors (most notable of which are the HLA genes) can lead to autoimmune diseases. Autoimmunity
• TLR3, TLR4, TLR7, TLR8, and TLR9:
  • Trigger Trigger The type of signal that initiates the inspiratory phase by the ventilator Invasive Mechanical Ventilation type-1 interferon ( IFN IFN Interferon (IFN) is a cytokine with antiviral properties (it interferes with viral infections) and various roles in immunoregulation. The different types are type I IFN (IFN-ɑ and IFN-β), type II IFN (IFN-ɣ), and type III IFN (IFN-ƛ). Interferons) production (e.g., IFN-α, IFN-β)
  • Antiviral Antiviral Antivirals for Hepatitis B activity

Description of different TLRs

RLRs

• Located intracellularly (cytoplasmic sensors): recognize the cytoplasm-invading pathogens
• RIG-I
• Recognize viral nucleic acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance 
• Activated RLRs increase the synthesis Synthesis Polymerase Chain Reaction (PCR) of IFN-α and IFN-β, which increases the response to virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology infection.

NLRs

• Located intracellularly (cytoplasmic sensors): recognize the cytoplasm-invading pathogens
• Nucleotide-binding oligomerization domain (NOD)
• Recognize the structures of bacterial peptidoglycans and muramyl dipeptides
• Involved in host defense against viruses Viruses Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells. Virology, parasites, fungi Fungi A kingdom of eukaryotic, heterotrophic organisms that live parasitically as saprobes, including mushrooms; yeasts; smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi, commonly known as molds, refer to those that grow as multicellular colonies. Mycology, and intracellular bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology (e.g., Listeria Listeria Listeria spp. are motile, flagellated, gram-positive, facultative intracellular bacilli. The major pathogenic species is Listeria monocytogenes. Listeria are part of the normal gastrointestinal flora of domestic mammals and poultry and are transmitted to humans through the ingestion of contaminated food, especially unpasteurized dairy products. Listeria Monocytogenes/Listeriosis) 
• Caspase 1 activation: ↑ proinflammatory cytokines Proinflammatory Cytokines Metabolic Syndrome, facilitates pyroptosis Pyroptosis Type of programmed cell death associated with infection by intracellular pathogens. It is characterized by inflammasome formation; activation of caspase 1; and cytokines mediated inflammation. Cell Injury and Death or inflammatory cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death
• Act synergistically with TLRs

CLRs

• Expressed on the cell surface with an associated transmembrane domain
• Recognize carbohydrates Carbohydrates A class of organic compounds composed of carbon, hydrogen, and oxygen in a ratio of cn(H2O)n. The largest class of organic compounds, including starch; glycogen; cellulose; polysaccharides; and simple monosaccharides. Basics of Carbohydrates on microorganisms such as bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology and fungi Fungi A kingdom of eukaryotic, heterotrophic organisms that live parasitically as saprobes, including mushrooms; yeasts; smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi, commonly known as molds, refer to those that grow as multicellular colonies. Mycology:
  • Bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology and yeasts have mannan on the surface ( polysaccharides Polysaccharides Basics of Carbohydrates not found in humans).
  • Mannan-binding lectin (MBL) (also known as mannose-binding protein):
    • Found in dendritic cells Dendritic cells Specialized cells of the hematopoietic system that have branch-like extensions. They are found throughout the lymphatic system, and in non-lymphoid tissues such as skin and the epithelia of the intestinal, respiratory, and reproductive tracts. They trap and process antigens, and present them to T-cells, thereby stimulating cell-mediated immunity. They are different from the non-hematopoietic follicular dendritic cells, which have a similar morphology and immune system function, but with respect to humoral immunity (antibody production). Skin: Structure and Functions and macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation binding mannose in microbes
    • Activates complement
    • Opsonin-enhancing phagocytosis Phagocytosis The engulfing and degradation of microorganisms; other cells that are dead, dying, or pathogenic; and foreign particles by phagocytic cells (phagocytes). Innate Immunity: Phagocytes and Antigen Presentation
  • Dectin-1: recognizes β-glucan in the fungal cell wall Fungal Cell Wall Echinocandins (e.g., Candida Candida Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis)
• Also responsible for recognizing endogenous proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis from necrotic host cells

Secreted and Circulating PRR

Secreted and circulating PRRs include many proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis (e.g., AMP, lectins, collectins).

AMPs

• Secreted PRRs: short, positively charged peptides with natural antimicrobial activity 
• Exhibit activity against bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology, fungi Fungi A kingdom of eukaryotic, heterotrophic organisms that live parasitically as saprobes, including mushrooms; yeasts; smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi, commonly known as molds, refer to those that grow as multicellular colonies. Mycology, viruses Viruses Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells. Virology, and protozoa Protozoa Nitroimidazoles
• Found primarily:
  • Within granules of neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation 
  • In secretions from epithelial cells covering skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions and mucosal surfaces
• Major functions:
  • Cationic AMPs are electrostatically attracted to the negatively charged bacterial surface (with phospholipids Phospholipids Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. Lipid Metabolism).
  • Interaction between peptides and the microbial membrane leads to:
    • Disruption and permeabilization of the microbial membrane
    • Bacterial death
  • AMPs disrupt cellular processes:
    • DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure/ RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure/protein synthesis Synthesis Polymerase Chain Reaction (PCR) 
    • Enzymatic activity
    • Cell-wall synthesis Synthesis Polymerase Chain Reaction (PCR)
  • Immunomodulatory activities:
    • Stimulation of chemotaxis Chemotaxis The movement of leukocytes in response to a chemical concentration gradient or to products formed in an immunologic reaction. Leukocyte Adhesion Deficiency Type 1 
    • Regulation of excessive proinflammatory response (e.g., TLR activity, cytokine production) to avoid harm to the host
    • Regulation of commensal microorganisms by restricting colonization Colonization Bacteriology and providing defense against opportunistic bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology

Types of AMPs

• Defensins:
  • Short peptides with 3 disulfide bonds (protect from protease Protease Enzyme of the human immunodeficiency virus that is required for post-translational cleavage of gag and gag-pol precursor polyproteins into functional products needed for viral assembly. HIV protease is an aspartic protease encoded by the amino terminus of the pol gene. HIV Infection and AIDS activity)
  • α-defensins:
    • Found in neutrophilic granules and intestinal Paneth cells
    • Able to kill microbes directly or indirectly through entrapment in nets
  • β-defensins:
    • Extensively found in epithelial surfaces (e.g., respiratory tract, GI tract)
    • Trauma or infection increases the production
• Cathelicidins:
  • LL-37: C-terminal peptide of cathelicidin antimicrobial peptide ( CAMP cAMP An adenine nucleotide containing one phosphate group which is esterified to both the 3′- and 5′-positions of the sugar moiety. It is a second messenger and a key intracellular regulator, functioning as a mediator of activity for a number of hormones, including epinephrine, glucagon, and acth. Phosphodiesterase Inhibitors) from neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation and epithelial cells induced by vitamin D Vitamin D A vitamin that includes both cholecalciferols and ergocalciferols, which have the common effect of preventing or curing rickets in animals. It can also be viewed as a hormone since it can be formed in skin by action of ultraviolet rays upon the precursors, 7-dehydrocholesterol and ergosterol, and acts on vitamin D receptors to regulate calcium in opposition to parathyroid hormone. Fat-soluble Vitamins and their Deficiencies
  • Play a role in wound healing Wound healing Wound healing is a physiological process involving tissue repair in response to injury. It involves a complex interaction of various cell types, cytokines, and inflammatory mediators. Wound healing stages include hemostasis, inflammation, granulation, and remodeling. Wound Healing, angiogenesis Angiogenesis Bartonella, and removal of dead cells
  • Neutralizing activity against LPS
• Other AMPs:
  • AMPs expressed in the eye:
    • C-terminal fragments of keratin Keratin A class of fibrous proteins or scleroproteins that represents the principal constituent of epidermis; hair; nails; horny tissues, and the organic matrix of tooth enamel. Two major conformational groups have been characterized, alpha-keratin, whose peptide backbone forms a coiled-coil alpha helical structure consisting of type I keratin and a type II keratin, and beta-keratin, whose backbone forms a zigzag or pleated sheet structure. Alpha-keratins have been classified into at least 20 subtypes. In addition multiple isoforms of subtypes have been found which may be due to gene duplication. Seborrheic Keratosis 
    • Lysozyme 
    • Lactoferrin 
    • Lipocalin 
  • AMPs expressed in the urinary tract Urinary tract The urinary tract is located in the abdomen and pelvis and consists of the kidneys, ureters, urinary bladder, and urethra. The structures permit the excretion of urine from the body. Urine flows from the kidneys through the ureters to the urinary bladder and out through the urethra. Urinary Tract: Anatomy:
    • Lipocalin 2: defends against uropathogenic Escherichia coli Escherichia coli The gram-negative bacterium Escherichia coli is a key component of the human gut microbiota. Most strains of E. coli are avirulent, but occasionally they escape the GI tract, infecting the urinary tract and other sites. Less common strains of E. coli are able to cause disease within the GI tract, most commonly presenting as abdominal pain and diarrhea. Escherichia coli 
    • Uromodulin: a protein binding the pili Pili Filamentous or elongated proteinaceous structures which extend from the cell surface in gram-negative bacteria that contain certain types of conjugative plasmid. These pili are the organs associated with genetic transfer and have essential roles in conjugation. Normally, only one or a few pili occur on a given donor cell. This preferred use of ‘pili’ refers to the sexual appendage, to be distinguished from bacterial fimbriae, also known as common pili, which are usually concerned with adhesion. Salmonella of bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology, limiting bacterial attachment, and facilitating flushing away by urine
  • Hepcidin Hepcidin Forms of hepcidin, a cationic amphipathic peptide synthesized in the liver as a prepropeptide which is first processed into prohepcidin and then into the biologically active hepcidin forms, including in human the 20-, 22-, and 25-amino acid residue peptide forms. Hepcidin acts as a homeostatic regulators of iron metabolism and also possesses antimicrobial activity. Hereditary Hemochromatosis:
    • Regulates iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements metabolism (dietary iron absorption Iron absorption Digestion and Absorption and distribution)
    • Relevant action against iron-dependent organisms such as malaria Malaria Malaria is an infectious parasitic disease affecting humans and other animals. Most commonly transmitted via the bite of a female Anopheles mosquito infected with microorganisms of the Plasmodium genus. Patients present with fever, chills, myalgia, headache, and diaphoresis. Plasmodium/Malaria, tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis, and HIV-1 HIV-1 The type species of lentivirus and the etiologic agent of aids. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte. HIV Infection and AIDS

Antibacterial Antibacterial Penicillins oligosaccharides Oligosaccharides Carbohydrates consisting of between two (disaccharides) and ten monosaccharides connected by either an alpha- or beta-glycosidic link. They are found throughout nature in both the free and bound form. Basics of Carbohydrates

• Found in human milk: provides newborn Newborn An infant during the first 28 days after birth. Physical Examination of the Newborn protection
• Biofilms Biofilms Encrustations formed from microbes (bacteria, algae, fungi, plankton, or protozoa) embedded in an extracellular polymeric substance matrix that is secreted by the microbes. They occur on body surfaces such as teeth (dental deposits); inanimate objects, and bodies of water. Biofilms are prevented from forming by treating surfaces with dentifrices; disinfectants; anti-infective agents; and anti-fouling agents. Proteus utilized by bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology (for protection) are broken down by oligosaccharides Oligosaccharides Carbohydrates consisting of between two (disaccharides) and ten monosaccharides connected by either an alpha- or beta-glycosidic link. They are found throughout nature in both the free and bound form. Basics of Carbohydrates.

Lectins

• Proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis binding to microbial carbohydrates Carbohydrates A class of organic compounds composed of carbon, hydrogen, and oxygen in a ratio of cn(H2O)n. The largest class of organic compounds, including starch; glycogen; cellulose; polysaccharides; and simple monosaccharides. Basics of Carbohydrates and triggering the lectin complement pathway
• Examples:
  • Galectin: disrupts bacterial membrane, inhibits influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology replication, and brings on cell apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage
  • MBL: identifies mannose residues and opsonizes; activates the complement pathway

Collectins

• A family of lectins with collagen-like proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis 
• Bind BIND Hyperbilirubinemia of the Newborn to carbohydrate or lipid microbial molecules
• Functions:
  • Complement activation Complement Activation The sequential activation of serum complement proteins to create the complement membrane attack complex. Factors initiating complement activation include antigen-antibody complexes, microbial antigens, or cell surface polysaccharides. Systemic Lupus Erythematosus
  • Opsonization
  • Microbial lysis
• Members of the family include:
  • C1q
  • MBL: a collectin and acute-phase reactant produced by the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy 
  • Surfactant Surfactant Substances and drugs that lower the surface tension of the mucoid layer lining the pulmonary alveoli. Acute Respiratory Distress Syndrome (ARDS) proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis A and D:
    • Produced by alveolar type II cells 
    • Major component of lung surfactant Surfactant Substances and drugs that lower the surface tension of the mucoid layer lining the pulmonary alveoli. Acute Respiratory Distress Syndrome (ARDS) (keeps alveoli Alveoli Small polyhedral outpouchings along the walls of the alveolar sacs, alveolar ducts and terminal bronchioles through the walls of which gas exchange between alveolar air and pulmonary capillary blood takes place. Acute Respiratory Distress Syndrome (ARDS) open)

Pentraxins

• Characterized by the C-terminal pentraxin domain with 5 subunits
• Function: activates the classical pathway of complement with microbial lysis and opsonization
• The family of proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis includes:
  • CRP: a classic, acute-phase reactant (secreted with TLR activation or as the effect of proinflammatory cytokines Proinflammatory Cytokines Metabolic Syndrome)
  • Serum amyloid P (SAP) component: implicated in amyloid deposition disorders such as amyloidosis Amyloidosis Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits. These proteins are frequently byproducts of other pathological processes (e.g., multiple myeloma). Amyloidosis and Alzheimer disease Alzheimer disease As the most common cause of dementia, Alzheimer disease affects not only many individuals but also their families. Alzheimer disease is a progressive neurodegenerative disease that causes brain atrophy and presents with a decline in memory, cognition, and social skills. Alzheimer Disease
  • Pentraxin 3 (PTX 3)

Complement

Immune responses follow the recognition of pathogen molecules. The complement system is 1 response activated in the cascading fashion to destroy microbes.

Complement system

• A major component of both innate and adaptive immunity
• Consists of nearly 60 plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products and membrane proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis with activation occurring in both immune cells and extracellular space. 
• C1q:
  • A circulating, cell-associated PRR
  • Part of C1: the 1st component of the complement system
  • When bound by an antibody (fixed to a microbe, immune complex, or damaged tissue) → the complement cascade Complement cascade The sequential activation of serum complement proteins to create the complement membrane attack complex. Factors initiating complement activation include antigen-antibody complexes, microbial antigens, or cell surface polysaccharides. C3 Deficiency is triggered
• Activated via different pathways

Activation pathways

Complement activation Complement Activation The sequential activation of serum complement proteins to create the complement membrane attack complex. Factors initiating complement activation include antigen-antibody complexes, microbial antigens, or cell surface polysaccharides. Systemic Lupus Erythematosus is through distinctive pathways (all start with a different initiating molecule), but all produce C3b (the central molecule of the complement cascade Complement cascade The sequential activation of serum complement proteins to create the complement membrane attack complex. Factors initiating complement activation include antigen-antibody complexes, microbial antigens, or cell surface polysaccharides. C3 Deficiency):

• Classical pathway (activity assessed by the CH50 CH50 Terminal Complement Pathway Deficiency test):
  • Triggered by antigen-binding antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions (primarily IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis and IgM IgM A class of immunoglobulin bearing mu chains (immunoglobulin mu-chains). Igm can fix complement. The name comes from its high molecular weight and originally being called a macroglobulin. Immunoglobulins: Types and Functions)
  • C1 is C1q in the complex with the 2 proteases Proteases Proteins and Peptides: C1r and C1s (C1q + C1r + C1s):
    • The C1q subcomponent attaches to the Fc Fc Crystallizable fragments composed of the carboxy-terminal halves of both immunoglobulin heavy chains linked to each other by disulfide bonds. Fc fragments contain the carboxy-terminal parts of the heavy chain constant regions that are responsible for the effector functions of an immunoglobulin (complement fixation, binding to the cell membrane via fc receptors, and placental transport). This fragment can be obtained by digestion of immunoglobulins with the proteolytic enzyme papain. Immunoglobulins: Types and Functions portion of the antibody.
    • C1r autoactivates and cleaves C1s.
  • C1s cleaves C4 and then C2 → fragments of C4 and C2 (C4b and C2b respectively) → C3 convertase c3 convertase Serine proteases that cleave complement C3 into complement C3a and complement C3b, or cleave complement C5 into complement C5a and complement C5b. These include the different forms of C3/c5 convertases in the classical and the alternative pathways of complement activation. Both cleavages take place at the c-terminal of an arginine residue. Nephritic Syndrome (C4b2b)
  • C3 convertase c3 convertase Serine proteases that cleave complement C3 into complement C3a and complement C3b, or cleave complement C5 into complement C5a and complement C5b. These include the different forms of C3/c5 convertases in the classical and the alternative pathways of complement activation. Both cleavages take place at the c-terminal of an arginine residue. Nephritic Syndrome cleaves C3 and produces C3b (acting as an opsonin) and C3a (acting as an anaphylatoxin).
  • C5 convertases (C4b2b3b) are formed from cleaved components.
  • C5 convertases → cleave C5 → C5a (an anaphylatoxin) and C5b (initiates the membrane attack complex Membrane attack complex A product of complement activation cascade, regardless of the pathways, that forms transmembrane channels causing disruption of the target cell membrane and cell lysis. It is formed by the sequential assembly of terminal complement components (complement C5b; complement C6; complement C7; complement C8; and complement C9) into the target membrane. The resultant C5b-8-poly-c9 is the ‘membrane attack complex’ or MAC. Type II Hypersensitivity Reaction (MAC))
• Lectin pathway:
  • Also known as the mannan- and mannose-binding pathway
  • Triggered by lectins ( proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis recognizing repetitive patterns of carbohydrates Carbohydrates A class of organic compounds composed of carbon, hydrogen, and oxygen in a ratio of cn(H2O)n. The largest class of organic compounds, including starch; glycogen; cellulose; polysaccharides; and simple monosaccharides. Basics of Carbohydrates (e.g., mannose, N-acetylglucosamine/GlcNAc))
  • MBL binds to mannose.
  • Leads to cleavage of C4 and C2 by MBL-associated serine Serine A non-essential amino acid occurring in natural form as the l-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines; pyrimidines; and other amino acids. Synthesis of Nonessential Amino Acids proteases Proteases Proteins and Peptides (MASPs) (similar to C1s and C1r) → C3 convertase c3 convertase Serine proteases that cleave complement C3 into complement C3a and complement C3b, or cleave complement C5 into complement C5a and complement C5b. These include the different forms of C3/c5 convertases in the classical and the alternative pathways of complement activation. Both cleavages take place at the c-terminal of an arginine residue. Nephritic Syndrome (C4b2b)
  • The cascade proceeds as the classical pathway.
• Alternative pathway:
  • Antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions or lectins are not needed to activate.
  • Dependent on the constant presence of C3 at low levels in the circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment (“C3 tickover”)
  • Tickover occurs at a rate of 1% per hour in the blood, with C3 landing on healthy tissue or engaging with pathogens or debris:
    • On healthy tissue, C3 undergoes inactivation.
    • Without a target, C3 is removed from circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment. 
    • C3 becomes activated upon encountering pathogens or cell debris.
  • Activated C3 binds factor B → bound factor B is lysed by factor D → produces Ba (released) and Bb → forms C3 convertase c3 convertase Serine proteases that cleave complement C3 into complement C3a and complement C3b, or cleave complement C5 into complement C5a and complement C5b. These include the different forms of C3/c5 convertases in the classical and the alternative pathways of complement activation. Both cleavages take place at the c-terminal of an arginine residue. Nephritic Syndrome (C3bBb) 
  • C3 convertase c3 convertase Serine proteases that cleave complement C3 into complement C3a and complement C3b, or cleave complement C5 into complement C5a and complement C5b. These include the different forms of C3/c5 convertases in the classical and the alternative pathways of complement activation. Both cleavages take place at the c-terminal of an arginine residue. Nephritic Syndrome (C3bBb) is stabilized by properdin → C3bBbP
  • C3 convertase c3 convertase Serine proteases that cleave complement C3 into complement C3a and complement C3b, or cleave complement C5 into complement C5a and complement C5b. These include the different forms of C3/c5 convertases in the classical and the alternative pathways of complement activation. Both cleavages take place at the c-terminal of an arginine residue. Nephritic Syndrome continues cleaving more C3 to C3b → amplification loop leads to large deposits of C3b on the target
  • C5 convertase is formed (C3bBb3b) and C5 is subsequently cleaved.
• Effectors produced from activated pathways:
  • Anaphylatoxins: C3a, C4a, and C5a (C5a also facilitates neutrophil chemotaxis Chemotaxis The movement of leukocytes in response to a chemical concentration gradient or to products formed in an immunologic reaction. Leukocyte Adhesion Deficiency Type 1)
  • Opsonin: C3b 
  • MAC: C5b to C5b-9 (cytolysis)
• Inhibitors regulate complement activation Complement Activation The sequential activation of serum complement proteins to create the complement membrane attack complex. Factors initiating complement activation include antigen-antibody complexes, microbial antigens, or cell surface polysaccharides. Systemic Lupus Erythematosus of self cells:
  • Decay-accelerating factor (CD55)
  • C1 inhibitor C1 inhibitor An endogenous 105-kda plasma glycoprotein produced primarily by the liver and monocytes. It inhibits a broad spectrum of proteases, including the complement C1r and the complement C1s proteases of the classical complement pathway, and the mannose-binding protein-associated serine proteases. C1-inh-deficient individuals suffer from hereditary angioedema types I and II. Angioedema (C1-INH)

Major functions

Ultimately, the complement pathways aim to eliminate microbes and cellular debris/apoptotic cells:

• Anaphylatoxins (C3a–C5a) cause:
  • Chemotaxis Chemotaxis The movement of leukocytes in response to a chemical concentration gradient or to products formed in an immunologic reaction. Leukocyte Adhesion Deficiency Type 1 (leading leukocytes Leukocytes White blood cells. These include granular leukocytes (basophils; eosinophils; and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). White Myeloid Cells: Histology to inflammatory sites)
  • Release of mediators (e.g., histamine from mast cells Mast cells Granulated cells that are found in almost all tissues, most abundantly in the skin and the gastrointestinal tract. Like the basophils, mast cells contain large amounts of histamine and heparin. Unlike basophils, mast cells normally remain in the tissues and do not circulate in the blood. Mast cells, derived from the bone marrow stem cells, are regulated by the stem cell factor. Innate Immunity: Phagocytes and Antigen Presentation)
  • Activation of nonimmune cell types (including epithelial and endothelial cells)
  • Contraction of smooth muscles Smooth muscles Unstriated and unstriped muscle, one of the muscles of the internal organs, blood vessels, hair follicles, etc. Contractile elements are elongated, usually spindle-shaped cells with centrally located nuclei. Smooth muscle fibers are bound together into sheets or bundles by reticular fibers and frequently elastic nets are also abundant. Muscle Tissue: Histology
  • Dilation of blood vessels and exudation of plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products/cells
• Opsonization through identification Identification Defense Mechanisms of foreign materials and damaged self, which facilitates:
  • The immediate killing of the opsonized target
  • Transfer by erythrocytes Erythrocytes Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology to tissue macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy or spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen: Anatomy
  • Activation of B cells B cells Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions (leading to antibody production and immunologic memory Memory Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. Psychiatric Assessment)
• Cell lysis via the MAC eliminates targets:
  • Disruption of the integrity of cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane (via pore-forming proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis)
  • Bacterial cell lysis

Cytokines

Cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response are soluble proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis released by different cells, which play overlapping roles in innate and adaptive immunity like the complement system.

Major cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response

• Target cell actions:
  • Autocrine (target cell is the same cell secreting the cytokine) 
  • Paracrine (nearby target cell)
  • Endocrine (cytokine is secreted into circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment to act on a distant target)
• General overview of key functions:
  • Inflammatory cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response in early response to infection (mediating fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever and sepsis Sepsis Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock. Sepsis and Septic Shock):
    • Tumor Tumor Inflammation necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage factor ( TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF))-ɑ
    • Interleukin-1 Interleukin-1 A soluble factor produced by monocytes; macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. Interleukin-1 is a general term refers to either of the two distinct proteins, interleukin-1alpha and interleukin-1beta. The biological effects of il-1 include the ability to replace macrophage requirements for t-cell activation. Interleukins (IL-1) 
    • Interleukin-6 Interleukin-6 A cytokine that stimulates the growth and differentiation of B-lymphocytes and is also a growth factor for hybridomas and plasmacytomas. It is produced by many different cells including T-lymphocytes; monocytes; and fibroblasts. Interleukins (IL-6)
  • Chemotaxis Chemotaxis The movement of leukocytes in response to a chemical concentration gradient or to products formed in an immunologic reaction. Leukocyte Adhesion Deficiency Type 1: interleukin-8 (IL-8)
  • T-cell proliferation and activation: interleukin-2 Interleukin-2 A soluble substance elaborated by antigen- or mitogen-stimulated T-lymphocytes which induces DNA synthesis in naive lymphocytes. Interleukins (IL-2)
  • Th2 Th2 A subset of helper-inducer T-lymphocytes which synthesize and secrete the interleukins il-4; il-5; il-6; and il-10. These cytokines influence b-cell development and antibody production as well as augmenting humoral responses. T cells: Types and Functions differentiation and proliferation: interleukin-4 Interleukin-4 A soluble factor produced by activated T-lymphocytes that induces the expression of mhc class II genes and fc receptors on B-lymphocytes and causes their proliferation and differentiation. It also acts on T-lymphocytes, mast cells, and several other hematopoietic lineage cells. Interleukins (IL-4)
  • B-cell class switching to IgE IgE An immunoglobulin associated with mast cells. Overexpression has been associated with allergic hypersensitivity. Immunoglobulins: Types and Functions and IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis: IL-4
  • B-cell class switching to IgA IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions: interleukin-5 Interleukin-5 A cytokine that promotes differentiation and activation of eosinophils. It also triggers activated B-lymphocytes to differentiate into immunoglobulin-secreting cells. Interleukins (IL-5)
  • Antiinflammatory (attenuates the immune response): interleukin-10 (IL-10), transforming growth factor-β
  • Antiviral Antiviral Antivirals for Hepatitis B ( DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure/ RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology) activity: IFN-ɑ, IFN-β, IFN-ɣ
• Notable sources:
  • Macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation secrete: IL-1, IL-6, IL-8, interleukin-12 Interleukin-12 A heterodimeric cytokine that plays a role in innate and adaptive immune responses. Interleukin-12 is a 70 kda protein that is composed of covalently linked 40 kda and 35 kda subunits. It is produced by dendritic cells; macrophages and a variety of other immune cells and plays a role in the stimulation of interferon-gamma production by T-lymphocytes and natural killer cells. IL-12 Receptor Deficiency (IL-12), TNF-ɑ
  • All T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions secrete: IL-2, interleukin-3 Interleukin-3 A multilineage cell growth factor secreted by lymphocytes; epithelial cells; and astrocytes which stimulates clonal proliferation and differentiation of various types of blood and tissue cells. Platelets: Histology (IL-3)
  • Th1 Th1 A subset of helper-inducer T-lymphocytes which synthesize and secrete interleukin-2; interferon-gamma; and interleukin-12. Due to their ability to kill antigen-presenting cells and their lymphokine-mediated effector activity, th1 cells are associated with vigorous delayed-type hypersensitivity reactions. T cells: Types and Functions cells secrete: IFN-ɣ
  • Th2 Th2 A subset of helper-inducer T-lymphocytes which synthesize and secrete the interleukins il-4; il-5; il-6; and il-10. These cytokines influence b-cell development and antibody production as well as augmenting humoral responses. T cells: Types and Functions cells secrete: IL-4, IL-5, IL-10

Description of cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response

Microbial Killing

After pathogen recognition and recruitment Recruitment Skeletal Muscle Contraction of immune cells (with coordinated help from complements and cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response), strategies are implemented to eliminate the microbes.

Pathogen elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy

• Phagocytosis Phagocytosis The engulfing and degradation of microorganisms; other cells that are dead, dying, or pathogenic; and foreign particles by phagocytic cells (phagocytes). Innate Immunity: Phagocytes and Antigen Presentation:
  • Phagocytes: macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation, monocytes Monocytes Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. Innate Immunity: Phagocytes and Antigen Presentation, neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation, dendritic cells Dendritic cells Specialized cells of the hematopoietic system that have branch-like extensions. They are found throughout the lymphatic system, and in non-lymphoid tissues such as skin and the epithelia of the intestinal, respiratory, and reproductive tracts. They trap and process antigens, and present them to T-cells, thereby stimulating cell-mediated immunity. They are different from the non-hematopoietic follicular dendritic cells, which have a similar morphology and immune system function, but with respect to humoral immunity (antibody production). Skin: Structure and Functions
  • Attachment is either by recognition of PRR or mediated by opsonins. 
  • Engulfment of the pathogen in a vesicle Vesicle Primary Skin Lesions follows
  • The phagocyte forms a pseudopod, which wraps around the pathogen and becomes a pinched-off membrane vesicle Vesicle Primary Skin Lesions (phagosome). 
  • A phagolysosome Phagolysosome Chédiak-Higashi Syndrome is formed as the phagosome fuses with a lysosome.
  • Microbial killing mechanisms:
    • Acidification within the phagolysosome Phagolysosome Chédiak-Higashi Syndrome is bacteriostatic Bacteriostatic Sulfonamides and Trimethoprim or bactericidal Bactericidal Penicillins. 
    • ↓ pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance activates pH-dependent, hydrolytic, lysosomal enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes (digest the pathogen)
    • Antimicrobial peptides
    • Production of toxic nitrogen- and oxygen-derived species (respiratory or oxidative burst)
  • When the pathogen is destroyed, the phagocyte undergoes apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage (e.g., pus), or the waste is eliminated by exocytosis Exocytosis Cellular release of material within membrane-limited vesicles by fusion of the vesicles with the cell membrane. The Cell: Cell Membrane.
• Other elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy strategies (if the pathogen is not engulfed):
  • Large pathogens (e.g., nematode Nematode A phylum of unsegmented helminths with fundamental bilateral symmetry and secondary triradiate symmetry of the oral and esophageal structures. Many species are parasites. Toxocariasis) cannot be ingested:
    • Groups of cells ( neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation, eosinophils Eosinophils Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. Innate Immunity: Phagocytes and Antigen Presentation, macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation) surround the pathogen.
    • Defensins, lysosomal, and other toxic products are released (degranulation) to sufficiently eliminate the pathogen.
  • Immune cells kill the pathogens or infected cells (e.g., neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation release neutrophil extracellular traps (NETs), NK cells NK cells A specialized subset of T-lymphocytes that exhibit features of innate immunity similar to that of natural killer cells. They are reactive to glycolipids presented in the context of the major histocompatibility complex (MHC) class I-like molecule, CD1D antigen. Lymphocytes: Histology induce apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage).

Respiratory burst Respiratory burst A large increase in oxygen uptake by neutrophils and most types of tissue macrophages through activation of an NADPH-cytochrome b-dependent oxidase that reduces oxygen to a superoxide. Individuals with an inherited defect in which the oxidase that reduces oxygen to superoxide is decreased or absent often die as a result of recurrent bacterial infections. Leukocyte Adhesion Deficiency Type 1

• Release of reactive oxygen species Reactive oxygen species Molecules or ions formed by the incomplete one-electron reduction of oxygen. These reactive oxygen intermediates include singlet oxygen; superoxides; peroxides; hydroxyl radical; and hypochlorous acid. They contribute to the microbicidal activity of phagocytes, regulation of signal transduction and gene expression, and the oxidative damage to nucleic acids; proteins; and lipids. Nonalcoholic Fatty Liver Disease (ROS) from various cells (e.g., macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation, neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation)
• Nicotinamide adenine dinucleotide Nicotinamide adenine dinucleotide A coenzyme composed of ribosylnicotinamide 5′-diphosphate coupled to adenosine 5′-phosphate by pyrophosphate linkage. It is found widely in nature and is involved in numerous enzymatic reactions in which it serves as an electron carrier by being alternately oxidized (NAD+) and reduced (NADH). Pentose Phosphate Pathway phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes ( NADPH NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5′-phosphate (nmn) coupled by pyrophosphate linkage to the 5′-phosphate adenosine 2. Pentose Phosphate Pathway)-oxidase complex reduces O₂ to an oxygen free radical Free Radical Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. Nitroimidazoles ( superoxide anion Superoxide anion Highly reactive compounds produced when oxygen is reduced by a single electron. In biological systems, they may be generated during the normal catalytic function of a number of enzymes and during the oxidation of hemoglobin to methemoglobin. In living organisms, superoxide dismutase protects the cell from the deleterious effects of superoxides. Chronic Granulomatous Disease (O₂•^–)) and then to hydrogen peroxide Hydrogen peroxide A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. Myeloperoxidase Deficiency (H₂O₂).
• Neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation and monocytes Monocytes Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. Innate Immunity: Phagocytes and Antigen Presentation (using myeloperoxidase Myeloperoxidase Acute Myeloid Leukemia) combine H₂O₂ with Cl^– → hypochlorite (HOCl•), which helps to destroy the bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology
• Myeloperoxidase Myeloperoxidase Acute Myeloid Leukemia contains a heme pigment, which produces a green color in secretions (e.g., mucus and sputum) or pus.

Clinical Relevance

• Hereditary angioedema Hereditary angioedema Forms of hereditary angioedema that occur due to mutations in the gene for complement C1 inhibitor protein. Type I hereditary angioedema is associated with reduced serum levels of complement C1 inhibitor protein. Type II hereditary angioedema is associated with the production of a non-functional complement C1 inhibitor protein. Hereditary Angioedema (C1 Esterase Inhibitor Deficiency): caused by deficiency or dysfunction of C1-INH, a protein regulating the classical pathway of complement activation Complement Activation The sequential activation of serum complement proteins to create the complement membrane attack complex. Factors initiating complement activation include antigen-antibody complexes, microbial antigens, or cell surface polysaccharides. Systemic Lupus Erythematosus. The condition is characterized by increased levels of bradykinin Bradykinin A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. Hereditary Angioedema (C1 Esterase Inhibitor Deficiency), which leads to enhanced vascular permeability. Symptoms include recurrent angioedemas ( swelling Swelling Inflammation of the face, lips Lips The lips are the soft and movable most external parts of the oral cavity. The blood supply of the lips originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy, and tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy). The GI tract may also be involved ( nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, abdominal pain Abdominal Pain Acute Abdomen, and vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia). Diagnosis involves measurement of complement levels (low levels of C4 and decreased levels/functionality of C1-INH). Treatment includes purified, human C1-INH, kallikrein inhibitors Kallikrein inhibitors Hereditary Angioedema (C1 Esterase Inhibitor Deficiency), and bradykinin Bradykinin A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. Hereditary Angioedema (C1 Esterase Inhibitor Deficiency) inhibitors. ACE inhibitors ACE inhibitors Truncus Arteriosus are contraindicated.
• C1q deficiency: a rare disorder characterized by either absent or defective C1q protein. The disorder is caused by mutations in 1 of the 3 genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure encoding C1q and has an autosomal-recessive inheritance. In most cases, the disease is associated with systemic lupus erythematosus Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus ( SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus). Other clinical manifestations include chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease, recurrent skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions lesions, chronic infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease, and alopecia Alopecia Alopecia is the loss of hair in areas anywhere on the body where hair normally grows. Alopecia may be defined as scarring or non-scarring, localized or diffuse, congenital or acquired, reversible or permanent, or confined to the scalp or universal; however, alopecia is usually classified using the 1st 3 factors. Alopecia. Treatment depends on the symptoms. Production of C1q can be restored by allogeneic HSC transplantation. 
• Terminal complement deficiencies (C5–C9): a genetic condition affecting MAC function. In the United States, deficiencies commonly found involve C5, C6, or C8. Because cell lysis still proceeds with C5–C8, deficiency of C9 causes less severe defects. The deficiency will appear as a low/undetectable CH50 CH50 Terminal Complement Pathway Deficiency titer. Individuals with terminal complement deficiency are at risk for recurrent Neisseria Neisseria Neisseria is a genus of bacteria commonly present on mucosal surfaces. Several species exist, but only 2 are pathogenic to humans: N. gonorrhoeae and N. meningitidis. Neisseria species are non-motile, gram-negative diplococci most commonly isolated on modified Thayer-Martin (MTM) agar. Neisseria infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease.
• Chronic granulomatous disease Granulomatous disease A defect of leukocyte function in which phagocytic cells ingest but fail to digest bacteria, resulting in recurring bacterial infections with granuloma formation. When chronic granulomatous disease is caused by mutations in the cybb gene, the condition is inherited in an X-linked recessive pattern. When chronic granulomatous disease is caused by cyba, ncf1, ncf2, or ncf4 gene mutations, the condition is inherited in an autosomal recessive pattern. Common Variable Immunodeficiency (CVID) ( CGD CGD Chronic granulomatous disease (CGD), as the name implies, is a chronic disorder that is characterized by granuloma formation. This disorder is a consequence of defective phagocytic cells that are unable to produce bactericidal superoxide because of a defect in nicotinamide adenine dinucleotide phosphate (NADPH), the oxidase responsible for the respiratory burst in phagocytic leukocytes. Chronic Granulomatous Disease): a genetic condition characterized by granuloma formation and recurrent, severe bacterial and fungal infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease. Defective NADPH NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5′-phosphate (nmn) coupled by pyrophosphate linkage to the 5′-phosphate adenosine 2. Pentose Phosphate Pathway oxidase Oxidase Neisseria (responsible for the respiratory burst Respiratory burst A large increase in oxygen uptake by neutrophils and most types of tissue macrophages through activation of an NADPH-cytochrome b-dependent oxidase that reduces oxygen to a superoxide. Individuals with an inherited defect in which the oxidase that reduces oxygen to superoxide is decreased or absent often die as a result of recurrent bacterial infections. Leukocyte Adhesion Deficiency Type 1) in neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation and macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation leads to impaired phagocytosis Phagocytosis The engulfing and degradation of microorganisms; other cells that are dead, dying, or pathogenic; and foreign particles by phagocytic cells (phagocytes). Innate Immunity: Phagocytes and Antigen Presentation. Infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease commonly affect the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs: Anatomy, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions, lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy, and liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy. Dihydrorhodamine (DHR) 123 (a neutrophil function test) is abnormal and genotyping Genotyping Methods used to determine individuals’ specific alleles or snps (single nucleotide polymorphisms). Polymerase Chain Reaction (PCR) confirms the diagnosis. 
• Systemic lupus erythematosus Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus: a chronic, autoimmune-inflammatory condition causing immune-complex deposition in organs resulting in systemic manifestations. Features include a malar rash Malar Rash Systemic Lupus Erythematosus, nondestructive arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis, nephritis, serositis Serositis Inflammation of a serous membrane. Systemic Lupus Erythematosus, cytopenias Cytopenias IPEX Syndrome, thromboembolic disease, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, and/or psychosis. Diagnosis is based on clinical findings and tests (e.g., antinuclear antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions, SLE-specific antibodies SLE-specific antibodies Systemic Lupus Erythematosus). Low C4 and C3 are noted in approximately 50% of cases because immune complexes Immune complexes The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. C3 Deficiency activate the classical complement pathway. Management aims to control symptoms and prevent organ damage. Treatment options include corticosteroids Corticosteroids Chorioretinitis, hydroxychloroquine Hydroxychloroquine A chemotherapeutic agent that acts against erythrocytic forms of malarial parasites. Hydroxychloroquine appears to concentrate in food vacuoles of affected protozoa. It inhibits plasmodial heme polymerase. Immunosuppressants, and immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants.