! ! THE TWO ARMS OF THE IMMUNE SYSTEM Monocytes/Macrophages,

! ! THE TWO ARMS OF THE IMMUNE SYSTEM Monocytes/Macrophages,
Dendritic cells, Granulocytes NK cells (complement system) B and T lymphocytes INNATE IMMUNITY immediate reaction not antigen-specific no memory ADAPTIVE IMMUNITY developes in several days specific has memory communication Humoral immunity Cellular immunity

! ! Innate immunity as a first line of defence
Innate immune cells recognize frequently found structures of pathogens by PRRs , these are not found in human cells! PRRs (pattern recognition receptors) are responsible for recognize conserved structures of the microbes Examples of recognited structures: duple strain RNA bacterial cell wall components bacterial flagellin…. The innate immune system does not react against the host. The innate immune system recognizes structures that are shared by various classes of microbes and are not present on normal host cells. The mechanisms of innate immunity recognize and respond to a limited number of microbial molecules, much less than the almost unlimited number of microbial and nonmicrobial antigens that are recognized by the adaptive immune system. Each component of innate immunity may recognize many bacteria, viruses, or fungi. For example, phagocytes express receptors for bacterial endotoxin, also called lipopolysaccharide (LPS), and other receptors for peptidoglycans, each of which is present in the cell walls of many bacterial species but is not produced by mammalian cells. Other receptors of phagocytes recognize terminal mannose residues, which are typical of bacterial but not mammalian glycoproteins. Mammalian cells recognize and respond to double-stranded ribonucleic acid (dsRNA), which is found in many viruses but not in mammalian cells, and to unmethylated CG-rich (CpG) oligonucleotides, which are common in microbial DNA but are not abundant in mammalian DNA. The microbial molecules that stimulate innate immunity are often called pathogen-associated molecular patterns (PAMPs), to indicate that they are present in infectious agents (pathogens) and shared by microbes of the same type (i.e., they are molecular patterns). The receptors of innate immunity that recognize these shared structures are called pattern recognition receptors. The components of innate immunity have evolved to recognize structures of microbes that are often essential for the survival and infectivity of these microbes. This characteristic of innate immunity makes it a highly effective defense mechanism because a microbe cannot evade innate immunity simply by mutating or not expressing the targets of innate immune recognition: Microbes that do not express functional forms of these structures lose their ability to infect and colonize the host. In contrast, microbes frequently evade adaptive immunity by mutating the antigens that are recognized by lymphocytes, because these antigens are usually not required for the life of the microbes. Recognition is inevitable

ACUTE INFLAMMATION AND ACUTE-PHASE RESPONSE

ACUTE INFLAMMATION A rapid response to an injurious agent that serves to deliver leukocytes and plasma proteins to the site of injury

THE INFLAMMATORY RESPONSE
Illustrated here are the events following an abrasion of the skin. Bacteria invade the underlying connective tissue and stimulate the innate immune response.

TRIGGERS OF ACUTE INFLAMMATION:
Infections Trauma Physical and Chemical agents (thermal injury, irradiation, chemicals) Tissue Necrosis Foreign bodies (splinters, dirt, sutures) Hypersensitivity or autoimmune reactions MAJOR COMPONENTS OF INFLAMMATION: Vascular response: Increased vascular diameter  Increased flood flow. Endothelial cell activation increased permeability that permits plasma proteins and leukocytes to leave the circulation and enter the tissue  edema increased expression of cell adhesion molecules e.g. E-selectin, ICAM Cellular response: Migration of leukocytes (diapedesis/extravasation), accumulation, effector functions

Immunitas = exemption, protection
Protection from / against what? Self or non-self substances? (What about the useful bacteria living together with us and what about tumors in this model?) „Danger model”: (Matzinger P., The danger model: a renewed sense of self. Science Apr 12;296(5566):301-5.) harmful self / harmless self harmful non-self / harmless non-self factors! DANGER SIGNAL / NO DANGER SIGNAL obligate pathogen facultative pathogen (Staphylococcus aureus)

CLASSICAL SYMPTOMES OF ACUTE INFLAMMATION:
Redness (rubor) Swelling (tumor) Heat (calor) Pain (dolor) Loss of function (functio laesa)

NEUTROPHIL GRANULOCYTES
68% of circulating leukocytes, 99% of circulating granulocytes Phagocytic cells Are not present in healthy tissues Migration  elimination of pathogens (enzymes, reactive oxygen intermediates) Main participants of acute inflammatory processes LFA-1: Lymphocyte-function associated antigen-1 Sialylated Lewis X Ag

Selectins, integrins, and chemokines work in concert to govern the leukocyte-endothelial interactions that are required for migration of leukocytes into tissues Selectin-mediated rolling of leukocytes on endothelium. In response to microbes and cytokines produced by cells (e.g., macrophages) that encounter the microbes, endothelial cells lining postcapillary venules at the site of infection rapidly increase surface expression of selectins. Leukocytes move close to the endothelium-lined walls of venules in sites of innate immune responses as a result of vasodilation and slowing of blood flow, and the selectin ligands on the microvilli of the leukocytes bind to the selectins on the endothelial cells. Because selectin-selectin ligand interactions are of low affinity (Kd ∼100 μm) with a fast off-rate, they are easily disrupted by the shear force of the flowing blood. As a result, the leukocytes repetitively detach and bind again and thus roll along the endothelial surface. This slowing of leukocytes on the endothelium allows the next set of stimuli in the multistep process to act on the leukocytes. Chemokine-mediated increase in affinity of integrins. As discussed earlier, chemokines are produced at an infection site by various cell types in response to a variety of pathogens or endogenous stimuli. Once secreted, they are transported to the luminal surface of the endothelial cells of postcapillary venules, where they are bound by heparan sulfate glycosaminoglycans and are displayed at high concentrations. At this location, the chemokines bind to specific chemokine receptors on the surface of the rolling leukocytes. Leukocyte integrins are in a low-affinity state in unactivated cells and ineffective in mediating adhesion interactions. Two consequences of chemokine receptor signaling are enhanced affinity of leukocyte integrins for their ligands and membrane clustering of the integrins, resulting in increased avidity of binding of leukocyte integrins to their ligands on the endothelial surface. Stable integrin-mediated adhesion of leukocytes to endothelium. In parallel with the activation of integrins and their conversion to the high-affinity state, cytokines (TNF and IL-1) also enhance endothelial expression of integrin ligands, mainly VCAM-1, the ligand for the VLA-4 integrin, and ICAM-1, the ligand for the LFA-1 and Mac-1 integrins. The net result of these changes is that the leukocytes attach firmly to the endothelium, their cytoskeleton is reorganized, and they spread out on the endothelial surface. Transmigration of leukocytes through the endothelium. Most often, leukocytes transmigrate between the borders of endothelial cells, a process called paracellular transmigration, to reach extravascular tissues. Paracellular transmigration depends on leukocyte integrins and their ligands on the endothelial cells as well as other proteins, notably CD31, which is expressed on the leukocytes and endothelial cells. This process requires a transient and reversible disruption of adherens junction proteins that hold postcapillary endothelial cells together, primarily the VE-cadherin complex. The mechanism responsible for disruption of the VE-cadherin complex is thought to involve activation of kinases when leukocyte integrins bind ICAM-1 or VCAM-1. The kinases phosphorylate the cytoplasmic tail of VE-cadherin and lead to reversible disruption of the adherens complex. Less often, leukocytes have been observed to move through endothelial cells rather then between them, by a less well understood process called transcellular migration. Cytokines (TNF and IL-1) secreted during the innate immune response to microbes induce the expression of adhesion molecules (selectins and integrin ligands) on endothelial cells and the local production of chemokines. Neutrophils and monocytes express distinct sets of adhesion molecules and chemokine receptors and therefore migrate into different inflammatory sites or into the same inflammatory site at different times.

MIGRATION OF NEUTROPHILS

PUS Pus = transudate (liquor puris) + dead pathogens + dead neutrophils + dead tissue cells Pus is a whitish-yellow, yellow, or yellow-brown exudate produced by vertebrates during inflammatory pyogenic bacterial infections. Pus consists of a thin, protein-rich fluid, known as liquor puris, and dead cells.

CONSEQUENCES OF MACROPHAGE ACTIVATION SYNTHESIS OF CYTOKINES

ACUTE-PHASE REACTION proinflammatory cytokines hypothalamic control of body temperature increased ‚set-point’ value fever

Mannose binding lectin/protein
ACUTE PHASE REACTION IL-6 Complement Liver C-reactive protein (CRP) Mannose binding lectin/protein MBL/MBP Fibrinogen Stimulation and synthesis of positive acute-phase reactants during inflammation. Inflammation caused by infection or tissue damage stimulates the circulating inflammation-associated cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF)-. These cytokines stimulate hepatocytes to increase the synthesis and release of positive acute-phase proteins, including CRP. IL-6 is the major cytokine stimulus for CRP production. Serum amyloid protein (SAP) UNDER THE INFLUENCE OF IL-6 THE LIVER PRODUCES A BUNCH OF ACUTE-PHASE PROTEINS

OPSONIZATION ! ! Opsonization facilitate and accelerate the recognition of the pathogen by phaogocytes, opsonins form a bridge between pathogen and a phagocyte connecting them. Main opsonins: antibodies Complement fragments Acute-phase proteins The process of coating particles for subsequent phagocytosis is called opsonization, and the molecules that coat microbes and enhance their phagocytosis are called opsonins. When several antibody molecules bind to a microbe, an array of Fc regions is formed projecting away from the microbial surface. If the antibodies belong to certain isotypes (IgG1 and IgG3 in humans), their Fc regions bind to a high-affinity receptor for the Fc regions of γ heavy chains, called FcγRI (CD64), which is expressed on neutrophils and macrophages. The phagocyte extends its plasma membrane around the attached microbe and ingests the microbe into a vesicle called a phagosome, which fuses with lysosomes. The binding of antibody Fc tails to FcγRI also activates the phagocytes, because the FcγRI contains a signaling chain that triggers numerous biochemical pathways in the phagocytes. The activated neutrophil or macrophage produces, in its lysosomes, large amounts of reactive oxygen species, nitric oxide, and proteolytic enzymes, all of which combine to destroy the ingested microbe. Antibody-mediated phagocytosis is the major mechanism of defense against encapsulated bacteria, such as pneumococci. The polysaccharide-rich capsules of these bacteria protect the organisms from phagocytosis in the absence of antibody, but opsonization by antibody promotes phagocytosis and destruction of the bacteria. The spleen contains large numbers of phagocytes and is an important site of phagocytic clearance of opsonized bacteria. This is why patients who have undergone splenectomy for traumatic rupture of the organ are susceptible to disseminated infections by encapsulated bacteria.

ACUTE-PHASE RESPONSE Pentraxin family:
CRP – opsonization, complement activation SAP – opsonization, complement activation, binding of mannose/galactose Collectin family: MBL – part of the complement system (SP-A/D – collectins of lungs) Complement proteins (C1-C9) Fibrinogen  blood clotting

Plasma cascade systems
The complement system, when activated, creates a cascade of chemical reactions that promotes opsonization, chemotaxis, and agglutination, and produces the MAC. The kinin system generates proteins capable of sustaining vasodilation and other physical inflammatory effects. The coagulation system or clotting cascade which forms a protective protein mesh over sites of injury. The fibrinolysis system, which acts in opposition to the coagulation system, to counterbalance clotting and generate several other inflammatory mediators.

CHEMICAL MEDIATORS Vasodilation Prostaglandins (PG), nitric oxide (NO)
Increased vascular permeability vasoactive amines (histamine, serotonin), C3a and C5a (complement system), bradykinin, leukotrienes (LT), PAF Chemotactic leukocyte activation C3a, C5a, LTB4, chemokines (e.g. IL-8) Fever IL-1, IL-6, TNFα, PGE2 Pain Prostaglandins, bradykinin Tissue damage Neutrophil and Macrophage products lysosomal enzymes Reactive oxygen species (ROS) NO NSAIDs and Paracetamol: inhibiting COX-1 and COX-2  preventing the synthesis of prostaglandins

Prosztaglandin-E2

Tissue factor : Subendothel sejtek (simaizom, kötőszövet) +endotél, makrofág TNF, edotoxin hatására Kinin rendszer a vérből kilépve aktiválódik +faktor XII prekallikrein-kalikrein—bradikinin PAF, állandóan termelődik. Pl. platlets, endotél, neutrofil, monocita De + makrofág, endotél stimulusra. No Makrofág (fagociták), endotél TNF-re fokoz Leukotrién: Hízósejt, leukociták aktiváció hatására Prostaglandinok: COX1 konstitutív COX 2 leukocita, makrofág stimulusra, hipotalamusz

RESOLUTION OF ACUTE INFLAMMATION

SEPTIC SHOCK Result: Triggering factors :
systemic infection (bacteraemia) microbial cell wall products and/or toxins released from the pathogens Result: Systemic activation of neutrophils and macrophages  High level of cytokine (TNF-alpha) production: „cytokine storm” Excessive inflammatory response

SEPTIC SHOCK The key molecule of the process: TNF-alpha
TNF-alpha and other inflammatory cytokines multiorgan failure (MOF) is caused by the systemic vasodilation and hypoperfusion in shock and by multiple tromboses in DIC DIC capillar permeability blood pressure high fever multiorgan failure disseminated intravascular coagulation Therapy: anti-TNF-alpha antibody

DIC Disseminated Intravascular Coagulation
pathologic activation of thrombotic process distress of thrombotic process, bleeding other causes: snake bite, septic abortion, acute obstetric complications, malignant tumors, leukemias Proinflammatory cytokines (IL-1, TNFα) and LPS/endotoxin leads to the release of Tissue Factor (TF) from cells which triggers the coagulation cascade. The complement system also has an effect on blood clothing.

DIC: Disseminated Intravascular Coagulation

2nd seminar: THE ANTIGEN
Definition and properties Antigenic determinant (epitope) Hapten, carrier Antigen recognition by B and T cells Superantigens ACUTE INFLAMMATION

DEFINITIONS ANTIGEN (Ag) - any substance, which is recognized by the mature immune system of a given organism Any chemical structure Soluble or corpuscle Simple or complex Originated from the body or comes from outside Genetically self or non-self Natural or artificial

DEFINITIONS ANTIGENICITY– capability of an antigen to bind specifically with certain product of the adaptive immunity: TCR or BCR/antibody, immunogenicity - capability of an antigen to induce an (adaptive) immune response, tolerogenicity - capability to induce immunological tolerance, specific immune non-responsiveness

FACTORS INFLUENCING IMMUNOGENICITY I.
From the aspect of our body: Genetics (self/non-self) species (evolutionarily nonconserved molecules) individual differences (e.g. MHC polymorphism – see later) Age newborn – less reactive immune system elderly – no new lymphocytes Physiological condition (pl. immunodeficiencies, starvation) Foreignness: evolutionary the farther the species are from each other the more their antigens induce immune response in another Size: i.e. haptenes (too small to induce immune response without carriers) Genetics: differences of the immune response between species from the same family/order and between individuals of the same species Age: the old mainly rely on the immunological memory, they can hardly get over a new kind of infection. Moreover there are differences in the immune response generated by EBV and mumps viruses in childhood and adulthood

FACTORS INFLUENCING IMMUNOGENICITY II.
From the aspect of the antigen: Physical-chemical properties of the Ag size/complexity (bigger  more epitopes, role of carrier) corpuscular (cell, colloid) or soluble denatured or native (different epitopes!) degradability (by APCs) Availability (crystalline proteins of the eye are not presented to lymphocytes)

FACTORS INFLUENCING IMMUNOGENICITY III.
From the aspect of vaccination: Dose Route intradermal/subcutan > intravenous > oral > intranasal (oral vaccine against polio virus!) Adjuvant enhance the response given to the antigen e.g.: alum, Freund-adjuvant, TLR ligands Complex effects: depot effect  long-lasting presence of antigen activation of innate immunity activation of bystander cells

077-298-32------------------218-329-10
HLA-C HLA-A HLA-B HLA-B HLA-A HLA-C maternal paternal

ANTIGEN RECOGNITION BY LYMPHOCYTES
antibodies (serum Ig) APC Antigen MHC BCR (membrane Ig) TCR T B B cells recognise native antigens T cells recognise processed antigens

Clonal proliferation

the cells of the immune system originate in and mature here
! ! LYMPHOID ORGANS Primary lymphoid organs: - Bone marrow - Thymus the cells of the immune system originate in and mature here Secondary lymphoid organs: - Spleen - Lymphatic vessels - Lymph nodes - Adenoids and tonsils - MALT (Mucosal Associated Lymphoid Tissue) GALT (Gut Associated Lymphoid Tissue) BALT (Bronchus Associated Lymphoid Tissue) SALT (Skin Associated Lymphoid Tissue) NALT (Nasal Associated Lymphoid Tissue) not for cell development. (final differentiation, activation may be performed) The cells of the adaptive immune system recognize here the pathogens Primary: the cells originate in and mature here. Here musnt appear any pathogen, The cells of adaptive immune system learn, here what does it mean self. Everything else will be handled as nonself. No lymph here, only blood circulation Secondary, not for cell development. (final differentiation, activation may be performed) The cells of the adaptive immune system recognize here the pathogens 42

DEFINITIONS ANTIGEN (Ag) - any substance, which is recognized by the mature immune system of a given organism Any chemical structure Soluble or corpuscle Simple or complex Originated from the body or comes from outside Genetically self or non-self Natural or artificial

Class I major histocompatibility complex pathway of processing of cytosolic antigens. Proteins enter the cytoplasm of cells either from phagocytosed microbes or from endogenous synthesis by microbes, such as viruses, that reside in the cytoplasm of infected cells. Cytoplasmic proteins are unfolded, ubiquitinated, and degraded in proteasomes (Ub, ubiquitin). The peptides that are produced are transported by the transporter associated with antigen processing (TAP) into the endoplasmic reticulum (ER), where the peptides may be further trimmed. Newly synthesized class I MHC molecules are attached to TAP by a linker protein called tapasin, so the MHC molecules are strategically located to receive peptides that are transported into the ER by TAP. The peptide–class I MHC complexes are transported to the cell surface and are recognized by CD8+ T cells. β2 m, β2 -microglobulin. Abbas, Abul K., MBBS, Basic Immunology: Functions and Disorders of the Immune System, Chapter 3, 49-69 Copyright © Copyright © 2014, 2011, 2009, 2006, 2004, 2001 by Saunders, an imprint of Elsevier Inc.

ANTIGENIC DETERMINANT (=EPITOPE)
Part of the antigen which directly interacts with the antigen-binding site of a defined immunoglobulin (BCR / antibody) or TCR

B cell epitope T cell epitope recognized by B cells proteins
polysaccharides lipids DNA steroids etc. (many artificial molecules) cell or matrix associated or soluble recognized by T cells proteins mainly (8-23 amino acids) requires processing by APC Some T cells are able to recognise glycolipids bound to non-conventional MHC molecules (e.g. CD1) too

Antigens may have several different epitopes

T CELL-DEPENDENT B CELL ACTIVATION Polysacharides are not presented!
cytokines CD4 TCR MHCII +peptide T cell 2 1 gr2 Polysacharides are not presented!

Theoretical structure of complex antigens
Epitopes „Carrier” no direct interaction with the antigen-binding site A hordozó fogalma a vakcinák kapcsán használatos, mikor kis méretű antigént/haptént kötünk fel valamire. A hagyományos/természetes antigének kapcsán használni kissé erőltetett! These terms can only be used to describe the interaction of particular antigenic determinant and single immunoglobulin or T cell receptor

EPITOPE AND „CARRIER” Antigén Antibody 1 Antibody 2 „carrier” (2)

TYPES (STRUCTURE) OF ANTIGEN DETERMINANTS
linear determinant conformational determinant (TCR, BCR, Ig) (BCR, Ig) conformational determinant Ab2 Ab1 surface/accessible determinants cleveage denaturation hidden/revealed determinant new/neoantigen determinant conformational/linear determinant

LPS – antigen or PAMP?! PAMP Antigen LPS if recognized by PRR (TLR4)
if recognised by TCR/BCR PAMP if recognized by PRR (TLR4) Fc LPS Fab side view Fab kék/narancs = TLR4 szürke/fekete = MD-2 (TLR4-asszociált molekula) piros = LPS specific antibody reactive to the glucoseamin epitope of LPS top view

T CELL-DEPENDENT B CELL ACTIVATION Polysacharides are not presented!
cytokines CD4 TCR MHCII +peptide T cell 2 1 Polysacharides are not presented!

B CELL ACTIVATION WITHOUT THE HELP OF T CELLS
T-INDEPENDENT ANTIGEN TI-1 T-INDEPENDENT ANTIGEN TI-2 B cell Simultaneous activation of BCR and other receptors on B cells (i.e. LPS binding protein /CD14) induces the B cells to proliferate and differentiate Strong crosslinking of BCR by repetitive polysaccharide or protein epitopes B CELL ACTIVATION (extra activation signal) (extensive receptor-aggregation)

B CELL ACTIVATION WITHOUT THE HELP OF T CELLS
(A lot of small ones or a large with multiple epitopes. Usually the same kind, like polysaccharides.) Gr1-gr9

HAPTEN molecules that are too small to provoke an immune response unless they are attached to carriers - hapten (e.g. DNP: dinitrofenil) + carrier + haptens

HAPTEN free haptens haptens attached to a carrier
receptor cross-linking  signalization

Antibody response generated against a hapten-carrier conjugate
carrier + hapten antibodies Hapten-carrier conjugates have native antigenic determinants of the carrier as well as new determinants of the hapten. carrier specific hapten specific carrier + hapten specific

ANTIGEN RECOGNITION ≠ CELL ACTIVATION

ANTIGEN RECOGNITION BY NAIVE T CELLS REQUIRES
PRESENTATION VIA MHC MOLECULES Recognition/ No activation The mature naive cytotoxic T cells (Tc) activate by recognizing antigens bound to MHC I molecules on the surface of antigen presenting cells (APCs) with the help of costimulatory molecules and then they are able to recognize these antigenes bound to MHC I molecules on the surface of host cells (HC) too. CD4 is the co-receptor of helper T cells (Th) and CD8 is the co-receptor of the cytotoxic T cells (Tc). Recognition/ Activation

+ EXAMPLE (Prevenar - pneumococus vaccine) Glu  Gly toxin toxoid
Purified bacterial polysacharides used for vaccination do not lead to long-lasting immunity because the activation of T cells is required for memory B cell formation Hence the polysaccharide chains are conjugated to protein carriers which can activate T cells Carrier: CRM197  modified diphteria toxin (toxoid) (a single aminoacid change (Glu  Gly) in the toxin can abolish toxicity) The toxoid acts the same way the toxin does; it activates specific T cells and may lead to the production of antitoxins by plasmacells toxin Glu  Gly toxoid Poliszaharidok nem prezentálódnak MHC molekulán – a felismerő B sejtek nem kapnak T sejt segítséget – gyenge aktiváció és nincs memória sejt képződés polysaccharides of different Streptococcus pneumoniae strains toxoid + complex antigen of vaccine

peptide antigen derived from toxoid specific to toxin/toxoid epitope
polysacharid MHCII TCR BCR T cell specific to toxin/toxoid epitope B cell specific to bacterial polysaccharid A toxin specifikus T sejtek, amik képesek a B sejtek segítésére létrejöhetnek DC-k segítségével is. A jó hordozó fehérjéjékre sok poliszaharid ráköthető – repetitív epitopok, hatékonyabb aktiváció (TI2) A komplex vakcina poliszaharidjait felismerő B sejtek bekebezik azt, és a toxoid fehérje peptidjeit képesek prezentálni MHC molekulákon. Ha ezt egy T sejt felismeri, akkor a poliszaharid specifikus ellenanyagot termelő B sejt kellő stimulációt kap, hogy memória B sejt válhasson belőle, de képes lesz akár izotípus váltásra, és affinitás érésre is. (TD) Eredményként létrejöhetnek: pneumokokkusz poliszaharid specifikus (memória) B sejtek, diftéria toxin specifikus (memória) B sejtek, diftéria toxin peptid specifikus T sejtek (esetleg a hordozóra és poliszaharid közös konformációs determinánsára együtt specifikus B sejtek is – haszontalanok, mert ilyen nem létezik a fertőzésekkor) (SLE vonatkozás: gyakran nagy fertőzések után jelenik meg bakteriális DNS-fehérje komplexek  anti-DNS ellenanyagok) cytokines, CD40-CD40L formation of pneumococcus-specific memory B cells

SUPERANTIGENS Microbial proteins that bind to and activate all the T cells that express a particular set or family of TCR molecules resulting in a polyclonal activation

SUPERANTIGENS Fever Microbial proteins that bind to and activate all the T cells that express a particular set or family of TCR molecules resulting in a polyclonal activation. Interaction is not via the peptide binding cleft of MHC molecule. The superantigens can aspecifically bind to the TCR and MHC molecules thereby stabilizing their connection, resulting in the activation of the T-cell subpopulation Hypotension Rash Desquamation

monoclonal/oligoclonal
SUPERANTIGENS Microbial proteins that bind to and activate all the T cells in an individual that express a particular set or family of TCR molecules conventional antigen superantigen polyclonal T cell response 1:4 - 1:10 monoclonal/oligoclonal T cell response 1: :105 activated T cells 107 – 108 / 1011 1010 / 1011

SUPERANTIGENS Classification Sources Endogenous Exogenous
Exogenous 1.Mouse mammary tomor virus (MMTV) Epstein-Barr virus (EBV) Staphylococcal enterotoxins (SEs): A, B, C1 to C3, D, E, G to Q Staphylococcal toxic shock syndrome toxin-1 (TSST-1) Staphylococcal exfoliative toxins: exoliatin A, exfoliatin B Staphylococcal enterotoxin-like toxins formed due to recombination within enterotoxin gene cluster: U2, V Streptococcal pyrogenic exotoxins (SPEs): A1 to A4, C, G to M Streptococcal mitogenic exotoxins: SMEZ Streptococcal superantigen :SSA Yersinia pseudotuberculosis: Yersinia pseudotuberculosis-derived mitogen (YAM) Mycoplasma species: Mycoplasma arthritidis-derived mitogen (MAM) Cholera toxin: subunit A of cholera toxin Prevotella intermedia* Mycobacterium tuberculosis* Viral superantigens: (a) Mouse leukemia virus (b) IDDMK1222- Ppol-ENV-U3 (c) HIV-Nef (d) Rabies virus-nucleoside protein The superantigens can be broadly classified into following families: i. Endogenous superantigens: These superantigens are encoded by various viruses integrated into the genome. Examples are superantigens produced by mouse mammary tumor virus (MMTV) and Epstein-Barr virus (EBV) associated superantigen. ii. Exogenous superantigens: These include the exotoxins secreted by microorganisms. Examples are staphylococcal enterotoxins (A, B, C1 to C3, etc.), streptococcal pyrogenic exotoxins (A1 to A4, C, etc) and others (see Table 1) [7, 12-18]. iii. B-cell superantigens: Those superantigens which stimulate predominantly B cells. Examples include staphylococcal protein A and protein Fv. .

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