Properties & Overview of IRs Dr. Nasser M. Kaplan JUST, Jordan. 10-Jul-16 NM Kaplan 1

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1 Properties & Overview of IRs Dr. Nasser M. Kaplan JUST, Jordan 10-Jul-16 NM Kaplan 1

2 Major components of IS & their properties Definitions IS = cells & molecules responsible for: 1- Physiologic; protective immunity (host defense against IDs, & elimination of non-infectious foreign substances). 2- Pathologic; hypersensitivity disorders (tissue injury & disease). IR = reaction to components of MOs + macromolecules (e.g. polysaccharides, proteins, nucleic acids & phospholipids), & small chemicals w are recognized as FOREIGN, regardless of its physiologic or pathologic outcome. Protective immunity against IDs is mediated by EARLY IRs of innate immunity & LATER IRs of adaptive immunity w function in concert in integrated & cooperative manner. Immunology = study of IRs + of cellular & molecular events w occur after encountering MOs & other foreign macromolecules. 10-Jul-16 NM Kaplan 2

3 Innate (natural, native, inborn, inherited, non-specific) immunity CCCs: 1- Initial early defense line, in place even before infection. 2- Rapid, within hours (to MOs & products of injured cells). 3- Specific for structures common to groups of related MOs & may NOT distinguish fine differences between MOs. 4- Similar response to repeated infections. cellular & biochemical factors: 1-Barriers: physical/ mechanical as epithelia & cellular/ chemical as antimicrobial chemicals (defensins) produced at epithelial surfaces; 2-Cells: phagocytic (neutrophils, macrophages), DCs, & NK; 3- Blood proteins, inc. complement & other mediators of inflammation; & 4-Cytokines. 10-Jul-16 NM Kaplan 3

4 Definitions Ags = all substances w are recognized by & bind specifically to Ab molecules or TCRs, whether or NOT they stimulate IRs. NOT all Ags are Immunogens (molecules able to stimulate IRs, activate lymphocytes, & generate specific Abs), but all immunogens are Ags. Naïve = individuals & lymphocytes have NOT previously been exposed to particular Ag (un-immunized or immunologically inexperienced). Immune individuals; who have responded to microbial Ag & are protected from subsequent exposures to that MO. Passive immunity; of individual without exposure or responding to Ag by transfer of serum or lymphocytes from other individual previously immunized specifically to that particular Ag. 10-Jul-16 NM Kaplan 4

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6 Adaptive (acquired, specific) Immunity (stimulated by exposure to foreign Ags) 10-Jul-16 NM Kaplan 6

7 CIL Immunity to previously encountered MO (Ag) is measured indirectly by: 1- assaying for presence of products of IRs (e.g. serum Abs specific for microbial Ags) 2- administering & measuring reactions to purified microbial Ag: Reaction is indication of sensitivity, is detectable only in sensitized individuals (indicates that sensitized individual is capable of mounting protective IR to previously encountered MO, & has NO protective function. 10-Jul-16 NM Kaplan 7

8 6 Cardinal features of Normal Adaptive IRs to foreign Ags w reflect properties of mediating lymphocytes 1- Specificity & diversity: (related to distinct antigenic molecular structures) Specificity to ensure that IR to Ag is targeted to that Ag. Individual lymphocytes express surface membrane receptors w recognize & respond to specific Epitopes = antigenic determinants (= parts of distinct foreign Ags as portions of single complex protein, polysaccharide, or other macromolecule). Lymphocyte repertoire (= total # of epitopes recognized by lymphocytes in individual) is extremely large ( ) due to Diversity (= variability in structures of Ag-binding sites of TCRs for Ags) w enables IS to respond to large variety/ #s of foreign Ags (microbial & non-microbial). 10-Jul-16 NM Kaplan 8

9 2- Immunologic memory: Mechanism: first exposure to Ag initial activation of T cells generation of expanded pool of Ag-specific Memory lymphocytes: 1- Re-circulate in lymphocyte pool abundant in lymphoid organs & peripheral nonlymphoid tissues (any infection site) as mucosal tissues, skin. 2- More numerous; after TCM-IR subside, # of persisting Ag-specific memory T cells of responding clone (1 in 10 4 ) > (typically fold) # of naive T cells specific for same Ag before Ag encounter. 3- Long-lived; survive for prolonged periods (many years) in quiescent resting state even after Ag elimination (e.g. without secreting Abs). Rationale: To remember & respond to subsequent exposure to same Ag (Secondary IR) with enhanced ability (more rapidly, with larger magnitude & more effectively defensive capabilities) than first exposure (Primary IR) to eliminate Ag by generating new effector cells than do naive cells (e.g. memory B cells produce Abs w bind Ags with higher affinities than do Abs produced in primary IRs, & memory T cells react much more rapidly & vigorously to Ag than do naive T cells) more efficient IRs to persistent or recurring exposure to same Ag & to combat prolonged or repeated infections. 10-Jul-16 NM Kaplan 9

10 3- Clonal expansion after Ag recognition = proliferation ( in #) of Agspecific lymphocytes clones (belong to a clone w expresses identical receptors for Ag) large # of Ag-specific cells required to eliminate Ag & keep pace with rapidly dividing infectious MOs. 10-Jul-16 NM Kaplan 10

11 4- Specialization: enables IS to generate IRs with effector mechanisms w are distinct & optimal for maximum effective protection against *different MOs (intracellular, helminthes & extracellular) or *same MO at different stages of infection (extracellular & intracellular virus). Even within IRs, nature of generated Abs or T lymphocytes may vary from one class of MO to another. 10-Jul-16 NM Kaplan 11

12 TCM-IRs decline after Ag is eliminated by effector cells 5- Contraction & homeostasis: All normal effective IRs elimination of foreign Ag lymphocytes are deprived of survival & activation stimuli normally provided by *Ag (w initiated this IR), *costimulators, & *cytokines produced D inflammatory reactions to Ag Contraction (إنكماش) phase in w majority (>90%) of Ag-specific activated effector T cells (other than memory cells), w arise by clonal expansion die by apoptosis recovery of IS from one IR & restoring of its equilibrium/ resting basal state (Homeostasis) to be prepared to effectively respond to other newly-encountered Ags. 10-Jul-16 NM Kaplan 12

13 6- Non-reactivity to self self-nonself discrimination: Prevents IS from reacting harmfully to self own autologous Ags (normal molecules, cells & tissues) while recognizing, responding to, & eliminating non-self foreign Ags. Tolerance = immunologic un-responsiveness. Immunologic self-tolerance = induced tolerance to self Ags w prevents maturation & activation of potentially harmful self-reactive lymphocytes (w express specific receptors able to recognize & react against self Ags) by (1) killing (elimination), (2) suppression (inactivation) by other (regulatory) cells or (3) change their specificity. Abnormalities in self-tolerance (induction or maintenance) IRs against self Ags Autoimmune diseases. 10-Jul-16 NM Kaplan 13

14 Cellular Components of Adaptive IS 1- Lymphocytes: different classes distinguished by expression of surface proteins (named CD/ cluster of differentiation molecules & numbered). 2- Ag-presenting cells (APCs): most specialized are DCs, w capture microbial Ags w enter from external environment, transport them to lymphoid organs, & display them to specific naive T cells to initiate & develop adaptive IRs. Other cell types function as APCs at different stages of CM- & H-IRs. 3- Effector cells: w mediate final effect of IR (elimination of Ags & MOs) following activation of lymphocytes by Ag (e.g. Activated T lymphocytes, mononuclear phagocytes, & other WBCs). Lymphocytes & APCs are concentrated in anatomically discrete lymphoid organs, where they interact with one another to initiate IRs. Lymphocytes are also present in PB where they can recirculate through lymphoid tissues & home to peripheral tissue sites of Ag exposure to eliminate Ag. 10-Jul-16 NM Kaplan 14

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16 Humoral Immunity (Activation of B Lymphocytes & Elimination of Extracellular MOs) On activation, some of progeny of expanded B cell clones Ab-secreting plasma cells; each plasma cell secretes Abs w have same Ag-binding site as cell surface Abs (BCRs) w first recognized Ag (specificity). B cells respond to: 1- Non-protein (Polysaccharides & lipids) Ags without participation of other cells mainly IgM Abs. 2- Protein Ags requiring ( help ) from CD4+ helper T cells *(Class switching); functionally different classes of Abs (IgG, IgA, IgE) with same specificity from single clone of B cells, & *(Affinity maturation); Abs with increased affinity for Ag). 10-Jul-16 NM Kaplan 16

17 Humoral IR combats microbes in many ways: Abs recognize, bind & (Neutralize) infectivity & colonization of MOs (Abs are only mechanisms of adaptive immunity w prevent infection from becoming established; this is why production of potent Abs is key goal of vaccination). Abs eliminate Ags by activating different effector mechanisms: 1- IgG Abs coat MOs & target them for phagocytosis as phagocytes (macrophages & neutrophils) express receptors for tails of IgG. 2- IgG & IgM activate classical complement pathway complement products w promote phagocytosis & destruction of MOs. 3- Active transport of some Abs at particular anatomic sites: *IgA secreted from mucosal epithelia into lumens of mucosal organs to provide defense against inhaled & ingested MOs in GI & RTs. *Maternal IgG cross placenta to protect newborn until baby s IS becomes mature. 10-Jul-16 NM Kaplan 17

18 CMI consists of: 1- development of effector T cells (from naive cells in peripheral lymphoid organs) w involves *Ag recognition, *clonal expansion & *differentiation (w is ccc of all adaptive IRs). 2- migration of effector T cells & other WBCs to sites of infection, 3- killing either by cytokine-mediated activation of WBCs to destroy MOs or by direct killing of infected cells. Both CD4+ & CD8+ T cells contribute to CMI, but each subset has unique effector functions for eradication of MOs. Different populations of T cells provide defense against different types of infectious MOs (specialization of adaptive immunity). 10-Jul-16 NM Kaplan 18

19 CMI (Activation of T Lymphocytes & Elimination of Intracellular MOs or killing of infected cells) 1- Activated CD4+ helper T lymphocytes proliferate & differentiate into effector cells w function through secreted cytokines (e.g. IL-2 (= growth factor w acts on Ag-activated lymphocytes & stimulates their proliferation (Clonal expansion). CD4+ effector T cells: 1- leave sites of their generation (lymphoid organs), migrate to sites of infection/ inflammation, & become activated to eliminate MOs when they again encounter cell-associated MOs. 2- secrete cytokines w recruit WBCs & stimulate production of microbicidal substances in phagocytes for intracellular killing. 3- secrete cytokines w stimulate IgE & activate eosinophils, w kill parasites too large to be phagocytosed. 4- stay in lymphoid organs & stimulate B cell IRs. 10-Jul-16 NM Kaplan 19

20 2- Activated CD8+ lymphocytes proliferate & differentiate into CTLs w kill cells infected by intracellular MOs (in cytoplasm) e.g. viruses or bacteria (inaccessible to intracellular killing of phagocytes largely confined to vesicles) & so eliminate reservoirs of infection. 10-Jul-16 NM Kaplan 20

21 Cytokines, Soluble Mediators messenger molecules of IS large & heterogeneous group of secreted plasma proteins. nomenclature is haphazard (e.g., TNF, interferons & ILs). many cytokines produced by many cell types NOT usually stored as preformed molecules. Synthesis is transient: (1) initiated by transient new gene transcription (2) encoding messenger RNAs are unstable & rapidly degraded. Some: proteolytic release of active product from inactive precursor. Rapidly secreted burst of release when needed. Bind to receptors, & action on different target cells: on same secreting cell (autocrine), on nearby cell (paracrine), or at distance from site of production (endocrine) e.g. TNF has local & distant (systemic) effects. T cells often secrete cytokines at site of contact with APCs (immune synapse). 10-Jul-16 NM Kaplan 21

22 share many other general properties: One cytokine can act on diverse cell types & have multiple biologic effects (pleiotropism). Conversely, multiple cytokines may have same action (redundant). One cytokine can stimulate or inhibit production of others, & cytokines may antagonize one another or produce additive or synergistic effects. Mediate, regulate & co-ordinate (all/ many) cellular IRs: 1- Innate: cytokines (produced by DCs, macrophages, & mast cells) drive process of inflammation or contribute to defense against viral infections. 2- Adaptive: cytokines (produced by helper T cells) activation & differentiation of T cells & B cells. Some cytokines are growth factors for hematopoiesis & regulate generation of different types of immune cells from precursors in BM. 10-Jul-16 NM Kaplan 22

23 Overview of IRs to MOs Principles of IRs to different types of MOs IS has to combat many & diverse infectious MOs IRs to all MOs share some common features, & may also have unique features to different classes of MOs?How these adaptive IRs are initiated, orchestrated, & controlled? 10-Jul-16 NM Kaplan 23

24 Early Innate IRs to MOs to control & eradicate infections 1- Barriers to prevent entry of MOs from external environment by continuous epithelia lining skin & GI & RTs & factors to eliminate or limit growth of MOs w are able to colonize tissues. 2- MOs w successfully breach epithelial barriers encounter cellular innate IRs: (1) Inflammation = recruitment of WBCs & plasma proteins from PB, their accumulation in tissues, & their activation to destroy MOs. Many of these reactions involve cytokines. Major WBCs recruited are phagocytes, neutrophils (w have short life spans in tissues), & monocytes ( tissue macrophages). These phagocytes express on their surfaces receptors w bind & ingest MOs & other receptors w recognize different microbial molecules & activate cells. On engagement of these receptors, phagocytes produce reactive oxygen & nitrogen spp & lysosomal Es, w destroy ingested MOs. Resident macrophages in tissues serve much the same functions. (2) Antiviral defense consists of cytokine-mediated reaction in w cells acquire R to viral infection & killing of virus-infected cells by NK cells. 10-Jul-16 NM Kaplan 24

25 3- MOs w successfully withstand cellular innate IRs in tissues may enter PB & encounter circulating plasma proteins of innate immunity e.g. complement system (1) alternative pathway of activation by microbial surfaces proteolytic cleavage products w mediate inflammatory responses, coat MOs for enhanced phagocytosis, & directly lyse MOs. (2) classical pathway of activation by Abs with same functional consequences. (3) Many of circulating plasma proteins enter sites of infection D inflammatory reactions & help combat MOs in extravascular tissues. 4- MOs w resist innate immunity will encounter more powerful & specialized mechanisms of adaptive immunity, w prevents them from invading & replicating in cells & tissues of host. 10-Jul-16 NM Kaplan 25

26 Adaptive IRs activate one or more of 3 defense mechanisms against diverse MOs w may be in different anatomic locations, as intestinal lumens, circulation, or inside cells: 1- Secreted Abs bind to extracellular MOs, block their ability to infect host cells, & promote their ingestion & subsequent destruction by phagocytes. 2- Phagocytes ingest MOs & kill them, & helper T cells enhance microbicidal abilities of phagocytes. 3- CTLs destroy cells infected by MOs w are inaccessible to Abs & phagocytic destruction. 10-Jul-16 NM Kaplan 26

27 All adaptive IRs develop in phases/ steps, each of w corresponds to particular reactions of lymphocytes 1- Capture & Display of Microbial Ags: to concentrate in recognizable form in correct anatomic location & to deliver to specific lymphocyte with receptors for Ag as # of naive lymphocytes specific for any Ag is very small (1 in 10 5 or 10 6 lymphocytes) & quantity of available Ag may also be small Maximum chance that T cells of particular specificity finding relevant Ag to recognize. *DCs are APCs w display microbial peptides to naive CD4+ & CD8+ T lymphocytes & initiate adaptive IRs to protein Ags. *DCs, in epithelial & CTs and spleen, capture MOs, process their proteins into antigenic peptides, display peptides-mhc complexes on their surface, transport them to draining LNs & reside in same regions of normal continuous recirculation of naive T lymphocytes. *Intact MOs or microbial Ags w enter LNs & spleen are recognized in unprocessed (native) form by specific B lymphocytes (specialized APCs) w display Ags to B lymphocytes. * B lymphocytes use their Ag receptors (membrane-bound Ab molecules) to recognize Ags of many different chemical types. 10-Jul-16 NM Kaplan 27

28 2- Recognition of Ag by lymphocytes; Clonal Selection Hypothesis: *To enable IS to recognize & respond to large # of MOs with variety of Ags. Before & independent of any exposure to Ag: molecular events D maturation of lymphocytes very large # of lymphocytes with different antigenic specificities/ Ag-specific clones ( Clone = lymphocyte of one specificity & its progeny) in un-immunized individuals, so exposure to particular Ag selection of specific clone w recognizes Ag, activation, increase in size, & differentiation into effector cells. Clonally distributed receptors: variation of Ag receptors among different clones of T & B cells. 10-Jul-16 NM Kaplan 28

29 3- Activation of naive T lymphocytes requires recognition of both: *Antigenic peptide-mhc complexes presented on DCs to ensure specificity. Nature of Ag ensures that these lymphocytes can interact only with other cells & NOT with free Ag. (necessary as all functions of T cells are dependent on their physical interactions with other cells). *Costimulators, other molecules induced on APCs by MOs. to ensure that T cells respond to MOs (inducers of co-stimulatory molecules) & NOT to harmless substances. Engagement of Ag receptors & other signals trigger lymphocyte proliferation & differentiation. 10-Jul-16 NM Kaplan 29

30 Regulatory mechanisms (feedback loops) of IRs = Balance between: (1) Positive amplification/ activating: to enable small # of activated specific T lymphocytes to amplify IR & eradicate infection: (activated T cells secrete cytokines w stimulate both T cell proliferation & differentiation into effector cells & send back signals to further enhance APCs' ability to activate T cells). (2) Negative control/ inhibitory: to prevent excessive activation of T lymphocytes, & so pathologic (damage to normal tissues) & inappropriate (against self Ags) IRs: (activated T cells' surface molecules & cytokines). 10-Jul-16 NM Kaplan 30