The Ultimate Immunology Study Guide Part 3

20 ------------------I. Humoral Immune Response = Ab produced by B-cells cause destruction of extracellular microorganisms & prevent spread of intracellular infections → Thymus-Independent Antigen = immunogen that can stimulate B-cells to syn. Ab w/o T-cells involvement - B-cell activation has 2 routes: 1) dependent on T H cells (thymus-dependent) 2) thymus-independent Thymus-Independent Antigen Type I Thymus-Independent Antigen Type II Thymus-Dependent Antigens 21 = Component of bacterial cell walls (LPS) - Mostly polyclonal B-cell activators (mitogens) Act through both Ig & innate immune receptors (toll-like receptors - TLR) Some TI-1 Ag @ high [] activate >30% of all B-cells (mature & immature) Lipopolysaccharides of gram(-) bacteria FUNCTION : activate B-cells regardless of specificity w/ cross linking (don’t require T-cell derived cytokines) = not B-cell mitogens; highly repeating polymers (polysaccharide Ag) - Polymeric proteins Bacterial cell wall polysaccharides Frequency bound by C4d & crosslink both mIG & CD21 activating B-cells No memory cells formed in TAI response; Ig is predominantly IgM Pneumococcal polysaccharide/polymerized flagellin = immunogen that requires T-cell cooperation w. B-cells to syn. specific Ab - Requires direct contact b/w B-cells & T H2 cells Requires T-cell cytokine secretion: IL-2, IL-4, IL-5, IL-6, IL-10 T-cells may be pre-activated by APC (macrophage, dendritic cell) FUNCTION : isotype switching, affinity maturation, & memory that require helper T-cell signals FUNCTION : causes crosslinking of specific B-cell receptors A. B-Cell Receptor (BCR) = composed of Ig that form type 1 transmembrane receptor protein usually located outside of B-cell ● Initiated by crosslinking of mIG by Ag ● Cytoplasmic tail of mIg too short for signal transduction ● Comprised of mIg & signal transducing Ig-α / Ig-β heterodimer 22 ● Ag crosslinks mIg (expression of MCHII & B7 inc.) ● Ag-Ab complex internalized, digested, peptides displayed w/ MHC II ● TCR+CD4 recognize foregin peptide + self MHCII T-cell activated ● T-cells express CD40L; interaction w/ CD40 provides signal 2; co-stimulation by CD28-B7 interaction ● B-cell expressed cytokine receptors; TH-secreted cytokines induced B-cell proliferation & differentiation B. TH Cell Activation → Antigen-Presenting Cell (APC) = cell that can “present” Ag in form that T-cells can recognize ● 2 subsets: TH1 activates Tc-cells & secrete IL-2, IFN- γ , TNF-β ● TH2 activates B-cells & secretes IL-2,IL-4, IL-5, IL-6, IL-10 ● Memory cells are long-lived generated secondary response ● Presents peptide Ag by MHC II expressed on surface of APCs ● Once activated, divide rapidly & secrete cytokines that regulate/assist immune response 23 We need to: 1.) Recognize foregin peptide: TCR 2.) Signal T-cell to get activated: CD3 3.) Recognize self MHC II: CD4 4.) Spend enough time w/ APC for step 1-2 (TCR affinity for peptide is weak): adhesion molecules CD2, LFA-1, CD45R 5.) Provide co-stimulatory signal: CD28 C. T-Cell Receptor (TCR) = protein complex found on T-cells responsible for recognizing fragments of Ag as peptide bound to MHC - 2 types of heterodimer of 2 chains: αβ & γ δ - Gene rearrangement provides variability of TCR - Cytoplasmic tails of TCR short - Need associated molecules (CD3) to single cell 1. 2. II. 24 αβ = vast majority of T-cells have & recognize foreign peptide w/ MHC restriction γ δ = found in peripheral blood & may contribute to innate immunity a. TCR-CD3 Complex = formed noncovalent association of TCR w/ CD3 signalling γ, δ, ε and ζ subunit ○ CD3 parcitates in signal transduction after interaction of TCR w/ Ag ○ CD3 complex of 5 invariant chains that form 3 dimers’ 1.) Heterodimer εδ 2.) Heterodimer γε 3.) Homodimer ζζ (heterodimer ζη, 10%) Cell-Mediated Cytotoxicity A. CTL Response ● Naϊve Tc cell (CTL precursors, CTL-P) = cannot kill target ● CTL-P have to be activated to become effector cells ● CTL are MHC I restricted, CD8+ *Target = any MHC II positive cell (any nucleated cell) + foregin peptide 1. Phase 1: CTL-P → effector CTL Sequential Signals for activation of CTL-P: a) Ag-specific induced by TCR recognition of MHC I + foregin peptide b) Activation of proliferation by IL-2 c) T H1 & CTL-P may not directly interact *T H1 is provides IL-2 to nearby preactivated CTL-P *more efficient if APC enabled *proliferation of memory CTL-P may not require T 2. H 25 / CD28-B7 signal (memory CTL-P can be activated by any infected cell) Phase 2: Effector (target elimination) ○ Some fully functional CTL lines lack perforin & granzymes ○ Fas way = (TNF receptor fam. protein); delivers apoptotic signal when cross linked by Fas ligand ○ Most mammalian cells express Fas ○ FasL expression more restricted primarily to WBC & immune system cells a) Conjugate formation - TH cell activation b) Programming for target death - indices target’s death by apoptosis (few hrs.) - Granulates of CTL concentrate near junction w/ target - Granules contain perforin & several serine proteases - granzymes - Upon entry into target cells granzyme induce apoptosis *Fas/FasL pathway can be utilized to protect privileged sites & used by tumors for “protection” against WBC B. Natural Killer (NK) Cells = WBC & component of innate immune system that play role in host-rejection of both tumours & virally infected cells ● 5-10% of circulating WBC pop. ● Involved in immune defense against viruses & tumors ● Produces cytokines stimulate other immune cells ● Killing similar to CTL (perforin/granzyme +Fas/FasL) - activating differs ● Constantly cytotoxic (do not have TCR / CD3 & aren’t MHC I restricted) 1. Opposing Signals Model ○ ○ ○ 26 Balance b/w activating & inhibiting Activating Receptor (AC) = expressed on plasmatic membrane of NK cells - helps inactivate to regulate functions of NK on hosted/transformed cells Inhibitory receptors = recognize MHC I downregulation in virus-infected cells C. Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) = cell-mediated immune defense where effector cell of immune system actively lyses target cell whose membrane-surface Ag have been bound by specific Ab ● Carried out by cytotoxic cells by Fc receptors: NK, macrophages, neutrophils, eosinophils ● Specificity of response by non-specific cells proved by opsonizing Ab III. Immunity to Infection A. Bacteria 1. Extracellular = outside bacteria 2. Intracellular = inside bacteria 3. Severity of Bacteria ● Presence of large # of forgein bodies ● Toxins (1) Endotoxins = part of gram(-) bacteria ○ Contains phospholipids (toxic) & polysaccharide (antigenicity) i. Effects - Release pyogenes from macrophages (causes high fever) - Destruction of neutrophils - Initiation of clotting => intravascular coagulation - Dilation of peripheral blood vessels => accumulation of blood in phiepehr regions, sharp fall of blood pressure, & collapse (endotoxic shock) (2) Exotoxins = proteins released primarily by gram(+) bacteria (a) Examples 27 Cholera ○ gram(-) which binds to intentional epithelial cells ○ Disturbs passage of ions & water across plasma membrane (ii) Diphtheria ○ Kills epithelial cells of throat & neutrophils (iii) Botulinum ○ Has affinity for nerve endings in muscle cells where it prevents release of acetylcholine causing paralysis Non-immunological Surface Protection a) Body Surfaces (i) Physical barriers: Skin, mucus, cilia of respiratory tract (ii) Body fluids: Tears, salvia, oils, urine, provide physical protection (flushing), chemical (low pH), biochemical (enzymes, lysozyme), & immunological (iii) Resident flora ● Protects against pathogens ● Adapted to harsh conditions existing @ body surfaces & low pathogenicity ● Advantage in competition for nutrients w/ foregin microorganisms ● Provides stimulus for immune system (i) 4. 5. b) Skin Protection: physical barriers, low humidity, fungal oils, resident bacterial flora c) Mouth Protection: saliva flushes, peroxidase from resident streptococci, digestive enzymes d) Respiratory Tract = turbulent filter ● ~5mm particle can alveolar ducts ● Large particles adhere to mucus & carried upward by ciliary system e) Gastrointestinal Tract: resident flora, flushing, digestive enzymes, low pH f) Urinary Tract: flushing, low pH Immunological Surface Protection a) Nonspecific: phagocytes/complement b) Specific (carried by IgA & IgE) ● IgA-producing B-cells have affinity for body surfaces & colonize them ● Provides protection for current & future infections (memory cells) ● MALT also has pop. of IgE-secreting B-cells & IgE-carrying mast cells ● Ag-induced mast cell degranulation => dilation of local blood vessels & arrival of IgE & complement proteins (a) Immunity to Extracellular Bacteria ○ Primarily humoral immune response (Ab) 28 (b) Immunity to Intracellular Bacteria ○ Primarily cell-mediated immune response: delayed type hypersensitivity carried out by CD4+ T-cells ○ CD$+ T-cells activated 2-6 weeks after injection & induce infiltration of macrophages that contain infection ○ Macrophage wall off organism inside granulomatous lesion - tubercle ○ Massive activation of macrophages & release of lytic enzymes destroys infected & healthy cells => calcified lesions (iii) Immunity to Viral Infections ○ Shuts down cellular macromolecular syn. ○ Toxic effect of viral proteins ○ Inc. permeability of lysosomal membranes - release of lysosomal enzymes into cell ○ Changes in permeability of plasma membrane leading to influx of water & bursting of cell - Body surface protection - Phagocytosis - Interferons ■ IFN-α produced by virus-infected leukocytes by macrophages & lymphocytes ■ IFN-β produced by infected fibroblasts ■ IFN-γ (immune interferon) produced by T-cells & macrophages, B- & NK-cells ■ Interferons prevent viral protein syn. 29 B. Viruses 1. Virus Evolution 2. Virus Evasion → Antigenic drift = minor changes in antigenicity through point mutations → Antigenic shift 3. = major changes in antigenicity through swapping of genetic material w/ other viruses Examples a) Influenza Virus ● Hemagglutinin & neuraminidase Ag - molecular sites to which human body can make Ab ○ Highly unstable, sloppy, unpredictable 30 ○ ○ Has subtypes that infect bird/pigs/humans (“avian flues” & “swine flues”) Some cells can be infected w/ both types @ same time => new alleles from both types can be crested b) Avian Flu (2003-2004) ● Person-person transmission C. Protozoa (single celled parasite) ● Plasmodium (malaria) ● Trypanosoma (sleeping sickness) ● Entamoeba histolytica ○ Ab response: may not be very effective due to evasion mechanism ○ Evades via antigenic variation D. Fungi E. Helminths (parasitic worms) ● Larvae: Ab & complement ● IgE - mast cells attract eosinophils ○ Eosinophils attached to Ab-coated parasites via Fc receptors & degranulate causing damage to cuticles ○ Adult helminths often easily evade immune system by mimicry of host Ag ○ Absorption of host Ag of their surface & antigenic variation IV. Hypersensitivity → Hypersensitivity = undesirable rxns produced by normal immune system (allergies & autoimmunity) ;immunological primer ⇨ 2nd exposure to same antigen ⇨ excessive rxn => tissue damage A. Type 1: Anaphylaxis * soluble fragments are released during complement activation; C2b and C4a that leave the cascade after being cleaved *C3b molecules made by alternative pathway also participate in opsonization ● ● ● Mediated by IgE & mast cells Certain Ag cross-link IgE on surface on mast cells (allergy) Degranulation of mast cells release # of factors i. Inc. vascular permeability ii. Smooth muscle contraction iii. Neutrophil &/ eosinophil chemotaxis 31 1) Systemic Anaphylaxis ○ Shock-like (fatal) ○ Occurs in min. of onset of rxn 2) Local Anaphylaxis ○ Allergic rhinitis, Asthma, Food allergies, Atopic dermatitis 32 B. Type II: Antibody-Mediated Cytotoxic (blood transfusions) ● Antigenic group A & B derived from H substance (oligosaccharide on erythrocyte membrane) by glycosyl transferases encoded by A & B genes ● Individuals w/ both genes have 2 Ag on RBC (group AB) ● Lackers have only substance H (group O) ○ Normal gut flora has Ag similar to A & B causing constant Ab production against molecules in individuals who do NOT have them in RB - tolerize them ○ Ab of IgM normally present in sig. quantities ○ Transfusion of A blood into => severe rxn (ADCC + phagocytosis) 1) Rhesus Incompatibility RhD Ag (ex): Mother: RhD- & Baby: RhD+ => mother getting large # of Ag @ birth when placental bleed releases baby’s erythrocytes into mother -- Next baby: RhD+ => anti-D IgG of mother cross placenta & destroy RBC of fetus releasing toxic bilirubin into blood steam (hemolytic disease of newborn) causing brain damage PREVENTION! Inject mother before birth w/ anti-D immunoglobulin (Rhogam) => destroy RhD+ erythrocytes in mother’s blood before can destroy her immune system 33 C. Type III: Immune Complex Deposition ● Ag-Ab interaction can lead to large insoluble immune complexes ● Presence of large amount of Ag => inability of organism to get rid of complex fast enough -- “clog” system ● Occurance in blood system => deposition of immune complexes on blood vessels/kidneys causing arthritis/nephritis → Arthus Rxn = in situ formation of Ag/Ab complexes after intradermal injection of Ag - immuniation of rabbits w/ Ag causes intensive Ab pord a) Ag penetrate into local blood vessels which already contain specific Ab b) Ag-Ab interaction & formation of large quantities of immune complexes locally c) Complexes deposited b/w epithelial cells & activation of complement d) Released chemoattractant attract neutrophils e) Arrival of large amount of neutrophils & death destroy local blood vessels f) After ~8 hrs. Macrophages arrive & become predom. after 24 hrs. => extensive damage to surrounding tissue (acute inflammation) D. Type IV: Delayed-Type Hypersensitivity (DTH) → Tuberculin rxn = injection of purified-protein-derivative (PPD) from tuberculin under skin caused local hypersensitivity if individual has tuberculosis - Mediated by T H1 subclass of T-cells -- cells primed by Ag & T H1 memory cell - Locally stimulated by same Ag & start produce large amount of lymphokines (MCF & MIF) attracting & keeping macrophages @ place of infection (chronic inflammation) 34 V. Cytokines & Growth Factors A. Cytokines = molecules secreted by certain cells of immune system & have effect on other cells - mediate wide range of activities ● Soluble growth factors involved in cell-cell communication throughout body → Interleukin (IL) = group of cytokines that first seen to be expressed by WBC - Initially IDed in leukocytes - Soluble factors involved in leukocyte-leukocyte interactions - Critical in differination & function of hematopoietic & lymphoid cells a) General Properties ○ Cytokines secretion brief & self-limiting ○ Produced by diverse cell types → Pleiotropic = acts on diverse cell types ○ Functions are redundant! ○ ○ ○ ○ ○ 35 Cascade induces syn. of other cytokines Act synergistically = interaction of 2+ to produce combined effect > sum of separate effects / antagonistically = opposition Binds to: autocine, paracrine, endocrine High affinity binding of cytokine to receptor: dissociation constant = 10 - 10 Unique signal transduction pathway B. Stem Cells ● Pluripotent HMP stem cell gives rise to ALL lineage of blood cells ● Can self-renew (replicate) / differentiate a) Growth Factors (1) KIT ligand (CD117) - stem cell (SCF) - steel factor ○ Produced by stromal cells from microenvironment (bone marrow/fetal liver) ○ Promotes survival of primitive HMP cells: self-perpetuation of stem cells ○ Protects stem cell: prevents apoptosis in presence of gamma irradiation ○ Receptors expressed on stem cells & progenitors ○ Synergies w/ cytokines (G-CSF, GM-CSF, IL-3, EPO) (2) FLK-2/FLT-3 Ligand ○ Promotes stem cell-renewal & expansion ○ Produced by endothelial & stromal cells ○ Synergies w/ various growth factors to promote survival, proliferation, differentiation, & mobilization of diff. Lineage early human & murine precursors *Differs from KIT: doesn’t stimulate erythroid/mast cells & does potentiate lymphoid lineage (B-cells) C. Progenitor Cells ● Self-renewal capacity ● Limited differentiation capacity ● Determined lineage D. Granulocyte Macrophage - Colony Stimulating Factor (GM-CSF) = protein that stimulates WBC ● Produced by activated T-cells, B-cells, macrophages, endothelial cells, & fibroblast ● GM-CSF R expressed on myeloid & erythroid progenitors & mature myeloid cells including PMNs, basophils, eosinophils, macrophages, & dendritic cells ○ Downregulate on lymphoid progenitor; lineage separation ● Mobilizes CD34+ cells into blood ○ Clinical use: reverse neutropenia => BMT - maturation of PMNs E. Interleukins IL-3 IL-7 IL-5 IL-1 IL-8 36 - Stimulate survival & proliferation of erythroid , myeloid, progenitor cells - Produced by activated NK, mast, & T-cells - Acts synergistically w/ other factors (GM-CSF, EPO) - Acts primarily on lymphoid progenitors - Produced by stromal cells in bone marrow, fetal liver, thymus FUNCTION: - Stimulate proliferation of CD4- CD8thymocytes & pre-pro-B-cells - Stimulate V(D)J rearrangement of T-cell receptor - Initiates maturation of NK (CD56+) from CD34+ stem cell - Stimulates production of cytokines (IL-1, IL-6, TNF, IL-8) by macrophages - Induces differentiation of eosinophils - Secreted by activated endothelial & Th2 cells FUNCTION: - Prolongs survival of delaying apoptotic death - Inc. adhesion to endothelial cells - Induces chemotaxis - Enhances killing of helminthes (worm) infection & allergic response - Function similar to TNF (redundant, synergistic) - Does Not induce apoptosis directly - Effects on vasculature is similar to TNF - Inc. permeability - Inc. inflammation - Inc. coagulation - Attract neutrophils only! - Inc. adhesion of neutrophils to endothelial cells - Pro-angiogenic effects - No IL-8 homolog in mice F. Function similar to TNF (redundant, synergistic) G. Does Not induce apoptosis directly H. Effects on vasculature is similar to TNF a) Inc. permeability b) Inc. inflammation c) Inc. coagulation I. Precursor Cells ● Lack self-renewal capacity ● Uni-directional differentiation pathway ● Replication & population amplification J. Erythropoietin (EPO) = promotes formation of RBC by bone marrow *late-acting, lineage-specific HMP growth factor - induces proliferation & maturation of progenitor cell committed to erythropoiesis ● Produced in kidney & liver (upregulated in hypoxia & anemia) ● Acts synergistically w/ KIT, GM-CSF, IL-3 to induce erythroid differentiation ● Induces new blood vessel - angiogenesis K. Inflammatory Cells: Innate & Adaptive Immunity