Innate and Adaptive Immunity

1. Innate and Adaptive Immunity • Innate is FIRST LINE OF DEFENCE: no prior exposure needed • Comprised of:- INTERFERONS- COMPLEMENT- NATURAL KILLER CELLS (NK)

3. INFLAMMATION: initiated by CELL DAMAGE - activates COMPLEMENT, MAST CELLS, etc. Symptoms are REDNESS, HEAT, SWELLING, PAIN. Neutrophil / macrophage chemotaxis into site of inflammation increases response, results in recruitment of T-cells, etc.

4. CHEMOKINES are often first sign that host is infected • Tend to act locally near cells that make them • Participate in:- CONTROL OF INFLAMMATION- INDUCTION OF ANTIVIRAL STATE- REGULATION OF ADAPTIVE IMMUNE RESPONSE • Invoke GLOBAL RESPONSES: act on nervous system, etc. Cause many classical signs of virus infection

5. Inflammatory cytokines IL-1, IL-6 and TNF act on BRAIN and LIVER to produce symptoms and ACUTE-PHASE PROTEINS - these have innate immune capability; eg: activate complement, lymphocyte production, etc.

6. SPECIFICALLY ANTIVIRAL RESPONSE: • produced by infected cells - triggered by dsRNA, some structural proteins, etc: induction rapid, and transient • secreted Ifn binds cell receptors: 1 for, 1 for  • ,  induce antiviral state: over 100 genes induced; leads to cell death by apoptosis if prolonged • blocks cell proliferation, inc. NK cell activity, etc. • induces dsRNA-activated Pkr, PO4ylates eIF2 • induces RNAse L and dsRNA-act. 2’-5’ oligoA synthetase; 2’-5’ oligoA act. RNAse L, degrades mRNAs

7. Ifn-/ and - have different cell surface receptors but sharecomponents Of the Jak/Statsignal transduction pathway.Binding of either type to thereceptors causes Tyr PO4ylationof the different receptor-associated kinases, and of thedifferent Stat proteins associatedwith these. Ifn-/ complex hasa unique pathway activating p113;both activate p91/p84. These pathways then converge inthe activation of Ifn-stimulatedresponse elements (ISREs); theydiverge in that Ifn-  can inducegamma-activated site (GAS) genes

8. Viruses can block effects of interferon:

9. COMPLEMENT - a complex collection of serum defence proteins that also amplifies immune reactions. • 18 serum and roughly same no. membrane proteins which act sequentially in a cascade - started by ANTIGEN-C’ or Ab-C’ interaction. • Form MEMBRANE ATTACK COMPLEX to lyse cells - MOs, viruses, RBCs, nucleated cells

10. Classical pathway activated by C1 binding Ab-Ag complex • Alternative pathway activated by C3b binding Ag directly

11. Natural Killer Cells • Large, granular lymphocytes, no Ag receptors • Can constitute up to 30% of circulating lymphocytes • Act early in infection, spontaneously kill infected cells • Numbers expand quickly with viral infection, decline with adaptive response • Lyse cells and secrete cytokines like Ifn- and Tnf- • Bind cells via many receptors, including lectins • Interaction with cells governed by ACTIVATION signals (eg: new CHO ligand) and NEGATIVE signal (eg: MHC class I protein).

13. Humoral and cellular response require activation and proliferation of Th cells

14. Humoral response begins when Ag cross-links several Ab receptors which are then endocytosed, and is processed by proteolysis, complexed with MHC class II molecules, and presented at the cell surface. The Th cell then recognises this by means of its T-cell receptor and secretes cytokines to activate the cell to divide and differentiate.

16. Cellular components of mucosa-associated lymphoid tissue in gut.M cells and intraepithelial lympho-cytes transfer antigen from gut to lymphoid tissue in Peyer’s patches Primary lymphatic systemshowing ducts and nodes:mobile dendritic cells meetcirculating lymphocytes in nodes

17. Cutaneous immune system:keratinocytes, Langerhans cells and T-cellsKeratinocytes secrete Tnf-, IL-1 and IL-6 and havephagocytic activity and have MHC-I and II and present Agto T and B cells if stimulated by Ifn-. Langerhans cellsare migratory dendritic cells and have MHC-I and II

18. B cells have 100 000-odd identical Ab monomers as receptors. T cells have about 100 000 identical receptors. T cells with CD4 receptors recognise peptides bound toMHC class II proteins and are generally Th cells. Cellswith CD8 receptors recognise peptides bound to MHC-Iand generally act as cytotoxic T cells.

19. Members of the Igsuperfamily of receptors Antibody: dimer of hetero-dimers; heavy and light chainsboth have variable regions T-cell receptor:heterodimer of an  and a  chain or and  chains, all withN-terminal V domains.

20. CD4 and CD8 are bothglycosylated type I membrane proteins, both of which have cytoplasmicdomains which interactwith tyrosine kinases, whichmeans they participate insignal transduction events.Both have Ig-like variabledomains. CD4 molecules are monomers and bind MHC class II proteins via the 1sttwo domains. CD8 proteinsare heterodimers linked bydisulphide bridges. Theybind MHC class I proteins.

21. Both are heterodimers,but MHC-I  chain has 3 domains and 2 only 1 while MHC-II  and  each have 2. MHC class I are found on nearly all nucleated cells, but at highest concentration on lymphocytes (500 000 vs 100/cell on liver cells). MHC-II are found only on specialist APCs. There are 3 loci for each type (A, B, C for I, DR, DP and DQ for II), but many alleles, meaning individual responses will differ considerably. Ifns stimulate MHC-I production.

24. Full activation of Th cells in many cases requires interaction of othersurface proteins and co-stimulators on the APC and T-cell as well as the TCR and MHC class II proteins. Activated Th cells make IL-2and IL-2 receptor resulting in autostimulation. CTLs (CD8+ T-cells)require at least 3 additional reactions, including TCR/MHC-I binding, binding of other surface proteins on the CTL with the target cell, and binding of cytokines produced by Th1 cells nearby.

25. Immature T-cells can differentiate into Th1 or Th2 classes, distinguished by the cytokines they produce. They have distinct functions and respond to Ag stimulation with a transient burst of cytokine stimulation that differentially influences the activation and proliferation of other immune cells. Th1 cells promote maturation of CTLs and arm APCs. IL-12 induces immature Th cells to mature to Th1s; IL-4 prompts -> Th2. These promote B cell maturation. Th1 Induce IgG2a, which activates C1 and binds macrophages; Th2 stimulate IgG4 and IgE, which do not. Th1 & Th2 see-saw…

26. The first Abs expressed by a VIRGIN B-CELL are MEMBRANERECEPTOR IgM/IgD. Binding and cross-linking of receptors byan antigen triggers a signal transduction cascade, which whenreinforced by Th2-produced cytokines and growth factors secretedby macrophages, result in cell proliferation and differentiation andincreased soluble Ab production, then CLASS-SWITCHING anddifferentiation to memory and plasma cells. Memory cells last formonths to years; plasma cells last only a week or so.

27. How antibodies can interfere in virus infection: normal cell entry isshown at left; what can happen with antibodies at right. Ab can (1) aggregate; (2) neutralise; (3) stabilise; (4) change virion structure;(5) potentially enter cell and interfere within

28. IgA secretory antibodies play a keyrole in antiviral defence at mucosalsurfaces:Plasma cells secrete polymeric IgA(pIgA) that binds a receptor on theinner side of an epithelial cell. ThepIgA is endocytosed and deliveredinto vesicles targetted to the outerside of the cell (TRANSCYTOSIS).pIgA is then released by proteolysisof the receptor pIgR by a surfaceprotease.The IgA can bind to Ag at any stageof the process: it can take Ag into thecell and across into the lumen; it canblock virus attachment in the lumen;it can bind internally and block virusmaturation / release