Innate and Adaptive Immunity

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

• 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.

• 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

• 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.

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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

Ifn  /  and  have different cell surface receptors but share components Of the Jak/Stat signal transduction pathway.

Binding of either type to the receptors causes Tyr PO4ylation of the different receptor associated kinases, and of the different Stat proteins associated with these. Ifn  /  complex has a unique pathway activating p113; both activate p91/p84. These pathways then converge in the activation of Ifn-stimulated response elements (ISREs); they diverge in that Ifn  can induce gamma-activated site (GAS) genes

Viruses can block effects of interferon:

• • •

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

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

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).

Humoral and cellular response require activation and proliferation of Th cells

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.

Primary lymphatic system showing ducts and nodes: mobile dendritic cells meet circulating lymphocytes in nodes 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

Cutaneous immune system: keratinocytes, Langerhans cells and T-cells Keratinocytes secrete Tnf  , IL-1 and IL-6 and have phagocytic activity and have MHC-I and II and present Ag to T and B cells if stimulated by Ifn  . Langerhans cells are migratory dendritic cells and have MHC-I and II

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 to MHC class II proteins and are generally Th cells. Cells with CD8 receptors recognise peptides bound to MHC-I and generally act as cytotoxic T cells.

T-cell receptor: heterodimer of an  and a  chain or  and  chains, all with N-terminal V domains.

Members of the Ig superfamily of receptors Antibody: dimer of hetero dimers; heavy and light chains both have variable regions

CD4 and CD8 are both glycosylated type I membrane proteins, both of which have cytoplasmic domains which interact with tyrosine kinases, which means they participate in signal transduction events.

Both have Ig-like variable domains.

CD4 molecules are monomers and bind MHC class II proteins via the 1 st two domains. CD8 proteins are heterodimers linked by disulphide bridges. They bind MHC class I proteins.

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.

Full activation of Th cells in many cases requires interaction of other surface 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-2 and 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.

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…

The first Abs expressed by a VIRGIN B-CELL are MEMBRANE RECEPTOR IgM/IgD. Binding and cross-linking of receptors by an antigen triggers a signal transduction cascade, which when reinforced by Th2-produced cytokines and growth factors secreted by macrophages, result in cell proliferation and differentiation and increased soluble Ab production, then CLASS-SWITCHING and differentiation to memory and plasma cells. Memory cells last for months to years; plasma cells last only a week or so.

How antibodies can interfere in virus infection: normal cell entry is shown 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

IgA secretory antibodies play a key role in antiviral defence at mucosal surfaces: Plasma cells secrete polymeric IgA (pIgA) that binds a receptor on the inner side of an epithelial cell. The pIgA is endocytosed and delivered into vesicles targetted to the outer side of the cell (TRANSCYTOSIS).

pIgA is then released by proteolysis of the receptor pIgR by a surface protease.

The IgA can bind to Ag at any stage of the process: it can take Ag into the cell and across into the lumen; it can block virus attachment in the lumen; it can bind internally and block virus maturation / release