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This is a NARRATED power point presentation so please make sure your sound system is functioning (If you cannot hear a voice over whilst viewing this slide your sound system is incorrectly adjusted) Topic: MHC polymorphism: The logic argument for a paradigm shift This Power. Point (copyright Microsoft Corp) Presentation should auto-advance To go back and hold the presentation press Pg. Up twice Press spacebar to restart & or skip a slide

• The MHC is remarkably polymorphic • Human MHC (HLA) is the most polymorphic of all • Accepted explanation is that diversity ensures binding of novel peptides • But if so why the need to have T cells bind and recognise peptide AND MHC together?

Population diversity versus individual diversity? BOTH Antibody receptor hypervariable region T-cell receptor hypervariable region extreme variability in binding site allows individual to detect virtually any protein or peptide = individual diversity HLA molecules also show extreme variability in binding site but across the population = population diversity individually limited, non-varying motifs approx 12 motifs to bind many 1000’s of peptides achieved by binding promiscuity* • binding of peptides to MHC confirmed to be “promiscuous” Engelhard et al. 2002

The logical implication of the different diversity patterns: The current explanation for MHC polymorphism is either wrong, or incomplete. There is a need for another explanation.

• Observation: • If one wished to design a biological system to prevent tissue type matching it would be difficult to produce a more effective system than HLA. • Maybe that is exactly the purpose: though not to prevent tissue transplantation, rather to prevent DUPLICATION • Could the MHC polymorphism be acting as a form of individual “security code” ? • And if so, what would it be keeping secure?

An exercise in logic ! The immune system detects invaders by sampling proteins as peptides MHC molecules bind peptide in groove Thymus selects T cells for MHC recognition, deletes T cells for self peptide recognition Thymus depletion incomplete T cells in periphery recognise cognate ligand peptide The peptide may be either: Invader Derived Peptide (IDP) Self Non-deleted Peptide (SNP)

How is the T cell decision (between self-peptide or invader peptide) made? Mechanisms proposed over last 20 years • “Ij” and suppressor cell networks • TH 1 versus TH 2 cytokine production • Absence of “danger signals” e. g. CD 28/B 7 • Many T cell-expressed molecules suggested to have a role in certain models • Tolerance inducing cytokines and molecules (IL-10, TGF beta, CTLA 4) • Regulatory/Anergic T cells

Logically: There must be a “switch off”mechanism that allows T cells to recognise SNP vs IDP There is good reason to suppose this is linked to the phenomenon of regulatory/ anergic/ suppressor cells defined both in vivo and in vitro

How close are we ? • 25 years research trying to identify the “suppressor signal” • Various candidate molecules but none proven • MHC bearing peptide ligand always present • Requires cell-cell contact • Not mediated by cytokines

But advances are being made: Inhibitory signalling pathways (Fox. P 3) Phenotype and characteristics of suppressor cells Still no mechanism which accounts for the T cell decision

One factor has not been taken into account: Any molecule that can be used to switch off the immune system represents a potentially disastrous breach in the body’s defences if it can be mimicked by an invader.

Consider what happened to antibiotics: Within 50 years micro-organisms have developed varied strategies to defeat virtually all our antibiotics How long would we survive as a species if we relied on a limited number of defined molecules to act as the “switch” off signal for our T cells?

The switch off mechanism must be: • Secure from invader duplication • Identify self from non-self • Subject to strong evolutionary pressure

A secure system requires either a lock or a code: A molecular code = high variability Only one molecular system fits this description: ………. . the MHC

Current concept: MHC + cognate ligand peptide = positive signal MHC + non-cognate ligand peptide = null signal NEW concept: MHC + cognate ligand peptide = positive signal, BUT MHC contact also delivers a separate inhibitory“self” signal which is used as the basis for suppression phenomena to avoid auto-immunity

MHC polymorphism – what’s it for? Current explanation: ensures someone binds a new peptide in a pandemic and survives TCR V-B useage restricted by MHC Inbred animals susceptible to disease Simplest obvious explanation MHC molecules bear the peptides which are the subject of the T cell decision Present explanation for MHC polymorphism has logical inadequacies: • Why the need to bind MHC • Promiscuous binding of peptide • Polymorphism outside binding groove Why use “within population” polymorphism for MHC but “within individual” polymorphism for TCR and BCR? New explanation: secures the T-cell decision from invader interference

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