05 - February 6, 2013.docx

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Laboratory Medicine and Pathobiology
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LMP403 – February 6, 2013 Mechanisms of hypersensitivity KNOW THE DIFFERENT MECHANISMS OF REACTIONS – they lead to diseases – how these mechiasms relate to the diseases, KNOW THIS Specific type of hypersensitivity reaction and what you might predict as to what happens as to the reaction – KNOW THIS Four mechanisms Type 1 hypersensitivity reactions – Hypersensitivity in general – implies that person`s immune system is responding to something in environment is is intrinsictly NOT HARMFUL – ex. Poison ivy is not deadly, but can elicit nasty reaction; ex. Ragweed An aberrant response of immune system – not intended as protective response, hence aberrant Four types of hypersensitivity reactions – mediated by antibody IgE Type 2 reactions that are cytotoxic – also antibody mediated – type 3 reactions also antibody mediated but not through immediate Type 4 – not antibody rection; cell mediated reaction; cells take time to get to site of reaction, so reaction delayed, hence name Hypersensitivity reaction Pictorial – Prevalence of allergic disease has skyrocketed – allergies in general and especialy those that are type 1 hypersentivity reactions, the prevalence has doubled Reasons: Allergic disease Genetics – polygenic – allergic disease is not caused by one single gene, or mutation Multiple factors in play No dominant pattern of inheritance of most types of allergies Changes in lifestyle – compelling way to account for increase in allergic disease – hygiene hypothesis, which says that we are born with Th2 bias, which is to say that were more prone to mount allergic responses in early developmental phases; as we come in contact with bacteria, and bacterial products, or become bacterially infected, shifts bias to Th1 bias – hwe this happens, less prone to developing allergies But live in hygeniec environment, little burden and exposure to bacteria and bacterial products, less likely to undergo switch from Th2 to Th1 bias, and more likely to retain predisposition to allergic disease Changes in lifestyle continued – only children tend to have ; youngest sibling tend to exposed to less hygienic environment; Changes in lifestyle – someone with a brisk immune system will have a stronger allergic reaction than those with immunosuppression or immunocompromised – in context of allergy, do nto want to boost immune system Immediate hypersensitivity reactions Immunologic non-IgE mediated reactions Pathway – sensitization gives rise to allergen-specific IgE, IgE leaves bone marrow, in circulation, lands on mast cells in tissue; mast cells have high affinity receptors for IgE; IgE binds to mast cells, waits until person is re exposed to allergen, which may set of allergic reaction but soneties people are exposed to substances that do not interact with IgE – no need for specific IgE – when substances activate mast cells, release variety of products Substances that can act directly on mast cells, no need for prior exposure, no prior sensitization with production of specific IgE – mast cells, once activated, release all the products that would have been released in IgE reaction, giving same manifestions – clinically, same because mediators are the same Drugs that can cause this listed – radio contrast agents Non-immunologic reactions Reactions that are not mediated by mast cells, mediated by conplement activation – generation of two complement split product – C3a and C5a – these act on vasculature – give rise to manifestations that look like immediate hypersensitivity reaction but are infact not – prototype for this is reaction to blood products – in course of hemodialysis, reaction to dialyszer membrane Spectrum of reactions Person makes specific IgE to binding site on pollen; IgE cross reacts with structurally similar proteins in some fruits, vegetables; immune systems that when consuming the product, thinks eating pollen – this is oral allergy syndrome Far right – clearly non-IgE mediated – IgE – without it, immune system does not have good way of interacting in specific sense with environment – IgE transmits signal from environment to effector cells (mast cells; basophils) IgE present in circulation in very low concentrations – prefers to sit on receptors IgE – most of it in tissue, with a tiny portion in serum When IgE binds to high affinity receptor on mast cells or basophils – termed sensitization of mast cells or basophils When IgE binds to high affinity receptors, molecule is stabilized – resistant to proteolytic digestion – so when in tissue, IgE is very stable; when in circulation, not protected fromn degradation, and half life is very short in circulation To mount IgE mediated reaction – needs IgE – needs prior exposure to allergen – in order for immune system to recognize it – in order for immune system to initiate IgE switch – release into circulation, allow recirculate, find its way onto mast cells receptors – nothing happens until the person is re-exposed to what is an allergen for them PRIOR EXPOSURE MUST OCCUR TO GIVE RISE TO REACTION IgE – C epsilon 3 is what binds to high affinity receptors on mast cells There is an antibody that binds to the Ce3 – usd to treat people with moderate to severe asthma Effector portion is Need a few IgE molecules to reside on surface of molecule – Mast cells activate – produce newly synthesized mediators – these mediators are mainly lipid mediators that are the nasty players in allergic reactions, give rise to life –threatening manifestations Mast cells – IgE on suface called SENSITIIZED MAST CELLS Transmembrane loops Allergen binding to continguous IgE molecules Granules Mast cells – Mast cell undergoes degranulations Pathogenic mechanisms Three classes of mediators – those that are preformed; newly formed; cytokines produced by activated mast cells Give rise to inflammatory second phase, called late phase reaction Immediate response – Late phase response – mediated by cytokines that recruit inflammatory cells, like monocytes, eosinophils, macrophages, lymphocytes – that give rise to late response that happens hours later Anti-histamine is not going to help with late response – this is cell-mediate response If blood vessels leaky, have surrounding edema If happens in gut, crampy abodominal pain; vomiting; diarrhea Later manifestations – give rise to inflammatory responses as opposed to allergic responses First phase is allergic; follow up phase is inflammatory Histamine – what do they do? Anti-histamines given for anaphylapsis – does not help; they get better because they’re young, healthy Platelet activating factor – newly formed lipid mediator – produced when mast cells and basophils are activated A lot of immediate hypersensitivity reactions are neuisances – can use anti-histamines But in situations where life is threatened, major mediator giving rise to the manifestations is the platelet activating factor Lowers blood pressure, etc. LDL cholesterol is the bad form of cholesterol Higher the LDL level, the more PAF acetyl hydrolase in bloodstream, the better at breaking down or inactivating platelet activating factor, which does bad stuff in allergic reactions Effect of human PAF-AH in two anaphylactic shock models Pretreat mouse with recombinant form of pAF AH – ouse better at inactivating PAF – and it’s protected from anaphylaxis in dose-dependent fashion Grade 3 is most severe anaphylactic reaction – levels of platelet activating factor in relation to severity – higher levels of platelet activating factors associated with worse reactions – worse levels of PAF associated with mildest reactions In same group of people, look at levels of PAF in relation to circulating PAF AH – those ppl with highest AH levels, rapidly inactivate PAF, and have lowest level of PAF People who have died of anaphylaxis – individuals who died of reaction to peanut Group 1 is important; others are controls Ultimately died due to peanut allergy – had lowest levels of AH – people who are deficient for this aenzyme are at highest risk for fatal anaphylaxis PAF and PAF AH In severe Pathway that leads to IgE mediated reactions B cells – ige isotype switch – form plasma cells that produce Ige – IgE resides on mast cells on basophil surfaces; expose to allergen again – release products that give rise to allergen – if allergen is localized, localized to that site of exposure; Depends on root of exposure and where the mast cells reside in body Laryngeal edema – can be fatal – Three types of anaphalytic reactions – 1. Majority of people – uniphasic reaction – acute reaction with proper treatment, normality resumes 2. Bipha
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