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March 19, 2013.docx

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Department
Immunology
Course
IMM250H1
Professor
All Professors
Semester
Winter

Description
March 19, 2013 – IMM430 [email protected] Allergy – multiple definitions Pirquet definition still valid – ACQUIRED (not innate); SPECIFIC; PHYSICAL SUBSTANCES Think about immune system going awry – either too much or too little Allergy is most common immune disorder there is Prevalence of allergies is increasing Remarkable change in incidence Causes of this dramatic change unknown Most common cause = hygiene hypothesis – too sterile a living environment – previously, immune system constantly challenged by the dirtiness Look at populations with endemic parasites – low rates of allergy – suggesting that the immune system arm for allergy is designed for something else, like parasites Birth time: born in spring, greater incidence of allergy; climate change; Western industrialized world, with its chemicals so exposure to things that previously were not exposed to Diesel particles – very immunogenic – great as adjuvants – diesel exhaust could be contributing to increased immune responses Fewer siblings; bottle feeding; diet; use of antibiotics (not only do they wipe out pathogenic bacteria, can wipe out commensal bacteria) – flora that exist in gut in probiotic fashion that contributes to health – use of antibiotics early in life has been linked to increased __________- Multiple possibilities – all add up to increasing burden with inappropriate immunity Allergic diseases – in general, allergic diseases can be local or systemic – the classic example of systemic allergic response is anaphylaxis – Most manifestations of allergy are localized to specific tissues and not surprisingly the tissues that are exposed to outside world tend to be targets – ex. Asthma, the airways are exposed to outside world Allergic rhinitis – hay fever Allergic diseases of gut Atopic dermatitis – allergic disease on surface of skin Atopic dermatitis – very complex – 50% of dermatitis patients will get asthma – move from skin to airways Correlation of skin colonization – difficult to demonstrate that one is the cause of the other AD characterized – inflammatory, itchy – inflammation characterized by mononuclear cell infiltration (macrophages, eosinophils, etc) Can be systemic and severe Susceptibility factors – a lot of genetic factors Skin barrier – surface of skin covered by keratinized layer of protein that is critical in protecting us from outside world – protein called filaggrin, which is involved in forming protective layer – mutations in filaggrin (children with these muations have high incidence of AD) Bacterial exposure linked to AD – but cannot definitively tell if the bacteria is cause or consequence of AD becase bacteria is endemic Defects in antimicrobrial immune responses – Genetic predisposition – difficult to tease apart genetic influences with high backgrounds – difference between linked and unlinked disease – background: general population is high for AD – if this is rare, genetic disease, easier to identify potential genetic factors Cytokines, chemokines, mast cell derived/associated genes, FC epsilon E1beta (IgE) There is nothing definitive to indicate that is cause of AD Understanding the disease is difficult because if there is barrier breakdown or mechanical trauma leads to cycle of inflammation or amplification circle Pruritus (itchiness) leads to mechanical trauma – sets up pro-inflammatory state on surface of skin and the presence of inflammation causes cytokines to be expressed and elaborated (cytokines and chemokines) – recruitment of leukocytes – bacterial products – exposed to whatever is out there – activated – when activated, they start secreting whole slew of additional cytokines, which go on and attract more mononuclear cells, get T cellr esonse, antibody response – release of things that cause itchiness and whole cycle begins again – items of cycle feed on each other Immune response Have cycle of inflammation but also many cells – in addition to cells of skin, epidermis and dermal layer – have variety of mononuclear cells, have antigen-presenting cells that pick up antigen and bring to draining lymph nodes – mast cells, eosinophils – eosinoshipls stimulated by cytokines – initially, get Th2 response, stimulates more inflammation leading to Th1 response – very complicated situation that changes over time, evolves over time – to study this, develop models – Characteristics of model – disease needs to be observable within reasonable amount of time; something that can be manipulated genetically (can tease apart factors to determine which are important, which are not); Mouse models – relatively homogenous – know how to manipulate; can knockout, can transgenic Which factors are important, which cell types important – if have model, can address critical questions Epicutaneous immunization Need efficient way to induce lesion of interest Remove barrier by tape stripping – exposing skin to antigen Antigen on patch placed on exposed skin Patch immunization – get strong IgE response to ovalbulmin antigen – in contrast, if immunize by IP, then got IgE and IgG2A (IgE is allergic; IgG2A associated with Th1 response) Repeated exposures – over time get continuous increase to IgE response – good simple way of inducing allergic response Skin at site of exposure – two things – first is that skin gets thicker (dermal and epidermal layer expand in size); get lot of infiltration (mononuclear cell) Quantitated Few rounds of sensitization – examined skin and what you can see is that in protein sensitized vrsion, large increases in neutrophils, eosinophils, mononcuealr cells (T cells) and mast cells Site of exposure – change in ecytokine expression – took the exposed skin and extracted RNA and looked at cytokine expression – not surprisingly –found large increase in IL4, IL5 (both Th2 cytokines), interferon gamma increases, Previous studies – is it a good model? Seems to be because reproduces things characteristic of AD (allergic resonse, local changes, skin thickening, lots of infiltration) – protein antigen can be used to elicit all these changes Roles of Th1 Knockout mice – Skin thickening - in all cases observed EXCEPT for IL5 knockout – in absence of interferon gamma, skin thickening happens but not as much as observed previously Cellular infiltrates – IL5 knockout – very strong decrease in eosinophil content in the skin – because IL5 is cytokine potent at stimulating eosinophils – strong decrease in number of eosinophils – reduced eosinophilia associated with the disease In absence of IL4 where you would expect, given that IL4 is important Th2 cytokine – see reduction in infiltration – in fact, IL4 is just as strong cellular infiltrate as wild-type Figure 4 – measure cytokine content in the skin Experimental ovservation that highlights model of how T cells function Did same epicutaneous immunization – looked at cytokine expression in skin of WT and KO animals In absence of Interferon gamma, - IL4 and IL5 dramatically increased in expression In absence of IL4 , get very dramatic increase in interferon gamma levels and IL2 levels Cross-regulation between Th1 and Th2 cells IL4 and IL10 can suppress Th1 production And Interferon gamma can suppress TH2 production No il4, interferon gamma increases Nice example of Th1 and Th2 cells – playing this immunoregulatory role Systemic effects – IgG and IgE expression – not surprisingly in absence of IL4 Do get a lot of IgG2A – consistent with dominant Th1 response in local area – anti-OVA IgE, get strong response in absence of IFN gamma Summary Th2 response Previous experiments looked at local effects at skin – but AD have atopic march – half of children will develop additional allergic diseases like asthma In this paper, make hthis connection Subsequent to ovalbulmin patch immunization sensitiation, followed by inhalation sensitization (blowing OVA into lungs of mice) In one case, sensitizing on skin After one or two exposures, get strong IgG1 and IGe response with epicutanous sensitization – consistent with other groups; IgG2A (TH1 associated response) is basically zero If look in lung – Large, strong induction of mononucleocyte infiltration – ly
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