Page # Lecture 8: Immune Dysfunction - Immunopathology. Four Types of Hypersensitivity. Friend of Foe? Autoimmune disease Immunodeficiency

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1 Lecture 8: Immune Dysfunction - Immunopathology Autoimmune disease Immunodeficiency Allergy and Asthma Graft rejection and Lupus Friend of Foe? Four Types of Hypersensitivity

2 Allergic Responses - Type I Antigen binds to B cell and activates it Antigen binds to IgE on mast cells Produces antibodies with unique constant region (IgE) IgE antibodies bind to mast cells Mast cells release histamines Type I hypersensitivity mediated by IgE on mast cells Wheal and flare Allergen Characteristics It is not fully understood how or why, but these type of antigens tend to stimulate IL-4 production IL-4 production tends to lead to more IL-4 production. IL-4 favors class switching to IgE

3 A Culprit Dust Mite Fecal Protein Mast Cell Activation Compounds Released from Eosinophils Cytokine-activated Eosinophils have Fce receptors (FceR)

4 Mast Cell Activation Biological Effects Common Symptom

5 Th2 mediated Chronic Airway Obstruction (asthma) Type I hypersensitivity because IgE-mediated Type IV hypersensitivity because T H 2 involvement Allergy Treatments Reverse T H 1/T H 2 balance (2006) desensitization make IgG response to compete with IgE Delayed-Type Hypersensitivity T H 1 from a previous immunization (memory)

6 Chemical Mediators of DTH A positive tuberculin skin test is a DTH reaction Before the distinction between T H 1 and T H 2 (circa 1990), there was T H cell and T DTH. T H is now T H 2 and T DTH is now T H 1 DTH as a Result of Contact Sensitizing Agent Contact Dermatitis Can be caused by poison ivy and mango sap *a contact-sensitizing agent is usually a small molecule that penetrates the skin then binds to selfproteins, making the protein look foreign Some Allergies and Autoimmunity can be Mapped to Specific Gene Loci Many others cannot yet be mapped to specific loci

7 Examples of Susceptibility Genes Genetics AND Environement Play a Role The hygiene hypothesis of allergy induction contends that too clean of an environment and lack of infections during childhood (along with a genetic susceptibility) promote a bias of the immune system toward T H 2 cells and IgE production Atopy: a increased tendency toward type I hypersensitivity (IgE allergies) Autoimmunity (I added this slide after the lecture as a summary) Most autoimmune diseases are polygenic (many genes involved), and affected individuals inherit multiple genetic polymorphisms that contribute to disease susceptibility. Estimated that 2-5% of human population suffers from autoimmune disease Autoimmunity results from a failure or breakdown of the mechanisms normally responsible for maintaining self-tolerance in B cells, T cells, or both. The major factors that contribute to the development of autoimmunity are genetic susceptibility and environmental triggers, such as infections.

8 Autoimmunity (I added this slide after the lecture as a summary) Covered in the book Autoimmunity Book does a nice job of discussing several autoimmune diseases Look at the various links on the webpage! The red boxed diseases on this slide and the next are mentioned in the book Autoimmunity Book does a nice job of discussing several autoimmune diseases Look at the various links on the webpage!

9 Summary of Abnormal Immune Responses Disorders caused by abnormal immune responses are called hypersensitivity diseases. Pathologic immune responses may be autoimmune responses directed against self antigens or uncontrolled and excessive responses to foreign antigens. Hypersensitivity diseases may result from antibodies that bind to cells or tissues, circulating immune complexes that are deposited in tissues, or T lymphocytes reactive with antigens in tissues. The effector mechanisms of antibody-mediated tissue injury are complement activation and Fc receptor-mediated inflammation. The effector mechanisms of T cell-mediated tissue injury are DTH reactions and cell lysis by CTLs. Autoimmunity results from a failure of self-tolerance. Most autoimmune diseases are polygenic, and numerous susceptibility genes contribute to disease development. Infections may predispose to autoimmunity through cross-reactions between microbial antigens and self antigens and enhanced expression of costimulators. TH1 cells promote cytotoxicity and destruction of intracellular pathogens IL-12 drives T-cells to develop into TH1 cells TH1 cells orchestrate a response directed to inhibit intracellular pathogens like viruses, certain bacteria (e.g. TB), or certain protozoan parasites (Leishmania) They secret Interferon gamma which activates intracellular killing mechanisms They activate macrophages and cytotoxic T-cells TH2 cells promote neutralizing antibodies and mast cell activity The choice towards a TH2 response is driven by the cytokine IL-4 TH2 cells suppress activation of macrophages and activate eosinophils and mast cells TH2 cells promote a strong antibody response based on neutralizing IgGs and IgEs A TH2 response is most effective to combat extracellular pathogens

10 Immune modulation by worms can be detrimental or beneficial Numerous recent epidemiological studies show that certain vaccines are less effective in children that are infected with worms than those that have been cured using drugs. (these are mostly vaccines that require a robust TH1 response) This is backed up by many studies in mice that use vaccination or co-infection. On the other hand worm infection can dampen autoimmune diseases and allergies (diseases due to an over-active immune system. The Hygiene Hypothesis There has been a considerable increase in the diagnosis of autoimmune diseases and allergies over the second half of the 20th century. Prevalence of allergies in urban areas appears higher than in rural environments. Environmental factors like pollution, nutrition etc. can be important for specific allergies but have shown little consistent overall association with allergies and autoimmunity. Childhood infections though show strong negative correlation with both autoimmune disease and allergies.

11 Inverse correlation of type I diabetes and chronic infectious diseases XX Th1 vs Th2 hypothesis T1D - Th1 mediated Yellow - atid _ND Red - _TID and Red delineates areas which harbour six or more of the low mortality neglected diseases (filariasis, leprosy, onchocerciasis, schistosomiasis, soil-transmitted helminths, and trachoma). Yellow delineates areas where there are relatively high incidences of T1D (> 8 per /year). Non coloured areas delineate where T1D < 8 per /year and where the neglected diseases are not endemic. From: Zaccone et al. Parasite Immunol : Inverse correlation of allergies with infections Among kids in various studies in different areas of the world around 30% have antibodies against dust mite allergen (suggesting they all are exposed) But whereas asthma is found in 12% of kids from Europe and Australia, only 3% have asthma in Gambia and Nigeria The Hygiene Hypothesis High pathogen burden stimulates the immune system to develop a robust regulatory network that keeps inflammation in check Worms set up long lasting chronic infections, they induce strong TH2 responses and promote regulation of this process Understanding this process in detail could point to new allergy interventions

12 The You Ecosystem