Lecture 7 CH0506 B cells, Hypersensitivity, autoimmunity PDF

B-Cells, Hypersensitivity/ Allergy, and Autoimmune Diseases Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com. Learning Objectives List the basic features of cell-mediated and humoral immunity. Explain the role of lymphocytes in the immune response....

B-Cells, Hypersensitivity/ Allergy, and Autoimmune Diseases Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com. Learning Objectives List the basic features of cell-mediated and humoral immunity. Explain the role of lymphocytes in the immune response. 2. List the five classes of antibodies, and explain how they differ from one another. 3. Describe the four types of hypersensitivity. Describe the pathogenesis of allergic manifestations and the role of IgE in allergy. 4. Explain why it is sometimes necessary to suppress the immune response, and describe how this is accomplished. 5. Understand how autoimmunity/hypersensitivity develops (failure of tolerance) 6. Compare and contrast tolerance and autoimmune disease, including the clinical manifestations and the methods of treatment. Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com 1. The Body’s Defense Mechanisms Two branches of adaptive immunity Specifically CD8 Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com ▪ Humoral immunity (B cells) ▪ Production of antibodies ▪ Main defense against bacteria and bacterial toxins ▪ Cell-mediated immunity (T cells- CD4, CD8) ▪ Formation of a population of lymphocytes that attack and destroy infected cells (CD8) ▪ Main defense against viruses, fungi, parasites, and some bacteria ▪ Mechanism by which body rejects transplanted organs ▪ Means of eliminating abnormal cells that arise spontaneously in cell division (cancer) Comparison of Humoral and Cell-Mediated Immunity Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Response of Lymphocytes to Foreign Antigens ▪ Recognition of foreign antigen ▪ Proliferation of individual lymphocytes that are programmed to respond to the antigen form a large group (clone) of cells ▪ Destruction of pathogen /infected cells by the responding lymphocytes main goal By apoptosis Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Entry of a foreign antigen into the body triggers a chain of events: Interaction of Humoral and Cell-Mediated Immunity ▪ T lymphocytes proliferate to form a diverse population of cells that regulate the immune response and generate a cell-mediated immune reaction to eliminate antigen (CD4/CD8) ▪ B lymphocytes proliferate and mature into antibody-forming plasma cells – require CD4 T cell help ▪ Both will retain some cells as memory cells present the antigen Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com When appropriately stimulated: T Lymphocyte Response to Antigen ▪Unable to respond to a foreign antigen (TCR) until a macrophage or dendritic cell (APC) cell has phagocytosed the antigen, digested it, and displayed on its cell membrane the antigen fragments combined with its own MHC proteins Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com T lymphocytes B Lymphocyte Response to Antigen ▪Move into the cell and is processed into fragments ▪Fragments displayed on the cell’s membrane with the MHC class II proteins ▪Presentation and recognition of antigen by CD4 T cells will upregulate and enhance antibody production Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com ▪Have immunoglobulin molecules (BCR) on their cell membranes that function as antigen receptors, and they can bind entire antigen molecules to their receptors (do not require MHC presentation) Antigen Presentation FIGURE 6-4 Antigen presentation. The antigen presenting cell (APC) cradles the antigen in the peptide arms of the MHC (HLA) molecule, allowing engagement by the T cell receptor. If the MHC (HLA) is class II, it will engage a T helper cell; if it is class I, it will engage a cytotoxic T cell. T helper cells are necessary for antibody production by B cells. Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Presenting to CD4 T cell and turning it on Antibodies ▪ Globulins produced by plasma cells Large amounts in plasma, represents 10-20% of plasma proteins in circulation Functions: ▪ Activation of complement ▪ Neutralization IgM is very good at this Depending on where they can bind to them ▪ Agglutination ▪ opsonization Binding chains, light chains and heavy chains are identical that are specific to this cell Pathogen is tagged for destruction Figure 6-8 Antibody Structure. (A) A three-dimensional model of an antibody showing the four chains. The molecule is T shaped before binding to antigen. As it binds, it becomes Y shaped. (B) A diagrammatic representation of the structure of an antibody molecule that shows the four protein chains, two large (heavy chains) and two small (light chains). Note that the antigen binds to the arms of the molecule. Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com ▪ Can react only with the specific antigen that induced its formation (binding to BCR) Antibody Types ▪Immunoglobulin A (IgA) ▪Immunoglobulin M (IgM) ▪Immunoglobulin E (IgE) ▪Immunoglobulin D (IgD) Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com ▪Immunoglobulin G (IgG) Antibodies IgG ▪ Smaller antibody ▪ Principal antibody molecule in response to majority of infectious agents All over body only produced if B cell gets max amount of stimulation Main antibody in vaccines Brings more complement to the site When B cell is activated ▪ Large antibody; a macroglobulin – early production before IgG is produced ▪ Responsible for immune control in early response ▪ Expressed on surface as monomer – secreted form (pentamer) ▪ Very efficient combining with fungi At this point, B cell has not gotten CD4 T-cell licensing IgE ▪ Found in minute quantities in blood; binds to mast cells, basophils/eosinophils ▪ concentration is increased in allergic individuals ▪ Important in controlling parasitic infections Associated with hypersensitivities https://en.wikipedia.org/wiki/Antibody#/media/File:Mono-und-Polymere.svg not much role in bacteria/viral Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com IgM Antibodies IgA Present in saliva, tears, breast milk IgD ▪ Found on cell membrane of B lymphocytes (Functions mainly as BCR) ▪ Present in minute quantities in blood Not really found much in the serum B-cells may just shed them when they are destroyed https://en.wikipedia.org/wiki/Antibody#/media/File:Mono-und-Polymere.svg Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com ▪ Produced by antibody-forming cells located in the respiratory and gastrointestinal mucosa (GI/respiratory and urogenital tract) ▪ Combines with harmful ingested or inhaled antigens, forming antigen–antibody complexes Antibody production – B cells Minor activation Naïve B cells have IgM and IgD on cell surface Process antigen and show to CD4 T-cell If T-cell binds, co-stimulation Processed antigen is then presented on MHCII – recognition - binding to CD4 (and costim molecules) for same antigen then stimulates transition to plasma cell: ▪ Proliferation/Increased Ab production ▪ Class switching – specialized effector functions ▪ Affinity Maturation – competition/ mutation Remodify antibody to get a better hold of antigen ▪ Memory (travel to spleen/BM) Without T cell help – Ab production is weak and short lived, no memory https://www.sciencedirect.com/science/article/pii/B9780123852458000054 Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Recognition of antigen results in activation, upregulates molecules similar to Dendritic/ Macrophage cells (APC) Adaptive immunity is an awesome weapon that allows vertebrates to have extended life spans due to infection control of various pathogens Methods of Control: •Cytokines (direct/control immune response) •Tolerance (central/peripheral) •Regulatory cells •Activation vs. Anergy/Apoptosis Opposite of a normal T-cell - any antigen they recognize shuts down an immune response Loss of Control…Leads to Hypersensitivity or Autoimmunity As soon as you have vaccinations, disease is nearly gone • very effective tool Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Also the tool that modern medicine had taken great advantage of with the advent of vaccination Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com The sources are mostly from T lymphocytes and NK cells Targets are T-cells and B-cells but also a lot of targets in innate immune system IL-2 If people lack this interleukin —> immune response is 0 Proliferation • Interleukin 2 is produced by T cells, It is the major growth factor for T cells. Also promotes the growth of B cells • IL-2 acts on T cells in paracrine/autocrine fashion. • Activation of T cells results in expression of IL-2R and the production of IL-2. promotes cell division. Support antibody production Proinflammatory vs. Th2- anti-inflammatory IL-5 • Interleukin 5 is produced by Th2 cells and it functions to promote the growth and differentiation of B cells and eosinophils. It also activates mature eosinophils. TGF-β • Transforming growth factor beta is produced by T cells and many other cell types. It is primarily an inhibitory cytokine. • It inhibits the proliferation of T cells and the activation of macrophages. It also acts on cells to block the effects of pro-inflammatory cytokines. INF-γ • Interferon gamma is an important cytokine produced by primarily by Th1 cells, although it can also be produced by Tc and NK cells to a lesser extent. • It has numerous functions in both the innate and adaptive immune systems. Has function in inhibiting viral replication Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com IL-4 • Interleukin 4 is produced by macrophages and Th2 cells. • stimulates the development of Th2 cells from naïve Th cells and it promotes the growth of differentiated Th2 cells resulting in the production of an antibody response. skews towards either Th1 or Th2 response through th production of cytokines Cytokines polarize the immune response to deal with encountered pathogens Th1- (cell based) geared towards viral/ bacterial attacks in blood/ tissues Polarize cells of adaptive and innate immunity to promote cellular immunity most effective against these invaders –PROINFLAMMATORY Cytokine effects are local and targeted to sites of infection • Positive feedback: Th1/2 cytokines enhance and encourage Th1/2 functions and uncommitted cells (IL-2/IL-4) •Negative feedback: Th1 inhibits Th2 functions and vice versa. (IFNgamma/IL-10) Whatever there is more of tips the balance and you either have an TH1 or Th2 environemnt Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Polarization affects how immune system is going to respond Th2- (humoral-antibody) geared towards parasitic/mucosal infections. -ANTIIFLAMMATORY -Antibody based -basis of hygiene Hypothesis, Allergy IgE Development of T and B Lymphocytes FIGURE 6-2 Development of T and B lymphocytes. Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Central tolerance - during when T and B cells are made Development of T and B Lymphocytes Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com FIGURE 6-2 Development of T and B lymphocytes. Central Tolerance Immature (lymphoid progenitor) T cells from bone marrow enter the thymus from the blood. B- cells remain in bone marrow as the develop/ mature Coreceptor for MHC1 Begin to proliferate and rearrange gene segments of the TCR to generate a TCR repertoire- incredible diversity Coreceptor for MHC2 Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com B and T cells must: •not react to self antigens •Be restricted to self MHC molecules (T cells), so they will only react to presented antigens Positive selection-MHC restriction Cells that recognize MHC-peptide complexes receive rescue signals that Cell that can bind to MHC2 better — Prevent apoptosis. > reinforce CD4 receptor Cell that can bind MH1 better —> (Positive Selection) reinforce CD8 receptor CD4 and CD8 T cells that survive MHC restriction migrate to the medulla of the thymus Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Selection is by the epithelial cells in the cortex, that express MHC molecules loaded with peptides Negative Selection-self Cells that survive positive selection exit the thymic cortex to the medulla where they are tested for tolerance to self antigens Do not want anything recognizing self AIRE (autoimmune regulator) gene causes transcription of a wide selection of organ-specific genes that create proteins that are usually only expressed in peripheral tissues Antigens presented by thymic dendritic cells are a “snap shot” of current antigens in the body T cells that bind to these MHC/self-peptide complexes are deleted T-reg cells are developed here • bind self-antigen well but instead of terminating they can shut down immune response due to alternative gene programming Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Thymic dendritic cells present self peptides acquired from throughout the body The rest are deleted by apoptosis and consumed by macrophages. Then more T cells are made over time Fetal development – full complement when born, activity of thymus decreases over time with large drop in thymic function after puberty Little bit of turn over to replace then but decreases as we age as thymus function decreases Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Out of 60 million t cells produced per day, only 2 million survive to exit the thymus as mature T cells (about 2-3%) B cell – central tolerance Not heavily restricted; just tested to see if it is functional ▪ Positive (proper function signaling of BCR) – will activate B cell maturation ▪ Followed by negative (reaction to self) recognition to self - results in receptor editing-second chance for BCR rearrangement Although B-cell development is not MHC restricted, they are indirectly MHC restricted through the requirement of T cell licensing to be fully activated Since B cells present antigens with MHCII to CD4T cells, additional selection against self is gained from T cell recognition Indirectly restricted by T cell recognition Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com B cells undergo similar developmental selection process in the bone marrow: Decreased stringency of central tolerance mechanisms compared to T cells (30-40% survive) – continued development throughout life Peripheral Tolerance Need this as we can’t control what is going to happen after these cells leave B-cell Need to find CD4 t-cell to be activated By location: naïve t cells stay in circulation, don’t stay in LN, or tissues so they Only encounter a portion of the antigens in our body (compartmentalization) Antigens that are encountered in the periphery are dealt with by a simple mechanism, engagement of TCR without proper co-stimulation (from innate immune cells) results in cell anergy/ apoptosis Repeated stimulation also results in activation induced cell death of a specific cell/clone coreceptor expression • recognized bacteria or pathogen by PPR No single method is perfect, but combined they Have great effectiveness, for this reason autoimmune disorders are relatively rare…. Non-functional • dies of old age in weeks/months Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com All antigens cannot be presented/ selected for/against during thymic selection Immune control - Cell Anergy Once infection has been effectively controlled, is it vital to “shut off” immune Responses. Indirectly, due to the fact that there is less antigen present to stimulate An immune response – DCs die after a few days Without continued support from Macrophages/DC, activated cells will die off Directly, Apoptosis and by molecular inhibition of immune functions (activated T cells are inherently pro apoptotic quiet down immune response •Tim-3 •PD1/ PD1L •CTLA-4 Activation of T cells results in the up-regulation of these molecules that produce Intracellular signals that de activates immune cells Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com This is done: T cells are activated through high affinity TCR engagement with MHC/ peptide complexes In order to become activated they also require costimulation As T cells are stimulated they upregulate CTLA4 molecules on the cell surface which out compete CD28 for B7 molecules (CD80/86). (1000x affinity) CTLA4-B7 binding: • makes less B7 molecules available for interaction with CD28 •CTLA:B7 binding represses activation and block CD28 signaling Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com T Cells typically express high amounts of CD28 on the cell surface, whereas CTLA4 is stored in intracellular reservoirs. Binds the exact same coreceptor as CD86 • signals cells to start shutting down B cell TolerancePeripheral ▪ Recognition by the T cell results in co-signalling (CD40L) and release of cytokines that will activate the B-cell ▪ Co-receptor signals can also be received from the presence of microbial components/complement ▪ Lack of co-receptor signals results in either anergy/ death or compartmentalization Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com ▪ B cells can present antigens thought MHC II to CD4 “helper” T cells Tolerance – B lymphocytes Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com 20-30% Autoreactive 50-70% Autoreactive Comparison- B and T cell Tolerance Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Repeated stimulation • says this is common self antigen Peripheral Tolerance- Regulatory T cells Natural T-reg cells 30 Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Treg cells: • T cells that regulate activation of other T cells • Necessary to maintain peripheral tolerance to self antigens • CD4+CD25+ FoxP3+ • Produce cytokines that shut down the immune system (IL-10/TGFβ) • Both of these cytokines bind surface receptors on activated T cells initiating A signaling cascade that de-activates the cell. Regulatory T cell generation •occurs in the thymus •About 5% of CD4 T cells in circulation are “natural” nTreg. •In contrast to T “helpers” who drive the immune response, nTreg cells turn down immune response to self antigens. •“Inducible” or adaptive Treg cells can be generated to self and foreign antigens after an inflammatory immune response. Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com •Subset of CD4 T cells which have a slightly higher affinity for self antigens (during negative selection) become nTreg cells. Hypersensitivity Reactions Environment – Allergy Self - Autoimmunity ▪ Type I: Allergy (immediate) ▪ Type II: Cytotoxic ▪ Type III: Immune complex ▪ Type IV: Delayed hypersensitivity or cell-mediated hypersensitivity Failure –Adaptive immunity Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Failure in Tolerance or immune control mechanisms can lead to the development of Hypersensitivity reactions: Hypersensitivity Reactions Anaphylaxis: Hypersensitivity reaction that may be life threatening ▪ Systemic response: peanuts, Bee sting, penicillin allergy Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Type I: Allergy and anaphylaxis (immediate) ▪ Allergy first develops through sensitization –IgE loading on mast cells, basophils, eosinophils ▪ IgE antibodies bind to mast cells and basophils – preloading (sensitization) ▪ Later contact with same antigen triggers release of mediators (histamine) and related clinical manifestations (sensitization) ▪ Localized response, such as hay fever, food allergy (peanuts), pets, mold Mild reaction: Typical presentation includes Uticaria (rash), itching, swelling (edema) Treatment: environmental control, antihistamines, steroids, leukotriene inhibitors, allergen immunotherapy ▪ Antihistamine drugs often relieve many allergic symptoms; histamine is one of the mediators released from IgE-coated cells Hypersensitivity Reactions A little bit of reaction but after 6-8-24 hours, stronger reaction due to more immune cells coming in All mast cells all around circulatory system will sync and all release histamin - very serious https://franklincardiovascular.com/do-i-have-mast-cell-activation-syndrome-mcas/ Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Type I: anaphylaxis (immediate) ▪ Sensitizing antigen circulates throughout the body, triggers widespread mediator release from Ig-coated mast cells and basophils ▪ May lead to anaphylaxis: Severe generalized IgE-mediated reaction (fall in blood pressure, severe respiratory distress) ▪ Unpredictable (food –peanuts, seafood, bee stings) ▪ Can be bi-phasic ▪ Prompt treatment required with epinephrine in cases of anaphylaxis Hypersensitivity Reactions not clear which tolerance response could be weaker/hypersenistive Prone to this if some cells escape central tolerance and react However, not everyone is going to experience these • ex. someone who has excezma may not experience anything else Atopic person: Allergy-prone individual – Atopic March Environmental susceptibility – hygiene hypothesis Hypersensitivity, asthma and autoimmune diseases are much less common in the developing world compared to the industrialized world extremely elevated in the blood stream TH2 mediated, B-cells, IgE (IL-4/IL-5, TGFbeta) Need to use peripheral tolerance - good to be exposed to everything when baby comes out proetective womb https://www.annallergy.org/article/S1081-1206(17)31196-1/fulltext Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Genetic susceptibility (multi factorial) can be passed on from parents Hypersensitivity Reactions ▪ Antibody combines with cell or tissue antigen, resulting in complement-mediated lysis of cells or other membrane damage ▪ Example: Autoimmune hemolytic anemia, blood transfusion reactions, Rh hemolytic disease, autoimmune glomerulonephritis if someone gets wrong blood type Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Type II: Cytotoxic – antibody dependent (IgM, IgG) Hypersensitivity Reactions ▪ Ag-Ab immune complexes deposited in tissues activate complement pathway; Neutrophils attracted to site, causing tissue damage ▪ Example: Rheumatoid arthritis, systemic lupus erythematosus (SLE), some types of glomerulonephritis - Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Type III: Immune complex Hypersensitivity Reactions T lymphocytes are sensitized and activated on second contact with same antigen ▪ Lymphokines induce inflammation and activate macrophages ▪ Example: contact dermatitis, Diabetes Mellitus (T1), Rheumatoid arthritis T-cells destroy islet cells Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Type IV: Cell-mediated, Delayed hypersensitivity – typically in 24-72 hours Autoimmune Diseases Ex. Bvalvular heart diseas largerly indirect and somewhat effective Take two pools of healthy antibodies and put them into patient Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Pathogenesis ▪ Failure of Tolerance mechanisms (central, peripheral) ▪ Alteration of patient’s own (self) antigens, causing them to become antigenic, provoking an immune reaction ▪ Formation of cross-reacting antibodies against foreign antigens that also attack patient’s own antigens ▪ Defective down regulation and control (hyperactivation) of the immune system ▪ Treatment: various immune suppressing therapies. Corticosteroids, cytotoxic drugs, NSAIDS, immunotherapy with various biologics, antibody treatments (monoclonal – blocking or IVIG), symptomatic. ▪ Immune suppression can also be an important treatment in transplant patients –especially BMT Autoimmunity e Autoimmune disease results when there is a defect in mechanisms meant e To preserve tolerance to self antigens. Roughly 2-5% of people develop autoimmune disorders. really is chance - not much genetic predisposition Autoimmunity can occur when: •Individual express MHC molecules that efficiently present self peptides Two particular types of MHCII increase chance of type1 diabetes by 20 fold •Production of T and/or B cells that have receptors that recognize self Random mix match, even identical twins will not share TCR repertoires (chance) •Breakdown of tolerance mechanisms designed to eliminate these cells also have ones that express viral components really well emphasizes luck component Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Genetic defects can lead to failures of immune control or balance between Activation/ control, but most are due to failure of self tolerance mechanisms which leads to the production/ survival of self reactive cells. Biggest thing is failure of central tolerance • made really reactive B or T cell that just did not get killed (could be due to a constellation of genetic effects) (20-50% in identical twins, 2-5% in nonSameidentical twins or siblings) in the general population Potential causes of Autoimmunity •Defects in central tolerance deletion/ survival •Defects in T Reg function/ numbers •Defective apoptosis mechanisms (+ve/-ve) •Inadequate inhibitory receptor functions (CTLA/ Fas) •Chronic activation of APC’s, excessive T cell activation can have cells that are long lived when they shouldn’t be Tend to be chronic, progressive and self perpetuating Complex polygenic traits contribute to development of autoimmunity Complex constellation a genetic polymorphism contribute to disease susceptibility combined with environmental factors lead to disease development Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com immmune system does not shut down fast enough Model of autoimmunity development 1. Genetic susceptibility 2. Failure of self tolerance/immune control presenting self-antigens 4. Activation of APC’s 5. Recruitment of auto-reactive lymphocytes 6. Activation of auto-reactive Lymphocytes 7. Tissue injury from auto immune attacks 8. Auto immune disease Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com 3. Infection/ injury Antigen presenting cells Autoimmune Diseases (organ specific) Myasthenia Gravis in neurone of the neurone synapse •Self reactive antibodies bind to acetylcholine receptors •Results in muscle weakness and paralysis Cross reacton •Polio proteins could be molecular mimics for acetylcholine receptors Multiple Sclerosis •CNS inflammatory disease •Initiated by reactive T cells/ Macrophages affect conduction •Chronic inflammation destroys myelin sheath protein, causing defect in sensory inputs •Cells thatCross react to myelin basic protein also react to proteins reaction from EBV and Herpes simplex virus (molecular mimicry?) 70-80% of us have been exposed to EBV •Particular MHCII allele associated with increased risk (HLAD1 1501) Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Insulin Dependent Diabetes Mellitus Very important to feed cells sugar T-cells •Immune system targets insulin producing Beta “Cure” through diet and insulin cells in the pancreas (Islets of Langerhans) •mediated predominantly by CTL activity, B cells also play a role •CTLA-4 genetic defects have shown to increase susceptibility •Dysfunctional natural Treg cells. Autoimmune Diseases (systemic) Rheumatoid Arthritis Lupus Erythematosus •Systemic: rash (forehead/ cheeks), inflammation of lungs, •kidneys, joints, paralysis, convulsions •Breakdown in both T an B cell tolerance •Production of diverse IgG antibodies against a range of DNA, DNA protein complexes, RNA-protein complexes that clog organs and cause chronic inflammation •More than a dozen MHC alleles have been identified that contribute to development • Lack of activation induced cell death may play a role. Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com •Systemic autoimmune disease •Cartilage protein targeted causing chronic joint inflammation And pain •Reactive T cells from patients also recognize molecular mimicry Mycobaterium tuberculosis protein (cross reactive?) •IgM, IgG antibody complexes form in joints and activate macrophages MHC alleles associated w/ disease or increased risk Development of autoimmune disorders is polygeneic and multifactorial. Genetic mutations associated with Autoimmune disorders include dysregulation of: •Treg (FoxP3) •Cell activation (IL-2, IL-12, CD2/58, Blk) •Activation inhibitors (IL-10, CTLA4) •Apoptosis (Bim, Fas) •HLA alleles (MHC) Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Can be too much activation, not enough shut down, too much cell growth, etc. • can also be a combination Table I Female:Male Ratios in Autoimmune Diseases 10: 1 Systemic lupus erythematosus 9:1 Sjogren’s syndrome 9:1 Antiphospholipid syndrome-secondary 9:1 Primary biliary cirrhosis 9:1 Autoimmune hepatitis 8:1 Graves’ disease 7:1 Scleroderma 3:1 Rheumatoid arthritis 2.5 :1 Antiphospholipid syndrome-primary 2:1 Autoimmune thrombocytopenic purpura (ITP) 2:1 Multiple sclerosis 2:1 Myasthenia gravis 2:1 •Stronger humoral and cellular immune reactions •Differences in Th1/Th2 responses? Estrogen turns down AIRE In thymus Post part is a time of susceiptibliyy to autoimmunity Th2 predominates •Hormones (increased susceptibility during/post pregnancy, flare ups with menstrual cycle) •Changes in disease severity associated with hormonal changes (SLE, RA, MS) •Most cells of immune system have estrogen receptors (B, Mono, NK, Neutrophils) •X linked gene expression? 1000 genes, 70% associated with human diseases •Overall, 3-4x greater proportion (as high as 80% of persons with AD are women) •When males have AD, tends to be more severe Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Hashimoto’s thyroiditis Treatments: Pain control/ physical therapy Symptomatic/ Drugs: https://cosmosmagazine.com/health/medicine/autoimmune-disease-on-the-rise/ ▪Corticosteroids/anti-inflammatory ▪Chemical T cell/ B cell inhibitors/Cytokine blockers (IL-2) ▪mAb to block immune receptors on T/B cells or cytokines (TNFa) ▪Pain control/physical therapy ▪IVIG – block Fc receptors on cells Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Immunosuppression Auto immunity -Conclusion Adaptive Immune system is a powerful weapon we use to defend against A wide variety of foreign pathogens •Direction/communication by cytokines •Specificity (anergy/apoptosis) •Tolerance to self antigens (peripheral/central) •Control/suppression of immune responses (Treg, CTLA4, apoptosis) Failure of any of these mechanisms leads to potential development of autoimmunity.. more failures (or more significant failures) = greater chance Even without any genetic predispositions, potential development of Autoimmunity still exists. Copyright © 2021 by Jones & Bartlett Learning, LLC an Ascend Learning Company. www.jblearning.com Control of Adaptive immunity is provided by: