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Self Tolerance, Regulation and Immune Imbalances (I.E. Autoimmunity & Immunodeficiency)

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Self Tolerance, Regulation and Immune Imbalances (I.E. Autoimmunity & Immunodeficiency) 1 Self Tolerance, Regulation and Immune imbalances (i.e. Autoimmunity & Immunodeficiency) Dr. Lavkush Dwivedi Dept. of Biomedical Sciences Bundelkhand University, Jhansi The immunological equilibrium: balancing3 lymphocyte activation and control Activation Tolerance Effector T cells Regulatory T cells Normal: reactions Controlled response to against pathogens pathogens Inflammatory No response to self disease, e.g. reactions against self 3 Central and peripheral tolerance to self The principal fate of lymphocytes that recognize self antigens in the generative organs is death (deletion), BUT: Some B cells may change their specificity (called “receptor editing”) Some T cells may differentiate into regulatory (suppressor) T lymphocytes Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011 c Elsevier 4 Consequences of self antigen recognition in thymus Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011 c Elsevier 5 What self antigens are seen in the thymus? • The thymus has a special mechanism for displaying peripheral tissue antigens in thymic medullary epithelial cells, where they signal self-reactive thymocytes for death. • AIRE Genes are there which control the maturation of only non-self reactive cells. • Failure of AIRE leads to autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia (APECED), 6 Deletion of self-reactive T cells in the thymus: Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 8th edition, 2014 AIRE (autoimmune regulator) is a regulator of gene transcription that stimulates thymic expression of many self antigens which are largely restricted to peripheral tissues 7 Peripheral T cell tolerance Abbas, Lichtman and Pillai. Basic Immunology, 4th edition, 2014 8 T cell anergy Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011 c Elsevier 9 CTLA-4 competitively inhibits B7-CD28 engagement APC APC B7 B7 CTLA-4 CD28 T Cell T cell (activated T cell or Treg) Costimulation → T cell activation CTLA-4 blocks and removes B7 → lack of costimulation → T cell inhibition 10 Major functions of selected B7-CD28 family members • CD28-B7: initiation of immune responses • ICOS-ICOS-L: T cell help in germinal Activation Activation center reactions (antibody responses) • CTLA-4-B7: inhibits early T cell responses in lymphoid organs • PD-1:PD-L1,2: inhibits effector T cell Inhibition responses in peripheral tissues 11 Blocking CTLA-4 promotes tumor rejection: CTLA-4 limits immune responses to tumors Administration of antibody that blocks CTLA-4 in tumor-bearing mouse leads to tumor regression 12 The PD-1 inhibitory pathway • PD-1 recognizes two widely expressed ligands (PD-L1, PD-L2) • Knockout of PD-1 leads to autoimmune disease (less severe than CTLA-4-KO) • Role of PD-1 in T cell suppression in chronic infections, tumors? 13 T cell “exhaustion” in chronic viral infections Memory T cells: Effector enhanced Naïve CD8+ T cells antiviral T cells Acute infection: responses clearance of virus Virus Chronic infection: persistence of virus Exhausted T cells: inability to respond to virus (expression of inhibitory receptors, e.g. CTLA-4, PD-1) 14 Actions of PD-1 • PD-1 attenuates TCR signaling in responding T cells • Limits harmful consequences of chronic stimulation with persistent antigen (self, tumors, chronic viral infections) • Greater role in CD8 than in CD4 T cells • Also expressed on follicular helper T cells; function? Checkpoint blockade for cancer immunotherapy e.g. ipilimumab Ribas A. N Engl J Med 2012;366:2517-2519. Checkpoint blockade for cancer immunotherapy 16 e.g. ipilimumab e.g. nivolumab, pembrolizumab Ribas A. N Engl J Med 2012;366:2517-2519. 17 Risks of blocking CTLA-4 or PD-1 • Blocking a mechanism of self-tolerance leads to: • Autoimmune reactions (a new cottage industry for clinicians?) – Colitis and dermatitis are common – Vitiligo, Endocrinopathies, hepatitis less common but described – Severity of adverse effects has to be balanced against potential for treating serious cancers – Less severe with anti-PD1 antibody 18 Regulatory T cells Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 8th edition, 2014, Elsevier 19 Properties of regulatory T cells • Phenotype: CD4+, high IL-2 receptor (CD25), low IL-7 receptor, Foxp3 transcription factor; other markers • Essential features of stable Tregs: – Foxp3 expression: Foxp3 mutations --> autoimmune disease (IPEX); in mice, disease can be corrected by providing normal Foxp3+ cells – CD25 (IL-2Ra) expression: IL-2 is a necessary survival factor – CTLA-4 expression: required for suppressive function of most Tregs 20 Mechanisms of action of Foxp3+ Treg cell • CTLA-4 on Tregs removes B7 on APCs, reduces CD28 engagement and T cell activation – Genetic deletion of CTLA-4 in Foxp3+ cells results in severe systemic autoimmunity and lymphoproliferation • Inhibitory cytokines produced by Tregs (TGF-b, IL-10) suppress immune responses (DCs, MACs, T cells) – IL-10 deletion in Foxp3+ cells results in colitis – IL-10 is also produced by Foxp3- cells • Consumption of IL-2 Functions of Interleukin-2: the dogma 21 22 Dual roles of IL-2 in T cell responses Surprising conclusion from knockout mice: the non-redundant function of IL-2 is in controlling immune responses Pathogenesis of autoimmunity 23 Therapy of immune disorders: rational approaches target 24 lymphocyte activation and subsequent inflammation 25 The landscape of T cell activating and inhibitory receptors TIGIT 26 Autoimmunity • Autoimmunity is a self- damaging immune effector response manifested in various autoimmune diseases (AID). • Any disease that results from such an aberrant immune response is termed an "autoimmune disease Immunodeficiency • Immunodeficiency is a state in which the immune system's ability to fight infectious disease and cancer is compromised or entirely absent. • Most cases of immunodeficiency are acquired ("secondary") due to extrinsic factors that affect the patient's immune system. 27 Immunodeficiency • Humoral – innate immunity - complement, MBL acquired immunity – immunoglobulins (B lymphocytes) • Cell mediated immunity – innate immunity – phagocytes - acquired immunity – T lymphocytes • Primary – congenital, genetically defined, symptoms predominantly at early age • Secondary – the onset of symptoms at any age chronic diseases effect of irradiation immunosuppression surgical intervention, injuries stress 28 Immunodeficiencies – major clinical features • Antibodies - microbial infections (encapsulated bacteria) respiratory - pneumonia, sinusitis, otitis GIT – diarrhea • Complement system – microbial infections (pyogenic), sepsis edema (HAE) – C1-INH deficiency • T lymphocytes - bacterial, fungal, viral GIT – diarrhoea respiratory – pneumonia, sinusitis • Phagocytes - abscesses, recurrent purulent skin infections granulomatous inflammation 29 I. Primary immunodeficiencies – phagocytic cell defects Qualitative – phagocytes functional disorders, various enzyme deficits, inability of phagocytes to degrade the ingested material Chronic Granulomatous Disease (CGD) • Approximately in 60% X-linked • Enzymatic inability to generate toxic oxygen metabolites (H2O2) during oxygen consumption) - defect in neutrophilic cytochrome b (part of complex containing NADPH oxidase) • Inability to kill catalase producing bacteria such as Staph.aureus, Pseud.aeruginosa • Clinical features: granulomas of skin, organs • Treatment: long-term ATB prophylaxis, in more severe cases BMT 30 II. Primary immunodeficiencies – B cell disorders X-linked hypogamaglobulinemia (XLA, Bruton’s agammaglobulinemia) • Most common X-linked form • Block of maturation of pre-B lymphocytes into B lymphocytes (Bruton’s tyrosine kinase defect) • Undetectable or very low serum levels of Ig, absence of B cells • Symptoms: pneumonias, pyogenic otitis, increased occurrence of pulmonary fibrosis • Treatment: life-long Ig replacement CVID – Common Variable Immunodeficiency • Heterogenous group of B cell functional defects • Low levels of IgG and IgA, B cell counts normal • Symptoms: onset mostly between 2nd and 3rd decade recurrent respiratory tract infections (pneumonia, sinusitis) • Treatment: life-long Ig replacement 31 II. Primary immunodeficiencies – B cell disorders Selective IgA deficiency • Disorder of B cell function: absence of IgA, levels of the other Ig normal • Recurrent mild/moderate infections or asymptomatic • Risk of reaction to live attenuated vaccines or generation of anti-IgA antibodies after blood transfusion Selective IgG subclasses deficiency, specific IgG deficiency • B cell functional disorder • Onset of symptoms in childhood, mostly respiratory tract infections caused by encapsulated bacteria (H.influenzae, Pneumococci) Transitory hypogammaglobulinemia of infancy • Milder and transitory decrease of IgG and IgA 32 III. Primary immunodeficiencies – T cell disorders diGeorge syndrome • Disorder of development of 3rd and 4th branchial pouch → congenital heart disease + absence of thymus + absence of parathyroid glands • Complete or partial • Symptoms: symptoms of cong.heart dis. – prominent immunodeficency – variable (mild functional → absence of T cells) hypocalcemic spasms – possible mental deficit • Treatment: symptomatic, in complete form BMT 33 IV. Primary immunodeficiencies – combined defects of T and B cells SCID – Severe Combined ImmunoDeficiency • X-linked recessive disease, combined disorder of humoral and cell mediated immunity • Severe disorder (patients often die during until 2nd year of
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