Lecture 19_Tolerance and Autoimmunity_2024.pdf

Tolerance and Autoimmunity A/Prof Li Zhang School of Biotechnology and Biomolecular Sciences RM 4106, E26 [email protected] faculty of science Learning outcomes On successful completion of this learning activity, you should be able to: Explain the establishment and maintenance of selftolerance at...

Tolerance and Autoimmunity A/Prof Li Zhang School of Biotechnology and Biomolecular Sciences RM 4106, E26 [email protected] faculty of science Learning outcomes On successful completion of this learning activity, you should be able to: Explain the establishment and maintenance of selftolerance at various levels. Understand the fundamental pathogenic mechanisms of autoimmune diseases, with examples provided. faculty of science Self-tolerance In healthy individuals, the immune system does not mount immune responses against their own tissues (self-tolerance). Central tolerance: established in thymus or bone marrow. Peripheral tolerance: induced in secondary lymphoid organs and sites of inflammation. 3 faculty of science T cell Central Tolerance faculty of science faculty of science T cell development 1. T-cell receptor gene rearrangement 2. Expression of CD4 and CD8 (double negative, double positive, single positive) 3. Positive selection (occurs in the cortex) 4. Negative selection (occurs in the medulla of the thymus). faculty of science T cell development in thymus R Male D et al. Immunology seventh edition In thymus, the negative selection deletes the majority of self-reactive T cells 7 faculty of science Deletion of specific tissue-reactive T cells Autoimmune regulatory (Aire) gene controls the expression of tissuespecific proteins in medullary epithelial cells in thymus. faculty of science Autoimmune regulatory (Aire) gene In humans: autoimmune polyendocrinopathy syndrome 1 (APS-1). Inherited form of autoimmunity. Aire gene (Chromosome 21, autosomal recessive) defective. Mice without AIRE protein (engineered): Mice do not express peripheral tissue proteins in thymus APS-1 syndrome. faculty of science T cell Peripheral Tolerance faculty of science T cell peripheral tolerance 1. Regulatory T cells (Tregs) (previous name: suppressor cells) Suppress the differentiation of T cells into effector cells and inhibit the function of effector T cells. Produce TGF-β and IL-10 CD4+CD25+Foxp3+ Foxp3 (forkhead box P3): A member of FOX protein family. A transcriptional regulator that plays an important role in regulating the function of regulatory T cells. Natural T reg: nTreg are programmed in the thymus to express FoxP3 in response to self antigens. Induced T reg: iTreg during immune responses in the presence of TGF-β CD4+CD25+Foxp3- (in intestinal tract, IL-10) 11 faculty of science T cell peripheral tolerance 2. Peripheral anergy. T cells not receiving proper costimulatory signals. 12 3. Sequestration of self antigens: inaccessible tissues faculty of science B cell Central tolerance faculty of science B cell development faculty of science B cell central tolerance 1. Clonal deletion (or Receptor editing) IgM on immature B cells Recognizing multivalent self antigens Apoptosis Receptor editing Not auto-reactive (IgM IgD on surface) Valence: the numbers of antigen binding sites 15 faculty of science B cell central tolerance 2. Permanent state of unresponsiveness to antigen (Anergy). IgM on immature B cells recognizes soluble self antigens that weakly cross link BCR, migrate to periphery, but not responsive. 3. Immunological ignorant (clonally ignorant) cells. IgM on immature B cells recognizes low affinity soluble self antigen, not cross link BCR, potentially self-reactive. 16 faculty of science B cell central tolerance faculty of science B cell peripheral tolerance faculty of science B cell peripheral tolerance 1. No help from T cells 2. Mature B cells interact with self antigen within germinal centers go through apoptosis 3. Sequestration of self antigens 19 faculty of science Autoimmunity and autoimmune diseases Autoimmunity: immune response attacks the body itself. Autoimmune diseases: Diseases caused by the immune system attacking self molecules/tissues are called autoimmune diseases. Type 1 diabetes mellitus Multiple sclerosis Rheumatoid arthritis Systemic lupus erythematosus Rheumatic fever ….. faculty of science Why people develop autoimmunity? Minority cases of autoimmune diseases have known gene defect, such as autoimmune polyendocrinopathy syndrome 1 (APS-1), immunodysregulation polyendocrinopathy enteropathy X-linked (defect in gene encoding forkhead box P3). For most of autoimmune disease cases, the factors that trigger the diseases are not known. Multiple factors are involved: -genetic predisposition -women are more likely to have autoimmune diseases -stress, hormone imbalance -infections …… faculty of science MHC molecules and autoimmune diseases faculty of science Pathogenic mechanisms of autoimmune diseases Failures of tolerance (e.g. defect in Aire gene). Release of sequenstered antigens Molecular mimicry due to immune response to infectious agents Autoantibodies, autoreactive T cells and inflammation mediators contribute to the pathogenesis, depending on individual diseases. faculty of science Rheumatic fever faculty of science Rheumatic fever / Rheumatic heart disease 1. Occurs following an infection of Group A Streptococcus pyogenes (GAS) 2. Polyarthritis, carditis …. 3. Antibody cross-reactions between streptococcal antigens and human proteins. Antibody-antigen complexes induce inflammation. S. pyogenes M protein (antiphagocytic, highly antigenic) Cross-reacts with Cardiac myofiber protein myosin Perivascular connective tissues Smooth muscle cell of blood faculty of science Aetiology of ARF relates to M surface proteins of GAS M surface proteins Most studied virulence factor of GAS Used for bacterial typing of GAS strains > 100 antigenic types Antigenic variation due primarily to single amino acid substitutions Antigenic epitopes of M protein Mimic those of mammalian muscle and connective tissue Acute Rheumatic fever Peptidoglycan Most commonly associated with M types (1,3,5,16,18) however many serotypes implicated Cytoplasmic M protein membrane Detection of antibodies to GAS faculty of science Rheumatic heart disease Most important consequence ARF Infection leads to damage to heart valves May occur following initial ARF or following repeated attacks of GAS infection with different M types faculty of science Rheumatic heart disease A major public health problem in developing countries and Australian Aboriginals Associated pathology Valves thickened Small vegetations occur on deformed valves Infective endocarditis faculty of science Rheumatoid arthritis A chronic disease that affects multiple joints of the body. Often starts in the small joints of the hands and feet. Synovium and other supporting tissues become inflamed. Deformities. Often 50 – 60 years old. F/M = 3/1 Presence of autoantibodies is a hallmark for the disease faculty of science Autoantibodies in rheumatoid arthritis Rheumatoid factor (RA). Autoantibodies against the Fc portion of IgG. RA can be any classes of Immunoglobulins. Antibody-antigen complexes induce inflammation. Antibodies against post-translational modified proteins such as citrullination (ACPA) and carbamylation (anti-CarP antibodies). faculty of science Type 1 diabetes Diabetes (diabetes mellitus): about 10% type 1, nearly 90% type 2, some gestational diabetes. High level of glucose in the blood. Glycated haemoglobin (HbA1c): non-fasting Fasting blood glucose Type 1: due to autoimmune response leading to selective destruction of the insulin-secreting beta cells. Tests to check antoantibodies: islet cell antibodies (against cytoplasmic proteins in the beta cell) antibodies to glutamic acid decarboxylase insulin autoantibodies antibodies to tyrosine phosphatase faculty of science Learning outcomes On successful completion of this learning activity, you should be able to: Explain the establishment and maintenance of selftolerance at various levels. Understand the fundamental pathogenic mechanisms of autoimmune diseases, with examples provided. faculty of science