Tolerance and autoimmunity Flashcards
What is autoimmunity?
An adaptive immune response (lymphocyte response) to self-antigens (autoantigens) i.e. breakdown of self-tolerance. NB: just because this is initiated by the adaptive immune response does not mean that the innate immune system is not involved – the innate immune system is actually very important in the physical manifestation of autoimmune diseases.
What are the criteria for diseases to be autoimmune? (x4)
There must be a disease-specific adaptive immune response present in the affected tissue. Transfer of the autoreactive cells or antibodies replicates the disease. Elimination of the autoimmune response modifies the disease. History of autoimmune disease and/or MHC associations.
What are the causes of breakdown of self-tolerance? (x6)
□ Family history – there is a genetic predisposition to breakdown of self-tolerance. □ Women are more susceptible. □ Infections: inflammatory environment can lead to breakdown of self-tolerance. □ Diet: obesity, high fat, effects on gut microbiome. □ Stress: physical and psychological, stress-related hormones. □ Microbiome: gut/oral microbiome helps shape immunity – perturbation (dysbiosis) may help trigger autoimmune disease.
What are the mechanisms of autoimmunity? !!!
□ Adaptive immune reactions against self, use the same mechanisms as immune reactions against pathogens. □ Autoimmune diseases involve breaking T-cell tolerance – because the response is almost always mediated by IgG antibodies, which require T cells for class switching. □ Because self-tissue is always present, autoimmune diseases are CHRONIC (often relapsing). □ Effector mechanisms resemble those of hypersensitivity reactions – Types II, III and IV.
What hypothesis explains the growing incidence of autoimmune conditions?
Hygiene hypothesis – we are no longer being exposed to as many pathogens as when the immune system was evolving.
What happens to autoimmune disease during and after pregnancy?
In many cases, autoimmune disease characteristics change during and after pregnancy. During pregnancy, the body tries to downregulate its inflammatory responses to infections as this is not ideal for the foetus. Immunological reactions therefore become less cell-mediated, and more Th2- and antibody-mediated. Therefore, conditions such as SLE get worse, and cell-mediated conditions such as Rheumatoid arthritis get better. After birth, the trends switch, and symptoms of cell-mediated conditions flare.
List examples of important autoimmune diseases. (x5)
Rheumatoid arthritis, Type I diabetes, Multiple sclerosis, SLE and autoimmune thyroid disease.
How are autoimmune diseases described? (x3)
Organs affected, involvement of specific autoantigens, and types of immune response (often using hypersensitivity type II, III and IV).
What are the three types of immune response that we look for in autoimmune diseases?
□ Antibody response to INSOLUBLE antigen i.e. antigens found on cellular or extracellular matrix (Type II hypersensitivity). Usually IgG antibody. □ Immune complex formed by antibody against SOLUBLE antigen i.e. in the blood (Type III hypersensitivity). Usually IgG antibody. □ T-cell mediated disease (Delayed hypersensitivity reaction, Type IV). However, just because T-cells do not produce antibodies doesn’t mean that antibodies are not involved in the disease – antibody responses can occur alongside the T-cell responses.
What is the immunopathogenesis of Grave’s disease?
TYPE II HYPERSENSITIVTY (antibody to insoluble antigen): antibody against thyroid-stimulating hormone receptor, leading to hyperthyroidism, activation of complement and recruitment of inflammatory cells.
What is the immunopathogenesis of autoimmune haemolytic anaemia?
TYPE II HYPERSENSITITY: antibody against Rh blood group antigens leading to destruction of RBCs by complement and phagocytes –> anaemia.
What is the immunopathogenesis of SLE?
TYPE III HYPERSENSITIVTY: immune complex deposition in glomerulus from IgG-antibodies against DNA, histones, ribosomes, snRNP and scRNP, leading to glomerulonephritis. Deposition of immune complexes in other areas of the body also leads to vasculitis and arthritis –> from complement activation and recruitment of inflammatory cells.
Why are Type III hypersensitivity responses more systemic that Type II responses?
Type III involves immune complex formation to SOLUBLE antigens – the complexes can therefore be deposited anywhere in the body from the blood to cause inflammation and complement activation. In Type II activation, immune complex formation occurs to INSOLUBLE antigens, so the complex cannot move around like soluble antigens can in the blood – inflammation and complement activation is therefore confined only to the tissue(s) that contains the antigen.
What is the immunopathogenesis of rheumatoid arthritis?
Immune response against synovial joint antigen leading to joint inflammation and destruction.
What is the immunopathogenesis of Type 1 diabetes?
T cell immune response against pancreatic beta-cell antigen leading to beta-cell destruction.
What is the immunopathogenesis of Multiple Sclerosis (MS)?
T cell immune response against myelin basic protein and proteolipid protein, leading to brain degeneration (demyelination) and weakness/paralysis.
What MHC association is there to autoimmune diseases?
Genome-wide association studies have found that the HUMAN MHC CLASS II GENE is the dominant genetic factor affecting susceptibility to all types of autoimmune disease i.e. genes that show strongest susceptibility are MHC Class II. MHC Class II are recognised by CD4+ T cells. This genetic susceptibility therefore tells us that CD4+ T cells are important in the mechanism of autoimmune diseases.
What is tolerance?
Defined as the acquired inability to respond to an antigenic stimulus - we all have lymphocytes capable of recognising self, so tolerance describes the mechanisms which prevent our immune system from attacking our own tissues.
What are the three ‘As’ of tolerance?
Tolerance is ACQUIRED (involved cells of the acquire immune system and is therefore learned – we are not just born with tolerance), ANTIGEN SPECIFIC, and an ACTIVE process in NEONATES (the effects of which are maintained throughout life).
What are the two types of tolerance?
CENTRAL tolerance: destroy self-reactive T or B cells before they enter the circulation – happens in the T cells in the thymus and B cells in the bone marrow; PERIPHERAL tolerance: destroy or control any self-reactive T or B cells which do enter the circulation. In addition, some cells may later become self-reactive – particularly B cells, from mutation in affinity maturation.
How does central tolerance occur for B cells? Two exceptions? !
• Immature B cells in bone marrow scans through self-antigens as they mature – if it encounters antigen in a form which can cross-link their IgM, apoptosis is triggered. • There are two exceptions: • (1) If, during maturation, immature B cell encounters a SOLUBLE self-antigen, apoptosis is not triggered, and they are allowed to mature and enter the periphery. However, they mature into ANERGIC B CELLS which cannot sufficiently mount an immune response and have a short lifespan. They are essentially useless, so although they are self-reactive, they do not do any damage to the body. • (2) If there is low-affinity non-cross-linking with a self-antigen, the immature B cell is also allowed to mature and enter the periphery. These are ‘clonally ignorant’ in the periphery and don’t really respond to the self-antigen even though they have the ability to. These have the potential to lead to autoimmune disease.
How does central tolerance for T cells occur? (x2)
• T-cells are selected by binding to self-MHCs on thymic epithelial cells (TEC) or dendritic cells in the thymus. • If binding to self MHC is too weak, it may not be enough to allow signalling when binding to MHC with foreign peptides bound in groove. They die by apoptosis. • If binding to self MHC is too strong, may allow signalling irrespective of whether self or foreign peptide is bound in groove. They also die by apoptosis – ‘negative selection’. • T cells are ‘positively selected’ if they bind to the MHC weakly. • RECAP: T cells are activated when a MATCHED TCR binds to a self-MHC AND a foreign peptide (found in MHC groove). T cells constantly survey and do nothing when a self-peptide is found in the MHC groove.)
What is the problem with exposure of self-proteins in the thymus and how is this overcome?
• T cells develop in thymus. But not all proteins in the body are encountered in the thymus. This would mean that there’s many self-proteins that T-cells aren’t removed for, so many T-cells will generate an autoimmune response. • AIRE (AutoImmune Regulator) is a transcription factor that allows thymic expression of genes that are expressed in peripheral tissues i.e. it expresses almost every protein in the body – MAINLY ENDOCRINE PROTEINS. Therefore, AIRE is what promotes self-tolerance of the whole body…by allowing the thymic expression of genes from other tissues.
What is APECED?
A genetic condition resulting from a mutation in AIRE, so there is a failure to negatively select T cells in the thymus. Leads to rare autoimmune diseases which affects the endocrine glands.
