Autoimmunity

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How do you define autoimmunity?

Autoimmunity is defined as the presence of immune responses against self-antigens. High titres of auto-antibodies or auto-reactive T cells could cause significant tissue/ organ damage and organ inflammation.

What is the process of tolerance with regard to B cell development?

B cells are the source of antibodies in the body and they originate from the stem cells in the bone marrow. They get tested for auto reactivity. If they react to self antigens, they die. Then, this occurs in the spleen once again. They then get released to go to the lymph nodes awaiting an infection. Any error at the self antigen checkpoints leads to a rise in autoimmunity.

How does the immune system deal with autoreactive T and B cells?

Autoreactive B and T cells are generated normally in primary lymphoid tissues but are normally killed/inactivated by ‘tolerance’ mechanisms.

Deletion of self reactive lymphocytes in primary lymphoid tissues (central tolerance)
Regulatory T cells (T reg cells) can help inactivate auto-reactive lymphocytes in peripheral tissues that escape central tolerance (peripheral tolerance).

What are the Regulatory T cells?

Regulatory T cells are products of the differentiation of the TH0 cell which is crucial for the suppression of hyper reactive or auto reactive T cells via the production of anti inflammatory cytokines. Signup and view all the answers

What is the normal Regulatory T cell make up within the CD4+ T cell population?

Regulatory T cells make up about 5-10% of the normal CD4+ T cell population. Signup and view all the answers

What are the two main contributing factors in having an autoimmune condition?

Genetics and environmental factors Signup and view all the answers

How do we categorise genetic disorders related to autoimmune conditions?

<ol> <li>Monogenic disorders- single gene defects causing autoimmune disease are rare- IPEX syndrome.</li> <li>Most autoimmune disease result from the complex genetic interplay such as the HLA genes, sex determining genes and other immune response genes.</li> </ol> Signup and view all the answers

What is IPEX syndrome?

IPEX syndrome is a rare X linked genetic disorder of immune dysregulation characterised by overwhelming systemic autoimmunity. It is caused by mutations of FOXP3 gene. It causes a failure of peripheral tolerance due to absence of Regulatory T cells. Signup and view all the answers

What are the symptoms and treatment options for IPEX?

Symptoms of IPEX are severe infection, eczema, diarrhoea, diabetes mellitus (early onset insulin dependant) and other autoimmune conditions. Treatment options could be haematopoietic stem cell transplant and immunosuppressants. Signup and view all the answers

How are HLA genes expressed on general nucleated cells?

All nucleated cells express six Class 1 molecules on their cell surface (3 maternally derived and 3 paternally derived)- 2x HLA-A, 2x HLA-B and 2x HLA-C. Signup and view all the answers

How are HLA molecules expressed on antigen presenting cells?

Specialised antigen presenting cells express six Class 1 molecules (HLA-A, HLA-B, HLA-C) and six Class 2 molecules (HLA-DR, HLA-DQ, HLA-DP) Signup and view all the answers

What is the role of HLA in autoimmune disease?

HLA genes encode for MHC molecules. There have been several HLA alleles have been identified which predispose individuals to autoimmune diseases. Some HLA alleles also provide a protective function to the cells. Signup and view all the answers

How are Predisposing HLA alleles and Protective HLA alleles different in mechanisms?

Presentation of disease relevant self-peptides by pre-disposing HLA alleles increases the risk of developing an autoimmune disease BUT Protective HLA alleles are less likely to bind and present disease relevant self-peptides, reducing the likelihood of auto reactive T cells being activated. Signup and view all the answers

How does an individual's sex determine their incidence of autoimmune disease?

There is a clear sex bias in a certain number of autoimmune diseases. Several autoimmune conditions are more likely to occur in females than males. Sex hormones are known to influence lymphocyte function in males versus females. Autoimmune conditions may get more adverse during pregnancy. Signup and view all the answers

What are the environmental factors in autoimmune diseases?

Environmental factors triggering autoimmunity in genetically predisposed individuals are:- <ol> <li>Infections</li> <li>Cigarette smoking</li> <li>Hormone levels</li> <li>Tissue damage</li> </ol> Signup and view all the answers

What are the mechanisms by which environmental factors can effect autoimmune conditions?

<ol> <li>Infection → cross-reactivity (molecular mimicry)</li> <li>Alteration of self-antigens e.g. due to conjugation of self-antigens with products of drug/chemical metabolism</li> <li>Super-antigens - bacteria responsible for toxic shock can reactivate autoreactive T cells which have been inactivated by TREG cells</li> <li>Antigen sequestration - antigens in tissues that do not normally communicate with blood/lymph (e.g. eye, brain) can be exposed due to trauma, causing an autoimmune reaction</li> </ol> Signup and view all the answers

How can autoimmune diseases be classified?

<ol> <li>Clinical classification- sort them in terms of organ specific diseases and non-organ specific/ multi system autoimmune diseases.</li> <li>Pathological classification- sort them in terms of types of hypersensitivity reactions.</li> </ol> Signup and view all the answers

What are the autoimmune diseases driven by Type 2 hypersensitivity reactions?

<ol> <li>Blood cells- autoimmune haemolytic anaemia</li> <li>Endocrine system- Graves disease</li> <li>Kidney/ Lung- Goodpasture's syndrome</li> <li>Nervous system- Guillan Barre syndrome</li> <li>Musculoskeletal system- Myasthenia Graves</li> <li>Skin- Pemphigus vulgaris</li> </ol> Signup and view all the answers

What are the autoimmune diseases driven by Type 3 hypersensitivity reactions?

<ol> <li>Systemic lupus erythematosus (SLE)</li> <li>Rheumatoid arthritis</li> <li>Glomerulonephritis (some types)</li> </ol> Signup and view all the answers

What are the autoimmune diseases driven by type 4 hypersensitivity reactions?

<ol> <li>Heart- autoimmune myocarditis</li> <li>Pancreas- diabetes mellitus type 1</li> <li>Thyroid- Hashimoto's thyroiditis</li> <li>Nervous system- Multiple sclerosis</li> <li>Musculoskeletal system- rheumatoid arthritis (also type 3 hypersensitivity)</li> </ol> Signup and view all the answers