L29: Autoimmunity Flashcards
Autoimmunity
Induction of an immune response against self molecules. Related to breakdown of tolerance and may be organ-specific, localised or systemic. Consequences may be minimal or lethal.
Graves’ disease: mechanism and consequence
DM: Autoantibodies against the thyroid-stimulating-hormone receptor
Consequence: Hyperthyroidism: overproduction of thyroid hormones
Hashimoto’s thyroiditis: mechanism and consequence
DM: Autoantibodies and autoreactive T cells against thyroid antigens
Consequence: destruction of thyroid tissue leading to hypothyroidism: underproduction of thyroid hormone
Type 1 diabetes (insulin-dependent diabetes mellitus): mechanism and consequence
DM: autoreactive T cells against pancreatic islet cell antigens
Consequence: destruction of pancreatic islet B cells leading to non-production of insulin
Multiple sclerosis: mechanism and consequence
DM: Autoreactive T cells against brain antigens
Consequence: formation of sclerotic plaques in brain with destruction of myelin sheats surrounding nerve cell axons, leading to muscle weakness, ataxia and other symptoms
Immunologuically priviledged sites
Brain, eye, testis, uterus (fetus), hamster cheek pouch
Loss of sequestration
Type of autommimunity, certain autoantigens are sequestered or hidden from the immune system. If these antigens become exposed to the immune system through trauma or infection, autoimmunity may result.
Sympathetic ophthalmia
- Eye trauma results in release of sequestered antigenic epitopes
- Released Ag is carried to lymph nodes and activates T cells
- Effector T cells return via bloodstream and encounter Ag in both eyes.
Activation of autoreactive T/B cells: Myasthenia gravis
B cell activation. Disease where ACh receptors are recognised as an antigen. Antibodies are produced against the alpha subunit of the ACh receptor which blocks Ach interacting with its receptor;. Binding of the autoantibody of the receptor induces internalisation of the receptor. No depolarisation to cause contraction and muscle will gradually atrophy.
Grave’s disease
Result of hyperthyrodisim, cause symptoms such as goitre, heat intolerance, fatigue, muscle weakness, weight loss and eye bulge due to oedema. TH produced in response to TSH and limit their own production. Pituitary gland secretes TSH which acts on the thyroid to induce release of TH. TH act on the pituitary through a negative feedback mechanism to prevent further synthesis. Autoantibodies to TSH receptor mimic TSH and result in receptor activation and overproduction of thyroid hormones. The autoantibiodies are not subject to the feedback control of TSH and so the thyroid is chronically stimulated = hyperactive thyroid and overproduction of thyroid hormones. Treatment: surgery or antithyroid drugs.
Hashimoto’s disease
B cell activation. Result of hypothyroidism and can cause symptoms such as goitre, fatigue, muscle weakness, weight gain. Develops due to autoantibodies and autoreactive T cells against thyroid antigens (thyroid peroxidase). Leads to destruction of thyroid tissue, resulting in underproduction of thyroid hormones. Treatment includes thyroid hormone replacement therapy.
Multiple sclerosis
T cell activation. T cell mediated chronic neurological disease caused by destructive immune response against brain receptors. Autoreactive T cells infiltrate brain tissue, setting up an inflammatory response that demyelinates neurones. If the blood brain barrier is broken down, activated CD4 T cells can migrate across it (mediated by VCAM). Microglial cells in brain (macrophage) act as APC for the autoantigen. Further infilitration of Th1 cells and activated macrophages driving inflammation. CTL attacks the oligodendrocytes and B cells produce antibodies against myelin. Results in destruction of the myelin sheath which is vital for action potentials. Therapy: immunosuppression, inteferon B therapy
Insulin-dependent diabetes mellitus (IDDM)
T cell activation. Chronic inflammatory destruction of insulin-producing islet cells of the pancreas. Both CD4+ and CD8+ T cells are involved. Predisposition is associated with HLA-DR3 and/or HLA-DR. Resistance associated with HLA-DR2. IDDM is an autoimmune repsonse against B cells which produce insulin.
IDDM complications
- Type 1 diabetes have vascular complications if blood sugar level is not kept strictly under control
- Often circulatory problems in peripheral vasculature and in kidney
- Diabetic nephropathy is most common cause of kidney failure in patients waiting for kidney transplants
- Involvement of inflammatory cytokines TGF which is usually antiinflammatory increases matrix production in the glomerulus, leading to initial blockage of filtration
APECED: Autoimmune polyendocrinpathy-candidiasis-ectodermal dystrophy
Autoimmune polyglandular syndrome1 (APS-1). Characterised by destruction of endocrine tissues, skin/nail/hair defects. Gene responsible is AIRE (autoimmune regulator). Product of AIRE is TF responsible for expression of many peripheral tissue antigens (e.g. insulin) in a subset of DCs in the thymus. In absence of AIRE, stromal cells in thymus do not present Ag properly and so thymocytes do not properly undergo self-tolerance
