Self Recognition and Autoimmune Disease

T and B cells are generated to have millions of random structures on their TcR and antibodies, so that they have the potential to recognise any structure of antigens. This results in TcR and antibodies that are specific to antigens that exist within the person’s own body. Therefore, there needs to be mechanisms of preventing T and B cells that are specific to organs in the body, and it is when these mechanisms fail that autoimmune disease occurs.

 

B Cell Self Tolerance

  • B cells develop their specific antibodies in the bone marrow.
  • The bone marrow contains no pathogenic material, but is full of self-antigens.
  • If the developing B cell creates antibodies that match antigens in the bone marrow environment (self-antigens), one of two things happen:
    • Clonal deletion: the cells die and are never released into the circulation
    • Clonal anergy: the cells are made inactive so that they can be released but make no response to antigens
  • The acts as a means for testing B cells before they are released to ensure they do not contain antibodies that could be active against self.

 

T Cell Self Tolerance

T cells leave the bone marrow as pro-thymocytes. They travel to the thymus where they become thymocytes. These thymocytes then undergo a complex process to develop their TcR and mature into CD4 or CD8 cells within the thymus gland. The eventual TcR must be specific for foreign-antigen and self-MHC. If they recognise self-antigen, they can cause autoimmune disease. If they cannot recognise self-MHC molecules then they are useless as T cells.

This involves a process called “T Cell education“:

  • Thymocytes start by arranging proteins to form random TcRs.
  • At first the T cells express CD4 and CD8. The first step is to stop expressing one of these, so that they become either CD4 or CD8 cells.
  • The second step is to meet cortical epithelial cells in the thymus, that present them with MHC proteins. If the thymocyte can recognise the MHC protein, they go to the next step. If they can’t recognise it, they are destroyed.
  • The third step is to meet dendritic cells in the thymus, that present them with self-antigens. If the thymocyte can recognise the self-antigen, they are destroyed. If they can’t recognise it, they are allowed to pass out of the thymus and become fully fledged T cells.

 

Autoimmune Disease

Autoimmune disease occurs where there components of the specific immune system start to recognise self-antigens. This leads to immune responses relating to the self-antigen that they recognise. The result of this varies, and the best way to illustrate it is with some examples:

  • Type 1 Diabetes: antibodies to islet cells (insulin producing cells in the pancreas) lead to destruction of those cells, and the loss of the ability of the pancreas to produce insulin.
  • Graves Disease: antibodies specific to thyroid stimulating hormone (TSH) receptors stimulate those receptors, leading to hyperthyroidism.
  • Systemic Lupus Erythematosus (SLE): autoantibodies against various body tissues lead to antibody-antigen complexes activating the complement system causing inflammation and damage to tissues throughout the body (such as the skin, joints, kidneys, heart and lungs).
  • Myasthenia Gravis: antibodies specific to cholinergic receptors on muscles bind to the receptors preventing them being activated by the neurotransmitter acetylcholine. This leads to progressive muscle weakness.
  • Pemphigus: antibodies specific to desmoglein, a protein that holds skin cells together bind to that protein and act as opsonins to destroy it. This results in skin cells separating from each and large fluid filled blisters to form.
  • Goodpastures Syndrome: antibodies specific to a type of collage in the the glomerular basement membrane in the kidneys and lungs lead to inflammation and destruction of the basement membrane leading to pulmonary haemorrhage and kidney failure.
  • Autoimmune Thrombocytopenia (ITP): antibodies bind to platelets and act as opsonins, resulting in them being consumed by phagocytes. This leads to a profound thrombocytopenia.
  • Pernicious Anaemia: antibodies specific to intrinsic factor (a molecule essential for the absorption of vitamin B12 in the intestine) block the function of intrinsic factor, preventing B12 from being absorbed. This leads vitamin B12 deficiency and a megaloblastic anaemia.
  • Autoimmune Haemolytic Anaemia: antibodies specific red blood cells activate complement on the red blood cell membrane. The complement activation leads to lysis of the red blood cells, resulting in anaemia.
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