Autoimmunity

Autoimmunity has classifications similar to that of hypersensitivies, there are types I, II, III, and IV. Type I is when there is an IgE antibody specific for self. Type II is when IgM or IgG is specific to self cell surface antigen. This antibody could cause cells to be killed, such as Fc receptors on MAC’s, Mast cells, or NK cells all via the complement cascade. A possible outcome of this would be the disease of autoimmune hemolytic anemia. The antibody could also block the receptor, eg; myasthenia gravis, which is where the antibody to nicotinic acetylcholine receptor on the skeletal muscle blocks the neuro-muscular transmission causing lack of firing, leading to muscle weakness and atrophy. The antibody may also stimulate the receptor, causing a known condition of Graves Disease, where and antibody to TSH receptor stimulates the production of the TSH and blocks the feedback look, leading to hyperthyroidism. Type III is when IgM or IgG is specific for soluble self antigen. A large amount of antigen can lead to a large amount of immune complexes by where the Ag is bound to the Ab. This can overwhelm the normal clearance mechanisms and the complexes tend to get lodged into places, such as capillaries. The lodging causes damage to surrounding tissues, eg; bacterial endocarditis which is where the bacteria adhere to cardiac valves, and the immune response to the bacteria then damages the valve which is irreparable. This response can also lead to systemic complications and even leas to damaged kidneys and skin conditions due to all of the clots. These responses then lead to damage of more cells due to the release of more auto-antigens, such as histones and transcription factors. An example of this is systemic lupus erythromytosis (SLE). The auto-antigens in this disease are nucleosomes, spliceosomes, ribonucleusproteins Ro and La. These proteins are all released when a cell dies are due to blebbing, causing the release of anti-nuclear antigens (ANA), in which it is now the bodies response to phagocytos them, leading to more damage in the body due to the anti-nuclear antibodies, which can cause discoid rashes or a butterfly rash. In conjunction of the rashes and blocking of dermal layer capillaries, it can lead to a deficiency of vitamin D due to the loss of transmission of UV to convert the cholecalciferol. A dysfunction in the innate immune system may attribute to Sjogren’s Syndrome, which is characterized by the dry mucosal membranes, such as dry mouth and eyes. This syndrome tends to show up in peri-menopausal women. The condition is due to IFN-alpha malfunctions, in which the B cell activating factor leads to the production of Ach antibodies, but it is unknown whethere the malfunctioning glands lead to the IFN alpha mishap, or vice versa. A type IV response is T cell mediated, in which most of us are all familiar with, commonly known as diabetes. Diabetes is hyperglycemia caused by the beta islet cells in the islet of langerhans in the pancreas, which are no longer producing insulin. Type I diabetes, also know as insulin dependent diabetes mellitus, is caused by the death of the beta islet cells being dead, or on their way out. Type II diabetes is not insulin dependent, this is due to a defect in the GLUT 4 transported for glucose across the cell membrane. This type can often easily be reversed thru careful diet considerations as the cells are still there and may be reactivated. Diabetes is linked thru a receiving of certain genetic HLA’s. HLA-DR3, HLA-DR4, HLA-DQ, especially HLA-DQB1*0302, all tend to bind or block insulin intake and can lead to type I diabetes. They are also the reason why over the years a persons insulin doses must be increased, due to these MHC’s blocking most all of the insulin uptake. HLA-DQB1*0302 has no aspartate in position 57, which means that it binds insulin very well. A protective MHC would be HLA-DR2. 

The process of insulin tolerance failure is a complicated process. The CD8 T cells specific for insulin, which have escaped the tolerance, get activated by APC’s the are presenting the insulin as if it is an infection. The CD8 T cells kill the beta-islet cells, all after the release of IL-12 from the macrophage and the binding of CD86 to CD28 on the CD4 cells. These then trigger a Th1 response leading to the release of IFN-gamma and cause a class switch of IgM to IgG, then activating the CD8 T killer cells to become specific for glutamic acid decarboxylase (GAD) of 38Kda secretory granules. GAD converts glutamic acid to GABA, GABA then triggers the release of insulin from the granules. So of these cells are killed in the process then this mechanism may never be complete, leaving the body in a deficiency of insulin to respond to elevated blood glucose levels. 

Multiple Sclerosis (MS) is a  form of autoimmunity in which numerous areas undergo demylination within the brain and spinal cord occur, without axonal degeneration. This disease is hereditary and is more prevalent in women with a ratio of 7:1. Progesterone shuts down the disease, there for many women that are pregnant experience no symptoms of the disease during the time of childbearing. The typical age of which the disease onsets are typically 25-30 years. This disease is more prevalent in the northern latitudes and is believed to be attributed to the lack of sun exposure, leading to vitamin d deficiencies. Although the occurrence rate is also going up in higher socioeconomic groups as well, and is believed to be attributed to the use of air conditioning and remaining indoors so frequently. HLA-DQB1 is found in the highest prevalence in Norwegians. HLA-DR2 is more capable of presenting myelin basic protein (MBP) very well, along with proteolipid protein (PLP).