Autoimmunity
[citation needed] In 1904, this theory was challenged by the discovery of a substance in the serum of patients with paroxysmal cold hemoglobinuria that reacted with red blood cells.The system does not randomly lose the ability to distinguish between self and non-self; the attack on cells may be the consequence of cycling metabolic processes necessary to keep the blood chemistry in homeostasis.Thus Stefanova et al. (2002) demonstrated that self-MHC recognition (which, if too strong may contribute to autoimmune disease) maintains the responsiveness of CD4+ T cells when foreign antigens are absent.[8] Pioneering work by Noel Rose and Ernst Witebsky in New York, and Roitt and Doniach at University College London provided clear evidence that, at least in terms of antibody-producing B cells (B lymphocytes), diseases such as rheumatoid arthritis and thyrotoxicosis are associated with loss of immunological tolerance, which is the ability of an individual to ignore "self", while reacting to "non-self".[9] Three hypotheses have gained widespread attention among immunologists: In addition, two other theories are under intense investigation: Tolerance can also be differentiated into "central" and "peripheral" tolerance, on whether or not the above-stated checking mechanisms operate in the central lymphoid organs (thymus and bone marrow) or the peripheral lymphoid organs (lymph node, spleen, etc., where self-reactive B-cells may be destroyed).These variations enable the immune system to respond to a very wide variety of invaders, but may also give rise to lymphocytes capable of self-reactivity.The contributions of genes outside the MHC complex remain the subject of research, in animal models of disease (Linda Wicker's extensive genetic studies of diabetes in the NOD mouse)[clarification needed], and in patients (Brian Kotzin's linkage analysis of susceptibility to lupus erythematosus).[23][24] Autoimmune conditions overrepresented in women include: lupus, primary biliary cholangitis, Graves' disease, Hashimoto's thyroiditis, and multiple sclerosis, among many others.A few autoimmune diseases that men are just as or more likely to develop as women include: ankylosing spondylitis, type 1 diabetes mellitus, granulomatosis with polyangiitis, primary sclerosing cholangitis, and psoriasis.Women appear to generally mount larger inflammatory responses than men when their immune systems are triggered, increasing the risk of autoimmunity.Involvement of sex steroids is indicated by that many autoimmune diseases tend to fluctuate in accordance with hormonal changes, for example: during pregnancy, in the menstrual cycle, or when using oral contraception.[26] The X-inactivation skew theory, proposed by Princeton University's Jeff Stewart, has recently been confirmed experimentally in scleroderma and autoimmune thyroiditis.While such an observation has been variously termed as spurious and ineffective, according to some studies, parasite infection is associated with reduced activity of autoimmune disease.This has been explained by the tendency of the infecting organism to produce super-antigens that are capable of polyclonal activation of B-lymphocytes, and production of large amounts of antibodies of varying specificities, some of which may be self-reactive (see below).[35] Diagnosis of autoimmune disorders largely rests on accurate history and physical examination of the patient, and high index of suspicion[clarification needed] against a backdrop of certain abnormalities in routine laboratory tests (example, elevated C-reactive protein).[36] Non-immunological therapies, such as hormone replacement in Hashimoto's thyroiditis or Type 1 diabetes mellitus treat outcomes of the autoaggressive response, thus these are palliative treatments.Specific immunomodulatory therapies, such as the TNFα antagonists (e.g. etanercept), the B cell depleting agent rituximab, the anti-IL-6 receptor tocilizumab and the costimulation blocker abatacept have been shown to be useful in treating RA.