Autoimmunity


In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". Prominent examples include celiac disease, diabetes mellitus type 1, Henoch–Schönlein purpura, systemic lupus erythematosus, Sjögren syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis, ankylosing spondylitis, polymyositis, dermatomyositis, and multiple sclerosis. Autoimmune diseases are very often treated with steroids.
Autoimmunity means presence of antibodies or T cells that react with self-protein and is present in all individuals, even in normal health state. It causes autoimmune diseases if self-reactivity can lead to tissue damage.

History

In the later 19th century, it was believed that the immune system was unable to react against the body's own tissues. Paul Ehrlich, at the turn of the 20th century, proposed the concept of horror autotoxicus. Ehrlich later adjusted his theory to recognize the possibility of autoimmune tissue attacks, but believed certain innate protection mechanisms would prevent the autoimmune response from becoming pathological.
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. During the following decades, a number of conditions could be linked to autoimmune responses. However, the authoritative status of Ehrlich's postulate hampered the understanding of these findings. Immunology became a biochemical rather than a clinical discipline. By the 1950s, the modern understanding of autoantibodies and autoimmune diseases started to spread.
More recently, it has become accepted that autoimmune responses are an integral part of vertebrate immune systems. Autoimmunity should not be confused with alloimmunity.

Low-level autoimmunity

Autoimmunity may have a role in allowing a rapid immune response in the early stages of an infection when the availability of foreign antigens limits the response. In their study, Stefanova et al. injected an anti-MHC class II antibody into mice expressing a single type of MHC Class II molecule to temporarily prevent CD4+ T cell-MHC interaction. Naive CD4+ T cells recovered from these mice 36 hours post-anti-MHC administration showed decreased responsiveness to the antigen pigeon cytochrome c peptide, as determined by ZAP70 phosphorylation, proliferation, and interleukin 2 production. Thus Stefanova et al. demonstrated that self-MHC recognition maintains the responsiveness of CD4+ T cells when foreign antigens are absent.

Immunological tolerance

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, 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". This breakage leads to the immune system mounting an effective and specific immune response against self antigens. The exact genesis of immunological tolerance is still elusive, but several theories have been proposed since the mid-twentieth century to explain its origin.
Three hypotheses have gained widespread attention among immunologists:
  • Clonal deletion 'theory, proposed by Burnet, according to which self-reactive lymphoid cells are destroyed during the development of the immune system in an individual. For their work Frank M. Burnet and Peter B. Medawar were awarded the 1960 Nobel Prize in Physiology or Medicine "for discovery of acquired immunological tolerance".
  • Clonal anergy theory, proposed by Nossal, in which self-reactive T- or B-cells become inactivated in the normal individual and cannot amplify the immune response.
  • Idiotype network theory, proposed by Jerne, wherein a network of antibodies capable of neutralizing self-reactive antibodies exists naturally within the body.
In addition, two other theories are under intense investigation:
  • Clonal ignorance theory, according to which autoreactive T cells that are not represented in the thymus will mature and migrate to the periphery, where they will not encounter the appropriate antigen because it is inaccessible tissues. Consequently, auto-reactive B cells, that escape deletion, cannot find the antigen or the specific helper T cell.
  • Suppressor population or Regulatory T cell theory', wherein regulatory T-lymphocytes function to prevent, downregulate, or limit autoaggressive immune responses in the immune system.
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 or the peripheral lymphoid organs. It must be emphasised that these theories are not mutually exclusive, and evidence has been mounting suggesting that all of these mechanisms may actively contribute to vertebrate immunological tolerance.
A puzzling feature of the documented loss of tolerance seen in spontaneous human autoimmunity is that it is almost entirely restricted to the autoantibody responses produced by B lymphocytes. Loss of tolerance by T cells has been extremely hard to demonstrate, and where there is evidence for an abnormal T cell response it is usually not to the antigen recognised by autoantibodies. Thus, in rheumatoid arthritis there are autoantibodies to IgG Fc but apparently no corresponding T cell response. In systemic lupus there are autoantibodies to DNA, which cannot evoke a T cell response, and limited evidence for T cell responses implicates nucleoprotein antigens. In Celiac disease there are autoantibodies to tissue transglutaminase but the T cell response is to the foreign protein gliadin. This disparity has led to the idea that human autoimmune disease is in most cases based on a loss of B cell tolerance which makes use of normal T cell responses to foreign antigens in a variety of aberrant ways.

Immunodeficiency and autoimmunity

There are a large number of immunodeficiency syndromes that present clinical and laboratory characteristics of autoimmunity. The decreased ability of the immune system to clear infections in these patients may be responsible for causing autoimmunity through perpetual immune system activation.
One example is common variable immunodeficiency, in which multiple autoimmune diseases are seen, e.g., inflammatory bowel disease, autoimmune thrombocytopenia and autoimmune thyroid disease.
Familial hemophagocytic lymphohistiocytosis, an autosomal recessive primary immunodeficiency, is another example. Pancytopenia, rashes, swollen lymph nodes and enlargement of the liver and spleen are commonly seen in such individuals. Presence of multiple uncleared viral infections due to lack of perforin are thought to be responsible.
In addition to chronic and/or recurrent infections many autoimmune diseases including arthritis, autoimmune hemolytic anemia, scleroderma and type 1 diabetes mellitus are also seen in X-linked agammaglobulinemia.
Recurrent bacterial and fungal infections and chronic inflammation of the gut and lungs are seen in chronic granulomatous disease as well. CGD is a caused by decreased production of nicotinamide adenine dinucleotide phosphate oxidase by neutrophils.
Hypomorphic RAG mutations are seen in patients with midline granulomatous disease; an autoimmune disorder that is commonly seen in patients with granulomatosis with polyangiitis and NK/T cell lymphomas.Wiskott–Aldrich syndrome patients also present with eczema, autoimmune manifestations, recurrent bacterial infections and lymphoma. In autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy also autoimmunity and infections coexist: organ-specific autoimmune manifestations and chronic mucocutaneous candidiasis.
Finally, IgA deficiency is also sometimes associated with the development of autoimmune and atopic phenomena.

Causes

Genetic factors

Certain individuals are genetically susceptible to developing autoimmune diseases. This susceptibility is associated with multiple genes plus other risk factors. Genetically predisposed individuals do not always develop autoimmune diseases. Three main sets of genes are suspected in many autoimmune diseases. These genes are related to:
The first two, which are involved in the recognition of antigens, are inherently variable and susceptible to recombination. 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.
Fewer correlations exist with MHC class I molecules. The most notable and consistent is the association between HLA B27 and spondyloarthropathies like ankylosing spondylitis and reactive arthritis. Correlations may exist between polymorphisms within class II MHC promoters and autoimmune disease.
The contributions of genes outside the MHC complex remain the subject of research, in animal models of disease, and in patients.
In recent studies, the gene PTPN22 has emerged as a significant factor linked to various autoimmune diseases, such as Type I diabetes, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, Graves' disease, Addison's disease, Myasthenia Gravis, vitiligo, systemic sclerosis, juvenile idiopathic arthritis, and psoriatic arthritis. PTPN22 is involved in regulating the activity of immune cells, and so variations in this gene can lead to dysregulation of the immune response, making individuals more susceptible to autoimmune diseases.