User:Jbarin/Autoimmune Disease draft

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Jbarin/Autoimmune Disease draft

Overview

Autoimmune diseases describes a family of diseases which arise from an overactive immune response against antigens and tissues normally present in the body. In other words, the body attacks its own cells or tissues. This may be restricted to certain organs (e.g. in Chagas disease), involve a particular tissue in different organs (e.g. Goodpasture's disease which may affect the basement membrane in both the lung and the kidney), or attack widely expressed antigens (e.g. in lupus erythematosus). The treatment of autoimmune diseases is typically with immunosuppression — medications which decrease the immune response.

There is an on-going debate about individual diseases being considered autoimmune, leading to various criteria such as Witebsky's postulates.

User:Jbarin/List of Autoimmune Diseases draft

Genetic Factors

A significant genetic component has been associated with susceptibility to autoimmune disease, although it is clear that a substantial environmental component also influences the development of most autoimmune diseases studied. Genetically-predisposed individuals may necessarily develop autoimmune diseases.

The most studied susceptibility genes in autoimmunity are the major histocompatibility complex (MHC), or human leukocyte antigen (HLA) genes. Genetic analyses have demonstrated that certain MHC class II haplotypes are strongly correlated with autoimmune disease:

Fewer correlations exist with MHC class I molecules. The most notable and consistent is the association between HLA B27 and ankylosing spondylitis. 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.

Pathogenesis of Autoimmune disease

Several mechanisms are thought to participate in the pathogenesis of autoimmune diseases, against a backdrop of genetic predisposition and environmental triggering or modulation. A variety of etiologic mechanisms have been posulated, many of which are not mutually exclusive. Evidence for and against each of these models varies, often depending on the specific autoimmune disease in question.

  • Molecular Mimicry - An exogenous antigen may share structural similarities with certain host antigens; thus, any antibody produced against this antigen (which mimics the self-antigens) can also, in theory, bind to the host antigens, and amplify the immune response. The idea of molecular mimicry arose in the context of Rheumatic Fever, which follows infection with Group A beta-haemolytic streptococci. Although rheumatic fever has been attributed to molecular mimicry for half a century no antigen has been formally identified (if anything too many have been proposed). Moreover, the complex tissue distribution of the disease (heart, joint, skin, basal ganglia) argues against a cardiac specific antigen. It remains entirely possible that the disease is due to e.g. an unusual interaction between immune complexes, complement components and endothelium.
  • T-Cell Bypass - A normal immune system requires the activation of B-cells by T-cells before the former can produce antibodies in large quantities. This requirement of a T-cell can be bypassed in rare instances, such as infection by organisms producing super-antigens, which are capable of initiating polyclonal activation of B-cells, or even of T-cells, by directly binding to the β-subunit of T-cell receptors in a non-specific fashion.
  • T-Cell-B-Cell discordance - B and T lymphocytes may recognize the same antigen, most likely different epitopes of the samge antigen. Linked recognition may become aberrant or imbalanced, leading to loss of tolerance.
  • Adjuvant effect - Some, but not all, autoimmune diseases have been associated with a preceding infection. Defenses to infection may precipitate autoimmunity by eliciting endogenous stimulatory signals, antigen-presentation, cytokines, and alarmins which in turn activate autoreactive immune responses [2]
  • Aberrant B cell receptor-mediated feedback - Together with the concept of T-cell-B-cell discordance this idea forms the basis of the hypothesis of self-perpetuating autoreactive B cells[3]. Autoreactive B cells in spontaneous autoimmunity are seen as surviving because of subversion both of the T cell help pathway and of the feedback signal through B cell receptor, thereby overcoming the negative signals responsible for B cell self-tolerance without necessarily requiring loss of T cell self-tolerance.
  • Cytokine Dysregulation or Immune Deviation - Cytokines have been recently divided into two groups according to the population of cells whose functions they promote: Helper T-cells type 1 or type 2. The second category of cytokines, which include IL-4, IL-10 and TGF-β (to name a few), seem to have a role in prevention of exaggeration of pro-inflammatory immune responses.
  • Dendritic cell apoptosis - immune system cells called dendritic cells present antigens to active lymphocytes. Dendritic cells that are defective in apoptosis can lead to inappropriate systemic lymphocyte activation and consequent decline in self-tolerance.[4]
  • Epitope spreading or epitope drift - when the immune reaction changes from targeting the primary epitope to also targeting other epitopes.[5] In contrast to molecular mimicry, the other epitopes need not be structurally similar to the primary one.
  • Idiotype Cross-Reaction - Idiotypes are antigenic epitopes found in the antigen-binding portion (Fab) of the immunoglobulin molecule. Plotz and Oldstone presented evidence that autoimmunity can arise as a result of a cross-reaction between the idiotype on an antiviral antibody and a host cell receptor for the virus in question. In this case, the host-cell receptor is envisioned as an internal image of the virus, and the anti-idiotype antibodies can react with the host cells.
  • Microchimerism - the discovery of fetal cells in postpartum mothers had led to the hypothesis that alloreactivity to fetal antigens precipitates autoreactivity, and subsequent autoimmune disease in mothers.
  • Dysregulation of central tolerance - the mutation responsible for the monogenic autoimmune disease autoimmune polyendocrine syndrome type 1 (APS1/APECED) has been mapped to a gene named autoimmune regulator]] (AIRE). Evidence from patients and animal models suggest that this gene functions in the thymus to negatively select autoreactive T cells during their development.
  • Dysregulation of peripheral tolerance - multiple mechanisms have been described to maintain tolerance in the periphery. Dysfunction in cell types, including regulatory T cells, NKT cells, and γδ T-cells, that participate in this maintenance of tolerance in the periphery may lead to the activation of autoreactive immunity.

Classification

Autoimmune diseases can be broadly divided into systemic and organ-specific or localised autoimmune disorders, depending on the principal clinico-pathologic features of each disease.

Using the traditional “tissue-specific” and “systemic” classification scheme, many diseases have been lumped together under the autoimmune disease umbrella. However, many chronic inflammatory human disorders lack the telltale associations of B and T cell driven immunopathology. In the last decade it has been firmly established that tissue "inflammation against self" does not necessarily rely on abnormal T and B cell responses.

It has recently been proposed that autoimmune disease should be viewed along an “immunological disease continuum,” with classical autoimmune diseases at one extreme and diseases driven by the innate immune system at the other extreme. Within this scheme, the full spectrum of autoimmunity can be included. Many common human autoimmune diseases can be seen to have a substantial innate immune mediated immunopathology using this new scheme. This new classification scheme has implications for understanding disease mechanisms and for therapy development [6].

Symptoms of Autoimmune Disease

The symptoms of autoimmune disease vary greatly depending on the disease as well as individual patient. Common symptoms include:

Inflammation, fatigue, dizziness, malaise, elevated fever and high body temperature, extreme sensitivity to cold in the hands and feet, weakness and stiffness in muscles and joints, weight changes, digestive or gastrointestinal problems, low or high blood pressure, irritability, anxiety, or depression, infertility or reduced sex drive (low libido), blood sugar changes, and depending on the type of autoimmune disease, an increase in the size of an organ or tissue or, the destruction of an organ or tissue can result.

Diagnosis

Diagnosis of autoimmune disorders largely rests on accurate history and physical examination of the patient, and high index of suspicion against a backdrop of certain abnormalities in routine laboratory tests (example, elevated C-reactive protein). In several disorders, serological assays which can detect specific autoantibodies can be employed. These tests vary in specificity and sensitivity, although levels of autoantibodies are often measured to determine the progress of the disease. Localised disorders are best diagnosed by immunofluorescence of biopsy specimens.

Treatments

Treatments for autoimmune disease have traditionally been immunosuppressive, anti-inflammatory, or palliative. Non-immunological therapies, such as hormone replacement in Hashimoto's thyroiditis or diabetes mellitus type 1 treat outcomes of the autoaggressive response. Dietary restrictions limit the severity of celiac disease. Steroidal or NSAID treatment limits inflammatory symptoms of many diseases. IVIG is used for CIDP and GBS. 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. Some of these immunotherapies may be associated with increased risk of adverse effects, such as susceptibility to infection, or exacerbation of other comorbidities.

Helminthic therapy is an experimental approach that involves inoculation of the patient with specific parasitic intestinal nematodes (helminths). There are currently two closely-related treatments available, inoculation with either Necator americanus, commonly known as hookworm, or Trichuris Suis eggs. [7][7][8][9][10][11]

T cell vaccination is also being explored as a possible future therapy for autoimmune disorders.

Development of therapies

In both autoimmune and inflammatory diseases the condition arises through aberrant reactions of the human adaptive or innate immune systems. In autoimmunity, the patient’s immune system is activated against the body's own proteins. In inflammatory diseases, it is the overreaction of the immune system, and its subsequent downstream signaling (TNF, IFN, etc), which causes problems.

A substantial minority of the population suffers from these diseases, which are often chronic, debilitating, and life-threatening. There are more than eighty commonly accepted autoimmune diseases, with many more suspected [12]. It has been estimated that autoimmune diseases are among the ten leading causes of death among women in all age groups up to 65 years.[13]

Currently, a considerable amount of research is being conducted into treatment of these conditions. According to a report from Frost & Sullivan, the total payouts by an alliance of leading pharmaceutical companies for drug discovery contract research in the autoimmune/inflammation segment from 1997 to 2002 totaled $489.8 million, where Eli Lilly, Suntory, Procter & Gamble, Encysive, and Novartis together account for 98.6 percent of payouts by that alliance.[14]

See also

References

  1. ^ Klein J, Sato A (September 2000). "The HLA system. Second of two parts". N. Engl. J. Med. 343 (11): 782–6. doi:10.1056/NEJM200009143431106. PMID 10984567.{{cite journal}}: CS1 maint: date and year (link)
  2. ^ Fairweather D, Kaya Z, Shellam GR, Lawson CM, Rose NR (2001). "From infection to autoimmunity". J Autoimmun. 16 (3): 175–186. doi:10.1006/jaut.2000.0492. PMID 11334481.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ Edwards JC, Cambridge G (2006). "B-cell targeting in rheumatoid arthritis and other autoimmune diseases". Nature Reviews Immunology. 6 (5): 394–403. doi:10.1038/nri1838. PMID 16622478.
  4. ^ Kubach J, Becker C, Schmitt E, Steinbrink K, Huter E, Tuettenberg A, Jonuleit H (2005). "Dendritic cells: sentinels of immunity and tolerance". Int J Hematol. 81 (3): 197–203. doi:10.1532/IJH97.04165. PMID 15814330.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ Induction of autoantibodies against tyrosinase-related proteins following DNA vaccination: Unexpected reactivity to a protein paralogue Roopa Srinivasan, Alan N. Houghton, and Jedd D. Wolchok
  6. ^ McGonagal D, McDermott MF (2006). "A proposed classification of the immunological diseases". PLOS Medicine. 3 (8): e297. doi:10.1371/journal.pmed.0030297. PMC 1564298. PMID 16942393.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  7. ^ a b Zaccone P, Fehervari Z, Phillips JM, Dunne DW, Cooke A (2006). "Parasitic worms and inflammatory diseases". Parasite Immunol. 28 (10): 515–23. doi:10.1111/j.1365-3024.2006.00879.x. PMC 1618732. PMID 16965287.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ Dunne DW, Cooke A (2005). "A worm's eye view of the immune system: consequences for evolution of human autoimmune disease". Nat. Rev. Immunol. 5 (5): 420–6. doi:10.1038/nri1601. PMID 15864275.
  9. ^ Dittrich AM, Erbacher A, Specht S; et al. (2008). "Helminth Infection with Litomosoides sigmodontis Induces Regulatory T Cells and Inhibits Allergic Sensitization, Airway Inflammation, and Hyperreactivity in a Murine Asthma Model". J. Immunol. 180 (3): 1792–9. doi:10.4049/jimmunol.180.3.1792. PMID 18209076. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  10. ^ Wohlleben G, Trujillo C, Müller J; et al. (2004). "Helminth infection modulates the development of allergen-induced airway inflammation". Int. Immunol. 16 (4): 585–96. doi:10.1093/intimm/dxh062. PMID 15039389. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  11. ^ Quinnell RJ, Bethony J, Pritchard DI (2004). "The immunoepidemiology of human hookworm infection". Parasite Immunol. 26 (11–12): 443–54. doi:10.1111/j.0141-9838.2004.00727.x. PMID 15771680.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ National Institutes of Health[1]
  13. ^ Noel R. Rose and Ian R. MacKay, “The Autoimmune Diseases” fourth edition
  14. ^ Frost & Sullivan Report, “Antibody Technology Developments” September 2005

External links

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