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Jbarin/Autoimmune Disease draft


Overview

Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to certain organs (e.g. in chagas disease) or involve a particular tissue in different places (e.g. Goodpasture's disease which may affect the basement membrane in both the lung and the kidney). The treatment of autoimmune diseases is typically with immunosuppression—medication which decreases the immune response.

There is an on-going discussion about when a disease should be considered autoimmune, leading to different criteria such as Witebsky's postulates.

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.

Scientists such as H. McDevitt, G. Nepom, J. Bell and J. Todd have also provided strong evidence to suggest that certain MHC class II allotypes are strongly correlated with

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 (Linda Wicker's extensive genetic studies of diabetes in the NOD mouse), and in patients (Brian Kotzin's linkage analysis of susceptibility to SLE).

Pathogenesis of autoimmunity

Several mechanisms are thought to be operative in the pathogenesis of autoimmune diseases, against a backdrop of genetic predisposition and environmental modulation. It is beyond the scope of this article to discuss each of these mechanisms exhaustively, but a summary of some of the important mechanisms have been described:

  • 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 - A normal immune response is assumed to involve B and T cell responses to the same antigen, even if we know that B cells and T cells recognise very different things: conformations on the surface of a molecule for B cells and pre-processed peptide fragments of proteins for T cells. However, there is nothing as far as we know that requires this. All that is required is that a B cell recognising antigen X endocytoses and processes a protein Y (normally =X) and presents it to a T cell. Roosnek and Lanzavecchia showed that B cells recognising IgGFc could get help from any T cell responding to an antigen co-endocytosed with IgG by the B cell as part of an immune complex. In coeliac disease it seems likely that B cells recognising tissue transglutamine are helped by T cells recognising gliadin.
  • Aberrant B cell receptor-mediated feedback - A feature of human autoimmune disease is that it is largely restricted to a small group of antigens, several of which have known signaling roles in the immune response (DNA, C1q, IgGFc, Ro, Con. A receptor, Peanut agglutinin receptor(PNAR)). This fact gave rise to the idea that spontaneous autoimmunity may result when the binding of antibody to certain antigens leads to aberrant signals being fed back to parent B cells through membrane bound ligands. These ligands include B cell receptor (for antigen), IgG Fc receptors, CD21, which binds complement C3d, Toll-like receptors 9 and 7 (which can bind DNA and nucleoproteins) and PNAR. More indirect aberrant activation of B cells can also be envisaged with autoantibodies to acetyl choline receptor (on thymic myoid cells) and hormone and hormone binding proteins. Together with the concept of T-cell-B-cell discordance this idea forms the basis of the hypothesis of self-perpetuating autoreactive B cells[2]. 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.
  • 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.
  • 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.
  • Cytokine Dysregulation - 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.[3]
  • Epitope spreading or epitope drift - when the immune reaction changes from targeting the primary epitope to also targeting other epitopes.[4] In contrast to molecular mimicry, the other epitopes need not be structurally similar to the primary one.

The roles of specialized immunoregulatory cell types, such as regulatory T cells, NKT cells, γδ T-cells in the pathogenesis of autoimmune disease are under investigation.

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 “organ specific” and “non-organ specific” 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.

This has led to the recent proposal that the spectrum of autoimmunity 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 (see PLoS Medicine article. http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0030297).

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 systemic disorders, serological assays which can detect specific autoantibodies can be employed. Localised disorders are best diagnosed by immunofluorescence of biopsy specimens. Autoantibodies are used to diagnose many autoimmune diseases. The levels of autoantibodies are measured to determine the progress of the disease.

Treatments

Treatments for autoimmune disease have traditionally been immunosuppressive, anti-inflammatory, or palliative.[5] 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. Dietary manipulation limits 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.

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 hookworms, or Trichuris Suis Ova, commonly known as Pig Whipworm Eggs. [6][6][7][8][9][10]

T cell vaccination is also being explored as a possible future therapy for auto-immune 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 illnesses caused by autoimmunity.[11] 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.[12]

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.[13]

Symptoms of Autoimmune Disease: The symptoms of autoimmune disease vary depending on the disease as well as the person’s immune system. 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.

See also

References

  1. ^ Klein J, Sato A (2000). "The HLA system. Second of two parts". N. Engl. J. Med. 343 (11): 782–6. doi:10.1056/NEJM200009143431106. PMID 10984567. {{cite journal}}: Unknown parameter |month= ignored (help)
  2. ^ 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.
  3. ^ 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)
  4. ^ 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
  5. ^ Cite error: The named reference scedu was invoked but never defined (see the help page).
  6. ^ 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)
  7. ^ 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.
  8. ^ 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. PMID 18209076. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  9. ^ 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)
  10. ^ 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)
  11. ^ National Institutes of Health[1]
  12. ^ Noel R. Rose and Ian R. MacKay, “The Autoimmune Diseases” fourth edition
  13. ^ Frost & Sullivan Report, “Antibody Technology Developments” September 2005
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