Editing Autoimmunity (section)

== 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:<ref>{{Cite journal |last1=Heward |first1=Joanne |last2=Gough |first2=Stephen C. L. |date=1997-12-01 |title=Genetic Susceptibility to the Development of Autoimmune Disease |url=https://portlandpress.com/clinsci/article/93/6/479/76820/Genetic-Susceptibility-to-the-Development-of |journal=Clinical Science |language=en |volume=93 |issue=6 |pages=479–491 |doi=10.1042/cs0930479 |pmid=9497784 |issn=0143-5221|url-access=subscription }}</ref>
* [[Immunoglobulins]]
* [[T-cell receptor]]s
* The [[major histocompatibility complex]]es (MHC).

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 [[lymphocyte]]s capable of self-reactivity.
* HLA DR2 is strongly positively correlated with [[systemic lupus erythematosus]], [[narcolepsy]]<ref name="pmid10984567">{{cite journal | vauthors = Klein J, Sato A | title = The HLA system. Second of two parts | journal = The New England Journal of Medicine | volume = 343 | issue = 11 | pages = 782–786 | date = September 2000 | pmid = 10984567 | doi = 10.1056/NEJM200009143431106 }}</ref> and [[multiple sclerosis]], and negatively correlated with DM Type 1.
* HLA DR3 is correlated strongly with [[Sjögren syndrome]], [[myasthenia gravis]], [[lupus erythematosus]], and [[type 1 diabetes mellitus]].
* HLA DR4 is correlated with the genesis of [[rheumatoid arthritis]], type 1 diabetes mellitus, and [[pemphigus vulgaris]].

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 [[Polymorphism (biology)|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){{clarify|What is an NOD mouse?|date=April 2024}}, and in patients (Brian Kotzin's linkage analysis of susceptibility to [[lupus erythematosus]]).

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.<ref>{{cite journal | vauthors = Gregersen PK, Olsson LM | title = Recent advances in the genetics of autoimmune disease | journal = Annual Review of Immunology | volume = 27 | pages = 363–391 | date = 2009-01-01 | pmid = 19302045 | pmc = 2992886 | doi = 10.1146/annurev.immunol.021908.132653 }}</ref> 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.<ref>{{Cite journal |last1=Chung |first1=Sharon A. |last2=Criswell |first2=Lindsey A. |date=January 2007 |title=PTPN22: Its role in SLE and autoimmunity |journal=Autoimmunity |language=en |volume=40 |issue=8 |pages=582–590 |doi=10.1080/08916930701510848 |issn=0891-6934 |pmc=2875134 |pmid=18075792}}</ref><ref>{{Cite journal |last1=Bottini |first1=Nunzio |last2=Peterson |first2=Erik J. |date=2014-03-21 |title=Tyrosine Phosphatase PTPN22: Multifunctional Regulator of Immune Signaling, Development, and Disease |journal=Annual Review of Immunology |language=en |volume=32 |issue=1 |pages=83–119 |doi=10.1146/annurev-immunol-032713-120249 |issn=0732-0582 |pmc=6402334 |pmid=24364806}}</ref>

=== Existential Factors (a.k.a Endogenous Environmental) ===
{| class="wikitable" style="float:right;"
|-
!colspan=2| Ratio of female/male [[incidence (epidemiology)|incidence]] <br> of autoimmune diseases
|-
| [[Hashimoto's thyroiditis]] || 10:1<ref name=McCoy>{{cite web | url = http://www.everydayhealth.com/autoimmune-disorders/understanding/women-and-autoimmune-diseases.aspx | title = Women and Autoimmune Disorders | vauthors = McCoy K | veditors = Marcellin L | date = 2 December 2009 }}</ref>
|-
| [[Graves' disease]] || 7:1<ref name=McCoy/>
|-
| [[Multiple sclerosis]] (MS) || 2:1<ref name=McCoy/>
|-
| [[Myasthenia gravis]] || 2:1<ref name=McCoy/>
|-
| [[Systemic lupus erythematosus]] || 9:1<ref name=McCoy/>
|-
| [[Rheumatoid arthritis]] || 5:2<ref name=McCoy/>
|-
| [[Primary sclerosing cholangitis]] || 1:2
|}

==== Sex<!-- NOTE:  In these articles, "sex" refers to sex as used in studies that largely study cisgender people. Unfortunately most research does not confirm karyotype, and rarely studies minority genders. Please do not replace "sex" with "gender". A transwoman is not known to have the same risks as a ciswoman. --> ====
Most autoimmune diseases are ''[[sex-related diseases|sex-related]]; ''as a whole, women are much more likely to develop autoimmune disease than men. Being female is the single greatest risk factor for developing autoimmune disease than any other genetic or environmental risk factor yet discovered.<ref>{{cite journal | vauthors = Voskuhl R | title = Sex differences in autoimmune diseases | journal = Biology of Sex Differences | volume = 2 | issue = 1 | pages = 1 | date = January 2011 | pmid = 21208397 | pmc = 3022636 | doi = 10.1186/2042-6410-2-1 | doi-access = free }}</ref><ref name="pmid39286970">{{cite journal |vauthors=Fairweather D, Beetler DJ, McCabe EJ, Lieberman SM |title=Mechanisms underlying sex differences in autoimmunity |journal=J Clin Invest |volume=134 |issue=18 |pages= |date=September 2024 |pmid=39286970 |pmc=11405048 |doi=10.1172/JCI180076 |url=}}</ref> 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]].

The reasons for the sex role in autoimmunity vary. 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. A history of pregnancy also appears to leave a persistent increased risk for autoimmune disease. It has been suggested that the slight, direct exchange of cells between mothers and their children during pregnancy may induce autoimmunity.<ref>{{cite journal | vauthors = Ainsworth C | date = 15 November 2003 | url = https://www.newscientist.com/article.ns?id=mg18024215.100 | title = The Stranger Within | archive-url = https://web.archive.org/web/20081022063630/http://www.newscientist.com/article.ns?id=mg18024215.100| archive-date=2008-10-22 | journal = [[New Scientist]] | volume = 180 | issue = 2421 | page = 34 | url-access = subscription }} (reprinted  [http://www.katewerk.com/chimera.html here])</ref> This would tip the gender balance in the direction of the female.

Another theory suggests the female high tendency to get autoimmunity is due to an imbalanced [[X-inactivation|X-chromosome inactivation]].<ref>{{Cite web | vauthors = Kruszelnicki KS |date=2004-02-12 |title=Hybrid Auto-Immune Women 3 |url=https://www.abc.net.au/science/articles/2004/02/12/1002754.htm |access-date=2023-01-03 |website=www.abc.net.au |language=en-AU}}</ref> The X-inactivation skew theory, proposed by Princeton University's Jeff Stewart, has recently been confirmed experimentally in [[scleroderma]] and [[autoimmune thyroiditis]].<ref>{{cite journal | vauthors = Uz E, Loubiere LS, Gadi VK, Ozbalkan Z, Stewart J, Nelson JL, Ozcelik T | title = Skewed X-chromosome inactivation in scleroderma | journal = Clinical Reviews in Allergy & Immunology | volume = 34 | issue = 3 | pages = 352–355 | date = June 2008 | pmid = 18157513 | pmc = 2716291 | doi = 10.1007/s12016-007-8044-z }}</ref> Other complex X-linked genetic susceptibility mechanisms are proposed and under investigation.

=== Environmental factors ===

==== Infectious diseases and parasites ====
An interesting inverse relationship exists between infectious diseases and autoimmune diseases. In areas where multiple infectious diseases are endemic, autoimmune diseases are quite rarely seen. The reverse, to some extent, seems to hold true. The [[hygiene hypothesis]] attributes these correlations to the immune-manipulating strategies of pathogens. 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.<ref>{{cite journal | vauthors = Saunders KA, Raine T, Cooke A, Lawrence CE | title = Inhibition of autoimmune type 1 diabetes by gastrointestinal helminth infection | journal = Infection and Immunity | volume = 75 | issue = 1 | pages = 397–407 | date = January 2007 | pmid = 17043101 | pmc = 1828378 | doi = 10.1128/IAI.00664-06 }}</ref><ref>{{cite web|url=https://www.sciencedaily.com/releases/2007/01/070117091058.htm|title=Parasite Infection May Benefit Multiple Sclerosis Patients<!-- Bot generated title -->|work=sciencedaily.com}}</ref><ref>{{cite journal | vauthors = Wållberg M, Harris RA | title = Co-infection with Trypanosoma brucei brucei prevents experimental autoimmune encephalomyelitis in DBA/1 mice through induction of suppressor APCs | journal = International Immunology | volume = 17 | issue = 6 | pages = 721–728 | date = June 2005 | pmid = 15899926 | doi = 10.1093/intimm/dxh253 | doi-access = free }}</ref>

The putative mechanism is that the parasite attenuates the host immune response in order to protect itself.  This may provide a serendipitous benefit to a host that also has autoimmune disease. The  details of parasite immune modulation are not yet known, but may include secretion of anti-inflammatory agents or interference with the host immune signaling.

A paradoxical observation has been the strong association of certain microbial organisms with autoimmune diseases.
For example, ''[[Klebsiella pneumoniae]]'' and [[Coxsackie B|coxsackievirus B]] have been strongly correlated with [[ankylosing spondylitis]] and [[diabetes mellitus type 1]], respectively. This has been explained by the tendency of the infecting organism to produce [[super-antigens]] that are capable of [[Polyclonal antibodies|polyclonal]] activation of [[B-lymphocytes]], and production of large amounts of antibodies of varying specificities, some of which may be self-reactive (see below).

==== Chemical agents and drugs ====
Certain chemical agents and drugs can also be associated with the genesis of autoimmune conditions, or conditions that simulate autoimmune diseases. The most striking of these is the [[drug-induced lupus erythematosus]]. Usually, withdrawal of the offending drug cures the symptoms in a patient.

Cigarette smoking is now established as a major risk factor for both incidence and severity of [[rheumatoid arthritis]]. This may relate to abnormal [[citrullination]] of proteins, since the effects of smoking correlate with the presence of [[antibodies]] to citrullinated [[peptides]].