Editing Crohn's disease (section)

== Etiology ==
The [[etiology]], or cause, of Crohn's disease is unknown. Many theories have been disputed, with four main theories hypothesized to be the primary mechanism of Crohn's disease. In [[autoimmune diseases]], [[Antibody|antibodies]] and [[T cell|T lymphocytes]] are the primary mode of inflammation. These cells and bodies are part of the [[adaptive immune system]], or the part of the immune system that learns to fight foreign bodies when first identified.<ref>{{Cite web|title=Definition of Autoimmunity & Autoimmune Disease - Autoimmune Disease {{!}} Johns Hopkins Pathology|url=https://pathology.jhu.edu/autoimmune/definitions|access-date=October 3, 2021|website=pathology.jhu.edu|archive-date=October 3, 2021|archive-url=https://web.archive.org/web/20211003015525/https://pathology.jhu.edu/autoimmune/definitions|url-status=live}}</ref> [[Autoinflammatory disease]]s are diseases where the [[innate immune system]], or the immune system we are genetically coded with, is designed to attack our own cells.<ref name="Ciccarelli 261–269">{{cite journal | vauthors = Ciccarelli F, De Martinis M, Ginaldi L | title = An update on autoinflammatory diseases | journal = Current Medicinal Chemistry | volume = 21 | issue = 3 | pages = 261–269 | date = January 2013 | pmid = 24164192 | pmc = 3905709 | doi = 10.2174/09298673113206660303 }}</ref> Crohn's disease likely has involvement of both the adaptive and innate immune systems.<ref name="Li 15–22">{{cite journal | vauthors = Li N, Shi RH | title = Updated review on immune factors in pathogenesis of Crohn's disease | journal = World Journal of Gastroenterology | volume = 24 | issue = 1 | pages = 15–22 | date = January 2018 | pmid = 29358878 | pmc = 5757119 | doi = 10.3748/wjg.v24.i1.15 | doi-access = free | title-link = doi }}</ref>

=== Autoinflammatory theory ===
Crohn's disease can be described as a multifactorial autoinflammatory disease. The etiopathogenesis of Crohn's disease is still unknown. In any event, a loss of the regulatory capacity of the immune apparatus would be implicated in the onset of the disease. In this respect interestingly enough, as for [[Blau syndrome|Blau's disease]] (a [[Monogenic (genetics)|monogenic]] autoinflammatory disease), the [[NOD2]] gene mutations have been linked to Crohn's disease. However, in Crohn's disease, NOD2 mutations act as a risk factor, being more common among people with Crohn's disease than the background population, while in Blau's disease NOD2 mutations are linked directly to this syndrome, as it is an [[Autosomal dominant|autosomal-dominant]] disease. All this new knowledge in the [[pathogenesis]] of Crohn's disease allows us to put this multifactorial disease in the group of [[Autoinflammatory diseases|autoinflammatory]] syndromes.<ref name="Ciccarelli 261–269" />

Some examples of how the innate immune system affects bowel inflammation have been described.<ref name="Li 15–22" /> A meta-analysis of Crohn's disease [[genome]]-wide association studies revealed 71 distinct Crohn's disease-susceptibility [[Locus (genetics)|loci]]. Interestingly, three very important Crohn's disease-susceptibility genes (the intracellular pathogen-recognition receptor, NOD2; the autophagy-related 16-like 1, [[ATG16L1]] and the immunity-related GTPase M, [[IRGM]]) are involved in innate immune responses against gut microbiota, while one (the X-box binding protein 1) is involved in regulation of the [adaptive] immune pathway via [[MHC class II]],<ref>{{cite journal | vauthors = Roggenbuck D, Reinhold D, Baumgart DC, Schierack P, Conrad K, Laass MW | title = Autoimmunity in Crohn's Disease-A Putative Stratification Factor of the Clinical Phenotype | journal = Advances in Clinical Chemistry | volume = 77 | pages = 77–101 | date = January 1, 2016 | pmid = 27717419 | doi = 10.1016/bs.acc.2016.06.002 | publisher = Elsevier | isbn = 978-0-12-804686-9 | veditors = Makowski GS }}</ref> resulting in autoinflammatory inflammation. Studies have also found that increased [[Type 3 innate lymphoid cells|ILC3]] can [[overexpress]] [[Major histocompatibility complex|major histocompatibility complex (MHC) II]]. MHC class II can induce [[CD4+ T cell]] [[apoptosis]], thus avoiding the [[T cell]] response to normal bowel micro bacteria. Further studies of people with IBD compared with people without IBD found that the expression of MHC II by ILC3 was significantly reduced in people with IBD, thus causing an immune reaction against intestinal cells or normal bowel bacteria and damaging the intestines. This can also make the intestines more susceptible to environmental factors, such as food or bacteria.<ref name="Li 15–22" />

The thinking is that because Crohn's disease has strong innate immune system involvement and has NOD2 mutations as a predisposition, Crohn's disease is more likely an autoinflammatory disease than an autoimmune disease.<ref name="Li 15–22" />

=== Immunodeficiency theory ===
{{Update section|date=May 2024|reason=All current sources are from 2010}}
A substantial body of data has emerged in recent years to suggest that the primary defect in Crohn's disease is actually one of relative [[immunodeficiency]].<ref name="Marks 20–31">{{cite journal | vauthors = Marks DJ, Rahman FZ, Sewell GW, Segal AW | title = Crohn's disease: an immune deficiency state | journal = Clinical Reviews in Allergy & Immunology | volume = 38 | issue = 1 | pages = 20–31 | date = February 2010 | pmid = 19437144 | pmc = 4568313 | doi = 10.1007/s12016-009-8133-2 }}</ref> This view has been bolstered recently by novel immunological and clinical studies that have confirmed gross aberrations in this early response, consistent with subsequent genetic studies that have highlighted molecules important for [[Innate immune system|innate immune function]]. The suggestion therefore is that Crohn's [[pathogenesis]] actually results from partial immunodeficiency, a theory that coincides with the frequent recognition of a virtually identical, non-infectious inflammatory bowel disease arising in people with [[congenital]] [[Monogenic (genetics)|monogenic]] disorders impairing [[phagocyte]] function.<ref name="Marks 20–31" />