Editing Sjögren's disease (section)

== Pathogenesis ==
The [[Pathogenesis|pathogenetic]] mechanisms of Sjögren's disease have not been fully elucidated, resulting in the lack of [[pathophysiology]] knowledge of the management of this autoimmune [[exocrinopathy]]. Although the numerous factors contributing to the progression of this disease have made discovering the exact origin and cause difficult, major advances over the past decade have contributed to a proposed set of pathogenic events that occur before the diagnosis of Sjögren's disease.<ref name=Voulgarelis2010/>

Sjögren's disease was originally proposed as a specific, [[Self-perpetuation|self-perpetuating]], immune system-mediated loss of exocrine glands, specifically [[acinar]] and [[ductal cells]]. Although this explains the more obvious symptoms (such as the lack of saliva and [[lacrimal fluid]]), it does not explain the more widespread systemic effects seen in the progression of the disease.{{citation needed|date=December 2020}}

In the presence of a susceptible [[Epistasis|genetic background]], both [[Environmental epidemiology|environmental]] and [[hormonal]] factors are thought capable of triggering the infiltration of lymphocytes, specifically [[CD4+ T cells]], [[B cells]], and [[plasma cells]], causing glandular dysfunction in the salivary and lacrimal glands.<ref name=Voulgarelis2010/><ref>Mohammad Dezfulian, Tomasz Kula, Thomas Pranzatelli, Nolan Kamitaki, Qingda Meng, Bhuwan Khatri, Paola Perez et al. "TScan-II: A genome-scale platform for the de novo identification of CD4+ T cell epitopes." Cell 186, no. 25 (2023): 5569-5586. DOI: [https://doi.org/10.1016/j.cell.2023.10.024 10.1016/j.cell.2023.10.024]</ref>

Sjögren's disease is associated with increased levels in [[cerebrospinal fluid]] (CSF) of [[IL-1RA]], an [[interleukin 1]] [[Receptor antagonist|antagonist]]. This suggests that the disease begins with increased activity in the interleukin 1 system, followed by an autoregulatory [[Downregulation and upregulation|upregulation]] of IL-1RA to reduce the successful binding of interleukin 1 to its receptors. Interleukin 1 likely is the [[Biomarker|marker]] for fatigue, but increased IL-1RA is observed in the CSF and is associated with increased [[fatigue (medical)|fatigue]] through [[cytokine]]-induced [[sickness behavior]].<ref>{{cite journal|doi=10.1016/j.bbi.2009.06.151|pmid=19560535|title=Fatigue in primary Sjögren's disease – A link to sickness behaviour in animals?|year=2009|last1=Harboe|first1=Erna|last2=Tjensvoll|first2=Anne Bolette|last3=Vefring|first3=Hege K.| last4= Gøransson |first4=Lasse G.|last5=Kvaløy|first5=Jan Terje|last6=Omdal|first6=Roald|journal=Brain, Behavior, and Immunity| volume= 23| issue=8|pages=1104–8|s2cid=43828817}}</ref> However, Sjögren's disease is characterized by decreased levels of IL-1ra in saliva, which could be responsible for mouth inflammation and dryness.<ref>{{cite journal |pmid= 9646842| year= 1998| last1= Perrier |first1= S| last2= Coussediere|first2=C|last3=Dubost|first3=JJ|last4=Albuisson|first4=E|last5=Sauvezie|first5=B|title=IL-1 receptor antagonist (IL-1RA) gene polymorphism in Sjögren's disease and rheumatoid arthritis|volume=87|issue=3|pages=309–13|journal=Clinical Immunology and Immunopathology|doi=10.1006/clin.1998.4520}}</ref> Patients with secondary Sjögren's disease also often exhibit signs and symptoms of their primary rheumatic disorders, such as [[systemic lupus erythematosus]], [[rheumatoid arthritis]], or [[systemic sclerosis]].{{citation needed|date=October 2020}}

=== Genetic predisposition ===
The [[genetic locus]] most significantly associated with primary SS is the [[major histocompatibility complex]]/[[human leukocyte antigen]] (MHC/HLA) region, as demonstrated by the preliminary results of the first [[genome-wide association study]].<ref>{{cite journal |last1=Reveille |first1=JD |title=The molecular genetics of systemic lupus erythematosus and Sjögren's disease |journal=Current Opinion in Rheumatology |date=October 1992 |volume=4 |issue=5 |pages=644–56 |pmid=1419498}}</ref> This study included data from a discovery cohort of 395 patients of European ancestry with primary Sjögren's disease, and 1,975 healthy [[Treatment and control groups|control individuals]], and from a replication study that comprised 1,234 cases and 4,779 healthy controls. Associations with [[Polymorphism (biology)|polymorphism]]s located at six independent loci were also detected; ''[[IRF5]], [[STAT4]], [[BLK (gene)|BLK]], [[IL12A]], [[TNIP1]],'' and ''[[CXCR5]]''. This also suggested the activation of the [[innate immune system]], notably through the IFN system, B-cell activation through ''CXCR5''-directed recruitment to [[lymphoid follicles]] and B-cell receptor (BCR) activation involving'' BLK'', and [[T-cell activation]] owing to HLA susceptibility and the IL-12-IFN-γ-axis.<ref name="LessardLi2014">{{cite journal |last1=Lessard |first1=C. J. |last2=Li |first2=H. |last3=Ice |first3=J. A. |last4=Adrianto |first4=I. |last5=Jonsson |first5=R. |last6=Illei |first6=G. G. |last7=Rischmueller |first7=M. |last8=Nordmark |first8=G. |last9=Mariette |first9=X. |last10=Miceli-Richard |first10=C. |last11=Wahren Herlenius |first11=M. |last12=Witte |first12=T. |last13=Brennan |first13=M. |last14=Omdal |first14=R. |last15=Gaffney |first15=P. M. |last16=Lessard |first16=J. A. |last17=Rönnblom |first17=L. |last18=Ng |first18=W.-F. |last19=Rhodus |first19=N. |last20=Segal |first20=B. |last21=Scofield |first21=R. H. |last22=James |first22=J. A. |last23=Anaya |first23=J.-M. |last24=Montgomery |first24=C. G. |last25=Harley |first25=J. B. |last26=Moser Sivils |first26=K. |title=OP0020 Identification of Multiple Sjögren's Syndrome Susceptibility Loci |journal=Annals of the Rheumatic Diseases |date=June 2013 |volume=72 |issue=Suppl 3 |pages=A54.3–A55 |doi=10.1136/annrheumdis-2013-eular.225 |s2cid=84998601 }}</ref>

Patients of different ethnic origins carry different HLA-susceptibility [[allele]]s, of which HLA-DR and HLA-DQ are involved in the pathogenesis of Sjögren's disease. For example, patients from Northern and Western Europe and North America show a high prevalence of ''B8, DRw52,'' and ''DR3'' genes.<ref name="pmid8468491">{{cite journal | vauthors = Kang HI, Fei HM, Saito I, Sawada S, Chen SL, Yi D, Chan E, Peebles C, Bugawan TL, Erlich HA | title = Comparison of HLA class II genes in Caucasoid, Chinese, and Japanese patients with primary Sjögren's syndrome | journal = J. Immunol. | volume = 150 | issue = 8 Pt 1 | pages = 3615–23 | date = April 1993 | doi = 10.4049/jimmunol.150.8.3615 | pmid = 8468491 | s2cid = 1453558 | doi-access = free }}</ref> HLA class II alleles are associated with the presence of specific subsets of [[autoantibodies]], rather than with the disease itself.<ref name="pmid11469461">{{cite journal | vauthors = Bolstad AI, Wassmuth R, Haga HJ, Jonsson R | title = HLA markers and clinical characteristics in Caucasians with primary Sjögren's syndrome | journal = J. Rheumatol. | volume = 28 | issue = 7 | pages = 1554–62 | date = July 2001 | pmid = 11469461 }}</ref> Autoantibodies refer to the loss of B-cell tolerance leading to the production of antibodies directed against diverse organ-specific and organ nonspecific antigens.<ref name=Voulgarelis2010/> Association between HLA and SS is restricted to patients with anti-SSA/Ro or anti-SSB/La antibodies. [[Seropositivity]] for anti-Ro and anti-La is associated with greater severity and longer duration of disease, and findings of their high abundance from the [[salivary glands]] of Sjögren's patients suggests their imperative role in the pathogenesis of SS.<ref name="pmid1685512">{{cite journal | vauthors = Fei HM, Kang H, Scharf S, Erlich H, Peebles C, Fox R | title = Specific HLA-DQA and HLA-DRB1 alleles confer susceptibility to Sjögren's disease and autoantibody production | journal = J. Clin. Lab. Anal. | volume = 5 | issue = 6 | pages = 382–91 | date = 1991 | pmid = 1685512 | doi = 10.1002/jcla.1860050604 | s2cid = 39754064 }}</ref>

Beyond genetics, [[Epigenetics|epigenetic]] abnormality related to [[DNA methylation]], [[histone acetylation]], or [[microRNA]] expression probably has a key role in the pathogenesis of autoimmune diseases, including Sjögren's disease, though research in this area is very limited.<ref>{{cite journal | author = Lu Q | year = 2013 | title = The critical importance of epigenetics in autoimmunity | journal = J. Autoimmun. | volume = 41 | pages = 1–5 | doi=10.1016/j.jaut.2013.01.010| pmid = 23375849 | url = https://tede.ufrrj.br/jspui/handle/jspui/3479 }}</ref>

=== Environmental triggers ===
Environmental factors, such as glandular [[viral infection]], could prompt [[epithelial cells]] to activate the HLA-independent innate immune system through [[toll-like receptors]].<ref name="pmid12524386">{{cite journal | vauthors = Takeda K, Kaisho T, Akira S | title = Toll-like receptors | journal = Annu. Rev. Immunol. | volume = 21 | pages = 335–76 | date = 2003 | pmid = 12524386 | doi = 10.1146/annurev.immunol.21.120601.141126 }}</ref> Although several infectious, [[exogenous]] agents have been implicated in the pathogenesis of Sjögren's disease, such as [[Epstein-Barr virus]] (EBV), [[human T-lymphotropic virus 1]], and [[hepatitis C virus]], their association with Sjögren's disease appears weak. While EBV is present in the salivary glands of normal individuals, a high incidence of EBV reactivation in Sjögren's patients has been reported with increased levels of EBV [[DNA]]. This indicates viral reactivation and the inability of lymphoid infiltrates to control EBV [[Viral replication|replication]] in Sjögren's disease, leading to the [[Initiation (chemistry)|initiation]] or perpetuation of an immune response in target organs. Nonetheless,  exactly how reactivation of EBV is induced in [[lesions]] of patients with Sjögren's disease, and which specific molecular mechanisms are involved in the process of viral reactivation,  remain to be clarified.<ref name="pmid8391219">{{cite journal | vauthors = Pflugfelder SC, Crouse CA, Monroy D, Yen M, Rowe M, Atherton SS | title = Epstein-Barr virus and the lacrimal gland pathology of Sjögren's syndrome | journal = Am. J. Pathol. | volume = 143 | issue = 1 | pages = 49–64 | date = July 1993 | pmid = 8391219 | pmc = 1886957 }}</ref>

=== Inflammation ===
Epithelial cells in Sjögren's disease lesions are active participants in the induction and perpetuation of the inflammatory process. Environmental and hormonal factors, in concert with an appropriate genetic background, are believed to trigger Sjögren's disease, which [[Dysregulation|dysregulates]] epithelial cells and allows aberrant [[Homing (hematopoietic)|homing]] and activation of [[dendritic cells]] (DCs), T cells, and B cells.<ref name="pmid18050195">{{cite journal | vauthors = Manoussakis MN, Boiu S, Korkolopoulou P, Kapsogeorgou EK, Kavantzas N, Ziakas P, Patsouris E, Moutsopoulos HM | title = Rates of infiltration by macrophages and dendritic cells and expression of interleukin-18 and interleukin-12 in the chronic inflammatory lesions of Sjögren's syndrome: correlation with certain features of immune hyperactivity and factors associated with high risk of lymphoma development | journal = Arthritis Rheum. | volume = 56 | issue = 12 | pages = 3977–88 | date = December 2007 | pmid = 18050195 | doi = 10.1002/art.23073 | doi-access = free }}</ref> Dendritic cells are [[antigen-presenting cells]] <!-- (APC) --> that process [[antigen]] material and present it to other T cells. Following the [[Cell migration|migration]] of lymphocytes into the glands in response to [[chemokines]] and specific [[adhesion molecule]]s, T cells interact with epithelial cells. Epithelial cells are further activated by [[proinflammatory cytokines]] (IL-1β, IFN-γ, and TNF), which are produced by adjacent T cells. The early accumulation of [[plasma cell|plasmacytoid]] dendritic cells in the target tissues, which produce high levels of type 1 IFNs, seems important, as these cells can further dysregulate the immune response through abnormal retention of lymphocytes in the tissues, and their subsequent activation. IFN-α stimulates the production of [[B-cell activating factor]] (BAFF) by epithelial cells, DCs, and T cells. BAFF stimulates aberrant B-cell maturation, leading to the emergence of self-reactive B cells, which locally produce autoantibodies, in a [[germinal centre]]-like structure (GC-like), which is also the location of [[lymphomagenesis]] (origin of [[lymphoma]]).<ref name=Voulgarelis2010/>

=== Programmed cell death ===
Dysregulation of [[apoptosis]] (programmed cell death) is believed to play a role in the pathogenesis of a variety of autoimmune diseases, though its role in Sjögren's disease is controversial. Both the [[Fas receptor|Fas]] and [[Fas ligand]] proteins are [[overexpress]]ed in primary Sjögren's patients, while expression of [[Cyclin D1|BCL-1]], which is known to downregulate apoptosis, was found significantly reduced in acinar and ductal [[epithelial cells]] of Sjögren's patients compared to healthy people.<ref name="pmid12472667">{{cite journal | vauthors = Ohlsson M, Szodoray P, Loro LL, Johannessen AC, Jonsson R | title = CD40, CD154, Bax and Bcl-2 expression in Sjögren's syndrome salivary glands: a putative anti-apoptotic role during its effector phases | journal = Scand. J. Immunol. | volume = 56 | issue = 6 | pages = 561–71 | date = December 2002 | pmid = 12472667 | doi = 10.1046/j.1365-3083.2002.01168.x| s2cid = 39543376 | doi-access = free }}</ref><ref name="pmid11204278">{{cite journal | vauthors = Ohlsson M, Skarstein K, Bolstad AI, Johannessen AC, Jonsson R | title = Fas-induced apoptosis is a rare event in Sjögren's syndrome | journal = Lab. Invest. | volume = 81 | issue = 1 | pages = 95–105 | date = January 2001 | pmid = 11204278 | doi = 10.1038/labinvest.3780215 | doi-access = free }}</ref> ''[[In situ]]'' studies did not show increased apoptosis among glandular epithelial cells but did show reduced apoptosis among infiltrating mononuclear cells. Reduced apoptosis was also implicated in the accumulation of autoreactive B-cells found in the glands. The relationship of autoantibodies expressed in Sjögren's syndrome with apoptosis is still being researched.<ref name="borchers"/>

=== Hormonal factors ===
[[Sex hormones]] seem to influence humoral and cell-mediated immune response, with [[estrogen]] being considered one of the biggest factors responsible for sex-[[immunologic]] [[Sexual dimorphism|dimorphism]].<ref name="pmid15485092">{{cite journal |vauthors=Cutolo M, Sulli A, Capellino S, Villaggio B, Montagna P, Seriolo B, Straub RH |title=Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity. |journal=Lupus |volume=13 |issue=9 |pages=635–8 |year=2004 |pmid=15485092 |doi=10.1191/0961203304lu1094oa|s2cid=23941507 }}</ref> [[Estrogen deficiency]] appears to play a role in the development of Sjögren's disease.<ref name=MavraganiFragoulis2012>{{cite journal|vauthors=Mavragani CP, Fragoulis GE, Moutsopoulos HM|title=Endocrine alterations in primary Sjögren's disease: an overview|journal=J Autoimmun|volume=39|issue=4|pages=354–8|date=Dec 2012|pmid=22695186|doi=10.1016/j.jaut.2012.05.011|type=Review}}</ref> It has been [[hypothesized]] that androgen administration to the ocular surface may serve as an effective therapy for dry eyes.<ref name="pmid10415627">{{cite journal |vauthors=Sullivan DA, Wickham LA, Rocha EM, Krenzer KL, Sullivan BD, Steagall R, Cermak JM, Dana MR, Ullman MD, Sato EH, Gao J, Rocha FJ, Ono M, Silveira LA, Lambert RW, Kelleher RS, Tolls DB, Toda I |title=Androgens and dry eye in Sjögren's syndrome |journal=Ann N Y Acad Sci |volume=876 |issue=1 |pages=312–24 |year=1999 |pmid=10415627 |doi=10.1111/j.1749-6632.1999.tb07656.x|bibcode=1999NYASA.876..312S |s2cid=33718591 }}</ref>