Sjögren's syndrome pathophysiology: Difference between revisions

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{{Sjögren's syndrome}}
{{Sjögren's syndrome}}
{{CMG}} {{AE}}[https://www.wikidoc.org/index.php/User:Farbod_Zahedi Farbod Zahedi Tajrishi, M.D.]
{{CMG}} {{AE}} {{F.K}}, [https://www.wikidoc.org/index.php/User:Farbod_Zahedi Farbod Zahedi Tajrishi, M.D.]


==Overview==
==Overview==
ُ[[Sjögren's syndrome]] is a chronic [[Autoimmune disease|auto-immune]] disorder that can affect several organ systems. Both genetic and immune factors contribute to the [[pathogenesis]] of the disease. [[Lymphocyte|Lymphocytes]] infiltrate the [[lacrimal]] and [[Salivary gland|salivary glands]] and impair their function, hence causing the main characteristic [[Symptom|symptoms]] of the disease- dry mouth ([[keratoconjunctivitis sicca]]) and eyes ([[xerostomia]]). [[CD4|CD4+]] [[T cell|T-cells]] are predominant in mild and moderate salivary gland infiltrations, while [[B cell|B cells]] play the major role in severe lesions <ref name="pmid19889514">{{cite journal| author=Christodoulou MI, Kapsogeorgou EK, Moutsopoulos HM| title=Characteristics of the minor salivary gland infiltrates in Sjögren's syndrome. | journal=J Autoimmun | year= 2010 | volume= 34 | issue= 4 | pages= 400-7 | pmid=19889514 | doi=10.1016/j.jaut.2009.10.004 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19889514  }}</ref>.  
[[Sjögren's syndrome]] (SS) is a chronic [[Autoimmunity|autoimmune disorder]] that can affect several [[Organ (anatomy)|organ systems]]. [[Sjögren's syndrome]] is classified into a "primary" form that is a separate entity from other well-defined [[Autoimmune disease|autoimmune]] disorders and a "secondary" form that is associated with other well-defined [[Autoimmunity|autoimmune]] conditions, such as [[SLE]], [[rheumatoid arthritis]], [[Progressive Systemic Sclerosis|progressive systemic sclerosis]], and [[primary biliary cirrhosis]]. These forms of [[Sjögren's syndrome]] are different in their [[Serology|serologic]] and [[Histopathology|histopathologic]] findings as well as their [[Genetics|genetic]] components. Both [[Genetics|genetic]] and immune factors contribute to the [[pathogenesis]] of the disease. In the most common presentation of [[Sjögren's syndrome]], [[Lymphocyte|lymphocytes]] infiltrate the [[lacrimal]] and [[Salivary gland|salivary glands]] and impair their function, hence causing the main characteristic [[Symptom|symptoms]] such as [[Xerostomia|dry mouth]] ([[xerostomia]]) and [[dry eyes]] ([[keratoconjunctivitis sicca]]). [[CD4|CD4+]] [[T cell|T-cells]] are predominant in mild and moderate [[salivary gland]] infiltrations, while [[B cell|B cells]] play the major role in severe lesions. [[Sjögren's syndrome]] may also manifest itself with dryness of [[skin]] and other [[Mucous membrane|mucosal surfaces]] or even cause systemic extraglandular disturbances such as [[arthritis]], [[vasculitis]], [[Kidney|renal]], [[Lung|pulmonary]], [[Hematopoiesis|hematopoietic]], and [[Neurology|neurologic]] involvement. In general, a combination of [[Lymphocyte|lymphocytic]] infiltration, [[B cell|B lymphocyte]] hyperreactivity, production of certain [[Autoantibody|autoantibodies]], [[Gene|genes]] mostly involved in the production of [[MHC]] molecules and certain [[Virus|viral infections]] which are all linked to the [[pathogenesis]] of [[Sjögren's syndrome]].        


==Pathophysiology==
== Pathophysiology ==
The [[pathogenesis]] of [[Sjögren's syndrome]] can be linked to both genetic and nongenetic components <ref name="pmid23846338">{{cite journal| author=Mavragani CP, Nezos A, Moutsopoulos HM| title=New advances in the classification, pathogenesis and treatment of Sjogren's syndrome. | journal=Curr Opin Rheumatol | year= 2013 | volume= 25 | issue= 5 | pages= 623-9 | pmid=23846338 | doi=10.1097/BOR.0b013e328363eaa5 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23846338  }} </ref>.  
The [[pathogenesis]] of [[Sjögren's syndrome]] can be linked to both genetic and nongenetic components. These factors are associated with disease susceptibility, development and progression:<ref name="pmid23846338">{{cite journal| author=Mavragani CP, Nezos A, Moutsopoulos HM| title=New advances in the classification, pathogenesis and treatment of Sjogren's syndrome. | journal=Curr Opin Rheumatol | year= 2013 | volume= 25 | issue= 5 | pages= 623-9 | pmid=23846338 | doi=10.1097/BOR.0b013e328363eaa5 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23846338  }} </ref>
* '''Genetic components:'''
 
Although multiple genes are found to be associated with ُ[[Sjögren's syndrome]], evidence suggests genes that encode [[Major histocompatibility complex|Major Histocompatibility Complex]] (MHC), particularly [[Human leukocyte antigen|HLA]] genes, play an important role in the disease.  
==== Genetic factors: ====
* '''Immune-mediated components:'''    
Multiple genes are involved in the pathogenesis of [[Sjögren's syndrome]]. [[Genome-wide association study|Genome-wide association]] and molecular studies of [[salivary gland]] [[Biopsy|biopsies]] from patients with [[Sjögren's syndrome]] have revealed [[HLA-DR]] molecules, homing [[Receptor (biochemistry)|receptors]], and genes encoding components of both [[Innate immune system|innate]] and [[Adaptive immune system|adaptive immune systems]] (particularly [[MHC]]<nowiki/>s, [[Interferon|interferons]] and [[Interleukin|interleukins]]) all play important roles in the disease, although ethnicity seems to affect them.<ref name="pmid24097067">{{cite journal| author=Lessard CJ, Li H, Adrianto I, Ice JA, Rasmussen A, Grundahl KM et al.| title=Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren's syndrome. | journal=Nat Genet | year= 2013 | volume= 45 | issue= 11 | pages= 1284-92 | pmid=24097067 | doi=10.1038/ng.2792 | pmc=3867192 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24097067  }}</ref><ref name="pmid24097066">{{cite journal| author=Li Y, Zhang K, Chen H, Sun F, Xu J, Wu Z et al.| title=A genome-wide association study in Han Chinese identifies a susceptibility locus for primary Sjögren's syndrome at 7q11.23. | journal=Nat Genet | year= 2013 | volume= 45 | issue= 11 | pages= 1361-5 | pmid=24097066 | doi=10.1038/ng.2779 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24097066  }}</ref><ref name="pmid8468491">{{cite journal| author=Kang HI, Fei HM, Saito I, Sawada S, Chen SL, Yi D et al.| title=Comparison of HLA class II genes in Caucasoid, Chinese, and Japanese patients with primary Sjögren's syndrome. | journal=J Immunol | year= 1993 | volume= 150 | issue= 8 Pt 1 | pages= 3615-23 | pmid=8468491 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8468491  }}</ref> 
 
==== Epigenetic factors: ====
As previously demonstrated for other systemic rheumatic diseases, factors affecting the regulation of [[gene expression]] such as [[genetic recombination]], [[Non-coding RNA|non-coding RNA molecules]] and [[histone methylation]], may also all contribute to the pathogenesis of [[Sjögren's syndrome]].<ref name="pmid24026248">{{cite journal| author=Gay S, Wilson AG| title=The emerging role of epigenetics in rheumatic diseases. | journal=Rheumatology (Oxford) | year= 2014 | volume= 53 | issue= 3 | pages= 406-14 | pmid=24026248 | doi=10.1093/rheumatology/ket292 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24026248  }}</ref> Moreover, evidence suggests that while the [[Sjögren's syndrome]] is more common in [[identical twins]], the [[Concordance (genetics)|concordance rate]] is only about 20 percent, further highlighting the role of [[epigenetics]].<ref name="pmid1732401">{{cite journal| author=Järvinen P, Kaprio J, Mäkitalo R, Koskenvuo M, Aho K| title=Systemic lupus erythematosus and related systemic diseases in a nationwide twin cohort: an increased prevalence of disease in MZ twins and concordance of disease features. | journal=J Intern Med | year= 1992 | volume= 231 | issue= 1 | pages= 67-72 | pmid=1732401 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1732401  }}</ref>
 
==== Viral infections: ====
Several studies have indicated an association between Sjögren's syndrome and some [[Virus|viral infections]]. Following transmission, some [[Virus|viruses]] invade and damage the secretory gland cells. This could later cause a cascade of events leading to [[Autoimmunity|autoimmune]] response and [[Immune-mediated disease|immune-mediated]] tissue injury. Though the evidence is not definitive yet, both [[Epstein Barr virus|EBV]] and [[Coxsackie virus]] are thought to be having a role in causing primary [[Sjögren's syndrome]].<ref name="pmid16014556">{{cite journal| author=Triantafyllopoulou A, Moutsopoulos HM| title=Autoimmunity and coxsackievirus infection in primary Sjogren's syndrome. | journal=Ann N Y Acad Sci | year= 2005 | volume= 1050 | issue=  | pages= 389-96 | pmid=16014556 | doi=10.1196/annals.1313.090 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16014556  }}</ref> There are also certain types of viruses including [[Human Immunodeficiency Virus (HIV)|HIV]], [[Human T-lymphotropic virus|HTLV-1]] and [[hepatitis C virus]] that can cause SS-like syndromes.<ref name="pmid7993708">{{cite journal| author=Fox RI| title=Epidemiology, pathogenesis, animal models, and treatment of Sjögren's syndrome. | journal=Curr Opin Rheumatol | year= 1994 | volume= 6 | issue= 5 | pages= 501-8 | pmid=7993708 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7993708  }}</ref>
 
==Pathogenesis==
The exact pathogenesis of [[Sjögren's syndrome]] is not fully understood. However, it has been suggested that a combination of [[Genetics|genetic]] predisposing factors, tissue damage (e.g. by [[Virus|viral]] insult), infiltration of [[Lymphocyte|lymphocytes]] to the excreting [[Gland|glands]], and production of certain [[Cytokine|cytokines]] and [[Autoantibody|autoantibodies]] contribute to the development and progression of the disease. The Immune-mediated components of the pathogenesis include: 
 
'''1. [[Lymphocyte|Lymphocytic]] infiltration and [[Cytokine|cytokines]]:'''
 
The basic mechanism underlying the symptoms of [[Sjögren's syndrome]] involves infiltration of [[Lymphocyte|lymphocytes]] into the [[Exocrine gland|exocrine glands]]. [[Lymphocyte|Lymphocytes]] within the [[Gland|glandular tissues]] or other sites trigger a set of [[Immune system|immune response]] reactions resulting in the release of [[Cytokine|cytokines]] such as [[Interferon-gamma]], [[Interleukin 17|IL-17]], [[B-cell activating factor]], and the production of characteristic [[Autoantibody|autoantibodies]]. Together with the activation of [[Metalloproteinase|metalloproteinases]], these events lead to [[Gland|glandular]] cell [[apoptosis]], dysfunction of residual [[Gland|glandular]] cells, disorganization of the secreting [[gland]] and [[Tissue (biology)|tissue]] injury. While the infiltrating [[B cell|B]] and [[T cell|T cells]] both remain somehow resistant to [[apoptosis]] themselves, it is mainly the [[T cell]] component that induces [[apoptosis]] signals to the glandular [[Epithelium|epithelial cells]]. [[T helper 17 cell|TH17]] cells and the [[Interleukin 17|IL-17]] they produce can also boost local [[inflammation]] in [[Sjögren's syndrome]] along with a change in [[cytokine]] balance between [[T helper cell|T helper 1]] and 2 cells in favor of [[T helper cell|T helper 1]].<ref name="pmid12067313">{{cite journal| author=Mitsias DI, Tzioufas AG, Veiopoulou C, Zintzaras E, Tassios IK, Kogopoulou O et al.| title=The Th1/Th2 cytokine balance changes with the progress of the immunopathological lesion of Sjogren's syndrome. | journal=Clin Exp Immunol | year= 2002 | volume= 128 | issue= 3 | pages= 562-8 | pmid=12067313 | doi= | pmc=1906267 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12067313  }}</ref>
 
'''2. [[Autoantibody|Autoantibodies]]:'''
 
Anti-Ro/SSA and Anti-La/SSB (both from [[Immunoglobulin G|IgG]] subclass) are the most common [[Autoantibody|autoantibodies]] found in [[Serum|sera]] of patients with [[Sjögren's syndrome]]. These [[antibodies]] may also be produced locally in [[Salivary gland|salivary glands]].<ref name="pmid9870881">{{cite journal| author=Tengnér P, Halse AK, Haga HJ, Jonsson R, Wahren-Herlenius M| title=Detection of anti-Ro/SSA and anti-La/SSB autoantibody-producing cells in salivary glands from patients with Sjögren's syndrome. | journal=Arthritis Rheum | year= 1998 | volume= 41 | issue= 12 | pages= 2238-48 | pmid=9870881 | doi=10.1002/1529-0131(199812)41:12<2238::AID-ART20>3.0.CO;2-V | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9870881  }}</ref> Other antibodies such as [[Antinuclear antibodies|ANA]], [[Rheumatoid factor|RF]] and those agains [[Acetylcholine receptor|acetylcholine receptors]] are also present in a variety of patients. 
* '''Anti-Ro/SSA'''
Anti-Ro/SSA is found in more than 70-90 percent<ref name="pmid11905842">{{cite journal| author=Gordon TP, Bolstad AI, Rischmueller M, Jonsson R, Waterman SA| title=Autoantibodies in primary Sjögren's syndrome: new insights into mechanisms of autoantibody diversification and disease pathogenesis. | journal=Autoimmunity | year= 2001 | volume= 34 | issue= 2 | pages= 123-32 | pmid=11905842 | doi=10.3109/08916930109001960 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11905842  }}</ref> of patients and is produced against an [[Autoimmunity|autoantigen]] consisting of a complex of two [[polypeptide]] (52 and 60 kDa) chains along with [[Cytoplasm|cytoplasmic]] [[RNA]]<nowiki/>s. Anti-52 kD [[antibodies]] are more strongly associated with the primary form of [[Sjögren's syndrome]], while anti-60 kD [[antibodies]] are common in [[Sjögren's syndrome]] associated with [[Systemic lupus erythematosus|SLE]].<ref name="pmid7945502">{{cite journal| author=St Clair EW, Burch JA, Saitta M| title=Specificity of autoantibodies for recombinant 60-kd and 52-kd Ro autoantigens. | journal=Arthritis Rheum | year= 1994 | volume= 37 | issue= 9 | pages= 1373-9 | pmid=7945502 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7945502  }}</ref>
* '''Anti-La/SSB'''
Fifty percent of [[Sjögren's syndrome]] patients have Anti-La/SSB [[Autoantibody|autoantibodies]]. The gene encoding SSB has two [[promoter]] sequence sites, allowing it to encode two different size [[Messenger RNA|mRNAs]]- a feature that increases the likelihood of [[gene]] switching under disease conditions.<ref name="pmid7964483">{{cite journal| author=Tröster H, Metzger TE, Semsei I, Schwemmle M, Winterpacht A, Zabel B et al.| title=One gene, two transcripts: isolation of an alternative transcript encoding for the autoantigen La/SS-B from a cDNA library of a patient with primary Sjögrens' syndrome. | journal=J Exp Med | year= 1994 | volume= 180 | issue= 6 | pages= 2059-67 | pmid=7964483 | doi= | pmc=2191769 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7964483  }}</ref>
 
== Genetic factors ==
It has been well-documented that [[genetics]] play an important role in [[Sjögren's syndrome]]. A familial and ethnic tendency to develop the disease in addition to an increased risk of [[Autoimmunity|autoimmune]] disorders in relatives of patients with [[Sjögren's syndrome]] support this concept. [[Gene|Genes]] in both [[Human leukocyte antigen|HLA]] and non-HLA regions of the [[genome]] have been proposed in the pathogenesis of [[Sjögren's syndrome]]:
 
==== HLA genes: ====
[[MHC]] genes, including those in the [[HLA-DR]] region are strongly associated with [[Sjögren's syndrome]]. However, there is significant [[Heterogeneous|heterogeneity]] of associations between different ethnic groups. For instance, there are reported associations for [[HLA-DR5]] in Greek patients<ref name="pmid3151145">{{cite journal| author=Papasteriades CA, Skopouli FN, Drosos AA, Andonopoulos AP, Moutsopoulos HM| title=HLA-alloantigen associations in Greek patients with Sjögren's syndrome. | journal=J Autoimmun | year= 1988 | volume= 1 | issue= 1 | pages= 85-90 | pmid=3151145 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3151145  }}</ref>, [[HLA-DRB1]]*15 in Spanish patients<ref name="pmid84684912">{{cite journal| author=Kang HI, Fei HM, Saito I, Sawada S, Chen SL, Yi D et al.| title=Comparison of HLA class II genes in Caucasoid, Chinese, and Japanese patients with primary Sjögren's syndrome. | journal=J Immunol | year= 1993 | volume= 150 | issue= 8 Pt 1 | pages= 3615-23 | pmid=8468491 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8468491  }}</ref> and a variety of other [[Human leukocyte antigen|HLA]] alleles among Han Chinese<ref name="pmid240970662">{{cite journal| author=Li Y, Zhang K, Chen H, Sun F, Xu J, Wu Z et al.| title=A genome-wide association study in Han Chinese identifies a susceptibility locus for primary Sjögren's syndrome at 7q11.23. | journal=Nat Genet | year= 2013 | volume= 45 | issue= 11 | pages= 1361-5 | pmid=24097066 | doi=10.1038/ng.2779 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24097066  }}</ref> and Japanese<ref name="pmid20300120">{{cite journal| author=Takahashi M, Kimura A| title=HLA and CTLA4 polymorphisms may confer a synergistic risk in the susceptibility to Graves' disease. | journal=J Hum Genet | year= 2010 | volume= 55 | issue= 5 | pages= 323-6 | pmid=20300120 | doi=10.1038/jhg.2010.20 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20300120  }}</ref> patients. Moreover, Caucasian patients with primary [[Sjögren's syndrome]] are reported to have higher amounts of [[HLA-DQB1]]*0201 and [[HLA-DQA1]]*0501. [[HLA-DR]] alleles are not the only [[Human leukocyte antigen|HLA]] alleles linked with [[Sjögren's syndrome]]. Evidence suggests that the presence of greater numbers of [[HLA-DQA1]] and [[HLA-DQB1]] alleles in a person markedly increases the risk of producing anti-Ro/SSA [[Autoantibody|autoantibodies]] with a [[gene]] dose effect.<ref name="pmid2033256">{{cite journal| author=Reveille JD, Macleod MJ, Whittington K, Arnett FC| title=Specific amino acid residues in the second hypervariable region of HLA-DQA1 and DQB1 chain genes promote the Ro (SS-A)/La (SS-B) autoantibody responses. | journal=J Immunol | year= 1991 | volume= 146 | issue= 11 | pages= 3871-6 | pmid=2033256 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2033256  }}</ref>   
 
==== Non-HLA genes: ====
Among non-HLA genes, [[TNIP1]], [[IRF5]], [[BLK (gene)|BLK]], [[STAT4]], [[IL12A]], and [[CXCR5]] are all reported to have a significant genome-wide association.<ref name="pmid23857130">{{cite journal| author=Nocturne G, Mariette X| title=Advances in understanding the pathogenesis of primary Sjögren's syndrome. | journal=Nat Rev Rheumatol | year= 2013 | volume= 9 | issue= 9 | pages= 544-56 | pmid=23857130 | doi=10.1038/nrrheum.2013.110 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23857130  }}</ref> [[TNIP1]] and [[IRF5]] are involved in [[innate immune system]] and the others play a role in [[Adaptive immune system|acquired immunity]]. [[TNIP1]] works alongside with [[TNFAIP3]] (A20) to suppress [[NF-kB]], which is associated with [[Inflammation|inflammatory]] response and the production of [[Lymphocyte|lymphocytes]] in [[Sjögren's syndrome]].<ref name="pmid23944604">{{cite journal| author=Nordmark G, Wang C, Vasaitis L, Eriksson P, Theander E, Kvarnström M et al.| title=Association of genes in the NF-κB pathway with antibody-positive primary Sjögren's syndrome. | journal=Scand J Immunol | year= 2013 | volume= 78 | issue= 5 | pages= 447-54 | pmid=23944604 | doi=10.1111/sji.12101 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23944604  }}</ref>
 
Other non-HLA genes have also been identified, but haven't reached a significant association level in [[Genome-wide association study|genome-wide association studies]]; these include:<ref name="pmid22294627">{{cite journal| author=Bolstad AI, Le Hellard S, Kristjansdottir G, Vasaitis L, Kvarnström M, Sjöwall C et al.| title=Association between genetic variants in the tumour necrosis factor/lymphotoxin α/lymphotoxin β locus and primary Sjogren's syndrome in Scandinavian samples. | journal=Ann Rheum Dis | year= 2012 | volume= 71 | issue= 6 | pages= 981-8 | pmid=22294627 | doi=10.1136/annrheumdis-2011-200446 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22294627  }}</ref>
* '''<small>Those involved in innate immunity:</small>'''
** MBL2
** [[FCGR2B]]
** LTA
** [[Tumor necrosis factors|TNF]]
** [[NCR3]]
** NFKBIA
* '''<small>Those involved in acquired immunity:</small>'''
** [[TAP2]]
** [[EBF1]]
** [[PTPN22]]
** TNFRSF4
** [[Interleukin 10|IL10]]
 
== Associations ==
The most important conditions associated with [[Sjögren's syndrome]] include:
* '''[[Lymphoma|Lymphomas]]:'''
** [[MALT lymphoma|MALT lymphomas]]
** [[Diffuse large B cell lymphoma|Diffuse B cell lymphoma]]
** [[T-cell lymphoma|T cell lymphoma]]
Lymphomas, particularly low-grade [[Non-Hodgkin lymphoma|non-Hodgkin lymphomas]] with [[MALT lymphoma|MALT]] pathology, occur more frequently in patients with [[Sjögren's syndrome]]. [[T-cell lymphoma|T-cell lymphomas]] and higher-grade diffuse [[B-cell lymphoma|B-cell lymphomas]] are other possible complications of [[Sjögren's syndrome]], but are much less common.<ref name="pmid22198497">{{cite journal| author=Voulgarelis M, Ziakas PD, Papageorgiou A, Baimpa E, Tzioufas AG, Moutsopoulos HM| title=Prognosis and outcome of non-Hodgkin lymphoma in primary Sjögren syndrome. | journal=Medicine (Baltimore) | year= 2012 | volume= 91 | issue= 1 | pages= 1-9 | pmid=22198497 | doi=10.1097/MD.0b013e31824125e4 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22198497  }}</ref> The most frequent sites of involvement in [[MALT lymphoma|MALT lymphomas]] are mucosal locations where [[Sjögren's syndrome]] affects, such as [[Salivary gland|salivary glands]] or the [[gastrointestinal tract]] (MALT); or in the lung, where [[Bronchial/tracheal-associated lymphoid tissue (BALT)|bronchial-associated lymphoid tumor]] (BALT) lymphomas can occur.<ref name="pmid15177490">{{cite journal| author=Ahmed S, Kussick SJ, Siddiqui AK, Bhuiya TA, Khan A, Sarewitz S et al.| title=Bronchial-associated lymphoid tissue lymphoma: a clinical study of a rare disease. | journal=Eur J Cancer | year= 2004 | volume= 40 | issue= 9 | pages= 1320-6 | pmid=15177490 | doi=10.1016/j.ejca.2004.02.006 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15177490  }}</ref> Additionally, MALT and [[Marginal zone lymphoma|diffuse large cell lymphomas of marginal zone origin]]<ref name="pmid6331831">{{cite journal| author=Wilke WS, Tubbs RR, Bukowski RM, Currie TE, Calabrese LH, Weiss RA et al.| title=T cell lymphoma occurring in Sjögren's syndrome. | journal=Arthritis Rheum | year= 1984 | volume= 27 | issue= 8 | pages= 951-5 | pmid=6331831 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6331831  }}</ref> frequently affect [[cervical lymph nodes]] and the [[Submandibular gland|submandibular]] and [[Parotid gland|parotid]] glands. A comparison between [[Biopsy|biopsies]] from [[Sjögren's syndrome]] patients who later presented with a [[Non-Hodgkin lymphoma|NHL]] and those without [[Non-Hodgkin lymphoma|NHL]] has linked the presence of [[germinal center]]-like structures with an elevated risk for developing [[lymphoma]].<ref name="pmid21715359">{{cite journal| author=Theander E, Vasaitis L, Baecklund E, Nordmark G, Warfvinge G, Liedholm R et al.| title=Lymphoid organisation in labial salivary gland biopsies is a possible predictor for the development of malignant lymphoma in primary Sjögren's syndrome. | journal=Ann Rheum Dis | year= 2011 | volume= 70 | issue= 8 | pages= 1363-8 | pmid=21715359 | doi=10.1136/ard.2010.144782 | pmc=3128323 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21715359  }}</ref> Moreover, [[Mutation|mutations]] and [[downregulation]] of A20 ([[TNFAIP3|TNFAIP3)]], a regulator of [[NF-kB]], is associated with increased [[germinal center]] formation and [[MALT lymphoma|MALT lymphomas]] in [[Sjögren's syndrome]].<ref name="pmid24159176">{{cite journal| author=Nocturne G, Boudaoud S, Miceli-Richard C, Viengchareun S, Lazure T, Nititham J et al.| title=Germline and somatic genetic variations of TNFAIP3 in lymphoma complicating primary Sjogren's syndrome. | journal=Blood | year= 2013 | volume= 122 | issue= 25 | pages= 4068-76 | pmid=24159176 | doi=10.1182/blood-2013-05-503383 | pmc=3862283 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24159176  }}</ref> [[Polymorphisms]] of [[CXCR5]], a [[gene]] involved in organizing these structures, are also linked with both [[Sjögren's syndrome|SS]] and [[Non-Hodgkin lymphoma|NHL]].<ref name="pmid22707196">{{cite journal| author=Song H, Tong D, Cha Z, Bai J| title=C-X-C chemokine receptor type 5 gene polymorphisms are associated with non-Hodgkin lymphoma. | journal=Mol Biol Rep | year= 2012 | volume= 39 | issue= 9 | pages= 8629-35 | pmid=22707196 | doi=10.1007/s11033-012-1717-6 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22707196  }}</ref>
* '''Other [[Rheumatology|rheumatologic]] disorders such as:'''
** [[SLE]]
** [[Rheumatoid arthritis]]
** [[Systemic sclerosis]]
** [[Primary biliary cirrhosis]]
 
== Gross pathology ==
* [[Sjögren's syndrome]] has no characteristic gross pathology. The findings are mainly non-specific, including enlargement of the [[Salivary gland|salivary glands]] because of the [[Lymphocyte|lymphocytic]] infiltration resulting in [[hyperplasia]] of salivary ductal [[epithelium]]. The infiltrates include focal aggregates (50 or more lymphocytes) starting around the ducts and progressing to involve the entire [[lobule]]. The process results in the destruction of some lobules. However, the overall architecture and the appearance of the gland remains intact.
 
== Microscopic pathology ==


==References==
==References==
{{reflist|2}}
{{reflist|2}}


[[Category:Medicine]]
[[Category:Immunology]]
[[Category:Rheumatology]]
[[Category:Rheumatology]]
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Farima Kahe M.D. [2], Farbod Zahedi Tajrishi, M.D.

Overview

Sjögren's syndrome (SS) is a chronic autoimmune disorder that can affect several organ systems. Sjögren's syndrome is classified into a "primary" form that is a separate entity from other well-defined autoimmune disorders and a "secondary" form that is associated with other well-defined autoimmune conditions, such as SLE, rheumatoid arthritis, progressive systemic sclerosis, and primary biliary cirrhosis. These forms of Sjögren's syndrome are different in their serologic and histopathologic findings as well as their genetic components. Both genetic and immune factors contribute to the pathogenesis of the disease. In the most common presentation of Sjögren's syndrome, lymphocytes infiltrate the lacrimal and salivary glands and impair their function, hence causing the main characteristic symptoms such as dry mouth (xerostomia) and dry eyes (keratoconjunctivitis sicca). CD4+ T-cells are predominant in mild and moderate salivary gland infiltrations, while B cells play the major role in severe lesions. Sjögren's syndrome may also manifest itself with dryness of skin and other mucosal surfaces or even cause systemic extraglandular disturbances such as arthritis, vasculitis, renal, pulmonary, hematopoietic, and neurologic involvement. In general, a combination of lymphocytic infiltration, B lymphocyte hyperreactivity, production of certain autoantibodies, genes mostly involved in the production of MHC molecules and certain viral infections which are all linked to the pathogenesis of Sjögren's syndrome.

Pathophysiology

The pathogenesis of Sjögren's syndrome can be linked to both genetic and nongenetic components. These factors are associated with disease susceptibility, development and progression:[1]

Genetic factors:

Multiple genes are involved in the pathogenesis of Sjögren's syndrome. Genome-wide association and molecular studies of salivary gland biopsies from patients with Sjögren's syndrome have revealed HLA-DR molecules, homing receptors, and genes encoding components of both innate and adaptive immune systems (particularly MHCs, interferons and interleukins) all play important roles in the disease, although ethnicity seems to affect them.[2][3][4]

Epigenetic factors:

As previously demonstrated for other systemic rheumatic diseases, factors affecting the regulation of gene expression such as genetic recombination, non-coding RNA molecules and histone methylation, may also all contribute to the pathogenesis of Sjögren's syndrome.[5] Moreover, evidence suggests that while the Sjögren's syndrome is more common in identical twins, the concordance rate is only about 20 percent, further highlighting the role of epigenetics.[6]

Viral infections:

Several studies have indicated an association between Sjögren's syndrome and some viral infections. Following transmission, some viruses invade and damage the secretory gland cells. This could later cause a cascade of events leading to autoimmune response and immune-mediated tissue injury. Though the evidence is not definitive yet, both EBV and Coxsackie virus are thought to be having a role in causing primary Sjögren's syndrome.[7] There are also certain types of viruses including HIV, HTLV-1 and hepatitis C virus that can cause SS-like syndromes.[8]

Pathogenesis

The exact pathogenesis of Sjögren's syndrome is not fully understood. However, it has been suggested that a combination of genetic predisposing factors, tissue damage (e.g. by viral insult), infiltration of lymphocytes to the excreting glands, and production of certain cytokines and autoantibodies contribute to the development and progression of the disease. The Immune-mediated components of the pathogenesis include:

1. Lymphocytic infiltration and cytokines:

The basic mechanism underlying the symptoms of Sjögren's syndrome involves infiltration of lymphocytes into the exocrine glands. Lymphocytes within the glandular tissues or other sites trigger a set of immune response reactions resulting in the release of cytokines such as Interferon-gamma, IL-17, B-cell activating factor, and the production of characteristic autoantibodies. Together with the activation of metalloproteinases, these events lead to glandular cell apoptosis, dysfunction of residual glandular cells, disorganization of the secreting gland and tissue injury. While the infiltrating B and T cells both remain somehow resistant to apoptosis themselves, it is mainly the T cell component that induces apoptosis signals to the glandular epithelial cells. TH17 cells and the IL-17 they produce can also boost local inflammation in Sjögren's syndrome along with a change in cytokine balance between T helper 1 and 2 cells in favor of T helper 1.[9]

2. Autoantibodies:

Anti-Ro/SSA and Anti-La/SSB (both from IgG subclass) are the most common autoantibodies found in sera of patients with Sjögren's syndrome. These antibodies may also be produced locally in salivary glands.[10] Other antibodies such as ANA, RF and those agains acetylcholine receptors are also present in a variety of patients.

  • Anti-Ro/SSA

Anti-Ro/SSA is found in more than 70-90 percent[11] of patients and is produced against an autoantigen consisting of a complex of two polypeptide (52 and 60 kDa) chains along with cytoplasmic RNAs. Anti-52 kD antibodies are more strongly associated with the primary form of Sjögren's syndrome, while anti-60 kD antibodies are common in Sjögren's syndrome associated with SLE.[12]

  • Anti-La/SSB

Fifty percent of Sjögren's syndrome patients have Anti-La/SSB autoantibodies. The gene encoding SSB has two promoter sequence sites, allowing it to encode two different size mRNAs- a feature that increases the likelihood of gene switching under disease conditions.[13]

Genetic factors

It has been well-documented that genetics play an important role in Sjögren's syndrome. A familial and ethnic tendency to develop the disease in addition to an increased risk of autoimmune disorders in relatives of patients with Sjögren's syndrome support this concept. Genes in both HLA and non-HLA regions of the genome have been proposed in the pathogenesis of Sjögren's syndrome:

HLA genes:

MHC genes, including those in the HLA-DR region are strongly associated with Sjögren's syndrome. However, there is significant heterogeneity of associations between different ethnic groups. For instance, there are reported associations for HLA-DR5 in Greek patients[14], HLA-DRB1*15 in Spanish patients[15] and a variety of other HLA alleles among Han Chinese[16] and Japanese[17] patients. Moreover, Caucasian patients with primary Sjögren's syndrome are reported to have higher amounts of HLA-DQB1*0201 and HLA-DQA1*0501. HLA-DR alleles are not the only HLA alleles linked with Sjögren's syndrome. Evidence suggests that the presence of greater numbers of HLA-DQA1 and HLA-DQB1 alleles in a person markedly increases the risk of producing anti-Ro/SSA autoantibodies with a gene dose effect.[18]

Non-HLA genes:

Among non-HLA genes, TNIP1, IRF5, BLK, STAT4, IL12A, and CXCR5 are all reported to have a significant genome-wide association.[19] TNIP1 and IRF5 are involved in innate immune system and the others play a role in acquired immunity. TNIP1 works alongside with TNFAIP3 (A20) to suppress NF-kB, which is associated with inflammatory response and the production of lymphocytes in Sjögren's syndrome.[20]

Other non-HLA genes have also been identified, but haven't reached a significant association level in genome-wide association studies; these include:[21]

Associations

The most important conditions associated with Sjögren's syndrome include:

Lymphomas, particularly low-grade non-Hodgkin lymphomas with MALT pathology, occur more frequently in patients with Sjögren's syndrome. T-cell lymphomas and higher-grade diffuse B-cell lymphomas are other possible complications of Sjögren's syndrome, but are much less common.[22] The most frequent sites of involvement in MALT lymphomas are mucosal locations where Sjögren's syndrome affects, such as salivary glands or the gastrointestinal tract (MALT); or in the lung, where bronchial-associated lymphoid tumor (BALT) lymphomas can occur.[23] Additionally, MALT and diffuse large cell lymphomas of marginal zone origin[24] frequently affect cervical lymph nodes and the submandibular and parotid glands. A comparison between biopsies from Sjögren's syndrome patients who later presented with a NHL and those without NHL has linked the presence of germinal center-like structures with an elevated risk for developing lymphoma.[25] Moreover, mutations and downregulation of A20 (TNFAIP3), a regulator of NF-kB, is associated with increased germinal center formation and MALT lymphomas in Sjögren's syndrome.[26] Polymorphisms of CXCR5, a gene involved in organizing these structures, are also linked with both SS and NHL.[27]

Gross pathology

  • Sjögren's syndrome has no characteristic gross pathology. The findings are mainly non-specific, including enlargement of the salivary glands because of the lymphocytic infiltration resulting in hyperplasia of salivary ductal epithelium. The infiltrates include focal aggregates (50 or more lymphocytes) starting around the ducts and progressing to involve the entire lobule. The process results in the destruction of some lobules. However, the overall architecture and the appearance of the gland remains intact.

Microscopic pathology

References

  1. ↑ Mavragani CP, Nezos A, Moutsopoulos HM (2013). "New advances in the classification, pathogenesis and treatment of Sjogren's syndrome". Curr Opin Rheumatol. 25 (5): 623–9. doi:10.1097/BOR.0b013e328363eaa5. PMID 23846338.
  2. ↑ Lessard CJ, Li H, Adrianto I, Ice JA, Rasmussen A, Grundahl KM; et al. (2013). "Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren's syndrome". Nat Genet. 45 (11): 1284–92. doi:10.1038/ng.2792. PMC 3867192. PMID 24097067.
  3. ↑ Li Y, Zhang K, Chen H, Sun F, Xu J, Wu Z; et al. (2013). "A genome-wide association study in Han Chinese identifies a susceptibility locus for primary Sjögren's syndrome at 7q11.23". Nat Genet. 45 (11): 1361–5. doi:10.1038/ng.2779. PMID 24097066.
  4. ↑ Kang HI, Fei HM, Saito I, Sawada S, Chen SL, Yi D; et al. (1993). "Comparison of HLA class II genes in Caucasoid, Chinese, and Japanese patients with primary Sjögren's syndrome". J Immunol. 150 (8 Pt 1): 3615–23. PMID 8468491.
  5. ↑ Gay S, Wilson AG (2014). "The emerging role of epigenetics in rheumatic diseases". Rheumatology (Oxford). 53 (3): 406–14. doi:10.1093/rheumatology/ket292. PMID 24026248.
  6. ↑ Järvinen P, Kaprio J, Mäkitalo R, Koskenvuo M, Aho K (1992). "Systemic lupus erythematosus and related systemic diseases in a nationwide twin cohort: an increased prevalence of disease in MZ twins and concordance of disease features". J Intern Med. 231 (1): 67–72. PMID 1732401.
  7. ↑ Triantafyllopoulou A, Moutsopoulos HM (2005). "Autoimmunity and coxsackievirus infection in primary Sjogren's syndrome". Ann N Y Acad Sci. 1050: 389–96. doi:10.1196/annals.1313.090. PMID 16014556.
  8. ↑ Fox RI (1994). "Epidemiology, pathogenesis, animal models, and treatment of Sjögren's syndrome". Curr Opin Rheumatol. 6 (5): 501–8. PMID 7993708.
  9. ↑ Mitsias DI, Tzioufas AG, Veiopoulou C, Zintzaras E, Tassios IK, Kogopoulou O; et al. (2002). "The Th1/Th2 cytokine balance changes with the progress of the immunopathological lesion of Sjogren's syndrome". Clin Exp Immunol. 128 (3): 562–8. PMC 1906267. PMID 12067313.
  10. ↑ Tengnér P, Halse AK, Haga HJ, Jonsson R, Wahren-Herlenius M (1998). "Detection of anti-Ro/SSA and anti-La/SSB autoantibody-producing cells in salivary glands from patients with Sjögren's syndrome". Arthritis Rheum. 41 (12): 2238–48. doi:10.1002/1529-0131(199812)41:12<2238::AID-ART20>3.0.CO;2-V. PMID 9870881.
  11. ↑ Gordon TP, Bolstad AI, Rischmueller M, Jonsson R, Waterman SA (2001). "Autoantibodies in primary Sjögren's syndrome: new insights into mechanisms of autoantibody diversification and disease pathogenesis". Autoimmunity. 34 (2): 123–32. doi:10.3109/08916930109001960. PMID 11905842.
  12. ↑ St Clair EW, Burch JA, Saitta M (1994). "Specificity of autoantibodies for recombinant 60-kd and 52-kd Ro autoantigens". Arthritis Rheum. 37 (9): 1373–9. PMID 7945502.
  13. ↑ Tröster H, Metzger TE, Semsei I, Schwemmle M, Winterpacht A, Zabel B; et al. (1994). "One gene, two transcripts: isolation of an alternative transcript encoding for the autoantigen La/SS-B from a cDNA library of a patient with primary Sjögrens' syndrome". J Exp Med. 180 (6): 2059–67. PMC 2191769. PMID 7964483.
  14. ↑ Papasteriades CA, Skopouli FN, Drosos AA, Andonopoulos AP, Moutsopoulos HM (1988). "HLA-alloantigen associations in Greek patients with Sjögren's syndrome". J Autoimmun. 1 (1): 85–90. PMID 3151145.
  15. ↑ Kang HI, Fei HM, Saito I, Sawada S, Chen SL, Yi D; et al. (1993). "Comparison of HLA class II genes in Caucasoid, Chinese, and Japanese patients with primary Sjögren's syndrome". J Immunol. 150 (8 Pt 1): 3615–23. PMID 8468491.
  16. ↑ Li Y, Zhang K, Chen H, Sun F, Xu J, Wu Z; et al. (2013). "A genome-wide association study in Han Chinese identifies a susceptibility locus for primary Sjögren's syndrome at 7q11.23". Nat Genet. 45 (11): 1361–5. doi:10.1038/ng.2779. PMID 24097066.
  17. ↑ Takahashi M, Kimura A (2010). "HLA and CTLA4 polymorphisms may confer a synergistic risk in the susceptibility to Graves' disease". J Hum Genet. 55 (5): 323–6. doi:10.1038/jhg.2010.20. PMID 20300120.
  18. ↑ Reveille JD, Macleod MJ, Whittington K, Arnett FC (1991). "Specific amino acid residues in the second hypervariable region of HLA-DQA1 and DQB1 chain genes promote the Ro (SS-A)/La (SS-B) autoantibody responses". J Immunol. 146 (11): 3871–6. PMID 2033256.
  19. ↑ Nocturne G, Mariette X (2013). "Advances in understanding the pathogenesis of primary Sjögren's syndrome". Nat Rev Rheumatol. 9 (9): 544–56. doi:10.1038/nrrheum.2013.110. PMID 23857130.
  20. ↑ Nordmark G, Wang C, Vasaitis L, Eriksson P, Theander E, Kvarnström M; et al. (2013). "Association of genes in the NF-κB pathway with antibody-positive primary Sjögren's syndrome". Scand J Immunol. 78 (5): 447–54. doi:10.1111/sji.12101. PMID 23944604.
  21. ↑ Bolstad AI, Le Hellard S, Kristjansdottir G, Vasaitis L, Kvarnström M, Sjöwall C; et al. (2012). "Association between genetic variants in the tumour necrosis factor/lymphotoxin α/lymphotoxin β locus and primary Sjogren's syndrome in Scandinavian samples". Ann Rheum Dis. 71 (6): 981–8. doi:10.1136/annrheumdis-2011-200446. PMID 22294627.
  22. ↑ Voulgarelis M, Ziakas PD, Papageorgiou A, Baimpa E, Tzioufas AG, Moutsopoulos HM (2012). "Prognosis and outcome of non-Hodgkin lymphoma in primary Sjögren syndrome". Medicine (Baltimore). 91 (1): 1–9. doi:10.1097/MD.0b013e31824125e4. PMID 22198497.
  23. ↑ Ahmed S, Kussick SJ, Siddiqui AK, Bhuiya TA, Khan A, Sarewitz S; et al. (2004). "Bronchial-associated lymphoid tissue lymphoma: a clinical study of a rare disease". Eur J Cancer. 40 (9): 1320–6. doi:10.1016/j.ejca.2004.02.006. PMID 15177490.
  24. ↑ Wilke WS, Tubbs RR, Bukowski RM, Currie TE, Calabrese LH, Weiss RA; et al. (1984). "T cell lymphoma occurring in Sjögren's syndrome". Arthritis Rheum. 27 (8): 951–5. PMID 6331831.
  25. ↑ Theander E, Vasaitis L, Baecklund E, Nordmark G, Warfvinge G, Liedholm R; et al. (2011). "Lymphoid organisation in labial salivary gland biopsies is a possible predictor for the development of malignant lymphoma in primary Sjögren's syndrome". Ann Rheum Dis. 70 (8): 1363–8. doi:10.1136/ard.2010.144782. PMC 3128323. PMID 21715359.
  26. ↑ Nocturne G, Boudaoud S, Miceli-Richard C, Viengchareun S, Lazure T, Nititham J; et al. (2013). "Germline and somatic genetic variations of TNFAIP3 in lymphoma complicating primary Sjogren's syndrome". Blood. 122 (25): 4068–76. doi:10.1182/blood-2013-05-503383. PMC 3862283. PMID 24159176.
  27. ↑ Song H, Tong D, Cha Z, Bai J (2012). "C-X-C chemokine receptor type 5 gene polymorphisms are associated with non-Hodgkin lymphoma". Mol Biol Rep. 39 (9): 8629–35. doi:10.1007/s11033-012-1717-6. PMID 22707196.
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