Sjögren's syndrome pathophysiology: Difference between revisions
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==== HLA genes: ==== | ==== HLA genes: ==== | ||
[[MHC]] genes, including those in the [[HLA-DR]] region are strongly associated with SS. However, there is significant heterogeneity of associations between different ethnic groups. For instance, there are reported associations between [[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 SS 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 SS. 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: ==== | ==== Non-HLA genes: ==== | ||
Among non-HLA genes, [[TNIP1]], [[IRF5]], [[BLK (gene)|BLK]], [[STAT4]], [[IL12A]], and [[CXCR5]] are all reported to have a significant 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>These genes mainly contribute to the production and activation pathways of several immune signal molecules such as , therefore facilitating the immune injury to the susceptible tissues. | Among non-HLA genes, [[TNIP1]], [[IRF5]], [[BLK (gene)|BLK]], [[STAT4]], [[IL12A]], and [[CXCR5]] are all reported to have a significant 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> These genes mainly contribute to the production and activation pathways of several immune signal molecules such as , therefore facilitating the immune injury to the susceptible tissues. | ||
== Associations == | == Associations == | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Farbod Zahedi Tajrishi, M.D.
Overview
Sjögren's syndrome (SS) is a chronic auto-immune disorder that can affect several organ systems. It 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 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 the disease, lymphocytes infiltrate the lacrimal and salivary glands and impair their function, hence causing the main characteristic symptoms- dry mouth (keratoconjunctivitis sicca) and eyes (xerostomia). CD4+ T-cells are predominant in mild and moderate salivary gland infiltrations, while B cells play the major role in severe lesions.[1] The disease may also manifest itself with dryness of skin and other mucosal surfaces or even cause systemic extraglandular disturbances such as arthritis, vasculitis and 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 are all linked to the pathogenesis of SS.
Risk factors pathology
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[2]:
Genetic factors:
Multiple genes are involved in the pathogenesis of Sjögren's syndrome. Genome-wide association and molecular studies of salivary gland biopsies from SS patients 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.[3][4][5]
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 SS.[6] Moreover, evidence suggests that while SS is more common in identical twins, the concordance rate is only about 20 percent, further highlighting the role of epigenetics.[7]
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 SS.[8] There are also certain types of viruses including HIV, HTLV-1 and Hepatitis C virus that can cause SS-like syndromes.[9]
Pathogenesis
Immune-mediated components:
- 1. Lymphocytic infiltration:
The basic mechanism underlying the symptoms of SS involves infiltration of lymphocytes into the exocrine glands. While the infiltrating B and T cells remain somehow resistant to apoptosis themselves, T cells induce apoptosis signals to the glandular epithelial cells, causing them to die and the gland to malfunction. The infiltrated T cells also produce several cytokines, all of which playing a part in tissue inflammation. TH17 cells and the IL-17 they produce, can boost local inflammation in SS along with a change in cytokine balance between T helper 1 and 2 cells (Th1 and Th2) in favor of Th1.[10]
- 2. Autoantibodies:
Anti-Ro/SSA and Anti-La/SSB are the most common autoantibodies (both from IgG subclass) found in patients with SS. 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 SS, while anti-60 kD antibodies are common in SS associated with Systemic Lupus Erythematosus (SLE).[12]
Genetic factors
It has been well-documented that genetics play an important role in SS. A familial and ethnic tendency to develop the disease in addition to an increased risk of autoimmune disorders in relatives of patients with SS support this concept. Genes in both HLA and non-HLA regions of the genome have been proposed in the pathogenesis of SS:
HLA genes:
MHC genes, including those in the HLA-DR region are strongly associated with SS. However, there is significant heterogeneity of associations between different ethnic groups. For instance, there are reported associations between HLA-DR5 in Greek patients[13], HLA-DRB1*15 in Spanish patients[14] and a variety of other HLA alleles among Han Chinese[15] and Japanese[16] patients. Moreover, Caucasian patients with primary SS 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 SS. 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.[17]
Non-HLA genes:
Among non-HLA genes, TNIP1, IRF5, BLK, STAT4, IL12A, and CXCR5 are all reported to have a significant association.[18] These genes mainly contribute to the production and activation pathways of several immune signal molecules such as , therefore facilitating the immune injury to the susceptible tissues.
Associations
Gross pathology
Microscopic pathology
References
- ↑ Christodoulou MI, Kapsogeorgou EK, Moutsopoulos HM (2010). "Characteristics of the minor salivary gland infiltrates in Sjögren's syndrome". J Autoimmun. 34 (4): 400–7. doi:10.1016/j.jaut.2009.10.004. PMID 19889514.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Fox RI (1994). "Epidemiology, pathogenesis, animal models, and treatment of Sjögren's syndrome". Curr Opin Rheumatol. 6 (5): 501–8. PMID 7993708.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.