Sjögren's syndrome pathophysiology
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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
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 SS 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 SS along with a change in cytokine balance between T helper 1 and 2 cells in favor of T helper 1.[10]
2. Autoantibodies:
Anti-Ro/SSA and Anti-La/SSB (both from IgG subclass) are the most common autoantibodies found in sera of patients with SS. These antibodies may also be produced locally in salivary glands.[11] Other antibodies such as
- Anti-Ro/SSA
Anti-Ro/SSA is found in more than 70-90 percent[12] 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 SLE.[13]
- Anti-La/SSB
Anti-La/SSB antibodies are found in 50 percent of patients with SS. These antibodies recognize a 47 kD phosphoprotein associated with newly synthesized RNA polymerase III transcripts. The gene encoding SSB is unusual in that it has two promoter sites, encoding for two different size mRNAs, and raising the possibility of gene switching under disease conditions [67].
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 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 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.[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 SS.[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]
- those involved in innate immunity:
- those involved in acquired immunity:
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 SS. T-cell lymphomas and higher-grade diffuse B-cell lymphomas are other possible complications of SS, but are much less common.[22] The most frequent sites of involvement in MALT lymphomas are mucosal locations where SS 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 SS 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 SS.[26] Polymorphisms of CXCR5, a gene involved in organizing these structures, are also linked with both SS and NHL.[27]
- Other rheumatologic disorders:
In its secondary form, SS is associated with other rheumatologic conditions. SLE, rheumatoid arthritis, systemic sclerosis and primary biliary cirrhosis are examples of known rheumatologic diseases that could accompany secondary SS.
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
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.