Sjögren's syndrome pathophysiology

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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.


Sjögren's syndrome (SS) is a chronic autoimmune disorder that can affect several organ systemsSjögren'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 SLErheumatoid arthritisprogressive 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 syndromelymphocytes 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 arthritisvasculitisrenalpulmonaryhematopoietic, and neurologic involvement. In general, a combination of lymphocytic infiltration, B lymphocyte hyperreactivity, production of certain autoantibodiesgenes mostly involved in the production of MHC molecules and certain viral infections which are all linked to the pathogenesis of Sjögren's syndrome.


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]


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]


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 syndromeT-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


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  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.
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