Pathophysiological mechanisms and clinical manifestations in primary Sjögren’s syndrome and Systemic lupus erythematosus (SLE)

Abstract

Primary Sjögren’s syndrome (pSS) is a systemic inflammatory autoimmune condition. The etiology of pSS is mainly unknown, but it has been suggested that environmental factors trigger an immune response in genetically susceptible individuals. The disease is characterized by chronic inflammation which results in progressive destruction of exocrine glands, primarily the salivary and lacrimal glands, leading to symptoms of dryness, mainly in the mouth and eyes. Patients may also experience symptoms of exocrine dysfunction and dryness in other parts of the body. Autoantibodies against the antigens Ro/SSA (Ro52 and Ro60) and La/SSB, are a well-known sign of dysregulation of the immune system. Extraglandular manifestations (EGM) are present in a subset of patients with pSS.

In a population based prospective study we included all patients referred to the Department of Rheumatology for suspected pSS during a five-year period. The patients were evaluated using a structured procedure according to the 2002 Revised American-European Consensus Criteria for Sjögren’s syndrome. Of referred individuals, 199 of 781 patients were diagnosed with pSS. We found an annual incidence rate of pSS in the Karolinska University Hospital catchment area of 3.1 (95% CI 2.3-4.3) cases per 100,000 adult inhabitants. In this cohort, we noted lower figures for severe EGM such as lung and neurological involvement than previously reported for prevalent pSS. Also, the frequency of autoantibodies including ANA, anti-Ro/SSA and anti-La/SSB was lower compared to other cohorts. Subsets of these patients were recruited and included in genetic studies.

We contributed with 79 pSS patients in a candidate-gene association case control study in 540 patients with pSS and 532 controls, from Sweden and Norway. Three novel gene loci, not previously associated with pSS, were identified: the early B-cell factor 1 (EBF1) gene, the family with sequence similarity 167 member A–B-lymphoid tyrosine kinase (FAM167A–BLK) locus, and the tumor necrosis factor superfamily (TNFSF4=Ox40L) gene. Variations in the gene loci for interferon regulation factor 5 (IRF5) and signal transducer and activator of transcription 4 (STAT4) were confirmed. The three novel gene variants are involved in B-cell development and activation.

In an international multicenter case control genome-wide association study (GWAS)/ large-scale association study of pSS, we contributed with 99 patients. The results confirmed associations with variations in the gene loci of the human leukocyte antigen (HLA) region, IRF5, STAT4, FAM167A-BLK, chemokine C-X-C motif receptor 5 (DX6-CXCR), and TNFAIP3 interacting protein 1 (TNIP1) at a genome-wide significance level. In addition, 29 further suggested associations (p meta < 5 × 10−5) were observed. The major part of these genes is involved in both innate and adaptive immune responses.

We observed that the autoantigen Ro52 was expressed and upregulated in salivary glands of patients with primary Sjögren’s syndrome. This was noted in biopsies from 28 pSS patients and 19 non-pSS controls from Sweden and Norway. The degree of expression was correlated with the level of inflammation in the tissue.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multiple organ manifestations and immunological dysregulation including production of a large set of autoantibodies targeting different epitopes. We showed that antibodies to the RING domain of Ro52, which is the functionally active domain with E3 ligase activity, were significantly correlated with disease activity as measured by the SLAM score in a well-characterized cohort of SLE patients.

In conclusion, the results of these studies have highlighted the role of the immune system in the pathogenesis in pSS and SLE.