Autoantibody synthesis in salivary glands of Sjögren's syndrome patients

doi:10.1016/0896-8411(89)90189-3

Journal of Autoimmunity

Volume 2, Issue 4, August 1989, Pages 559-568

https://doi.org/10.1016/0896-8411(89)90189-3 Get rights and content

Abstract

We investigated the possibility that autoantibodies are locally synthesized and secreted within salivary glands of patients with Sjögren's syndrome by measuring specific autoantibody as a proportion of the total immunoglobulin present both in serum and saliva. Of 25 patients studied, 21 showed salivary enrichment of IgA anti-La, in three cases IgA anti-La being detected in saliva when IgG anti-La was negative (by ELISA) in serum. Twenty-four showed enrichment of salivary rheumatoid factors and IgA and/or IgM carrying the 17–109 idiotype, a marker of κIIIb light chains.

These data suggest that autoantibodies, especially of the IgA class, are synthesized primarily in salivary gland and that they can be detected in saliva before they become apparent in the peripheral circulation. The subsequent deposition of these antibodies within salivary glands may be a contributory factor to the pathogenesis of Sjögren's syndrome.

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Cited by (85)

Defective DNA methylation in salivary gland epithelial acini from patients with Sjögren's syndrome is associated with SSB gene expression, anti-SSB/LA detection, and lymphocyte infiltration
2016, Journal of Autoimmunity
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The mechanisms that control cell-type specific balance between methylation and demethylation activities need further exploration in pSS. The origin and mechanisms leading to production of anti-SSB/La Ab in pSS, although incompletely understood, involve a multistep process including (i) SSB overexpression in SGEC [31], (ii) SSB protein post-translational phosphorylation leading to its association with the HLA molecules in SGEC [32], an association between anti-SSB/La Ab and HLA-DR3 has been reported [33], (iii) presentation to the immune system, (iv) B cell activation, proliferation, local production of the anti-SSB/La Ab, (v) SGEC apoptosis leading to cell surface and apoptotic blebs redistribution of the autoantigens SSA/Ro and SSB/La [34,35] and finally (vi), in response to this autoamplification loop, anti-SSB/La Ab detection together with anti-SSA/Ro Ab in peripheral blood of pSS patients [36]. In agreement with this general scenario, SSB mRNA and protein upregulation were observed in MSG from pSS patients who were positive for anti-SSB/La Ab.
The pathogenesis of primary Sjögren's syndrome (pSS) is complex, in part due to DNA methylation abnormalities. This study was undertaken to evaluate the importance of global DNA methylation (^5mC) as determined in minor salivary glands (MSG) from well characterized pSS patients. Twenty-two pSS patients and ten controls were selected, and MSG were stained with anti-^5mC, anti-^5mC/anti-cytokeratin (KRT)19, or with anti-SSB/La antibodies (Ab). The DNA methylation status at the SSB gene promoter P1 and P1′ was evaluated by methylation-sensitive restriction enzymes (MSRE) coupled with PCR. The effect of the DNA demethylating drug 5 azacytidine (5-Aza) was tested in the human salivary gland (HSG) cell line. In pSS, the reduction of global DNA methylation (^5mC) was associated with lymphocyte infiltration, the emergence of ^5mC^low and KRT19^high acini, and the detection of circulating anti-SSB/La Ab, but not with disease activity (ESSDAI). Next, treating HSG cells with 5-Aza was effective in inducing SSB expression. Finally in pSS patients positive for anti-SSB/La Ab, we further observed DNA demethylation at the SSB gene promoter P1 with consequent SSB overexpression at both the transcriptional and protein levels in salivary gland epithelial cells. In conclusion, our results highlight the importance of DNA methylation in the pathophysiology of pSS and to the emergence of anti-SSB/La Ab.
Autoantibodies in Sjögren's syndrome: Clinical presentation and regulatory mechanisms
2012, Presse Medicale
Citation Excerpt :
Moreover, it has been indicated that some autoantibodies are produced in the immunopathological lesion. Notably, previous studies have demonstrated that anti-Ro/SSA and anti-La/SSB autoantibodies are enriched in saliva of pSS patients [80–82] while B cells infiltrating the salivary glands contain intracytoplasmic immunoglobulins with anti-Ro/SSA and anti-La/SSB activity [83,84]. Taken together, the affected salivary glands in SS appear to be a major site of autoantibody production.
Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease mostly affecting the exocrine glands. A large number of autoantibodies have been detected in the serum of patients with pSS. Among them, anti-Ro/SSA and anti-La/SSB autoantibodies are the most common; they serve as disease markers and are involved in the pathogenesis of neonatal lupus syndrome (NLS). Other autoantibodies are associated with significant clinical phenotypes, such as cryoglobulins with development of non-Hodgkin's lymphoma, anti-centromere antibodies with Raynaud's phenomenon and anti-mitochondrial antibodies with liver pathology. As a result, pSS patients can be schematically categorized in subgroups according to their serological profile. Although the clinical utility of these autoantibodies is appreciated, little is known about the mechanisms related to their production and the regulation of the autoimmune response. In the present review, the clinical subsets of patients with pSS related to different autoantibodies as well as the regulating mechanisms of their production with special emphasis on idiotypic/anti-idiotypic network are discussed.
Subgroups of Sjögren syndrome patients according to serological profiles
2012, Journal of Autoimmunity
Sjögren Syndrome (SS) is a systemic, autoimmune disorder characterized by lymphocytic infiltration of the exocrine glands. Different clinical associations have been described for each of the diverse autoantibodies found in SS patients. Antibodies directed against the Ro/La ribonucleoprotein complexes have been correlated with younger age, more severe dysfunction of the exocrine glands and a higher prevalence of extraglandular manifestations. Anti-nuclear antibodies and rheumatoid factors have been associated to extraglandular manifestations and an active immunological profile, while cryoglobulins are markers of more severe disease and correlate to lymphoma development and death. Antibodies to cyclic citrullinated peptides are scarce in SS and have been linked in some cases to the development of non-erosive arthritis. Furthermore, the presence of anti-mitochondrial antibodies and anti-smooth muscle antibodies in the sera of primary SS patients is considered indicative of primary biliary cirrhosis and autoimmune hepatitis, respectively. In addition, anti-centromere antibodies have been associated with a clinical phenotype intermediate between primary SS and systemic sclerosis, while antibodies against carbonic anhydrase have been related to renal tubular acidosis. Finally, an association of anti-muscarinic antibodies with cytopenias and a higher disease activity has also been described in primary SS. In conclusion, although not all of the above mentioned antibodies are useful for predicting distinct patient subgroups in SS, knowledge of the clinical associations of the different autoantibody specificities encountered in SS can advance our understanding of the disease and improve patient management.
Cellular microRNAs (miRNAs) and Sjögren's syndrome: Candidate regulators of autoimmune response and autoantigen expression
2011, Journal of Autoimmunity
Citation Excerpt :
The autoimmune responses appear to take place in the affected salivary glands. In fact, saliva of SS patients has been shown to contain large amounts of autoantibodies [4], while B cells infiltrating the salivary glands contain intracytoplasmic immunoglobulins with autoantibody reactivity [5]. In addition, upregulated expression of Ro/SSA and La/SSB mRNA and proteins, as well as La/SSB redistribution in the cytoplasm and the cell membrane has been reported in the salivary gland epithelia of SS patients [2,3,6].
MicroRNAs (miRNAs) are small non-coding RNA molecules that suppress gene expression at post-transcriptional level. miRNAs are considered as fine-tuning regulators of diverse biological processes, including the development and function of the immune system. Emerging data have implicated the deregulated expression of certain miRNAs or miRNA networks in the pathogenesis of autoimmune diseases. Sjögren’s syndrome (SS) is a common chronic autoimmune disease, characterized by destruction and dysfunction of the exocrine glands (predominantly of the salivary and lachrymal glands). Humoral autoimmune responses observed in the disease, primarily target Ro/SSA and La/SSB ribonucleoproteins, whilst aberrantly increased expression of these autoantigens has been described in the salivary glands (SG) and the salivary gland epithelial cells (SGEC) of SS patients. Comparative array analysis of miRNA expression in the SGs of SS and control subjects had revealed distinctive miRNA signatures in SS patients, associated with glandular inflammation and dysfunction. Furthermore, the expression analysis of miRNAs that are predicted to target Ro/SSA and La/SSB autoantigens revealed differential expression of certain miRNAs in the SG tissues, SGECs and peripheral blood mononuclear cells (PBMC) of SS patients and controls. Although these association data implicate miRNAs in SS pathogenesis, thorough functional studies are needed to delineate their role in disease.
Induction of autoimmunity by pristane and other naturally occurring hydrocarbons
2009, Trends in Immunology
Citation Excerpt :
Lymphocytic foci in rheumatoid synovium exhibit restricted κ-light chain rearrangements and evidence of somatic hypermutation [83,84]. Removal of self-reactive B-cells might be inefficient in ectopic lymphoid tissue [85], and B-cells specific for the Ro (SS-A) and La (SS-B) ribonucleoprotein autoantigens can be detected in the salivary glands of patients with Sjögren's syndrome, rheumatoid factor-specific B-cells in rheumatoid synovium [86,87], and anti-nRNP specific B-cells in TMPD lipogranulomas (see below). Cytokines produced in the ectopic lymphoid tissue [60] might play a role in autoantibody production, since IFNα or β and IL-6 promote plasma cell development [88].
Tetramethylpentadecane (TMPD, or commonly known as pristane)-induced lupus is a murine model of systemic lupus erythematosus (SLE). Renal disease and autoantibody production strictly depend on signaling through the interferon (IFN)-I receptor. The major source of IFN-I is immature monocytes bearing high levels of the surface marker Ly6C. Interferon production is mediated exclusively by signaling through TLR7 and the adapter protein MyD88. It is likely that endogenous TLR7 ligands such as components of small nuclear ribonucleoprotein complexes are involved in triggering disease. Lupus autoantibodies are produced in ectopic lymphoid tissue developing in response to TMPD. This model is well suited for examining links between dysregulated IFN-I production and the pathogenesis of human SLE, which like TMPD-lupus, is associated with high levels of IFN-I.
Immunoassay Detects Salivary Anti-SSA/Ro-52 Autoantibodies in Seronegative Patients with Primary Sjögren’s Syndrome
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Autoantibody synthesis in salivary glands of Sjögren's syndrome patients

Abstract

Semin. Arthritis Rheum.

Mol. Immunol.

J. Immunol. Methods

J. Immunol. Methods

J. Mol. Biol.

Am. J. Med.

Purification and characterisation of the Sjögren's syndrome A and B antigens

Clin. Exp. Immunol.

Two novel classes of small ribonucleoproteins detected by antibodies associated with lupus erythematosus

Science

IgA rheumatoid factor in the sera and saliva of patients with rheumatoid arthritis and Sjögren's syndrome

Ann. Rheum. Dis.

IgA and IgM rheumatoid factors in serum, saliva and other secretions: relationship to immunoglobulin ratios in systemic sicca syndrome and rheumatoid arthritis

Clin. Exp. Immunol.