Rheumatology Clinic, Scripps Memorial Hospital and Research Foundation, La Jolla, CA 92037, USA. The Lancet
(Impact Factor: 45.22).
07/2005; 366(9482):321-31. DOI: 10.1016/S0140-6736(05)66990-5
Sjögren's syndrome is a chronic autoimmune disorder of the exocrine glands with associated lymphocytic infiltrates of the affected glands. Dryness of the mouth and eyes results from involvement of the salivary and lacrimal glands. The accessibility of these glands to biopsy enables study of the molecular biology of a tissue-specific autoimmune process. The exocrinopathy can be encountered alone (primary Sjögren's syndrome) or in the presence of another autoimmune disorder such as rheumatoid arthritis, systemic lupus erythematosus, or progressive systemic sclerosis. A new international consensus for diagnosis requires objective signs and symptoms of dryness including a characteristic appearance of a biopsy sample from a minor salivary gland or autoantibody such as anti-SS-A. Exclusions to the diagnosis include infections with HIV, human T-lymphotropic virus type I, or hepatitis C virus. Therapy includes topical agents to improve moisture and decrease inflammation. Systemic therapy includes steroidal and non-steroidal anti-inflammatory agents, disease-modifying agents, and cytotoxic agents to address the extraglandular manifestations involving skin, lung, heart, kidneys, and nervous system (peripheral and central) and haematological and lymphoproliferative disorders. The most difficult challenge in diagnosis and therapy is patients with symptoms of fibromyalgia (arthralgia, myalgia, fatigue) and oral and ocular dryness in the presence of circulating antinuclear antibodies.
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- "Immune hyperactivity, characterized by strong polyclonal B cell activation and production of autoantibodies , is a key feature of the disease. The major autoantibodies present in SS include Rheumatoid factor (RF), anti-nuclear (ANA), anti-Ro, and anti-La Abs, with roughly 60% and 40% of SS patients testing positive for Ro and La antibodies, respectively (Fox, 2005; Tincani et al., 2013). "
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ABSTRACT: Ectopic follicles are non-encapsulated organized lymphoid structures that form at sites of inflammation and presumably contribute to the activation and differentiation of cells with autoreactive potential within target tissues. As such, directed targeting of ectopic follicles in settings of autoimmunity may provide a means to specifically inhibit the activation of autoreactive cells without impairing protective immune responses ongoing in peripheral lymphoid tissues. NOD·H2h4 mice are a non-diabetic strain of NOD mice which develop a Sjögren's syndrome-like disease which includes the formation of ectopic follicles in the salivary gland and characteristic Sjögren's autoantibodies. The goal of these studies was to better characterize the formation of ectopic follicles in this model and to explore their contribution to autoimmunity. Our studies show that by 8 weeks of age, young NOD·H2h4 mice spontaneously develop an abundance of splenic germinal centers, prior to the emergence of lymphocyte infiltration in the salivary gland tissue. Ectopic follicle formation in the salivary gland begins to appear in these mice between 12 and 16 weeks of age. Interestingly, anti-Ro and anti-La autoantibodies precede the development of ectopic follicles in young NOD·H2h4 mice. In contrast, production of anti-dsDNA antibodies is delayed and largely coincides with the formation of ectopic follicles in these mice. These data suggest that tertiary lymphoid structures may arise from the trafficking of activated T and B cells to sites of inflammation in non-lymphoid tissues. Furthermore, local presentation of autoantigens may then promote the expansion of autoreactive cells with specificities distinct from those generated in the splenic micro-environment.
Available from: PubMed Central
- "Sjögren's syndrome (SS) is a chronic, autoimmune disease causing dry mouth and eyes in ∼4 million Americans , . A prominent histopathological feature of SS is the presence of lymphocytic infiltrates in the salivary and lachrymal glands. "
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ABSTRACT: A prominent histopathological feature of Sjögren's syndrome, an autoimmune disease, is the presence of lymphocytic infiltrates in the salivary and lachrymal glands. Such infiltrates are comprised of activated lymphocytes and macrophages, and known to produce multiple cytokines including interferon-gamma (IFN-γ). In this study, we have demonstrated that IFN-γ strongly induces the expression of immunoproteasome beta subunits (β1i, β2i and β5i) and immunoproteasome activity but conversely inhibits the expression of proteasome beta subunits (β1, β2 and β5) in human salivary gland (HSG) cells. Mass spectrometric analysis has revealed potential MHC I-associated peptides on the HSG cells, including a tryptic peptide derived from salivary amylase, due to IFN-γ stimulation. These results suggest that IFN-γ induces immunoproteasomes in HSG cells, leading to enhanced presentation of MHC I-associated peptides on cell surface. These peptide-presenting salivary gland cells may be recognized and targeted by auto-reactive T lymphocytes. We have also found that lactacystin, a proteasome inhibitor, inhibits the expression of β1 subunit in HSG cells and blocks the IFN-γ-induced expression of β1i and immunoproteasome activity. However, the expression of β2i and β5i in HSG cells is not affected by lactacystin. These results may add new insight into the mechanism regarding how lactacystin blocks the action of proteasomes or immunoproteasomes.
- "Lung and kidney disease tend to occur late in the disease process. About 5% of the patients with SS develop B cell lymphoma, most commonly occurring in the salivary glands and gastrointestinal tract [1, 2, 3]. "
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The purpose of this report is to describe 2 patients with persistent severe dry eyes, positive Schirmer tests for Sjogren's syndrome (SS) but lacking antibodies to either Ro or La. These patients were diagnosed to have SS by detecting antibodies to salivary gland protein 1 (Sp1) and parotid secretory protein (PSP). This report emphasizes the existence of patients with SS who lack antibodies to either Ro or La and may therefore be misdiagnosed. Detection of novel autoantibodies, including antibodies to Sp1 and PSP, are helpful in identifying these patients. Initial presentation may simply be dry eyes.
Two patients who presented to our ophthalmology clinic are described. One of the patients underwent multiple procedures over a period of 10 years for severe xerophthalmia. The other patient had rheumatoid arthritis and xerophthalmia. However, in both patients, chronic xerophthalmia had been considered to be idiopathic because antibodies Ro and La were negative. Further serologic testing revealed antibodies to Sp1 and PSP.
Two patients who lacked antibodies to Ro and La but not to Sp1 and PSP were diagnosed as having SS.
Patients presenting with unexplained dry eyes may not always show the serology markers in the current criteria for SS, anti-Ro and anti-La. In these cases, investigation for novel, early antibodies to Sp1 and PSP is of importance in the diagnosis of SS.
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