ReviewSjögren's syndrome: A forty-year scientific journey
Introduction
My journey started in July 1974. Upon completion of my training in Internal Medicine at Georgetown University Hospitals System, in Washington, DC, I was lucky and honored to be accepted as a fellow to study autoimmune diseases at the University Hospitals System in San Francisco. My mentor was Norman Talal, an innovating and devoted investigator of human and experimental systemic autoimmune disorders and a major researcher of Sjögren's syndrome (SS). Patients from all US states and abroad were referred to our SS clinic for evaluation. Dr T. Daniels was performing the tests for the evaluation of dry mouth. An ophthalmologist – I cannot recall his name – was testing the eyes for keratoconjunctivitis sicca. Dr H. Fudenberg was evaluating the patients' sera for autoantibodies. Through reading [1], [2], [3], [4], enthusiastic N. Talal's teaching, evaluating patients and more importantly being in a highly stimulating scientific environment with young people dedicated to explore novel ideas, I was convinced to devote my efforts to study this disorder which is an ideal model to study autoimmune disorders and lymphomagenesis. Why? Because the disorder can present either as single entity or in association with almost every other autoimmune systemic rheumatic disorder. Furthermore, it has a wide clinical spectrum expanding from organ-specific autoimmune disorder (autoimmune exocrinopathy) [5] to systemic disease. More importantly, in some patients, the disorder can evolve to lymphoid malignancy [6]. With the acquired knowledge and experience from San Francisco, I was accepted in January 1976 as an associate investigator at the National Institutes of Health in Bethesda, Maryland under the mentorship of Drs T. Chused and J.L. Decker. Because of my accomplishments as a physician-scientist, in June 1977 I was promoted to the level of an independent investigator. During that period of time, I had the unique opportunity to collaborate with and taught by giants in autoimmune diseases such as Drs A.D. Steinberg, P. Plotz, A.D. Fauci, S. Katz and many others. During my tenure at the NIH in addition to the studies using the experimental animal model for systemic autoimmune diseases the (NZBXNZW)F1 hybrid mice we also studied the clinical, serologic and immunogenetic similarities and differences in patients with SS as a single entity in comparison with SS patients associated with rheumatoid arthritis (RA). Furthermore, the development of SS-like syndrome in patients with chronic graft vs host disease (GVHD), the presence of circulating antiviral interferon in the sera of patients with active systemic autoimmune disorders, as well as the identification of monoclonal B cell products together with polyclonal B cell activation in SS patients with systemic manifestations were described. In January 1980, I returned to Greece as Professor and Head of Internal Medicine at the newly established Medical School in Ioannina, Greece, position I held up to the end of 1993. My first goal was to establish a referral center – both clinical and laboratory – to diagnose, understand and treat systemic autoimmune rheumatic disorders. Pretty soon, a large number of patients were recruited. Based on the newly formed cohort, we described in detail the systemic manifestations of SS, their particular immunogenetic and serological associations as well as the primary site of lymphomagenesis. From 1994 to present, I worked at the Department of Pathophysiology at the Medical School of the National University in Athens. Our research clearly indicated that the salivary gland epithelial cells are activated and play a significant role in the initiation and perpetuation of the autoimmune lesion and the target(s)/epitope(s) on Ro/SSA and La/SSB autoantigens were identified and studied. Subsequently, our research unraveled clinical, laboratory and molecular parameters which confer increased risk for lymphoma development in SS patients. Follow-up studies of large cohorts of patients with liver and kidney involvement taught us the natural course and evolution of these pathologies. Furthermore, the clinical, laboratory and pathologic characteristics of lymphoma in SS patients and strategies for its effective treatment were described. Our scientific work was confirmed and acknowledged by many SS investigators and was honored with National, European and American awards [7], [8].
Section snippets
Pathology of the minor salivary glands
Investigators from NIH and San Francisco described in the 70s that the typical pathologic lesion in the labial minor salivary gland biopsies consisted of clusters of round cell infiltrates containing at least 50 mononuclear cells. Derrick Chisholm, John Greenspan and Tom Tarpley organized different grading systems to quantify the degree of lymphocytic infiltration [9], [10], [11]. From the mid 70s and early 80s, there was much controversy on the predominating cell population (T- or B-cells)
Studies of the autoantibodies and autoantigens
From the early 60s, it was recognized that sera of SS patients contain antibodies directed to immunoglobulins and cellular autoantigens. Subsequently, Reichlin and Tan described in detail the antibodies to cellular antigens and named them respectively Ro/SSA and La/SSB [28], [29]. Work in the 80s revealed that these autoantigens are ribonucleoproteins consisting of cytoplasmic RNA and three proteins, called now Ro52/TRIM21, Ro60/TROVE-2 and La48KD. In the 80s in our clinical immunology
Pathogenetic aspects [40]
In the 70s and 80s, different groups of investigators began to study immunocytes from humans and experimental animals in an effort to identify functional defects that could possibly explain the events leading to recognition of self antigens and autoreactivity in autoimmune diseases [41]. In the late 70s seminal observations from our research group at the NIH clearly indicated that humans with GVHD, due to allogeneic bone marrow transplantation, developed autoimmune diseases. This nature
Diagnosis-differential diagnosis
The diagnosis of SS in the everyday clinical practice is straightforward if the patient presents with symptoms and signs of dry eyes and/or mouth and has in the serum circulating autoantibodies to Ro/SSA and La/SSB autoantigens as well as immunoglobulins (rheumatoid factors). In the 70s and 80s several SS investigators around the world had used their own criteria to substantiate the diagnosis. Swedish, Japanese and Greeks had developed their own criteria. Americans used criteria developed by R.
Systemic manifestations
In the early 70s, the only well characterized extraglandular (systemic) disease manifestations of SS were bronchitis sicca, interstitial nephritis leading primarily to distal (renal tubular acidosis) and less often to proximal tubular dysfunction, as well as the tendency of some patients to develop lymphoma [3], [6]. In the late 70s, Talals group showed that the SS-related lymphoma is of B-lymphocyte origin [70]. Later, in the same decade, our group at the NIH, with a well-controlled study,
Risk factors for lymphoma development
In the beginning of the 80s, the presence of serum and urine monoclonal light chains was identified in SS patients with systemic manifestations [85], [86]. This was the first indication that in some SS patients the monoclonal B-cell process starts together with the polyclonal B-cell activation [87], [88]. Subsequently, we described that in around 30% of SS patients tested, cryoprecipitable monoclonal IgMks with rheumatoid factor activity circulate in their blood and correlate with the presence
Primary vs secondary SS
From Bunim's days at the NIH, it was proposed that SS patients can present as an entity alone or in association with other rheumatic disorders primarily with RA [99].
During my tenure at NIH, our studies evaluating clinical, immunologic and immunogenetic profile of SS patients presenting as a single entity or in association with RA revealed the presence of differences in clinical presentation, antibody profile and association with class II HLA alloantigens. More specifically, the former group
New therapeutic interventions
Despite the fact that SS is a rather common disease affecting 0.5% of the female population [111] the medical community has not have at hand an effective therapeutic intervention. There is no available effective intervention to ameliorate the disturbing sicca manifestations other than replacement or stimulation of the diminished exocrine gland secretions. In the 80s and 90s efforts to identify effective immunomodulatory therapies were unsuccessful. More specifically, administration of
Future perspectives
Although intense research has been implemented, the exact etiology of SS is still unknown. Identification of primary triggers initiating autoreactivity remains a major challenge for the coming years. Furthermore, the clarification of intrinsic or extrinsic factors accounting for the epithelial cell activation, which appears significant not only for the initiation of autoreactivity as well as the perpetuation of the process is of paramount importance. Since SS occurs as a single entity but also
Acknowledgments
I dedicate this work to my students, collaborators and colleagues, who despite difficulties, were determined and devoted to produce and disseminate novel scientific work.
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2021, Journal of AutoimmunityCitation Excerpt :Furthermore, SS is characterized by an enhanced risk for non-Hodgkin's Lymphoma (NHL) [3] and therefore it represents an ideal model for studying the shift from autoimmunity to lymphoid malignancy. Despite several clinical, laboratory, histopathological and molecular contributors to lymphomagenesis in the context of SS have been identified [4–9] critical pathogenetic questions remain still unanswered [10]. Interferons (IFNs) have been previously shown to significantly contribute to the pathophysiology of several autoimmune disorders, including SS and endogenous retroviral like elements have been postulated as potential triggers for excessive IFN production [11,12].
Effect of Myd88 deficiency on gene expression profiling in salivary glands of female non-obese diabetic (NOD) mice
2021, Journal of Oral BiosciencesCitation Excerpt :Under several pathological conditions, ligand recognition by these TLRs occasionally induces excessive inflammatory responses through MyD88-dependent signaling, which ultimately results in the development of autoimmune diseases, at least partly through overexpression of type I IFNs and type I IFN-regulated genes, referred to as the IFN signature [3]. Sjögren's syndrome (SS), an autoimmune disease predominantly more common in post-menopausal women, is characterized by chronic inflammatory changes in the salivary and lacrimal glands caused by focal lymphocytic infiltrates, which leads to hypofunction of these glands, thereby resulting in symptoms of oral and ocular dryness [4]. Crucial causative factors have not yet been identified, but SS development is thought to be intricately exhibited through temporal expression or activation of multiple genes, signaling pathways, molecular networks, and immunological processes.
Autoantibodies against C5aR1, C3aR1, CXCR3, and CXCR4 are decreased in primary Sjogren's syndrome
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2021, Journal of Translational AutoimmunityChinese herbal medicine SS-1 inhibits T cell activation and abrogates T<inf>H</inf> responses in Sjögren's syndrome
2021, Journal of the Formosan Medical AssociationCitation Excerpt :Current therapeutic options for SS include hydroxychloroquine for immune modulation, pilocarpine and cevimeline for xerostomia relief, and rituximab for B cell depletion.7 Some SS patients also use artificial tears and saliva substitutes to counteract dryness symptoms.8,9 Despite alleviating those sicca symptoms, these medicines induce limited clinical responses10 and cause adverse effects in some SS patients.8,11,12