Elsevier

Journal of Autoimmunity

Volume 51, June 2014, Pages 1-9
Journal of Autoimmunity

Review
Sjögren's syndrome: A forty-year scientific journey

https://doi.org/10.1016/j.jaut.2014.01.001Get rights and content

Highlights

  • In depth study of the wide clinical spectrum of Sjogren's syndrome.

  • Identification of clinical, laboratory and molecular factors leading to lymphomagenesis.

  • Identification of epithelial cells as orchestrators of autoimmune process.

  • Discovery and study of epitopes on autoantigens in autoimmune disorders.

  • Discovery of factors against which targeted therapy should be instituted.

Abstract

My long scientific journey studying as a disease model Sjogren's syndrome (SS) gave me the opportunity to uncover the mysteries of systemic autoimmune diseases. After an extensive training, under the supervision of the major autoimmune disease investigators, I was able to convey and expand the acquired knowledge through inspiring my students and collaborators. Our research enriches the understanding of the wide clinical spectrum of the syndrome and the clinical, laboratory and molecular events predicting or being responsible for lymphomagenesis. Our molecular and cellular studies indicated that the target of autoimmunity in SS, the activated glandular epithelial cells, play significant role in the initiation and perpetuation of the autoimmune process. Furthermore, discovery of the epitopes on autoantigens where the autoimmune humoral reactivity is directed against, provided us tools to develop specific and sensitive diagnostic assays, to unmask similarities of the epitope sequence with infectious agents and gave us the potential to use them as therapeutic modalities.

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.

References (145)

  • A. Roitberg-Tambur et al.

    Molecular analysis of HLA class II genes in primary Sjogren's syndrome. A study of Israeli Jewish and Greek non-Jewish patients

    Hum Immunol

    (1993)
  • J.A. Ice et al.

    Genetics of Sjogren's syndrome in the genome-wide association era

    J Autoimmun

    (2012)
  • C.P. Mavragani et al.

    Activation of the type I interferon pathway in primary Sjogren's syndrome

    J Autoimmun

    (2010)
  • C.P. Mavragani et al.

    Endocrine alterations in primary Sjogren's syndrome: an overview

    J Autoimmun

    (2012)
  • H.M. Moutsopoulos et al.

    Immune complex glomerulonephritis in sicca syndrome

    Am J Med

    (1978)
  • F.N. Skopouli et al.

    Clinical evolution, and morbidity and mortality of primary Sjogren's syndrome

    Semin Arthritis Rheum

    (2000)
  • E.V. Tsianos et al.

    Sjogren's syndrome and the gut

    Bailliere's Clin Rheumatol

    (1989)
  • A. Nezos et al.

    B-cell activating factor genetic variants in lymphomagenesis associated with primary Sjogren's syndrome

    J Autoimmun

    (2014)
  • H.M. Moutsopoulos et al.

    Differences in the clinical manifestations of sicca syndrome in the presence and absence of rheumatoid arthritis

    Am J Med

    (1979)
  • J.J. Bunim

    A broader spectrum of Sjogren's syndrome and its pathogenetic implications

    Ann Rheum Dis

    (1961)
  • K.J. Bloch et al.

    Sjoegren's syndrome. A clinical, pathological, and serological study of sixty-two cases

    Medicine

    (1965)
  • N. Talal

    Sjogren's syndrome, lymphoproliferation, and renal tubular acidosis

    Ann Intern Med

    (1971)
  • N. Talal

    Sjogren's syndrome

    Bull Rheum Dis

    (1966)
  • V. Strand et al.

    Advances in the diagnosis and concept of Sjogren's syndrome (autoimmune exocrinopathy)

    Bull Rheum Dis

    (1979)
  • C. Krimbas

    On Prof. Haralampos Moutsopoulos: the academic perspective

    Autoimmun Rev

    (2004)
  • D.M. Chisholm et al.

    Labial salivary gland biopsy in Sjogren's disease

    J Clin Pathol

    (1968)
  • N. Talal et al.

    T and B lymphocytes in peripheral blood and tissue lesions in Sjogren's syndrome

    J Clin Invest

    (1974)
  • T.M. Chused et al.

    Identification of cells infiltrating the minor salivary glands in patients with Sjogren's syndrome

    J Immunol

    (1974)
  • A.G. Tzioufas et al.

    Sjogren's syndrome

  • H. Moutsopoulos

    Sjogren's syndrome

  • E.K. Kapsogeorgou et al.

    Minor salivary gland inflammatory lesions in Sjogren syndrome: do they evolve?

    J Rheumatol

    (2013)
  • D. Boumba et al.

    Cytokine mRNA expression in the labial salivary gland tissues from patients with primary Sjogren's syndrome

    Br J Rheumatol

    (1995)
  • D.I. Mitsias et al.

    The Th1/Th2 cytokine balance changes with the progress of the immunopathological lesion of Sjogren's syndrome

    Clin Exp Immunol

    (2002)
  • A.G. Tzioufas et al.

    Pathogenesis of Sjogren's syndrome: what we know and what we should learn

    J Autoimmun

    (2013)
  • E.K. Kapsogeorgou et al.

    Salivary gland epithelial cell exosomes: a source of autoantigenic ribonucleoproteins

    Arthritis Rheum

    (2005)
  • L. Casciola-Rosen et al.

    Cleavage by granzyme B is strongly predictive of autoantigen status: implications for initiation of autoimmunity

    J Exp Med

    (1999)
  • M. Polihronis et al.

    Modes of epithelial cell death and repair in Sjogren's syndrome (SS)

    Clin Exp Immunol

    (1998)
  • D.I. Mitsias et al.

    Sjogren's syndrome: why autoimmune epithelitis?

    Oral Dis

    (2006)
  • A. Triantafyllopoulou et al.

    Autoimmunity and coxsackievirus infection in primary Sjogren's syndrome

    Ann NY Acad Sci

    (2005)
  • M.A. Aslpaugh et al.

    Serum antibody in rheumatoid arthritis reactive with a cell-associated antigen. Demonstration by precipitation and immunofluorescence

    Arthritis Rheum

    (1976)
  • A.L. Sestak et al.

    Lupus/Sjogren's autoantibody specificities in sera with paraproteins

    J Clin Invest

    (1987)
  • H.M. Moutsopoulos et al.

    Anti-Ro(SSA) positive rheumatoid arthritis (RA): a clinicoserological group of patients with high incidence of d-penicillamine side effects

    Ann Rheum Dis

    (1985)
  • J.G. Routsias et al.

    Unmasking the anti-La/SSB response in sera from patients with Sjogren's syndrome by specific blocking of anti-idiotypic antibodies to La/SSB antigenic determinants

    Mol Med (Cambridge, Mass)

    (2002)
  • E. Yiannaki et al.

    Study of antibody and T cell responses in rabbits immunized with synthetic human B cell epitope analogues of La (SSB) autoantigen

    Clin Exp Immunol

    (2000)
  • E.V. Staikou et al.

    Calreticulin binds preferentially with B cell linear epitopes of Ro60 kD autoantigen, enhancing recognition by anti-Ro60 kD autoantibodies

    Clin Exp Immunol

    (2003)
  • E.A. Stea et al.

    Analysis of parotid glands of primary Sjogren's syndrome patients using proteomic technology reveals altered autoantigen composition and novel antigenic targets

    Clin Exp Immunol

    (2007)
  • A.G. Terzoglou et al.

    Post-translational modifications of the major linear epitope 169-190aa of Ro60 kDa autoantigen alter the autoantibody binding

    Clin Exp Immunol

    (2006)
  • E.A. Stea et al.

    Anti-La/SSB antiidiotypic antibodies in maternal serum: a marker of low risk for neonatal lupus in an offspring

    Arthritis Rheum

    (2006)
  • C.P. Mavragani et al.

    Sjogren's syndrome

    Annu Rev Pathol Mech Dis

    (2014)
  • C.R. Stiller et al.

    Autoimmunity: present concepts

    Ann Intern Med

    (1975)
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