Elsevier

Autoimmunity Reviews

Volume 2, Issue 1, January 2003, Pages 13-18
Autoimmunity Reviews

Pathogenesis of Sjögren's syndrome

https://doi.org/10.1016/S1568-9972(02)00121-0Get rights and content

Abstract

The pathogenesis of Sjögren's syndrome is poorly understood. Genetic and environmental factors appear to contribute to the development of this syndrome. Viral infection is one of the most likely environmental factors. The primary lesion of Sjögren's syndrome is in the exocrine glands. A majority of the infiltrating cells in the lesion are CD4+ CD45RO+ memory T cells. Although antigen-presentation to T cells seems to occur in the exocrine tissues, these T cells are not fully activated. On the other hand, B cells comprise approximately 20% of the infiltrating cells, and several features of this syndrome are attributed to stimulated B cells. The presence of autoantibodies, such as anti-SS-A/Ro and SS-B/La antibodies, is one of the characteristic features and is associated with severe disorders. Some antibodies appear to play a direct pathogenic role, for example, in cases of congenital heart block and sicca symptoms. Chronic inflammation with possible T cell-dependent antigen stimulation appears to induce neoplastic transformation of lymphocytes.

Introduction

Sjögren's syndrome (SS) is manifested by keratoconjunctivitis sicca (dry eye), xerostomia (dry mouth) and other extraglandular abnormalities. Primary SS is defined as the presence of the above manifestations without additional connective tissue disease. Secondary SS involves an association with RA, SLE or other connective tissue diseases. Patients with fibromyalgia and chronic fatigue syndrome frequently present with sicca symptoms but may fail to meet strict criteria for the diagnosis of SS. The epidemiological data on SS sometimes because the definition of SS in not consistent. For example, the frequency of primary SS was estimated to be 0.2–0.8% when using the Copenhagen criteria, but 0.6–2.1% when using the preliminary European criteria [1].

SS is primarily a disorder of women, occurring 9–10 times more commonly in women than men. This predominance of SS in women seems to be related to the immunoregulatory properties of the sex hormones. Most women with SS are afflicted in their perimenopausal years. SS is a disorder that may possess important clues to the etiology, pathogenesis and treatment of autoimmunity as well as malignancy. This short review summarizes some of these points.

Section snippets

Immunopathologic features

Some of the clinical manifestations of SS are caused by tissue-infiltrating cells. Many of the infiltrating cells into the salivary and lacrimal glands are T cells. The majority of T cells in the lymphocytic infiltrate are CD4+, CD45RO+ and express the α/β TCR. They secrete IFN-γ and IL-10. However, it is interesting to note that only a low level of IL-2 was observed, and few T cells appeared to proliferate as determined by cell-cycle studies and autoradiography. The memory T cells in the

Genetic factors

There are several reports suggesting a familial tendency to SS. However, no studies on concordance in identical twins with primary SS have been published. Autoantibodies such as anti-SS-B/La and anti-SS-A/Ro are frequently found in the relatives of patients [7].

The development of primary SS is strongly associated with MHC class II genes, most specifically HLA-DR and DQ alleles. This HLA-mediated risk appears to be more strongly linked with the anti-SS-A/Ro antibody response than with the

Role of viruses

Among several environmental factors, viral infection is one of the most likely candidates for the induction of SS. Infection of C57BL/6-lpr/lpr mice with murine cytomegalovirus induced sialadenitis as well as anti-SS-A/Ro and anti-SS-B/La autoantibodies [10]. Salivary glands are a site of latent infection by certain viruses. However, no single virus has been clearly implicated in the pathogenesis.

Epstein Barr virus (EBV) frequently infects the salivary glands, and this could induce strong T

Lymphoid neogenesis and development of lymphomas

The estimated prevalence of malignant lymphoma in SS was 4.3%, with the majority being low-grade marginal zone B-cell lymphomas, particularly of mucosa-associated lymphoid tissue (MALT) origin [25]. Chronic inflammation involves ectopic de novo formation of organized lymphoid tissue. Lymphotoxin-α (LT-α, TNF-β) appears to be crucial for the development of this lymphoid neogenesis. In fact, Sjögren's syndrome has been shown to be characterized by morphological and functional features of lymphoid

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