Sjögren's syndrome.

Sjogren's syndrome (SS) is a chronic autoimmune disease affecting the exocrine glands, primarily the salivary and lacrimal glands. It has been suggested that exogenous agents may trigger SS in genetically predisposed individuals. However, at present, the etiology of SS is far from being understood, and no direct evidence for any of these triggers has been presented. The salivary and lacrimal glands from patients with SS harbor unique and highly selected T- and B-cell populations. Disturbance in glandular cell apoptosis may be one possible explanation for the sicca symptoms in SS. However, discrepancies between glandular destruction and salivary flow give rise to processes causing glandular dysfunction preceding or triggering glandular cell destruction. Recent reports suggested autoantibodies inhibiting neuronal innervation of acinar cells and defective water transport to be implicated in salivary secretion deficiency observed in SS. Several types of autoantibodies have been suggested to contribute to the pathogenesis of SS. However, how the tolerance to these structures is broken down is unknown at present. Studies on B-cell activating factor indicated that diminished apoptosis and disturbed B-cell maturation could be responsible for the occurrence of autoreactive B-cells and B-cell hyperreactivity. B-cell activation may also provide a basis for lymphoma development observed in up to 5% of the patients with SS.

How the immune response matures from recognizing a single or a few structures of the antigen to many is an obviously important process. Models of B-cell epitope spreading have been developed in a variety of systems. For example, immunization of animals with PPPGMRPP, one of the earliest B-cell epitopes in the anti-Sm response found in human lupus, leads to antispliceosomal autoimmunity and features of lupus. The humoral immune response spreads from PPPGMRPP to other structures of the spliceosome in an apparently reproducible sequence. B-cell epitope spreading has provided the experimental basis from which a relationship between lupus and Epstein-Barr virus was suspected. An understanding of B-cell epitope spreading is likely to lead to important principles in basic immunology and to answers to human disease problems.

B-cell epitope spreading in autoimmunity

The presence of autoantibodies is the hallmark of systemic autoimmune diseases. During the past 30 years, intense clinical and basic research have dissected the clinical value of autoantibodies in many autoimmune diseases and offered new insights into a better understanding of the molecular and functional properties of the targeted autoantigens. Unraveling the immunologic mechanisms underlying the autoimmune tissue injury, provided useful conclusions on the generation of autoantibodies and the perpetuation of the autoimmune response. Primary Sjogren’s syndrome (pSS) is characterized by the presence of autoantibodies binding on a vast array of organ and non-organ specific autoantigens. The most common autoantibodies are those targeting the Ro/La RNP complex, and they serve as disease markers, as they are included in the European–American Diagnostic Criteria for pSS. Other autoantibodies are associated with particular disease manifestations, such as anti-centromere antibodies with Raynaud’s phenomenon, anti-carbonic anhydrase II with distal renal tubular acidosis, anti-mitochondrial antibodies with liver pathology, and cryoglobulins with the evolution to non-Hodgkin’s lymphoma. Finally, autoantibodies against autoantigens such as alpha- and beta-fodrin, islet cell autoantigen, poly(ADP)ribose polymerase (PARP), NuMA, Golgins, and NOR-90 are found in a subpopulation of SS patients without disease specificity, and their utility remains to be elucidated. In this review, the molecular and clinical characteristics (divided according to their clinical utility) of the autoantigens and autoantibodies associated with pSS are discussed.

Sjögren's syndrome--study of autoantigens and autoantibodies.

Anti-Ro autoantibodies are frequently found in the sera of patients with Sjogren's syndrome, systemic lupus erythematosus, and subacute cutaneous lupus erythematosus as well as in the sera of mothers of infants with the neonatal lupus syndrome. Close associations have been found between anti-Ro and a number of clinical manifestations, particularly including hematologic cytopenias, heart block, and photosensitive skin rashes. Serologic and genetic associations have been found between anti-Ro and anti-La, rheumatoid factor, hypergammaglobulinemia, the histocompatibility alleles DQ1 and DQ2, and alleles of the T-cell receptor beta chain gene. The origin of anti-Ro and other autoantigens is thought to relate to the etiology of Sjogren's syndrome and systemic lupus erythematosus and remains the most fundamental unanswered question preventing a comprehensive understanding of these diseases.

ANTI-Ro IN SJÖGREN’S SYNDROME AND SYSTEMIC LUPUS ERYTHEMATOSUS

The Ro ribonucleoprotein is composed of hY RNA and a 60.7-kD peptide that is antigenic for autoantibodies produced by many patients with systemic lupus erythematosus or Sjogren's syndrome and mothers of newborns with complete congenital heart block. A major immunoreactive fragment (13 kD) of the 60-kD Ro is bound by 28 of 45 (62%) of the anti-Ro sera tested. Amino acid sequence analysis localizes this fragment to the carboxyl end of the 60-kD Ro peptide. All possible overlapping octapeptides of this 13-kD peptide of 60-kD Ro have been assessed for antigenicity. Sera that bind the 13-kD peptide fragment in immunoblot generally also bind the octapeptides of Ro spanning the sequence AIALREYRKKMDIPA (P<0.01). Inhibition studies with synthetic peptides and purified Ro have established specificity for reference serum antibody binding to an antigenic octapeptide, EYRKKMDI, from this region. The closely related sequence EYRKKLMD is found in the nucleocapsid protein of vesicular stomatitis virus and may portend an immunologic link to this or a related viral antigen. These results also demonstrate that despite fine specificity variation between human sera, there are recurring patterns of anti-Ro binding shared by some patients who have precipitating anti-Ro autoantibodies.

Kenneth W. Jackson

Papers

A common autoepitope near the carboxyl terminus of the 60-kD Ro ribonucleoprotein: sequence similarity with a viral protein.