Etiology
The etiology of Sjogren syndrome remains uncertain.[16]
There are few data concerning heritability or relative genetic risk. HLA class II markers HLA-A1, -B8, or -DR3/DQ2 haplotype in white patients are linked with susceptibility to Sjogren syndrome. HLA-DR3 is linked with both anti-60 kD Ro and anti-La production. HLA class II phenotype is thought to support epitope spreading.[17] In addition to the HLA-DR3 haplotype, the HLA-DR2 haplotype is also well documented to be strongly associated with Ro/La-positive Sjogren syndrome. Several chromosomal intervals have shown genetic association, but the causative alleles have not been identified.[18]
The greater prevalence in females has raised the possibility of estrogen and/or androgen deficiency playing a role in the etiology of this and other autoimmune diseases.
The lymphocytic infiltrates and salivary gland epithelial cells on biopsy have been found to have EBV DNA and antigens. Antibodies to EBV antigens have been shown to be elevated in the serum.[19] However, these findings are not specific to Sjogren syndrome and their association may be nonspecific as well. Molecular mimicry between SS-B/La and a retroviral gag protein has been shown, which suggests that retrovirus might play a role in pathogenesis. Adenovirus infection has been shown to induce a redistribution of SS-B/La localization, possibly inducing autoimmunity.[20]
Pathophysiology
The pathogenesis of salivary gland damage is multifactorial, thought to involve immunologic, genetic, hormonal, and viral components.[1]
Hyper-reactive polyclonal B lymphocytes produce various autoantibodies in this syndrome.[21] Antibodies binding components of the Ro/La ribonucleoprotein complex are very common (75% to 90% of patients), and are the most unifying immunological feature of the illness.[22] Antinuclear antibodies (90%), rheumatoid factor (approximately 50%), anti-thyroglobulin antibodies (25%), and antibodies to lacrimal and salivary gland extracts are also seen.[21] Recent studies suggest a role for relative complement deficiencies slowing the clearance of apoptotic debris, which may then provide immunogenic Ro/La particles; other work suggests possible T-cell-independent mechanisms of furthering the autoimmune cascade.
Salivary gland biopsies show foci of infiltrates characterized by lymphocytes. Studies have shown that anti-Ro and anti-La-producing B-cells are present in the infiltrates. The infiltrating cells are thought to interfere with glandular function by: a) secretion of cytokines, b) production of autoantibodies that interfere with muscarinic receptors, and c) secretion of metalloproteinases that interfere with the interaction of the glandular cell with its extracellular matrix.[2][23]
There is some evidence to suggest that estrogen may be the major cause of the sex difference. Estrogen strongly affects the course of autoimmune diseases with profoundly contradictory effects and itself is critical for initiation of autoimmunity.[24] Variable expression of estrogen receptor isoforms and distinct estrogen potency (affinity for receptor) has been suggested to contribute to specific cellular sensitivities to female hormones. Females have higher immunoglobulin levels at baseline and produce more immunoglobulin in response to infection or immunization compared with age-matched males. This difference persists only throughout the female reproductive years after first becoming apparent during puberty.[25] Androgens may protect from autoimmunity, and women with Sjogren syndrome may be androgen deficient.[26][27] However, another study showed that X-chromosome gene dose effect may play a role in the sex bias found in Sjogren syndrome. The mechanism for female bias is poorly understood. The trisomy X (47,XXX) was significantly increased in systemic lupus erythematosus and primary Sjogren syndrome, but not in other diseases such as primary biliary cirrhosis, rheumatoid arthritis (both of which have a female bias), sarcoidosis (no female predominance), and normal controls.[28] These results support the idea of further pathways to sex bias in autoimmunity. Another study found an excess of Klinefelter men in Sjogren syndrome compared with Klinefelter in normal control men and men with rheumatoid arthritis.[29]
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