The influence of sex steroids on Sjögren's syndrome.

Sjögren's syndrome is an autoimmune disease affecting the exocrine glands, most typically salivary and lacrimal glands. In Sjögren's syndrome, the acinar cells of these glands are damaged and destroyed, leading to diminished secretion of saliva and tear fluid. Accordingly, the current American-European criteria of Sjögren's syndrome include xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). In addition to these sicca symptoms and signs, the diagnostic criteria require autoimmune features in the form of Sjögren's syndrome SS-A and/or SS-B autoantibodies and lymphocyte infiltrates in labial salivary glands. Majority of patients with Sjögren's syndrome are women and the diagnosis is usually done when they are 40-50 years old. The cause of Sjögren's syndrome is unknown, but taking into account the female dominance and the late onset, our hypothesis is that sex steroids play a key role in the etiology of Sjögren's syndrome. More specifically, we believe that the driving factor behind Sjögren's syndrome could be lack of androgens. It has been shown that patients with Sjögren's syndrome have low concentrations of circulating dehydroepiandrosterone sulfate (DHEA-S) compared to age-matched healthy controls. Our hypothesis is that patients with Sjögren's syndrome suffer from an insufficient local androgen effect in the exocrine target tissues of the disease because of low systemic levels and/or ineffective local intracrine handling of DHEA-S prohormone. To further clarify the role of sex steroids and the eventual deficiency of androgens, salivary glands are studied using protein markers regulated by androgens or estrogens.

Immunohistopathology of Sjögren's syndrome.

Sjögren's syndrome (SS) is characterized by keratoconjunctivitis sicca and xerostomia, which occur in an autoimmune lacrimal and salivary gland disease characterized by lymphocyte infiltrates of exocrine glands and/or Sjögren's syndrome autoantibody production. It has been reported that aquaporin-5 distribution is abnormal in SS, perhaps as a result of paracrine effect of TNF-alpha. Also the neurogenic regulation of the salivary gland is impaired in SS. Apart from functional changes, the syndrome is also characterized by structural abnormalities of the secretory acinar apparatus. The acinar basement membrane is abnormal as it lacks laminin alpha1 chain, which may impair its capability to induce the progenitor cells to differentiate to acinar cells. CRISP-3 and TMPRSS-2 can be used as androgen markers and LIV-1 and Cyr61 as estrogen markers to study the sexual dimorphism of the salivary glands. Patients with SS seem to have low concentrations of dehydroepiandrosterone, which may predispose women and the exocrine glands to this syndrome.

Increased expression and processing of ADAM 12 (meltrin-alpha) in osteolysis associated with aseptic loosening of total hip replacement implants.

OBJECTIVE: To assess the expression and processing of a disintegrin and metalloproteinase, ADAM 12 (meltrin-alpha), in the formation of multinuclear cells. Methods. In situ hybridization, immunohistochemical staining, and Western blotting of interface membrane around loosened total hip replacement implants. Macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor-kappaB ligand (RANKL) costimulation of human monocytes followed by FACS, immunofluorescence staining, Western blotting, and bone resorption assay. RESULTS: ADAM 12 mRNA-containing mononuclear cells were often seen in a close spatial relationship with ADAM 12-positive multinuclear cells. Morphometric analysis of ADAM 12 disclosed that 53% +/- 2% of all interface cells were ADAM 12-positive compared to 5% +/- 1% in controls (p < 0.001). M-CSF and RANKL were richly present in interface tissue around loosening implants. Upon M-CSF and RANKL costimulation of human monocytes in vitro, the ADAM 12 staining pattern changed over time, and ADAM 12-positive cells formed large mono-, bi-, and multinuclear cells at Day 7 and many multinuclear giant cells and/or osteoclasts at Day 14. Western blot disclosed 90 kDa latent ADAM 12L but also the metalloproteinase-cleaved, fusion-active 60 kDa form transiently just before the burst of fusion. CONCLUSION: ADAM 12, well recognized for participation in cell-cell fusion in myoblast formation, is upregulated and processed upon formation of multinuclear giant cells and osteoclasts. It may play a role in formation of giant cells and osteoclasts around loosened total hip replacement implants.