Time course of cytokine upregulation in the lacrimal gland and presence of autoantibodies in a predisposed mouse model of Sjögren's Syndrome: the influence of sex hormones and genetic background.

Sjögren's Syndrome (SS) is a chronic, inflammatory autoimmune disease characterized by lacrimal gland lymphocytic infiltration and epithelial cell death, as well as by the presence of serum autoantibodies. Although the symptoms of this syndrome are well characterized, patients are not diagnosed until 5-10 years into disease progression; furthermore, the early series of events leading to the initiation of SS are not well understood. In order to better understand the early events of the disease, we have been using ovariectomized (OVX) NOD.B10.H2(b) mice as a genetically predisposed model of SS. Previously, we have shown that removal of ovarian hormones through ovariectomy accelerated the symptoms of this disease, and in early events of SS in the lacrimal glands, lymphocytic infiltration preceded acinar cell apoptosis. To further elucidate the earlier events of this disease in the SS animal model, we investigated the expression and concentration of pro-inflammatory cytokines in the lacrimal glands as well as the presence of autoantibodies in both lacrimal glands and serum. Six weeks old NOD.B10.H2(b) and C57BL/10 control mice were either sham-operated, OVX, OVX and treated with 17ß-estradiol (E2), or OVX and treated with dihydrotestosterone (DHT). Lacrimal glands were collected at 3, 7, 21, and 30 days after surgery and analyzed for cytokines IL-1ß, TNF-α, IFN-γ, IL-10, and IL-4 gene expression by using quantitative RT-PCR and for cytokine levels using ELISA. Furthermore, anti-Ro/SSA and anti-La/SSB autoantibodies were measured in the serum and lacrimal glands supernatants using ELISA. The results of this study showed that OVX caused a significant increase in the expression and levels of the cytokines IL-1ß, TNF-α, and IL-4 in the lacrimal glands of the NOD.B10.H2(b) mice starting at 3 days after OVX, while a significant increase of IL-10 gene expression and levels was observed only at later experimental time points. A small but significant increase in the expression of IL-1ß and IL-4 was observed only at later experimental time points in the lacrimal glands of OVX C57BL/10 mice, while no significant changes in the expression of TNF-α and IL-10 were seen at any experimental times in this group. No significant differences were observed in the levels of the cytokines IL-1ß, TNF-α, IL-4, and IL-10 in the lacrimal glands of the OVX C57BL/10 mice at any of the experimental times studied compared to the sham-operated group. IFN-γ was not detected in either mouse strains at the level of mRNA and protein. OVX in the NOD.B10.H2(b) mice also caused an increase in the levels of anti-Ro/SSA autoantibodies in the serum only, while no anti-La/SSB autoantibodies were found in the serum or lacrimal gland supernatants. Physiological doses of E2 or DHT at time of OVX prevented the upregulation of cytokines and the presence of anti-Ro/SSA autoantibodies in these animals. These results showed that a decrease in the concentrations of ovarian hormones in the genetically predisposed mice accelerated the onset of the disease by upregulating various pro-inflammatory cytokines at different time points and promoting the formation of anti-Ro/SSA serum autoantibodies, creating an environment favorable for the initiation of SS.

Antibiotic-associated psychosis during treatment of urinary tract infections: a systematic review.

There have been a number of case reports of antibiotic-associated psychosis in the literature that have not been systematically reviewed. Urinary tract infections (UTIs) are among the most common bacterial infections and have also been associated with acute psychosis. We performed a systematic review of cases of antibiotic-associated acute psychosis during treatment of a UTI and evaluated the strength of the association for each case. We identified reports by searching PubMed, PsychINFO, and Web of Knowledge, and the reference lists of identified reports. We systematically evaluated the quality of the causal relationship between antibiotic treatment of UTI and psychosis. Fourteen articles (describing 15 different cases) met the inclusion criteria. The primary findings were as follows: (1) a majority (60%) of reported cases were "highly suggestive" of a potential causal relationship between antibiotic treatment and psychosis, including 3 cases with a recurrence of psychosis after rechallenge with the same antibiotic; (2) 3 different classes of antibiotics were implicated in this association, including fluoroquinolones, penicillins, and trimethoprim-sulfamethoxazole; (3) for most of the reported cases, both the onset and resolution of psychosis occurred within 1 week of initiation and discontinuation of the antibiotic, respectively; (4) approximately half of the cases did not require treatment with antipsychotics; and (5) affected men were significantly more likely to have a psychiatric history. Our findings suggest that acute psychosis is a potential adverse effect of antibiotic treatment of UTI, although the mechanism(s) underlying this association remains unclear.

Influence of sex hormones and genetic predisposition in Sjögren's syndrome: a new clue to the immunopathogenesis of dry eye disease.

Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltration, destruction of lacrimal and salivary glands and the presence of serum autoantibodies. Most women that suffer from SS are post-menopausal however, not all post-menopausal women develop SS, suggesting that other factors, in addition to the decrease in ovarian hormones, are necessary for the development of SS. The purposes of this study were to investigate a) the time course of lymphocytic infiltration and apoptosis in the lacrimal gland after ovariectomy, b) if a predisposed genetic background for SS aggravates the effects of decreasing levels of sex hormones in the lacrimal glands and c) if physiological doses of estrogen or androgen prevent the effects observed after ovariectomy. Six weeks old mice that are genetically predisposed to SS (NOD.B10.H2(b)) and control (C57BL/10) mice were either sham operated, ovariectomized (OVX), OVX + 17ß estradiol (E(2)) or OVX + Dihydrotestosterone (DHT). Lacrimal glands were collected at 3, 7, 21 or 30 days after surgery and processed for immunohistochemistry to measure CD4(+), CD8(+) T cells, B220(+) B cells, nuclear DNA degradation and cleaved caspase-3 activity. Quantification of the staining was done by light microscopy and Image Pro Plus software. The results of our study show that lymphocytic infiltration preceded lacrimal gland apoptosis after ovariectomy. Moreover, removal of ovarian sex hormones accelerated these effects in the genetically predisposed animal and these effects were more severe and persistent compared to control animals. In addition, sex hormone replacement at physiological levels prevented these symptoms. The mechanisms by which decreased levels of sex hormones caused lymphocytic infiltration and apoptosis and the interaction of lack of sex hormones with the genetic elements remain to be elucidated.