We report 10 cases of glomerulonephritis following methicillin-resistant Staphylococcus aureus (MRSA) infection. The clinical features of this syndrome were an abrupt or insidious onset of rapidly progressive glomerulonephritis (RPGN) with nephrotic syndrome and occasionally purpura, following MRSA infection. The renal histologic findings showed a variety of types of proliferative glomerulonephritis with varying degrees of crescent formation; immunofluorescence revealed of glomerular deposition of IgA, IgG, and C3. Laboratory findings showed polyclonal increases of serum IgA and IgG, with high levels of circulating immune complexes (ICs). Increased numbers of DR+CD4+, and DR+CD8+T cells were observed in the peripheral circulation, with a high frequency of T cell receptor (TCR) V beta + cells. MRSA produced enterotoxins C and A and toxic shock syndrome toxin (TSST)-1, all of which are known to act as superantigens. From the above observations, we speculate that post-MRSA glomerulonephritis may be induced by superantigens causing production of high levels of cytokines, and polyclonal activation of IgG and IgA. The formation of ICs containing IgA and IgG in the circulation result in development of glomerulonephritis and vasculitis. Accordingly, microbial superantigens may play an important role in the pathogenesis of this unique syndrome of nephritis and vasculitis.

S. aureus cell envelope antigen is a new candidate for the induction of IgA nephropathy.

UV radiation is an important environmental factor in the pathogenesis of skin aging and cancer. Many harmful effects of UV radiation are associated with generation of reactive oxygen species. Cellular antioxidants prevent the occurrence and reduce the severity of UV-induced photoaging and diseases of the skin. The transcription factor Nrf2 (NF-E2-related factor 2) and its negative regulator protein, Keap1 (Kelch-like-ECH-associated protein 1), are central regulators of cellular antioxidant responses. We used nrf2-null mice to investigate the roles of the Nrf2-Keap1 system in protection of skin from harmful effects of UVB irradiation. A single irradiation with UVB induced stronger and longer lasting sunburn reaction in nrf2-null mice. Histological changes, including epidermal necrosis, dermal edema, inflammatory cell infiltration, sunburn cell formation, TUNEL-positive apoptotic cell formation, and accumulation of oxidative DNA products such as 8-hydroxy-2'-deoxyguanosine after UVB irradiation, were more prominent in nrf2-null mice. These findings indicate that the Nrf2-Keap1 pathway plays an important role in protection of the skin against acute UVB reactions, including cutaneous cell apoptosis and oxidative damage. However, there were no significant differences in skin carcinogenesis between nrf2-null and wild-type mice exposed to chronic UVB irradiation, suggesting that there is a complex and subtle balance between factors promoting and preventing photocarcinogenesis. Journal of Investigative Dermatology (2008) 128, 1773-1779; doi:10.1038/sj.jid.5701245; published online 17 January 2008.

Previous studies of epidermal-specific gene promoters suggested that a limited set of transcription factors regulate keratinocyte-specific and differentiation-specific gene expression in the epidermis. In the present study, we investigated the functional importance of AP-1- and Sp1-binding elements in the determination of cell type-specific and differentiation-specific gene expression by transient transfection into undifferentiated and differentiated keratinocytes as well as into various non-epidermal cell lines. Synthesized short AP-1- and/or Sp1-binding elements were inserted into a minimal reporter vector, and the artificial promoter containing both AP-1 and Sp1 elements showed high levels of transcriptional activity only when transfected into differentiated keratinocytes. Promoters containing either the AP-1 or the Sp1 motif alone showed little activity in any of the cells examined. We also found that close proximity of the Sp1 and AP-1 sites is essential for transcriptional activity, suggesting that the physical interaction between Sp1 and AP-1 factors is important for functional activity. These results clearly demonstrate that the combination of ubiquitously expressed transcription factors AP-1 and Sp1 confers keratinocyte specificity and differentiation specificity on the gene expression. Our findings also provide a simple model of the mechanisms underlying regulation of cell type-specific and cell differentiation-specific gene expression by ubiquitously expressed transcription factors.

Loricrin is a major component of the epidermal cornified cell envelope, and is expressed only in terminally differentiated keratinocytes. This cell differentiation-specific expression pattern suggests specific suppression of loricrin gene expression in undifferentiated keratinocytes as well as its activation in differentiated keratinocytes. We identified a negative regulatory sequence element in the first intron of the mouse loricrin gene involved in suppression of loricrin gene expression in undifferentiated keratinocytes. A database search indicated that this sequence contained the putative inverted Yin-Yang 1 (YY1)-binding motif. Constructs with point mutations in the putative YY1-binding motif showed increased reporter activity, indicating that YY1 negatively regulates loricrin gene transcription. Co-transfection experiments using a YY1 expression vector revealed that YY1 represses loricrin promoter activity. Western blotting and immunohistochemical analyses indicated that YY1 is more abundant in undifferentiated than in differentiated keratinocytes. These findings suggest that YY1 contributes to specific loricrin gene expression in differentiated keratinocytes by suppression of its transcription in undifferentiated keratinocytes. Furthermore, we demonstrated that forced expression of YY1 in differentiated keratinocytes results in specific downregulation of expression of other early and late differentiation markers.

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