Hitoshi Ogasawara

Exacerbation of systemic lupus erythematosus related to cytomegalovirus infection

We report two patients with systemic lupus erythematosus (SLE) in whom cytomegalovirus (CMV) infection may have played a significant role in the exacerbation or onset of symptoms. The first patient had thrombocytopenia and the second had proteinuria. CMV infection was observed in both patients when their symptoms developed.

Possible mechanisms of gender bias in SLE: a new hypothesis involving a comparison of SLE with atopy.

The prevalence of systemic lupus erythematosus (SLE) is far higher in females than in males, and numerous investigations of this gender bias have been performed from several perspectives. Sex hormones, particularly estrogens, may be significant in causing the gender discrepancy. This article discusses the possible importance of estrogens in regulating the expression of and responsivity to autoantigens in SLE and in atopic disorders, which are associated with hyperreactivity to exogenous antigens. Estrogens seem to play an important role in the overexpressionof endogenousautoantigens, such as human endogenousretroviruses (HERV), and this may be related to the existence of a gender bias in the incidence of SLE but not atopy.

DNA methylation: its contribution to systemic lupus erythematosus.

AbstractRecent studies on epigenetics, including the methylation of DNA and the enzymes regulating methylation, seem likely to contribute to understanding the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). In fact, the relationship between DNA methylation and SLE has long been the subject of investigation. To obtain a deeper understanding of the role of DNA methylation in the onset of SLE, we reviewed the findings reported in the literature and our own data about DNA methylation and SLE. Various studies have indicated the possible importance of DNA methylation, especially hypomethylation, in the aetiology of SLE. Epigenetic studies may provide clues for elucidating the pathogenesis of SLE and for developing new strategies to treat this disease.

Analysis of human immunodeficiency virus type 1 integration by using a specific, sensitive and quantitative assay based on real-time polymerase chain reaction.

A novel real-time nested-PCR assay was developed to quantify integrated human immunodeficiency virus type-1 (HIV-1) DNA with high specificity and sensitivity. This assay reproducibly allowed the detection of three copies of integrated HIV DNA in a background of 100,000 cell equivalents of human chromosomal DNA. The non-specific amplification of unintegrated HIV-1 DNA was significantly inhibited in this assay and the specificity of this assay was much higher than the previously reported method. This assay showed that kinetics in viral DNA sysnthesis was cell-type dependent and that the kinetics of HIV-1 DNA integration was very rapid in Jurkat T cell line. This method may provide new insights into the integration processes and be useful in evaluating future integrase inhibitors.

DNA methylation in systemic lupus erythematosus.

Recent studies on epigenetics, including DNA methylation and its regulatory enzymes, seem likely to contribute to elucidation of the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE), although the relationship between DNA methylation and SLE has long been the subject of investigation.To obtain a deeper understandingof the role of DNA methylation in the induction of SLE, we reviewed the relationship between DNA methylation and SLE based on findings reported in the literature and our own data. Various studies, including ours, have indicated the possible importance of DNA methylation, especially hypomethylation, in the etiology of SLE. These epigenetic studies may give us clues towards elucidation of the pathogenesis of SLE and development of new therapeutic strategies for this disease.

Estrogen receptor expression by peripheral blood mononuclear cells of patients with systemic lupus erythematosus

To investigate the influence of sex hormones on the development of systemic lupus erythematosus (SLE), we examined the estrogen receptor (ER) expression by peripheral blood mononuclear cells (PBMC) in patients with SLE using the real-time quantitative polymerase chain reaction (TaqMan) method. The expression of messenger RNA (mRNA) for ER alpha (ERa) was increased and expression of ER beta (ERb) mRNA was decreased in PBMC from SLE patients compared with PBMC from normal controls. These findings may be useful for elucidation of the pathophysiology of SLE.

Immune Abnormalities Induced by Human Endogenous Retroviral Peptides: With Reference to the Pathogenesis of Systemic Lupus Erythematosus

P15E is a specific sequence among the envelope gene (env)-encoded transmembrane proteins of exogenous and endogenous retroviruses. A synthetic peptide (CKS-17) that shows homology to this p15E region in several species of retrovirus is known to induce immune abnormalities. In this study, we examined the effect of a synthetic peptide derived from a region of human endogenous retrovirus (HERV) clone 4-1 (λ 4-1) similar to sequences of CKS-17 on the induction of systemic lupus erythematosus (SLE)-related immune abnormalities. Our results indicated that this peptide could induce T-cell activation and anergy in normal peripheral blood mononuclear cells, and the peptide could also promote the production of interleukins IL-6 and IL-16. These phenomena are representative immune abnormalities observed in SLE patients. Thus, our findings support the possibility that HERV acts as a pathogen in human SLE.

Sequence Analysis of Human Endogenous Retrovirus Clone 4-1 in Systemic Lupus Erythematosus

Human endogenous retroviruses (HERV) have emerged as a possible cause of systemic lupus erythematosus (SLE). We previously detected serum antibodies to the gag region of HERV clone 4-1 in patients with SLE, but not in normal volunteers. In the present study, we detected clone 4-1 messenger RNA (mRNA) in peripheral blood mononuclear cells (PBMC) from SLE patients and performed sequence analysis of the cDNA or genomic DNA from clone 4-1 in these patients. Clone 4-1 mRNA was detected in all of the SLE patients tested, although it was not found in normal controls. Sequence analysis of clone 4-1 in these SLE patients revealed inactivation of the stop codons in part of the gag region. In addition, a computer search of current sequence libraries revealed that the clone 4-1 gag genomic DNA from SLE patients was more highly homologous with the clone 4-1 sequence in chromosome 11 from normal individuals when compared with the sequence of clone 4-1 integrated in the other chromosomes. It is possible that transcription of clone 4-1 from chromosome 11 occurs in SLE, and that the stop codon inactivation contributes to the translation of clone 4-1 gag proteins in patients with this disease

Expression of DNMT-1 in patients with atopic dermatitis.

DNA methylation is known to play an important role in gene transcription and alterations of methylation that contribute to the development of certain disorders such as cancer, immunodeficiency, and autoimmune diseases. We investigated the DNA methylation profiles in patients with atopic dermatitis (AD). Messenger RNA (mRNA) levels for DNA methyltransferase-1 (DNMT-1) in peripheral blood mononuclear cells (PBMC) were examined using a real-time quantitative polymerase chain reaction method. The levels of DNMT-1 mRNA were significantly lower in PBMC from the AD patients who had higher serum IgE levels compared with normal controls. Our observations suggest that suppression of DNMT-1 might be related to the pathogenesis of AD, especially in whom serum IgE level is high. This is the first report of DNMT-1 expression in AD patients.

Very low-dose cyclosporin treatment of steroid-resistant interstitial pneumonitis associated with Sjögren's syndrome.

Cyclosporin is known to be effective for both transplantation and a spectrum of immune-mediated diseases. Because this agent also causes severe adverse effects, especially nephrotoxicity, careful monitoring is required for the development of such reactions. Here we report the successful treatment with extremely low-dose cyclosporin (1 mg/kg/day) of a patient who had steroidresistant interstitial pneumonitis and Sjögrens syndrome.