Antibody against chromatin assembly factor-1 is a novel autoantibody specifically recognized in systemic lupus erythematosus.

Autoantibodies to proliferating cell nuclear antigen (PCNA) are specifically, if rarely, present in systemic lupus erythematosus (SLE) patient sera. Even SLE patients lacking PCNA reactivity often show reaction to PCNA-binding protein. Here, immunoreactivity to chromatin assembly factor-1 (CAF-1), an essential molecule for DNA replication and a PCNA-binding protein, was compared for the sera of SLE patients, normal healthy controls (NHCs) and other disease controls, and in autoimmune sera reactive to standard autoantigens, by enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescence, and immunoblotting. CAF1 and IRF1 expression in SLE and NHC peripheral mononuclear cells were compared by quantitative real-time polymerase chain reaction. Serum interferon-γ-inducing protein-10 and anti-double-stranded (ds)DNA antibody levels were measured by ELISA. Increased CAF-1 autoimmune reactivity was recognized in SLE or serum anti-dsDNA antibody-positive patients. Significantly greater central nervous system (CNS) involvement (aseptic meningitis) and serum anti-dsDNA antibody titers were present more often in anti-CAF-1 antibody-positive than antibody-negative SLE patients. IFN-γ positively regulated CAF-1 expression in vitro and was associated with anti-CAF-1 antibody production in SLE. Thus, a novel anti-CAF-1 autoantibody is frequently found in patients with SLE and is a useful biomarker for diagnosis, especially in cases with CNS involvement. Aberrant IFN-γ regulation appears to play an important role in anti-CAF-1 antibody production in SLE.

Possible role of the JAK/STAT pathways in the regulation of T cell-interferon related genes in systemic lupus erythematosus.

Changes in gene expression in CD3+ T cells associated with disease progression in systemic lupus erythematosus (SLE) patients were determined. The genes related to SLE disease-related activities were identified and their gene regulatory networks were investigated. Analyses of gene expression were performed by both DNA microarray and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). The expression of certain genes including interferon (IFN) regulatory factor (IRF)-related genes, such as IFN-regulated, -related, and -signature genes was increased in the active phase of SLE. Pathway network analyses suggested that these IRF-related genes are regulated through the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. JAK/STAT pathway-mediated regulation of IRF-related genes may have an important role in the disease activity of SLE. Inhibitors of JAK/STAT cascade may be useful as therapeutic agents.

Changes in the gene expression of peripheral blood mononuclear cells during the menstrual cycle of females is associated with a gender bias in the incidence of systemic lupus erythematosus.

OBJECTIVE: The incidence of systemic lupus erythematosus (SLE) is far higher in females than in males and the onset and/or disease activity is influenced by pregnancy and the menstrual cycle. Sex hormones seem to influence the pathogenesis of SLE, therefore, changes in gene expression in peripheral blood mononuclear cells (PBMC) were examined during the menstrual cycle in females, under the comparison of gene expression of patients with SLE. METHODS: The detection and a quantitative analysis of the gene expression was performed by DNA microarray or real-time quantitative polymerase chain reaction (RQ-PCR) method. RESULTS: There were thirteen known genes which showed significant quantitative changes during the menstrual cycles of females, but not in males. Among these genes, statistical quantitative differences between normal controls and SLE patients were observed in six genes. CONCLUSION: Based on these findings, certain genes (such as the tumor necrosis factor receptor superfamily, member 14; TNFRSF14, and signal regulatory protein, gamma; SIRPG) appear to contribute to gender difference of SLE.

Protein biomarker analysis by mass spectrometry in patients with rheumatoid arthritis receiving anti-tumor necrosis factor-alpha antibody therapy.

OBJECTIVE: To investigate the mechanism of action of anti-tumor necrosis factor-alpha (TNF-alpha) antibody in patients with rheumatoid arthritis (RA), we analyzed serum or plasma proteins by mass spectrometry system. METHODS: Ten RA patients who received treatment with anti-TNF-alpha antibody were studied. Samples obtained before and after therapy were analyzed by a two-dimensional liquid chromatography tandem mass spectrometry (2D LC-MS/MS) system after pretreatment by a recently developed method to remove high molecular weight proteins. RESULTS: Using this system, certain proteins were identified after treatment with anti-TNF-alpha antibody, including proteins related to the TNF-alpha-mediated pathway for nuclear factor kappa B (NF-kappaB) activation and/or to the metabolism (including regeneration) of articular cartilage. CONCLUSION: Our mass spectrometry system appears to be useful for proteomic analysis. The efficacy of anti-TNF-alpha antibody therapy for RA may be related to various consequence of the inhibition of TNF-alpha activity.

DNA methylation: its contribution to systemic lupus erythematosus.

Recent 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.

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 overexpression of endogenous autoantigens, such as human endogenous retroviruses (HERV), and this may be related to the existence of a gender bias in the incidence of SLE but not atopy.

Possible importance of immunoglobulin E in foetal loss by mothers with anti-SSA antibody.

OBJECTIVE: The incidence of foetal loss and/or adverse foetal outcomes, including congenital heart block (CHB), has been investigated in mothers with anti-SSA antibody detected by immunodiffusion or counter-immunoelectrophoresis methods. We investigated the relationship between several serum parameters (such as autoantibodies and immunoglobulins) and foetal loss in patients with anti-SSA antibody, measured by enzyme-linked immunosorbent assay (ELISA). MATERIAL AND METHODS: Thirty-seven women who showed positivity for anti-SSA antibody and had a history of pregnancy were included in this study. Immunoglobulins and several autoantibodies were assayed by routine laboratory methods at our hospital. RESULTS: Our data indicated that immunoglobulin E (IgE) levels were significantly higher in the anti-SSA antibody positive women with foetal loss than in those without, and that a strong positive correlation between IgE and anti-SSA antibody levels was observed in the former group, but not in the latter. CONCLUSION: The serum IgE level seems to be an important factor in the occurrence of foetal loss in mothers with anti-SSA antibody detected by ELISA.

Systemic lupus erythematosus-like autoimmune abnormalities induced by bacterial infection.

Recent evidence has revealed that bacterial DNA can promote several of the autoimmune abnormalities observed in systemic lupus erythematosus (SLE), and a possible pathogenic role in the induction of SLE has been highlighted. We have recently encountered patients in whom bacterial infection (septicemia) triggered the production of several autoantibodies. This seems to be interesting with respect to the consideration of the relationship between SLE and bacterial infection.

Allergic diseases in systemic lupus erythematosus: prevalence and immunological considerations.

We attempted to obtain a deeper understanding of the relationship between systemic lupus erythematosus (SLE) and allergic diseases through comparative studies. Accordingly, we reviewed the association of both disorders and compared their immunological features based on the literature and our own findings. Recent studies (including ours) have indicated that the risk of IgE-mediated and/or associated allergic diseases is not markedly increased in SLE patients despite their more allergic family history when compared with controls, in contrast with earlier studies. This may be related to a change of the environmental factors contributing to allergy. In addition, assessment of the immunological similarities and differences between SLE and various allergic diseases seems to be useful for understanding the relationship between them.

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 understanding of 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.

Possible role of DNA hypomethylation in the induction of SLE: relationship to the transcription of human endogenous retroviruses.

OBJECTIVE: We investigated the contribution of DNA methyltransferase activity to the transcription of human endogenous retroviruses (HERV), which have been reported to be a plausible causative agent for systemic lupus erythematosus (SLE). METHODS: The reverse transcriptase-polymerase chain reaction (RT-PCR) and real-time quantitative-PCR (RQ-PCR) were used. RESULTS: Our results indicated that treatment with 5-aza-deoxycytidine (5-aza C), a demethylating agent, increased the transcription of messenger RNA (mRNA) for HERV clone 4-1 and decreased mRNA for DNA methyltransferase-1 (DNMT-1; methylation-regulating enzyme) in peripheral blood mononuclear cells (PBMC) from normal individuals. Also, transcription of DNMT-1 mRNA in PBMC from patients with SLE was lower than in cells from normal controls. CONCLUSION: DNA hypomethylation seems to play a significant role in the transcription of HERV clone 4-1 and may be related to the pathogenesis of SLE.

Allergic disorders in systemic lupus erythematosus: prevalence and family history.

The relationship between allergic disorders (such as atopic dermatitis, asthma, allergic rhinitis and allergic conjunctivitis) and systemic lupus erythematosus (SLE) is still unclear and controversial. We investigated the prevalence of these allergic disorders in SLE patients and their families. A questionnaire about the history of allergy was completed by 52 SLE patients and by 52 matched (including race, age, sex and region) non-SLE controls. Our results indicated that there was a significantly lower incidence of these allergic diseases in SLE patients, especially those who had an allergic family histories, when compared with the controls. These findings may be related to the immunological similarities and differences between SLE and various allergic diseases.

Cytomegalovirus infection in patients with systemic lupus erythematosus.

Cytomegalovirus (CMV) infection is known to induce several autoimmune abnormalities in mice that resemble those found in systemic lupus erythematosus (SLE). In addition, a potential role for CMV in the development and/or progression of SLE has been suggested. In order to further clarify this issue, we reviewed the relationship between SLE and CMV infection on the basis of the clinical and immunological features of cases reported in the literature and our own patients.

Lessons from similarities between SLE and HIV infection.

OBJECTIVE: We attempted to obtain deeper understanding of systemic lupus erythematosus (SLE) and human immunodeficiency virus (HIV) infection through comparative studies between both diseases. METHOD: For this purpose, we reviewed and discussed lessons from similarities in both diseases based on our own and reported findings in literatures. RESULT: Such comparative studies may contribute to the progress in understanding the clinical or pathogenetic features of these diseases. CONCLUSION: Further studies into the relationship between SLE and HIV infection may bring to light important clues to assist in the development of better treatments for each disease.