Sekigawa I

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.

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.

Relationship between CD4+/CD8+ T cell ratio and T cell activation in systemic lupus erythematosus

We investigated the relationship between the ratio of CD4+ to CD8+ T cells (CD4/CD8 ratio) and T cell activation, indicated by human leukocyte antigen (HLA)-DR expression, in patients with systemic lupus erythematosus (SLE). We found that the ratio was decreased in SLE patients and that this was significantly related to expression of HLA-DR by CD8+ (but not CD4+) T cells. These findings may assist in understanding the pathogenesis of SLE. In some SLE patients, the CD4/CD8 ratio and HLA-DR expression may be good indicators of therapeutic efficacy.

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

A possible pathogenic role of CD8+ T cells and their derived cytokine, IL-16, in SLE.

Current investigations into the role of CD8+ T cells and their derived cytokine, interleukin (IL)-16, in the induction ofCD4+ T cell abnormalities in systemic lupus erythematosus (SLE) were reviewed and discussed on the basis of results mainly obtained in our laboratory

The possible role of interleukin-16 in the low incidence of HIV infection in patients with systemic lupus erythematosus.

Sir ± Systemic lupus erythematosus (SLE) and human immunode®ciency virus (HIV) infection are rarely seen in the same patient,1 ± 3 although autoimmune phenomena observed in SLE are common in HIV infected patients.4,5 It has been estimated that at least 400 people in the United States should have both SLE and HIV based on prevalence data for SLE and HIV infection.6 To date, however, only 20 patients with diagnoses of both SLE and HIV infection have been reported.1 ± 3 Many of the cases of combined HIV infection and SLE reported in the literature involve patients with SLE before HIV infection, and the improvement of SLE is reported to occur with HIV infection and=or deterioration of HIV-related immunode®ciency.1,3 It is unclear why the coexistence of SLE and HIV should be mutually exclusive. Demographic factors may be important, in that SLE tends to be more prevalent in adult women, whereas HIV occurs more frequently in homosexual men. Marked antibody production in SLE may be related to protection against HIV infection.4 In fact, the absence of HIV in patients with SLE who received unscreened blood transfusions between 1978 and 1983 has been reported.6 In addition, chloroquine and its derivatives, which are used in SLE as immunosuppressants, may have potential anti-HIV action.6 Because the important role of CD4x87 T cells in the pathogenesis of SLE has been reported,7 a decline in the number and function of CD4x87 T cells induced by HIV likely explains the reciprocal improvement in SLE and worsening HIV infection. Interleukin (IL)-16 is produced from CD8x87 T cells, and its receptor is located on CD4 molecules.8 Several reports indicate that IL-16 can inhibit HIV-1 infection in vitro,9 ± 11 though there is a contrary report regarding this issue, probably due to a difference in the experimental system used.12 This inhibition is thought to be unrelated to interference of HIV-1 attachment to CD4 because of the difference of binding sites on CD4 between HIV-1 envelope glycoprotein (gp120) and IL-16 (the former is D1, and the latter is probably the D4 domain on CD4),8 and to be caused by suppression of viral mRNA replication through the inhibition of HIV promoter activity via CD4-related signaling of IL-16.10,11 CD8x87 T cells and=or their derived factors in HIV infected patients have been reported to inhibit HIV infection in vitro, though it is still unclear whether IL16 is involved in such factors.13 Furthermore, IL-16 can induce CD4x87 T cell activation, indicated by the expression of human leucocyte antigen (HLA) class II molecules, and anergy such as a suppression of the mixed lymphocyte reaction (MLR) or mitogeninduced IL-2 production.8,14 These abnormalities are also observed in SLE-CD4x87 T cells and in HIV-1 gp120-stimulated CD4x87 T cells.5,7 We recently reported that the serum level of IL-16 in SLE patients is much higher than that in healthy volunteers, and that an increase in serum IL-16 is observed in proportion to the activity of SLE assessed by the SLE Disease Activity Index (SLEDAI) score.15 Furthermore, our results indicated serum IL-16 levels in other connective tissue diseases such as rheumatoid arthritis were signi®cantly lower than those in SLE.15 We think that IL-16 is a useful cytokine in explaining the induction of CD4x87 T cell abnormalities in SLE, and is a good indicator of disease activity. In addition, this cytokine may be one of the protective agents against HIV infection in SLE patients and contributes to the low incidence of HIV infection in the patients with SLE. Although the assay of serum IL-16 is still not widely performed in clinical studies, this cytokine seems to provide valuable insight into possible interacting pathomechanisms of these diseases.

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 and human endogenous retroviruses

Abstract u2002Human endogenous retroviruses (HERV) are known to be widely present in the human genome. Several investigations have suggested a possible etiological role of HERV in certain human disorders, including systemic lupus erythematosus (SLE). Here we review and discuss the possible role of HERV, especially HERV clone 4-1, in the onset of SLE, based on recent findings including our own data.