Toshiaki Yamagata

Blockade of IL-18 Receptor Signaling Delays the Onset of Autoimmune Disease in MRL-Faslpr Mice

Autoimmune disease in Fas-deficient MRL-Faslpr mice is dependent on infiltrating autoreactive leukocytes and autoantibodies, and IFN-γ plays an important role in the pathogenesis. As IL-18 is capable of inducing IFN-γ production in T cells, we hypothesized that signaling through IL-18R is involved in the pathogenesis. To investigate the impact of IL-18 in this autoimmune disease, we generated an MRL-Faslpr strain deficient in IL-18Rα. Compared with the wild-type strain, IL-18Rα-deficient MRL-Faslpr mice survived longer and showed a significant reduction in renal pathology, including glomerular IgG deposits, proteinuria, and serum anti-DNA Abs. Intrarenal transcripts encoding IFN-γ, TNF-α, IL-12, and IL-10, which have been linked to nephritis, were all markedly reduced. Skin lesions, lymphadenopathy, and lung pathology characteristic of the MRL-Faslpr mouse disease were diminished in IL-18Rα-deficient MRL-Faslpr mice. Thus, we conclude that IL-18Rα signaling is critical to the pathogenesis of autoimmune disease in MRL-Faslpr mice.

The beneficial effects of treatment with all-trans-retinoic acid plus corticosteroid on autoimmune nephritis in NZB/WF1 mice

Corticosteroids are highly effective anti‐inflammatory or immunosuppressive drugs used commonly to treat human systemic lupus erythematosus (SLE). All‐trans‐retinoic acid (ATRA), which belongs to a class of retinoids that exert immunomodulatory and anti‐inflammatory functions, can also suppress the development of lupus nephritis in an animal model. However, both agents can inflict serious adverse effects. Here, we have asked whether ATRA can serve as a steroid‐sparing drug in the treatment of lupus nephritis. To examine the efficacy of combining predonisolone (PSL) with ATRA, we treated intraperitoneally New Zealand black/white F1 (NZB/W F1) mice with PSL, ATRA or both agents. Survival rate and proteinuria were determined once a month. Cytokine and anti‐DNA antibody production were determined by enzyme‐linked immunosorbent assay (ELISA) and reverse transcription‐polymerase chain reaction (RT‐PCR). Renal histopathology was observed by haematoxylin and periodic acid Schiff (PAS), immunoperoxidase and immunohistochemical assay. Survival rate and proteinuria were improved in all experimental groups, and were much improved in the mice receiving the combination of ATRA and PSL (P < 0·05). A single administration of ATRA reduced the Th1 [interleukin (IL)‐2, interferon (IFN)‐γ and IL‐12], and a Th2 (IL‐4) cytokine level, as effectively as administration of PSL. ATRA also suppressed the expression of inducible nitric oxide synthetase (iNOS) and monocyte chemoattractant protein‐1 (MCP‐1) in the kidney. The combination of PSL and ATRA significantly reduced IgG2 (especially IgG2b)‐specific anti‐DNA antibody levels in comparison with administration of either agent alone. These data suggest that ATRA might have the potential to act as a new therapeutic and steroid‐sparing drug against lupus nephritis.

Survival study by organ disorders in 306 Japanese patients with systemic lupus erythematosus: results from a single center

Survival rate and causes of death according to the period of diagnosis and four accompanying organ disorders were analyzed in 306 Japanese patients with systemic lupus erythematosus. The survival rate was gradually improved, and the survival rate during 5- and 10-year periods of the patients diagnosed in 1990–2004 was 94 and 92%, 20-year period of those in 1980–1989 was 77%, 30-year period of those in 1975–1979 was 71%, respectively. Survival rate of those with serositis, pulmonary hypertension, and positive family history tended to be reduced, while that of the cases with neuropsychiatric disorder and renal disorder was significantly reduced. Overlapping of these organ disorders was an important factor for a poor prognosis. Bronchopneumonia and cerebrovascular accidents were frequent causes of death, and treatment for anti-phospholipid antibody syndrome and life-style diseases such as hypertension and arteriosclerosis was thought to be important for a good outcome.

Predominant inhibition of Th1 cytokines in New Zealand black/white F1 mice treated with FK506.

The T‐helper 1/T‐helper 2 (Th1/Th2) cell balance was examined in 6‐month‐old New Zealand black/white F1 (B/WF1) mice treated with an immunosuppressive agent, FK506. The survival rate of mice treated with 10 mg/kg/day of FK506 was 7/8, while that of those treated with 2.5 mg/kg/day was 5/8, and 4/8 after treatment for 8 weeks with placebo. Proteinuria, which was already positive in all mice before the treatment, in the seven of eight mice treated with 10 mg/kg/day remained mildly positive (≤1+), while seven of eight mice treated with 2.5 mg/kg/day and six of eight mice treated with the placebo showed severe proteinuria (≥2+). Pathological changes in the kidneys of mice treated with 10 mg/kg/day of FK506 were less severe than in mice treated with the placebo or 2.5 mg/kg/day of FK506. Expression of mRNA was unchanged for all cytokines determined in the groups treated with 2.5 mg/kg/day of FK506 or placebo. In contrast, expression of mRNA for interleukin (IL)‐2, and interferon (IFN)‐γ was suppressed, while that for IL‐4 and IL‐10 was not suppressed in the group treated with 10 mg/kg of FK506. The serum levels of IgG‐class anti‐DNA antibodies, which had been elevated before the treatment, were suppressed — especially in the IgG2a subclass — and the deposition of IgG2a and IgG2b in the glomeruli was reduced in the group treated with 10 mg/kg/day of FK506 compared with the other groups. These findings suggest that an improvement in the lupus nephritis of 6‐month‐old B/WF1 mice induced by FK506 might be associated with a predominant inhibition of Th1 cytokine.

All-trans-retinoic acid suppresses interferon-γ and tumor necrosis factor-α; a possible therapeutic agent for rheumatoid arthritis

Objectives: To study the effects of all-trans-retinoic acid (ATRA), we determined the proliferation and cytokine production by peripheral blood mononuclear cells (PBMCs) and CD4+ T cells in healthy volunteers and patients with rheumatoid arthritis (RA), and explored the possibility of using ATRA as a therapeutic agent for autoimmune diseases. Methods: Proliferation of these cells was determined by modified MTT assay, and expression of CC chemokine receptors 4 (CCR4) and CCR5 was determined by flow cytometry. Production and expression of interferon (IFN)-γ, interleukin (IL)-2, IL-4, and tumor necrosis factor (TNF)-α was determined by Enzyme-Linked Immunosorbent Assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR). The presence of STAT6 protein was determined by Western blot analysis. Results: ATRA did not affect the proliferation or production of IL-2 and IL-4. We did not detect STAT6 protein, and saw no evidence of the differentiation of PBMCs to Th1 or Th2 cells. In contrast, ATRA suppressed the production of IFN-γ and TNF-α significantly. There were no significant differences between the healthy volunteers and RA patients. Conclusions: ATRA was demonstrated to affect the cytokine production of IFN-γ and TNF-α. ATRA might be useful in the treatment of autoimmune diseases such as RA.

μ-Heavy Chain Disease Associated with Systemic Amyloidosis

Abstract μ-heavy chain disease (HCD) is very rare, with only 30 cases reported in the literature. We report a patient with μ-HCD associated with systemic amyloidosis. The diagnosis of μ-HCD was based on findings of μ-heavy chain fragments in the serum, Bence Jones proteinuria and vacuolated plasma cells in the bone marrow. To our knowledge, this is the third case in which systemic amyloidosis led to the patients death.

A case of systemic lupus erythematosus that manifested in the course of schizophrenia

A case of schizophrenia is presented in which SLE was diagnosed after 14-year duration. Antibodies to single and double-stranded DNAs, but not to histone, were detected. This case suggests that similar immunological abnormalities as SLE are associated with the pathogenesis of a group of schizophrenia and that class-switch of anti-dsDNA antibodies are important in the pathogenesis of SLE.

全身性エリテマトーデス患者の生活の質(Quality of life, QOL) : 簡便法による予備的検討

Because the prognosis of systemic lupus erythematosus (SLE) has been much improved by recent progress in the treatment of this disease, improvement of quality of life (QOL) will be required more and more. However, QOL in SLE has not been well studied in comparison to that in rheumatoid arthritis. Fifty-four patients with systemic lupus erythematosus were asked about healthy feeling, acceptance of disease and the extent of satisfaction with their life. The percentage of patients who gave affirmative answers to healthy feeling, acceptance, and satisfaction was 64, 87, and 50, respectively. These three parameters were correlated with the following factors; 1. physical activity, especially that for daily living, 2. understanding in the family and workplace, and 3. depression and anxiety, whereas acceptance was not correlated with disease activity. Due to having a chronic disease, there are depression and anxiety derived from loss of existence in the family or workplace in their minds. In order to resolve these issues, education and explanation about the disease is needed for the family and society as well as for the patients. Although compliance of the patients in answering the questionnaire was easily obtained, the reliability and reproducibility, and the relationship between the items and the low-ranking factors should be investigated using a larger number of patients.

Electric charge and sugar chains of immunoglobulin G in systemic lupus erythematosus

BackgroundThe charge condition of anti-DNA antibody is thought to be closely related to the pathology of renal disorders in systemic lupus erythematosus (SLE).MethodsWe examined the relationships among the electric charge of IgG, proteinuria, and DNA binding capacity in SLE patients. Abnormal sugar chains, which affect the IgG charge, were also studied.ResultsIgG in SLE patients with proteinuria had a higher positive electric charge than that in SLE patients without proteinuria, healthy individuals, and patients with other collagen diseases. Anti-DNA antibody titers measured by enzyme-linked immunosorbent assay (ELISA) were high in the positive charge regions of the IgG fractions obtained by a cationic exchange column. The binding capacity of double-stranded (ds)DNA measured by the Farr assay tended to be present specifically in the positive charge region in SLE patients with proteinuria. In affinoblotting using lectins, the percentage of IgG deficient in negative-charged sugar chains was found to be high in patients with a preponderant positive charge on anti-DNA antibody.ConclusionsAbnormal IgG-bound sugar chains result in a preponderantly positive charge and are involved in the etiology of SLE nephritis.

A case of autoimmune polyglandular syndrome type III with a slowly progressive form of type‐1 diabetes mellitus that manifested in the course of autoimmune diseases

Autoimmune polyglandular syndrome (APS) is a group of disorders with multiple autoimmune endocrinopathies. Although the exact cause is not clear, genetic background and autoimmunity are known to be associated with its pathogenesis. There are three types of APS, some of which are often complicated by type-1 diabetes mellitus or Sjögren’s syndrome. However, Sjögren’s syndrome is an autoimmune exocrinopathy and is also complicated by various autoimmune disorders. Here we present a rare case of APS type III with a slowly progressive form of type-1 diabetes mellitus complicated by Sjögren’s syndrome, autoimmune thyroiditis, and probable systemic lupus erythematosus.