Jun Koide

Upregulated expression and function of integrin adhesive receptors in systemic lupus erythematosus patients with vasculitis.

Upregulation of integrin adhesive receptors has been implicated in various pathological conditions. We examined expression and function of integrin adhesive receptors on peripheral blood lymphocytes from patients with systemic lupus erythematosus (SLE), particularly those with the complication of vasculitis, and found that VLA-4 and LFA-1 expression was increased in SLE patients with vasculitis, while LFA-1 but not VLA-4 expression was increased in those without vasculitis. These results suggested a role of VLA-4 in the pathogenesis of vasculitis in SLE. Functional studies further demonstrated that adhesion to cytokine-activated human umbilical cord vein endothelial cells and to the CS-1 alternatively spliced domain of fibronectin was significantly increased in SLE patients with vasculitis. Analysis of the functional epitopes on the alpha 4 chain demonstrated that antigen densities of all the functional epitopes were increased in those with vasculitis, indicating that the increased expression of VLA-4 resulted from the increased number of VLA-4 molecules, and was not secondary to an increase in one particular functional epitope. Immunoprecipitation studies further support these results. Interestingly, high molecular weight bands associated with VLA-4 were observed in about half of the SLE patients with vasculitis. These results introduce a possibility that upregulation of integrin adhesive receptors has a potential role in the pathogenesis of vasculitis in SLE.

Up-regulation of αEβ7, a novel integrin adhesion molecule, on T cells from systemic lupus erythematosus patients with specific epithelial involvement

OBJECTIVE To determine the possible role of a novel integrin, alphaEbeta7, in the pathogenesis of systemic lupus erythematosus (SLE). METHODS Expression of alphaEbeta7 was examined on peripheral blood lymphocytes (PBL) from normal subjects (n = 25) and patients with SLE (n = 31), primary Sjogrens syndrome (n = 7), or polymyositis/dermatomyositis (n = 8) by cytofluorometry and/or immunoprecipitation. Adhesion of alphaEbeta7+ T cells to HSG epithelial cells was investigated using a confocal image analyzer. RESULTS After phytohemagglutinin stimulation, expression of alphaEbeta7 on PBL, especially on CD8+ T cells, was significantly higher in SLE patients than in normal subjects (P<0.01). Elevated alphaEbeta7 expression was associated with the presence of oral ulcers or serositis (P<0.05). Activated SLE T cells with enhanced alphaEbeta7 expression strongly adhered to HSG; this adhesion was partially blocked by anti-alphaEbeta7. CONCLUSION Expression and adhesion of alphaEbeta7 on activated PBL was significantly increased in patients with SLE with epithelial involvement. This suggests a role of this novel integrin in tissue-specific retention of activated PBL, due to increased alphaEbeta7-E-cadherin interaction, which may contribute to epithelial inflammation.

In vitro immune response of SLE lymphocytes. The mechanism involved in B-cell activation

Peripheral blood lymphocytes from 26 patients with systemic lupus erythematosus (SLE) and six normal individuals were tested for IgG synthesis in the presence or absence of PWM. Lymphocytes from patients with active SLE synthesized increased amounts of IgG in the absence of PWM and reduced amounts of IgG in the presence of PWM. Serum from patients with active SLE had an enhancing effect on the in vitro IgG synthesis of normal lymphocytes. The IgG or F(ab′)2 fractions of SLE serum retained the enhancing effect on in vitro IgG synthesis, and the enhancing activity was absorbed by human spleen cells. As little as 4 h of incubation with SLE serum was needed for the enhancing activity of normal lymphocytes. Treatment of B lymphocytes appeared to be of main importance for an increase in the in vitro IgG synthesis of SLE serum‐treated lymphocytes. These results suggest that anti‐B‐lymphocyte antibodies from patients with active SLE are responsible in part for the hyperactive response of SLE B lymphocytes.

Thrombotic thrombocytopenic purpura in two patients with systemic lupus erythematosus: clinical significance of anti-platelet antibodies.

Thrombotic thrombocytopenic purpura (TTP) is a clinical syndrome of unknown etiology and has a high mortality rate due to disseminated platelet thrombi. However, the mechanism of platelet agglutination is not understood. Although an immunological mechanism has been suggested as the basis for the pathogenesis of TTP, any possible immune-mediated etiology remains unclear. The association of TTP with systemic lupus erythematosus (SLE) affords a unique opportunity to study such possibilities, because SLE is a prototype of autoimmune disease. This report describes two patients with SLE who developed TTP. The development of anti-platelet antibodies is one possible immunological mechanism for platelet agglutination in patients with SLE complicated by TTP. More importantly, patient J.Y., who had anti-platelet antibodies, responded dramatically to high doses of prednisolone.

Granulomatous amoebic encephalitis caused by Acanthamoeba in a patient with systemic lupus erythematosus.

A 25-year-old chronically immunosuppressed woman with systemic lupus erythematosus (SLE) died after developing subacute granulomatous encephalitis caused byAcanthamoeba. Amoebic trophozoites were also found in the lung, suggesting a primary pulmonary focus of infection. The infectious encephalitis was difficult to differentiate from a flare-up of central nervous system lupus. This case illustrates thatAcanthamoeba can cause fatal encephalitis in lupus patients, as well as in patients with acquired immunodeficiency syndrome as previously reported. To our knowledge, this is the first reported case of granulomatous amoebic encephalitis due toAcanthamoeba in a patient with SLE.

Systemic lupus erythematosus with necrotizing vasculitis and upregulated expression of VLA-4 antigen

SummaryWe report on a patient (S.A.), with well-defind SLE who developed a perforation of the ileum due to pathologically confirmed necrotizing vasculitis. No anti-DNA antibody was detected at the ileal perforation, and the serum complement level was normal. These findings rais ethe alternative possibility of a cellmediated immune mechanism as a cause of necrotizing vaculitis. Upregulateed expression and function of VLA-4 antigen on peripheral blood T cells were oberved, suggesting that T cells with VLA-4 antigen may participate in the onset and/or perpetuation of vascular inflammation.

CCA [N-(2-carboxyphenyl)-4-Chloroanthranilic acid disodium salt], a newly developed immunomodulating drug, suppresses T-cell activation by acting on macrophages

The cellular mechanism of action of a newly developed drug, CCA,N-(2-carboxyphenyl)-4-chloroanthranilic acid disodium salt, on PHA-, autologous mixed lymphocyte reaction (AMLR)-, and phorbol myristate acetate (PMA)-stimulated T-cell proliferation was investigated. Addition of 50 μg of CCA per milliliter suppressed PHA- and AMLR-stimulaled T-cell proliferation. In contrast. CCA failed to suppress PMA-stimulated macrophage-depleted T-cell proliferation. After treatment of T cells or macrophages with CCA for 12 h, recombined T cells and macrophages were stimulated with phytohemagglutinin. [3H]Thymidine incorporation by T cells was suppressed when macrophages but not T cells were treated with CCA. These results indicate that CCA suppresses T-cell proliferation by acting on macrophages. The mechanism involved in this suppression of CCA was due to the loss of Ia antigen on macrophages and the loss of interleukin-1 (IL-1) secretion from macrophages.

Defects of Autologous Mixed Lymphocyte Reaction‐Activated Immunoregulatory T Cells in Patients with Systemic Lupus Erythematosus

The present study was undertaken to determine the nature of the immunoregulatory T‐cell defect after autologous mixed lymphocyte reaction (AMLR) activation in patients with systemic lupus erythematosus (SLE). Although AMLR was decreased in patients with SLE compared with normals, there was no difference in major proliferative cells (T4 cells and T4+JRA+ subset) in response to AMLR. Functional activity of AMLR‐stimulated T4 subsets in patients with SLE and normals was examined in helper and suppressor/inducer assay, using pokeweed mitogen (PWM)‐driven IgG synthesis. The T4+JRA− (helper) subset from SLE patients showed no greater activity than normals. However the T4+JRA+ (suppressor/inducer) subset from SLE patients showed decreased suppression induction compared with normals. This defect in the suppressor/inducer function was demonstrated even in patients with inactive SLR or in remission.

The Presence of Anti‐Protein A Antibodies in Patients with Rheumatoid Arthritis

Sixteen patients with rheumatoid arthritis (RA) were examined for the presence of anti‐protein A antibodies. The F(ab′)2 preparations from five RA patients showed significant binding lo IgG‐free protein A on ELISA. The protein A binding was further examined by immunoblotting. The F(ab′)2 preparations of high protein A‐binding protein gave A specific reaction with IgG‐free protein A on nitrocellulose paper. This demonstrates the presence of anti‐protein A antibodies in patients with RA. Those RA patients with anti‐protein A antibodies had more active disease as judged by the Lansburys activity index. The level of serum rheumatoid factor (RAHA) was significantly higher in patients with anti‐protein A antibodies than in those without anti‐protein A antibodies.

Suppression of in vitro production of anti-U1-ribonucleoprotein antibody by monoclonal anti-idiotypic antibody to anti-U1-ribonucleoprotein antibody

We produced monoclonal anti‐idiotypic antibody against immunoaffinity purified anti‐U1‐ribonucleoprotein (RNP) antibody from a patient (K.T.), by the cell fusion procedure. The specificity of monoclonal anti‐idiotypic antibody (IgG1, x) was determined by inhibition studies. With the monoclonal anti‐idiotypic antibody, cross‐reactive idiotypes on anti‐U1‐RNP antibodies from unrelated patients with anti‐U1‐RNP antibody was detected in 57% of the samples. The anti‐idiotypic antibody specifically suppressed the in vitro production of anti‐U1‐RNP antibody by lymphocytes from the patient K T., and unrelated patients with a cross‐reactive idiotype, in whom idiotype‐reactive T cells were demonstrated. The results indicate that anti‐idiotypic antibody may modulate the regulation of in vitro anti‐U1‐RNP antibody production.