Lack of association between the Met196Arg polymorphism in the TNFR2 gene and autoimmune diseases accompanied by vasculitis including SLE in Japanese

A polymorphism in high-affinity receptor of TNF (TNFR2) gene, Met196Arg, was reported to be associated with systemic lupus erythematosus (SLE) in Japanese, whereas the association could not be found in Europeans at all and this represents an apparent discrepancy. The association, then, should be tested in other populations to clarify the possible involvement, if any, of the TNFR2 polymorphism in SLE or other related autoimmune diseases. The purposes of this study were to examine the TNFR2 polymorphism in Japanese patients with SLE and to investigate its association with other autoimmune diseases accompanied by vasculitis, mixed connective tissue disease, Buerger's disease, and Takayasu's arteritis. We found no association at all between the TNFR2 polymorphism and any autoimmune diseases including SLE in Japanese.     

An HLA-binding-motif-aided peptide epitope library: A novel library design for the screening of HLA-DR4-restricted antigenic peptides recognized by CD4+T cells

Susceptibility to a series of autoimmune diseases is strongly associated with particular HLA class II alleles. Identification of T cell clones and antigenic epitopes bound by HLA class II molecules involved in autoimmune diseases is critical to understanding the etiology of these HLA class II-associated diseases. However, establishment of T cell clones in autoimmune diseases is difficult because the antigenic peptides are unknown. Peptide library methods which include all possible peptide sequences offer a potentially powerful tool for the detection of cross-reactive antigenic peptides recognized by T cells. Here, we reduced the number of peptides per mixture by utilizing the known binding motifs of peptides for the HLA-DRB1*0405 molecule and evaluated the effectiveness of this library design. Each library mixture evoked a strong proliferative response in the unprimed peripheral blood lymphocytes (PBL) from HLA-DRB1*0405-positive donors but little or no response in the PBL from HLA-DRB1*0405-negative donors. The library also detected antigenic peptides that activated three antigen-specific T cell lines restricted by HLA-DRB1*0405, with different specificities. The motif-based approach thus presents a powerful method for monitoring T cells in large, heterogeneous T cell populations and is useful for the identification of the mimic peptide epitopes of T cell lines and clones. Received: October 3, 1997 / Accepted: October 23, 1997     

Identification of an HLA-DQ6-derived peptide recognized by mouse MHC class I H-2Db-restricted CD8+ T cells in HLA-DQ6 transgenic mice

Summary CD8⁺ T cells from C57BL/6(B6) mice show cytotoxicity to B cell blasts prepared from syngeneic transgenic mice expressing HLA-DQ6 molecules in a mouse MHC class I H-2D^b restricted manner. Although these results suggest that CD8⁺ T cells recognize peptides derived from DQ6 molecule bound to H-2D^b on target cells, no direct evidence so far has been obtained. To clarify this, we synthesized 23 peptides corresponding to DQ6α orβ chain and carrying the motifs of D^b-binding peptides, and examined their capacity to induce cytotoxicity in the CD8⁺ T cell line. We show here that DQA1-2, one of these peptides, induced cytotoxicity of the CD8⁺ T cells when this peptide was pulsed to H-2D^b expressing target cells, as efficiently as HLA-DQ6 expressing target cells did. Thus, our results suggest that DQA1-2 can be naturally processed from DQ6 molecules and recognized by the CD8⁺ T cells in the context of H-2D^b molecules. These results suggest that allogeneic HLA class II molecules are involved in the rejection not only as the ligand for T cell receptor of alloreactive CD4⁺ T cells but also as self-peptides bound to HLA class I molecules recognized by CD8⁺ T cells.     

The levels of cerebrospinal fluid Abeta40 and Abeta42(43) are regulated age-dependently

Decreased levels of cerebrospinal fluid (CSF) Abeta42 is a diagnostic marker of Alzheimer's disease. To clarify the biological basis of this marker, the physiological alterations of CSF Abeta40 and Abeta42 by aging were studied. CSF samples from 92 normal subjects between 8 and 89 years old were measured using a specific ELISA for Abeta40 and Abeta42(43). High concentrations of Abeta40 and Abeta42(43) in the young group, under 29 years old, changed to be at low concentrations in the adult group between 30 and 59 years old. Subsequently, the levels increased again with age. Third order regression analysis showed a significant correlation between the levels of Abeta40 and age (Y = - 169 X(3) + 3.1X(2)- 0.02X + 4135; P < 0.034) and between the levels of Abeta42(43) and age (Y = - 46 X(3) + 0.9 X(2)- 0.005X + 992; P < 0.005). The levels of CSF Abeta40 and Abeta42(43) were physiologically regulated to show a U-shaped natural course in normal aging. These findings suggested that the physiological increase of Abeta42(43) over 59 years of age is selectively inhibited in Alzheimer's disease.     

DNA typing of HLA in the patients with moyamoya disease

Summary Moyamoya disease is a clinical entity demonstrating a chronic occlusion of the cerebrovascular system. Although some possible etiological factors have been postulated, the etiology of this disease is still unknown. So far, some investigations have suggested the association between moyamoya disease and HLA in the serological typing. However, DNA typing of HLA have not been performed yet. Thus, we performed DNA-typing of HLA in the unrelated Japanese patients with definite moyamoya disease, using the polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) technique. In the total patients,DQB1*0502 had a positive association with the disease. On the other hand,DRB1*0405 andDQB1*0401 showed a negative association. In comparing the early-onset and late-onset groups, two groups did not share the same disease associated alleles at all. Thus, the etiology of moyamoya disease seem to have a genetic background. Furthermore, different genetic factors might also be involved in the difference between the early-onset and late-onset groups.     

Activation of human CD8+ suppressor T cells by an antigen-specific CD4+ T-cell line in vitro

We generated an antigen (streptococcal cell wall antigen)-specific T-cell line from peripheral blood mononuclear cells of a healthy donor with an intermediate response to streptococcal cell wall antigen. Proliferation of the T-cell line was completely blocked by a monoclonal antibody to HLA-DR. This line activated autologous CD8+ T cells in an antigen-specific manner in the presence of autologous monocytes. This activation was mediated by a factor derived from this line and was blocked by a monoclonal antibody against HLA class I molecules. The resultant CD8+ T blasts showed antigen-nonspecific suppression but no cytolytic activity. This antigen-specific generation of the CD8+ T-cell line in vitro by the antigen-specific CD4+ T-cell line is expected to contribute to analyses of functions of CD8+ T-cell subsets, particularly in the down-regulating system, at both cellular and molecular levels.