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X-linked agammaglobulinaemia (XLA) is an inherited immunodeficiency that is caused by a block in early B-cell differentiation. Whereas early B precursors in the bone marrow are present in substantial numbers, XLA-affected individuals have dramatically reduced numbers of circulating mature B cells, plasma cells and immunoglobulins of all isotypes. We report on a Japanese family with 3 XLA patients, in whom the serum immunoglobulin levels and number of B cells showed a significant difference among them in spite of harbouring the same splice donor site mutation in the BTK gene. We developed concise method for detection of this mutation, which is helpful for discovering the carrier. Patient 2 showed a significant serum immunoglobulin levels of all isotypes, including allergen-specific IgE. Expression of a normal and truncated size BTK gene was detected in patient 2′s peripheral blood mononuclear cells (PBMCs). Expression of BTK protein was also detected in some B cells. These results suggest that the leaky phenotype in patient 2 was caused in part by the expression of a normal BTK gene transcript. The increased frequency of infection with age expanded the number of B cells with normal BTK gene expression and produced the serum immunoglobulin, including IgE. [ABSTRACT FROM AUTHOR]

The alanine-rich repeating region (A-region) in the surface protein antigen (PAc) of Streptococcus mutans has received much attention as an antigenic component for vaccines against dental caries. The PAc (residue 361–386) peptide in the A-region possesses a multiple binding motif (L- -V-K- -A) to various HLA-DR molecules and a B-cell core epitope (- Y- - -L- -Y- - - -) that recognizes the inhibiting antibody to S. mutans. In the present study, we investigated the immunogenicity of the PAc (361–386) peptide in humans and regulators of induction of the anti-PAc (361–386) peptide IgA antibody (aPPA) in saliva. The PAc (361–386) peptide was confirmed as an ideal peptide antigen for induction of the inhibiting antibody to S. mutans in 151 healthy human subjects (36·6 ± 12·6 years old) by quantitative analyses of oral bacteria and ELISA, as the aPPA titre in human saliva decreased significantly in an age-dependent manner. Homozygous DRB1* 0405 and 1502, and heterozygous DRB1* 0405/1502 showed a negative association with production of aPPA and tended to reduce the number of total streptococci in saliva. In contrast, the DRB1* 1501 allele was significantly correlated with a high level of induction of the antibodies, and also tended to reduce lactobacilli and mutans streptococci. Further, peptide immunogenicity was confirmed in NOD-SCID mice grafted with human peripheral blood mononuclear cells. Our results indicate that the interplay between regulators such as age, DRB1 genotype, cytokines, and peptide immunogenicity may provide a potential means for developing a vaccine useful for the prevention of dental caries as well as their diagnosis. [ABSTRACT FROM AUTHOR]

Selective IgA deficiency is the most common form of primary immunodeficiency, the molecular basis of which is unknown. To investigate the cause of selective IgA deficiency, we examined what stage of B-cell differentiation was blocked. DNA and RNA were extracted from three Japanese patients with selective IgA deficiency and three with a partial IgA deficiency. In selective IgA deficiency patients, I α germline transcript expression levels decreased and α circle transcripts were not detected. Stimulation with PMA and TGF- β1 up-regulated I α germline and α circle transcripts. In some patients, IgA secretion was induced by stimulation with anti-CD40, IL-4 and IL-10. In partial IgA deficiency patients, I α germline, α circle transcripts and C α mature transcripts were detected in the absence of stimulation. Our findings suggest that the decreased expression level of I α germline transcripts before a class switch might be critical for the pathogenesis of some patients with selective IgA deficiency. However, in patients with a partial IgA deficiency, B-cell differentiation might be disturbed after a class switch. [ABSTRACT FROM AUTHOR]

CD4+ cells from autoimmune-prone C57BL/6 lpr/lpr mice contain two subpopulations. B220- CD4+ and B220+CD4+ cells. Highly purified B220- CD4+ cells from C57BL/6 +/+ and lpr/lpr mice were examined by comparing functional characteristics and expression of cell surface antigens and T cell receptor (TcR)/CD3 complex. Both lpr B220+CD4+ and B220+CD4- CD8- cells, most of which were PgP-1 positive, expressed TcR/CD3 complex on the cell surface at lower level as compared with B220- CD4+ cells of age-matched normal mice. In addition, the B220- CD4+ cells were heterogeneous on the basis of surface expression of PgP-1 and CD3 antigens. Normal levels of TcR Cα-. Cβ- and Vβ8-specific mRNA were found in the B220-CD4+ cells and B220+CD4+ cells as compared with normal B220+CD4+ cells, while Vβ8-specific mRNA was preferentially expressed only by B220+CD4--CD8- cells. Either B220+CD4+ cells and B220+CD4- CD8- cells failed to respond to anti-CD3 monoclonal antibody (MoAb) as assessed by proliferative responses and production of interleukin-2 (IL-2). However, appreciable levels of reactivity to anti-CD3 MoAb were detected in the B220- CD4+ cells, although the responsiveness of this subset to such stimuli were reduced, compared with those of normal control. These results indicate that the B220- CD4+ cells in lpr mice are phenotypically and functionally distinct from normal B220-CD4+ cells. [ABSTRACT FROM AUTHOR]

Autoimmune-prone mice homozygous for the 1pr gene develop prominent lymphadenopathy composed mainly of Thy-1+ CD8- CD4- B220+ cells. Expression patterns of B220vsCD4 on lymph node cells from 1pr mice were analysed using two-colour flow microfluorometry. B220+CD4+ cells, which were hardly seen in lymph nodes of B6-+ / + mice, increased significantly in B6-lpr mice with ageing. Functional analysis of purified B220+ CD4+ cells from 1pr mice revealed that these cells scarcely responded to T cell mitogens with or without rIL-2. Furthermore, B220+ CD4+ cells were defective in IL-2 production when cultured with Con A. On the other hand, B220-CD4+ cells from B6-lpr mice showed an ability to respond to T cell mitogens similar to that of B220- CD4+ cells from B6-+/+ mice. These results indicate that an unusual T cell subset expressing both B220 and CD4 in 1pr mice is functionally defective, but the intrinsic ability of B220- CD4+ cells is almost intact as compared with the counterpart in normal mice. [ABSTRACT FROM AUTHOR]

An autosomal recessive gene, lpr, is responsible for lymphoproliferation and autoimmunity of lpr mice, in which background genes are also known to influence the development of autoimmune disease. To define the differences in abnormally proliferating T cells between C57BL/6-lpr/lpr and MRL/Mp-lpr/lpr mice, and to try and understand the influence of background in the differing expression of autoimmune disease in both strains, we analysed the sequences of T cell antigen receptor Vβ genes expressed in the cells from the enlarged lymph nodes of C57BL/6-lpr/lpr mice. Eleven β cDNAs out of the 38 Cβ-specific cDNAs contained sequences with open reading frames from the beginning of the variable region to the expected termination codons at the end of the constant regions. Notably, 36% of the functional β-chain mRNAs expressed Vβ8.3 genes, whereas Vβ8.3 and Vβ8.2 genes were not found. These results are consistent with a relatively lower frequency of the Vβ8.1 or Vβ8.2 expressing cells in the hypertrophic lymph nodes of C57BL/6-lpr/lpr mice, detected by KJI6-133 monoclonal antibody. Interestingly, other Vβ genes expressed in these mice were completely distinct from those in MRL/Mp-lpr/lpr mice as described by Singer et al (1986), The different distribution of Vβ genes expressed in C57BL/6-lpr/lpr from that in MRL/Mp-lpr/lpr mice might be related to the differences in the genetic background and the expression of lpr gene-associated autoimmunity. [ABSTRACT FROM AUTHOR]