Hm. Wolf

Anti-inflammatory properties of human serum IgA : induction of IL-1 receptor antagonist and FcαR (CD89)-mediated down-regulation of tumour necrosis factor-alpha (TNF-α) and IL-6 in human monocytes

A deregulated expression and/or release of large amounts of inflammatory cytokines such as IL‐1 and TNF‐α accounts for most pathophysiological events in a variety of systemic inflammatory diseases, the effect being mediated by the interaction of these cytokines with their respective receptors. IL‐1 receptor antagonist (IL‐1Ra), mainly produced by monocytes/macrophages, is an inhibitor of IL‐1 activity. The present study shows that human serum IgA induces significant IL‐1Ra release in human peripheral blood mononuclear cells and adherent monocytes. IgA induced higher levels of IL‐1Ra than Haemophilus influenzae type b (Hib) expressing lipopolysaccharide (LPS), purified LPS or phorbol myristate acetate (PMA), without induction of IL‐1β release, and even inhibited LPS‐induced IL‐1β release. Induction of IL‐1Ra by IgA could be detected both at the mRNA and protein levels in resting and activated monocytes. Ligation of FcαR with MoAb MY‐43 or treatment with human serum IgA induced protein tyrosine phosphorylation in human monocytes, and herbimycin A, a specific inhibitor of protein tyrosine kinase activity, inhibited IgA‐induced IL‐1Ra production, suggesting that FcαR‐mediated induction of tyrosine phosphorylation is required for the IgA‐induced stimulation of IL‐1Ra release. In addition, triggering of FcαR with MoAb specifically down‐regulated TNF‐α and IL‐6 release in human monocytes activated with Hib. By the induction of IL‐1Ra and down‐regulation of the release of inflammatory cytokines such as IL‐1β, TNF‐α and IL‐6, interaction of IgA with human monocytes may actively contribute to the regulation of the inflammatory response.

Defective integration of activating signals derived from the T cell receptor (TCR) and costimulatory molecules in both CD4+ and CD8+ T lymphocytes of common variable immunodeficiency (CVID) patients

CVID is characterized by hypogammaglobulinaemia and impaired antibody production. Previous studies demonstrated defects at the T cell level. In the present study the response of purified CD4+ and CD8+ T lymphocytes to stimulation with anti‐TCR monoclonal antibody (the first signal) in combination with anti‐CD4 or anti‐CD8, anti‐CD2 and anti‐CD28 MoAbs (the costimulatory signals) was investigated. Both CD4+ and CD8+ T cells from the patients showed significantly reduced IL‐2 release following stimulation via TCR and costimulation via CD4 or CD8 and CD2, respectively. However, normal IL‐2 production following TCR plus phorbol myristate acetate (PMA) costimulation and normal expression of an early activation marker, CD69, after TCR + CD28 stimulation indicated that TCR was able to transduce a signal. Furthermore, both IL‐2 and IL‐4 release were impaired in CD4+ lymphocytes following TCR + CD28 stimulation. In addition, stimulation via TCR + CD28 resulted in significantly decreased expression of CD40 ligand in the patients. These results suggest that the integration of activating signals derived from the TCR and costimulatory molecules is defective in CVID patients; the defect is not confined to costimulation via a single molecule, or restricted to cells producing Thl‐type cytokines such as IL‐2, and is expressed in both CD4+ and CD8+T cell subsets.

Antigen presentation by common variable immunodeficiency (CVID) B cells and monocytes is unimpaired.

CVID is a primary immunodeficiency syndrome comprising a heterogeneous group of patients with hypogammaglobulinaemia and defective formation of specific antibodies. Previous studies demonstrated defective T cell responsiveness to antigen in a major subgroup of patients. In the present study we investigated the capacity of peripheral blood monocytes and Epstein–Barr virus (EBV)‐transformed B cell lines from seven patients with CVID, including two patients expressing an extended MHC haplotype described to be associated with CVID, to present antigen (Tet. Tox.) to CD4+ antigen‐specific T cell lines from healthy controls. The results presented show an unimpaired capacity of peripheral blood monocytes to present antigen in all patients studied. In addition, the present study demonstrates for the first time that CVID B cells function normally as antigen‐presenting cells (APC). These findings indicate that expression of a certain MHC phenotype in CVID is not associated with a defect in the presentation of recall antigen by monocytes and B cells. Based on these studies, uptake, processing and re‐expression of recall antigen in association with MHC class II molecules on the APC surface are functional and there is no indication for structural abnormalities of the MHC class II molecules expressed by the patients studied that could be essential for their function in antigen binding and presentation.

T cell differentiation and generation of the antigen‐specific T cell repertoire in man: observations in MHC class II deficiency

The circulating T cell pool of an MHC class II‐deficient patient was shown to lack the MHC class II‐specific T cell functions. This was demonstrated by the absence of MHC class Il‐specific alloreactive T cells and a substantially decreased number of circulating CD4+ lymphocytes. The patients T cells did respond to an allostimulus, although the restriction pattern of this reaction remains speculative. The function and distribution of peripheral T cell subsets from the patient resemble findings in MHC class II‐deficient mice, which also lack interaction of T cell precursors with MHC class Il‐bearing accessory cells during thymic differentiation. Our data support the concept that Tcell differentiation in humans is similar, and that the human MHC‐restricted Tcell repertoire depends on prior interaction of T cell precursors with self MHC.