Three distinct stages of B-cell defects in common varied immunodeficiency.

Abstract

B-lymphocyte function of 15 patients with primary common varied immunodeficiency or related disease were examined. All patients had low serum levels of IgM, IgG, and IgA, but 12 of 15 patients had nearly normal numbers of peripheral blood B lymphocytes. Mononuclear cells and B cells from peripheral blood were assayed for B-cell mitogenic responses to anti-Ig mu chain antibodies or to Staphylococcus aureus strain Cowan I (referred to as Cowan I), and for differentiation to Ig-secreting cells of IgM, IgG, and IgA classes in the presence of Cowan I and pokeweed mitogen or T-cell factor. The patients all showed profound B-cell defects in one or more of the assays and could be divided into three approximately equal groups based on their responses. The first group showed normal proliferation in response to the two B-cell mitogens and near normal numbers of IgM-secreting cells but no IgG- or IgA-secreting cells. B cells in the second group showed proliferative responses to Cowan I or anti-mu, but no differentiation to Ig-secreting cells. The third group had no B-cell proliferative responses or differentiation in our assays. In several patients from each group, (i) helper T cells were functional in Ig-secreting-cell responses with purified normal B cells, (ii) patient T cells did not significantly suppress formation of Ig-secreting cells by normal cells in coculture, and (iii) removal of T cells with addition of T-cell-replacing factor, or partial removal of monocytes, did not alleviate any of the defects. These studies show that primary B-cell defects in common varied immunodeficiency occur at several levels, probably representing blocks at different stages of differentiation.

L-selectin in patients with common variable immunodeficiency (CVID): a comparative study with normal individuals

“…The heterogeneity of the disease in clinical and immunological terms makes it difficult to identify a clear and consistent pattern of abnormalities. In order to overcome this difficulty attempts have been made by many researchers to divide CVID patients into subgroups based on CVID lymphocyte responses to stimulations, such as Staphylococcus aureus Cowan (SAC) or SAC IL-2 [3], SAC pokeweed mitogen (PWM) [4]. A method has also been developed using B-enriched peripheral blood lymphocytes stimulated with immobilized anti-human IgM and IL-2 [5], and three subgroups are identified as groups A, B and C. Analysis of the groups reveals different patterns of abnormalities in B and T cell phenotypes in the peripheral blood of CVID patients [6], and it also appears that certain clinical features are correlated with the subgroups, for example, splenomegaly with group A [7].…”

The costimulatory signal CD28 is fully functional but cannot correct the impaired antigen response in T cells of patients with common variable immunodeficiency

“…due to either intrinsic B cell defects [1,2] or impairment of antigen presentation (3.4|. More recenily.…”

The capacity of interleukin-4 to inducein vitroIgE synthesis by B cells of patients with common variable immunodeficiency

“…The reduced levels of immunoglobulin produced in CVI patients have been attributed to defects in regulatory T cells, and/or B cells or defective monocyte functions (Waldman et al, 1974;Siegal et al, 1976;Schwaber et al, 1978;Mitsuya et al, 1981;Reinherz et al, 1981aReinherz et al, , 1981bLopez-Botet et al, 1982;Saiki et al, 1982Saiki et al, , 1984Jones, 1984;Perri & Weisdorf, 1985;Matheson & Green, 1987), Here we demonstrate that PBMC of two out of eight patients with CVI (patients B and C) could be induced to produce IgE in vitro by IL-4, showing that their B cells, like B cells of the majority of healthy donors, can be induced to switch to IgE producing cells upon interaction with IL-4, Although IL-4 is the sole inducer of IgE synthesis (Pene et al, 1988a(Pene et al, , 1988b) the capacity ofIL-4 to induce IgE synthesis by B cells of healthy individuals is completely dependent on CD4+ T cells (Pene et al, 1989), enhanced by monocytes (Pene et al, 1988a(Pene et al, , 1989 and suppressed by autologous CD8+ T cells (Pene et al, 1989, manuscript in preparation) indicating the multiple cells or factors are involved in a cascade of events finally resulting in IgE synthesis.…”

“…Common variable immunodeficiency (CVI) is a heterogeneous disorder characterized by the failure of B cells to differentiate into antibody-secreting plasma cells (Cooper, Lawton & Bockman, 1971;Preud'homme, Griscelli & Seligman, 1973;Geha et al, 1974;Wu, Lawton & Cooper, 1974;de la Concha et al, 1977;Siegal & Good, 1977;Schwaber, Lazaurus & Rosen, 1978;Saiki et al, 1982), Patients with CVI consequently have reduced levels of serum immunoglobulins and are unable to generate antibody responses against common antigens. The block in B cell differentiation has been attributed to intrinsic B cell defects (Schwaber et al, 1978;Saiki et al, 1982;Jones, 1984;Perri & Weisdorf, 1985), defects in immunoregulatory T cells (Reinherz et al, 1981a(Reinherz et al, , 1981bLopez-Botet et al, 1982;Saiki et al, 1984;Matheson & Green, 1987), defects in monocyte functions (Siegal, Siegal & Good, 1976) or to increased T suppressor cell activity (Waldmanef a/,, 1974;Siegal era/,, 1976;Mitsuya era/,, 1981;Jones, 1984), Normal B cell differentiation procedes through a series of events which require B cell growth and differentiation factors produced by T cells or monocytes (Kishimoto, 1987), However, attempts to induce immunoglobulin production by B cells of Correspondence: Dr Jan E, de Vries, Department of Human Immunology, DNAX Research Institute, 901 California Avenue, Palo Alto, CA 94304-1104, USA, patients with CVI by Epstein-Barr virus (EBV), pokeweed mitogen (PWM) or supernatants of activated T cells containing the necessary B cell growth and differentiation factors, generally results in IgM secretion with no or very low levels of IgG and IgA production (de Gast etal.,\ 980;Perreira, Webster & PlattsMills, 1982;Haber, Kubagawa & Cooper, 1983;Mayer et al, 1984;Perri & Weisdorf, 1985), In addition to the reduced levels of the three major immunoglobulin isotypes, patients with CVI generally have red...…”

“…The block in B cell differentiation has been attributed to intrinsic B cell defects (Schwaber et al, 1978;Saiki et al, 1982;Jones, 1984;Perri & Weisdorf, 1985), defects in immunoregulatory T cells (Reinherz et al, 1981a(Reinherz et al, , 1981bLopez-Botet et al, 1982;Saiki et al, 1984;Matheson & Green, 1987), defects in monocyte functions (Siegal, Siegal & Good, 1976) or to increased T suppressor cell activity (Waldmanef a/,, 1974;Siegal era/,, 1976;Mitsuya era/,, 1981;Jones, 1984), Normal B cell differentiation procedes through a series of events which require B cell growth and differentiation factors produced by T cells or monocytes (Kishimoto, 1987), However, attempts to induce immunoglobulin production by B cells of Correspondence: Dr Jan E, de Vries, Department of Human Immunology, DNAX Research Institute, 901 California Avenue, Palo Alto, CA 94304-1104, USA, patients with CVI by Epstein-Barr virus (EBV), pokeweed mitogen (PWM) or supernatants of activated T cells containing the necessary B cell growth and differentiation factors, generally results in IgM secretion with no or very low levels of IgG and IgA production (de Gast etal.,\ 980;Perreira, Webster & PlattsMills, 1982;Haber, Kubagawa & Cooper, 1983;Mayer et al, 1984;Perri & Weisdorf, 1985), In addition to the reduced levels of the three major immunoglobulin isotypes, patients with CVI generally have reduced serum IgE levels. Recently we demonstrated that both recombinant and natural interleukin-4 (IL-4) can induce IgE synthesis by mononuclear eells derived from healthy donors (Pene et al, 1988a), This IgE-inducing effect of IL-4 is completely dependent of autologous CD4+ T cells (Pene et al, 1989), In addition, it was shown that the IgE inducing effect of IL-4 was inhibited by interferon-gamma (IFN-y) and interferon-alpha (IFN-a) (Pene et al, 1988a) and enhanced by interleukin-5 (IL-5) (Pene et al, 1988c) and interleukin-6 (IL-6) (Pene et al, unpublished results).…”