Common Varied Immunodeficiency Research Articles

In vitro induction of T cell-dependent B cell differentiation in patients with common varied immunodeficiency

Patients with common varied immunodeficiency (CVI) are characterized by hypogammaglobulinemia. We investigated in vitro T cell-dependent B cell differentiation in CVI peripheral blood mononuclear cells by stimulating the T cells with an anti-CD3 (T3) monoclonal antibody. In cultures from CVI patients with no detectable circulating B cells, little immunoglobulin (Ig) was produced following anti-CD3 stimulation. In cultures from CVI patients with near-normal numbers of circulating B cells, anti-CD3 stimulation induced a normal percentage increase in Ig-secreting cells and appreciable (albeit subnormal) increases in IgG and IgM secretion. Cell-mixing experiments pointed to a quantitative, rather than qualitative, defect in B cell function in most of these CVI patients. Nevertheless, CVI T cells can induce substantial differentiation of autologous (and normal) B cells following anti-CD3 stimulation (which may mimic physiologic stimulation). This raises the possibility of correcting the hypogammaglobulinemia of CVI by in vivo or ex vivo administration of appropriate T cell stimuli.

Incidence of cancer in 98 patients with common varied immunodeficiency.

Ninety-eight patients with common varied immunodeficiency have been observed for periods of 1-13 years. In 1986, 78 were alive, 19 had died, and 1 could not be located. Eleven patients in the group had developed cancer; two patients had had two cancers. Of the total number of neoplastic malignancies, seven were non-Hodgkin's lymphoma, one patient had a Waldenstrom's macroglobulinemia, and nine of the patients who developed cancer were female. Cancer developed in the fifth or sixth decade of life for 10 of the 11 patients. These data show an 8- to 13-fold increase in cancer in general for patients who have this immunodeficiency and a 438-fold increase in lymphoma for females.

Modulation of the immune response by immunoglobulin for intravenous use: II. Inhibitory effects of sera from treated patients

Sera were collected from patients with common varied immunodeficiency (CVI) prior to and following intravenous γ-globulin (IVGG) infusion. Cultures of pokeweed mitogen (PWM)-stimulated peripheral blood mononuclear cells from normal donors in medium containing post-IVGG infusion sera generated significantly fewer plaque-forming cells (PFC) than those cultures in medium containing the corresponding pre-IVGG infusion sera. However, preinfusion CVI sera were found to be similar to normal sera in their capacities to support PWM-induced PFC generation, despite the disparity in Ig levels between the two groups of sera. Furthermore, serum collected from a CVI patient 24 hr or more after IVGG infusion no longer possessed the same inhibitory capacity as serum collected 10 min after IVGG infusion despite elevated IgG levels compared to baseline. These studies suggest that IVGG infusion may induce an immunosuppressive effect which is transient in nature, raising the possibility of in vivo counterbalancing homeostatic mechanisms responding to this immune perturbation.

Dietary bovine antigens and immune complex formation after intravenous immunoglobulin in common varied immunodeficiency.

Previously we have shown that the sera of hypogammaglobulinemic patients may contain large amounts of antigenically intact foreign protein of dietary origin, presumably due to the absence of an adequate gastrointestinal secretory immune barrier. In these studies we show that the intravenous infusion of immunoglobulin in these patients may result in high levels of immune complexes postinfusion and that at least one constituent of these complexes is likely to be bovine casein.

Rescue of IgM, IgG, and IgA production in common varied immunodeficiency by T cell-independent stimulation with Epstein-Barr virus.

We previously defined three categories of B-cell defects in common varied immunodeficiency (CVI): failure to produce IgG and IgA in response to T cell-dependent (TD) stimulation by Staphylococcus bacteria (Sac) plus pokeweed mitogen or B-cell inducing factor (BIF), failure to produce any immunoglobulin, and failure of Sac-induced proliferation and differentiation. The present study includes the responses of 22 CVI patients to T cell-independent (TI) stimulation by Epstein-Barr virus (EBV). In the majority of patients, EBV-stimulated B cells showed normal proliferation and IgM production. In addition, IgG and IgA production was in the range of that for EBV-stimulated normal cells in many patients. Among 11 patients with no TD production of immunoglobulin of any isotype, two showed normal IgM secretion in response to EBV and five others had significant but subnormal responses. Four patients never had humoral responses despite repeated testing and removal of potentially suppressing T cells and monocytes. Concanavalin A stimulation of the T cells from all the patients tested resulted in the production of B-cell inducing factor at higher levels than for normal donor T cells, as assayed on normal Sac-stimulated B cells. These results show that many cases of B-cell defects in CVI patients involving TD production of IgM, switching to TD production of IgG and IgA, and mitogen responses to Sac are not absolute defects. The B cells will respond normally to some stimuli.

Normalization of serum C1q after intravenous immunoglobulin infusions in hypogammaglobulinemia: Dependence upon methods of immunoglobulin preparation

Low levels of serum complement subcomponent C1q may accompany primary humoral immunodeficiency diseases such as sex-linked agammaglobulinemia, severe combined immunodeficiency, and common varied immunodeficiency. This selective depression of C1q is proportional to the degree of hypogammaglobulinemia, and is corrected in severe combined immunodeficiency by bone marrow transplantation or in hypogammaglobulinemia by immunoglobulin infusions, possibly because C1q is stabilized by IgG by reversible interactions which reduce extravascular degradation. In this study it is shown that a pH 4.0 treated intravenous γ-globulin (ivGG) and a reduced and alkylated ivGG can equally increase levels of serum IgG, but that only the pH 4.0 preparation can raise C1q levels into the normal range. These findings show that some of the methods used to produce immunoglobulins suitable for intravenous use may hinder the ability of these molecules to stabilize C1q. The clinical implications of this observation remain unclear.

Interleukin-2 correction of defective in vitro T-cell mitogenesis in patients with common varied immunodeficiency.

We studied the ability of phytohemagglutinin (PHA) and two anti-T-cell monoclonal antibodies, OKT3 and Pan T2, to induce interleukin-2 (IL2) production and proliferation in peripheral blood lymphocytes (PBL) from 14 patients with combined varied immunodeficiency (CVI). The median values of endogenous IL2 produced by mitogen-stimulated PBL was significantly lower in patients than controls irrespective of the mitogen used. The patients, taken as a group, had a significantly decreased in vitro PBL response to mitogen stimulation when compared to controls. With the addition of a highly purified human IL2 preparation, the proliferative response in the majority of patients was significantly improved with all mitogens. Three patient groups could be distinguished: Group A (3/14) had full restoration of proliferative response with the addition of IL2, Group B (5/14) had partial restoration, and Group C (6/14) had no significant response. The monoclonal antibody, Pan T2, recognized a T-cell proliferative defect in 5 of 14 patients which neither PHA nor OKT3 recognized. This was not significantly corrected by the addition of IL2. This T-cell proliferative defect correlated with the lack of B-cell proliferation and immunoglobulin production in response to B-cell mitogens in three-fourths of the patients assayed. These data show that CVI patients are a heterogeneous group but have in common a decreased in vitro production of IL2 resulting in a proliferative defect which is correctable at least in part, in vitro, in the majority by the addition of purified IL2.

Transient Immunoglobulin and Antibody Production

• Two patients with common varied immunodeficiency both had increased immunoglobulin responses for a limited period of time on acquiring a bacterial infection. In one patient a relatively short-lived high-antibody response was produced on vaccination with tetanus toxoid. Although the patients varied in their course of immunoglobulin and/or antibody production, our results demonstrate that some patients with common varied immunodeficiency are able to produce both under certain circumstances. (<i>Arch Intern Med</i>1983;143:1937-1940)

Correction: Three Distinct Stages of B-Cell Defects in Common Varied Immunodeficiency

Correction: Three Distinct Stages of B-Cell Defects in Common Varied Immunodeficiency

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

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

Defective macrophage—T-cell interaction in common varied immunodeficiency

Macrophage—T-cell interaction (MTI) was studied in 9 patients with common varied immunodeficiency (CVID) and in 23 healthy control individuals. Adherent cells of patients and of controls were pulsed with Escherichia coli and subsequently cultured with autologous T-cell-enriched populations (TCE). The proliferative response of the TCE population was estimated by measuring [ 3H]thymidine incorporation after a 7-day culture period. Mean values in controls were 22,852 dpm ± 3263, in patients 3284 ± 1420. respectively ( P < 0.001). Eight of nine patients showed reduced proliferation on the 7th day, in two patients TCE population proliferated with a different kinetic (peak on the 11th day), while MTI of the remaining six patients stayed low. We suggest that defective MTI may contribute to defective immunoglobulin production in CVID.

Zinc deficiency, depressed thymic hormones, and T lymphocyte dysfunction in patients with hypogammaglobulinemia

Zinc deficient humans and animals have depressed thymic mass and increased susceptibility to infection. In the present studies, we investigated the relationship between cellular immunity, thymic hormones, and serum zinc levels in 19 patients with common varied immunodeficiency. Five (26%) had serum zinc levels 2 SD below normal and 11 (58%) had abnormally low lymphocyte proliferation to at least one mitogen. A significant statistical correlation between zinc levels and lymphocyte proliferation to phytohemagglutinin and concanavalin A was identified. Forty-two percent had abnormally low levels of facteur thymique serique and 74% had low levels of thymopoietin, although no statistical relationship between the levels of these hormones, zinc levels, or lymphocyte proliferation could be identified. Three patients with the most profound zinc deficiency had substantial increases in thymic hormones after zinc repletion, and two had complete resolution of intractable diarrhea. A therapeutic potential of zinc for certain patients with hypogammaglobulinemia is suggested.

690 LYMPHOCYTE SUBPOPULATIONS AND FUNCTIONS IN COMMON VARIED IMMUNODEFICIENCY

The clinical and immunological profile of 30 cases with common varied immunodeficiency were analyzed.The common modes of presentation were recurrent or severe infection and allergy. There was a wide variation of immunoglobulin (Ig) levels and of the Ig class affected among patients and their family members. Within individual patients, the Ig concentrations were largely constant, but in 9 children, the levels fluctuated over a wide range. Rosette-forming T cells were reduced in number in one child. The number of B lymphocytes bearing surface Ig was reduced in 2 patients, of pre-B lymphocytes in the bone marrow in 1, and of T cells bearing receptors for IgM-Fc in 3 of 14 patients studied. The number of T cells bearing receptors for IgG-Fc was increased in 3 cases. Suppressor cell activity was demonstrated by coculture of lymphocyte subsets from the patients and healthy adults in one instance. Mitogen-induced lymphocyte DNA synthesis was reduced in 2 children. The study showed the heterogeneity of pathogenetic mechanisms that may underlie the syndrome of common varied immunodeficiency.