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PubMedDate not supplied

Unusual course of the hepatitis C virus infection in one patient diagnosed of common variable immunodeficiency.

Common variable immunodeficiency (CV1) is defined by low serum IgG and IgA levels, and it is the second most frequent primary immunodeficiency. The indication for treatment with human gammaglobulin in patients with this syndrome has been well established. Here we report a case history of a patient diagnosed of common variable immunodeficiency, and she had treatment with i.v. commercial gammaglobulin. In the course of the disease, she developed symptoms that make us think about the possibility of hepatitis virus infection. HBV-associated antigens and antibodies, and HCV-Ab were all negative. So, amplification of HCV-RNA by polymerase chain reaction (PCR) was performed, and it became positive in two different determinations. Liver failure got worse quickly and the patient died. About the course of the HCV infection, only 30% of patients with acute hepatitis get biochemical resolution, and 50-70% become carriers and have persistent chronic hepatitis or active chronic hepatitis. In this case, HCV infection showed an unusual acute and fatal course, it is possible that the impaired immune status of the patient could play a role in the acute course of the disease. Therefore, every patient who have intravenous immunoglobulin replacement must be monitored regularly for liver function tests, and by PCR for HCV infection.

Adult↗
PubMed1993

Polyautoimmune syndrome in common variable immunodeficiency.

Common variable immunodeficiency (CVI) is a heterogenous disorder with hypogammaglobulinaemia and multiple bacterial infections primarily involving the sinopulmonary tract. CVI patients have been known to have an increased tendency to develop autoimmune manifestations. Commonly associated autoimmune diseases include immune thrombocytopenic purpura, autoimmune haemolytic anaemia, and rheumatoid arthritis. In this paper we report a case of CVI presenting with multiple unusual autoimmune diseases including parotitis, vitiligo, atrophic gastritis, pernicious anaemia, and primary biliary cirrhosis. To our knowledge, this is the first case of CVI with polyautoimmunity and antimitochondria antibody. Recognition of this association is important because early diagnosis and treatment can greatly influence the prognosis.

Aged↗
PubMed1993

NIH conference. New insights into common variable immunodeficiency.

Common variable immunodeficiency (CVI) is a heterogenous immunodeficiency syndrome characterized by hypogammaglobulinemia, recurrent bacterial infections, and various immunologic abnormalities. In addition to recurrent infections, patients with this syndrome also have an increased incidence of autoimmune disease and malignancy. Because the spectrum of associated diseases is broad, patients with CVI are seen by various medical specialists. This review discusses the pathogenesis, clinical manifestations, diagnosis, and treatment of CVI.

B-Lymphocytes↗
PubMed1994

Tumor necrosis factor and intravenous gammaglobulins in common variable immunodeficiency.

Common variable immunodeficiency (CVI) patients require regular intravenous immunoglobulin substitution therapy (IVGG). We studied eight patients; four of whom had adverse reactions to IVGG, and found that those coincided with elevated tumor necrosis factor-alpha (TNF-alpha) levels during infusion. Those reactions and TNF production were abolished by switching from one IVGG preparation to another in two patients. Reappearance of adverse reactions after switching preparation was preceded by a progressive rise in peak TNF levels in one patient.

Adolescent↗
PubMed1994

Clinical and immunologic studies of common variable immunodeficiency.

Common variable immunodeficiency is a complex primary immuno-deficiency disease that has as its hallmark subnormal amounts of at least two of the three main serum immunoglobulin isotypes. About 45% of cases are diagnosed before the patients reach 21 years of age, but the time of diagnosis may be delayed until even the sixth or seventh decade of life. The main clinical manifestations include sinopulmonary or gastrointestinal infections, autoimmunity, and neoplasia. The molecular defects of this disease are unknown and may involve intrinsic B-cell or T-cell defects, or both. At present, the mainstay of treatment is intravenous immunoglobulin, but experimental methods have shown that other in vivo methods might ultimately be found to ameliorate this immune deficiency disease.

Child↗
PubMed1994

A defect in the early phase of T-cell receptor-mediated T-cell activation in patients with common variable immunodeficiency.

Common variable immunodeficiency (CVID) is characterized by an impairment of specific antibody production and a decrease in all or selected Ig isotypes. Abnormalities at the level of the B cells, T cells, and antigen-presenting cells have been described. In the present study, we have focused our attention on T-cell activation in CVID. T cells from 15 of 24 patients failed to respond to recall antigens (eg, tetanus toxoid, Escherichia coli). Of these 15 patients, 11 were studied in detail and showed significantly decreased T-cell proliferative responses and/or decreased interleukin-2 and interferon-gamma production on T-cell receptor-mediated stimulation with recall antigens and superantigens (staphylococcal enterotoxins [SE]); however, T-cell response to mitogens (anti-CD3 monoclonal antibody, phytohemagglutinin) was normal. The defect in interleukin-2 and interferon-gamma release on tetanus toxoid stimulation could also be documented in purified CD4 T cells of the patients and was present in patients with high and normal CD8 counts alike. Furthermore, patients' T cells failed to mount a significant elevation in free intracellular calcium (Ca++ flux) in response to superantigen, whereas the response to phorbol myristate acetate and ionomycin, bypassing receptor-mediated signaling, was unimpaired. These results indicate a defect in the early phase of T-cell activation after triggering of the T-cell receptor in a significant subgroup of CVID patients.

Adolescent↗
PubMed1994

CD40 ligand expression is defective in a subset of patients with common variable immunodeficiency.

Common variable immunodeficiency (CVI) is characterized by hypogammaglobulinemia and recurrent bacterial infections due to failure of CVI B cells to differentiate in vivo into immunoglobulin-secreting plasma cells. We hypothesized that T-cell dysfunction resulting in abnormal contact-mediated B-cell activation may play a prominent role in the failure of CVI B cells to produce specific antibody. We have previously shown that B-cell proliferation and IgE production after stimulation with anti-CD40 and interleukin (IL) 4 were normal in 22 CVI patients evaluated, indicating that CVI B cells respond to signals delivered via CD40. Here we report that CD40 ligand (gp39) mRNA expression by activated lymphocytes from CVI patients (n = 31) as a group was significantly depressed (P < 0.0001) compared with normal controls (n = 32). gp39 mRNA expression by activated lymphocytes from 13 CVI patients fell below the normal control range. T-cell surface expression of functional gp39 protein was correspondingly low in those patients with gp39 mRNA levels below normal control range and normal in patients with gp39 mRNA levels within normal control range. In CVI patients as a group, gp39 mRNA levels correlated with IL-2 mRNA levels (P < 0.002, r = 0.6) and production (P < 0.001, r = 0.7) but not with gene expression or production of other lymphokines evaluated, suggesting an as-yet-undetermined association between gp39 and IL-2 gene regulation. Of the 13 patients whose activated T cells exhibited gp39 mRNA expression below the normal control range, 2 had normal T-cell-derived lymphokine production, whereas the remaining 11 exhibited broader T-cell dysfunction, resulting in IL-2 deficiency, and in some patients deficient production of other lymphokines as well, reflecting a heterogeneity in the underlying mechanisms leading to depressed gp39 expression in these patients. The observation that both gene and surface expression of gp39 by activated T cells is depressed in a subgroup of CVI patients suggests that inefficient signaling via CD40 may be responsible, in part, for failure of B-cell differentiation in these patients.

Adolescent↗
PubMed1989

Clinical and immunologic analyses of 103 patients with common variable immunodeficiency.

Common variable immunodeficiency (CVI) or hypogammaglobulinemia is a heterogeneous primary immunodeficiency disease in which B cells produce little or no antibody. Since the disease is relatively rare and the spectrum of associated illnesses is broad, patients are given care by a variety of specialists. Thus it has been difficult to determine the incidence of specific complications. In these studies we analyzed 103 consecutively referred CVI patients of age range 3-71 years (average, 29 years) who were followed for a period of 1-13 years (total of 750 patient years). The average serum IgG was 174.4 mg/dl for untreated patients and 301 mg/dl for patients treated with intramuscular immunoglobulin at the time of the first visit. The average IgA was 14.5, and the average IgM was 80.7, with no difference between or after immunoglobulin treatment. About one-half of the patients had T-cell dysfunction, but lymphocyte stimulation responses were inversely related to age, which implies worsened T-cell immunity with age. Serum IgG and IgA levels were found to be statistically associated (P = 0.008), and serum IgG was related to lymphocyte stimulation with concanavalin A (P = 0.01). By 1986, 79 patients were alive, 23 had died, and 1 could not be located. Recurrent bacterial illnesses were common to all patients, and 22% had developed chronic lung disease, 22% autoimmune disease, 15% cancer, 13% hepatitis, and 9% malabsorption. Autoimmune disease was more common in females, and cancer was more likely to develop in the fifth and sixth decades. In 11% of the group, other family members were found to be immunodeficient (hypogammaglobulinemic or IgA deficient). Nine patients died of respiratory insufficiency (with or without other complications), and seven patients died of cancer. These data provide valuable information about the immunologic abnormalities and the spectrum and frequency of illnesses associated with hypogammaglobulinemia.

Adolescent↗
PubMed1992

Possible role of IL-2 deficiency for hypogammaglobulinaemia in patients with common variable immunodeficiency.

Common variable immunodeficiency (CVID) patients are unable to produce specific immunoglobulins after antigen contact in vivo. The aim of this study was to investigate whether in some cases of CVID a decreased de novo synthesis of IL-2 might be the cause of immunodeficiency and whether this deficiency can be corrected by IL-2 supplementation in vitro. Mononuclear cells from 17 CVID patients and from 10 healthy controls were cultured with monoclonal anti-CD3 antibody OKT3, pokeweed mitogen (PWM) or tetanus toxoid (TT) to stimulate IL-2 synthesis. In parallel, in vitro IgG and IgM synthesis was stimulated with Staphylococcus aureus Cowan I (SAC), PWM or TT in the presence or absence of IL-2. While lymphocytes of 11 out of 17 patients produced low to normal amounts of IL-2 upon stimulation with anti-CD3, only three patients showed low IL-2 production in response to PWM and five in response to TT. Regarding immunoglobulin synthesis in vitro, five patients completely failed to produce IgM or IgG upon stimulation with PWM, SAC or TT irrespective of the addition of IL-2. By contrast, four patients did not show any defect in vitro and synthesized normal amounts of IgM and IgG with any of the three stimuli. Finally, eight patients could be reconstituted for PWM-, SAC- and TT-induced IgM and/or IgG synthesis in vitro, by adding IL-2 to the culture system. This enhancing effect of IL-2 could be blocked by adding anti-IL-2 receptor antibodies to the cultures. Our findings indicate that a defective IL-2 synthesis after antigen stimulation may be one reason for the impaired immunoglobulin production in some cases of CVID.

Adult↗
PubMed1993

T-cell abnormalities in common variable immunodeficiency.

Common variable immunodeficiency (CVI) is a heterogeneous condition marked by a number of different immunologic defects. One group of patients, perhaps 60% of the CVI group as a whole, is characterized by T cells that produce reduced amounts of IL-2 (mRNA and protein product), IL-4, and IL-5 (mRNA) when stimulated with phytohemagglutinin. This defect does not extend to all lymphokines, however, because the cells produce normal amounts of interferon-gamma (mRNA and protein product) when exogenous IL-2 is present. Recently, we have reexamined the T cell lymphokine production defect using a panoply of T-cell activation stimuli and have shown that the defect is a subtle one that depends on activation of the cell via the CD3-T-cell receptor complex. Because T cells proliferate normally when stimulated via this receptor, this finding suggests the presence of a "downstream" defect, perhaps one involving the factors that are necessary for activation of lymphokine genes. A second form of CVI, in this case involving approximately 30% of the CVI group as a whole, is characterized by a reduced CD4/CD8 ratio and elevated numbers of CD8+ T cells bearing the CD57 marker. Although the CD4+ T cells in this patient group elaborate normal amounts of IL-2 under various activation conditions, their CD8+ T cells produce increased amounts of interferon-gamma. Furthermore, the CD8+ T cells in this case act as "suppressor" T cells, which suppress IgG production but not IgM production of purified (normal) SAC+, IL-2-induced B cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens, CD↗
PubMed1990

Abnormalities of lymphokine gene expression in patients with common variable immunodeficiency.

Common variable immunodeficiency (CVI) is a syndrome characterized by hypogammaglobulinemia, recurrent bacterial infections, and increased occurrence of both autoimmune disease and malignancy. In our study we examine the expression of lymphokine genes in mitogen-activated T cells from four patients with CVI. T cells from patients with CVI did not differ significantly from normals in total T cell number, CD4/CD8 ratio, CD45R expression, or proliferation in response to PHA. However, T cells from this group of patients did exhibit significant abnormalities of mitogen-induced lymphokine gene expression. T cells from patients exhibited significantly decreased expression of IL-2, IL-4, IL-5, and IFN-gamma when compared to normal controls. In contrast to these abnormal findings, mitogen-activated T cells from patients with CVI expressed normal amounts of IL-2R alpha and c-myc suggesting that these patients have a selective abnormality of T cell activation. Furthermore, it is likely that the deficient production of IFN-gamma by patient T cells is partially due to the abnormality of IL-2 production as the levels of IFN-gamma mRNA detected during the initial IL-2-independent phase of T cell activation were normal and the addition of exogenous rIL-2 was able to normalize IFN-gamma production by PHA-stimulated patient cells. Finally, supernatants from PHA-activated cultures of patients PBMC were deficient in their ability to support Ig secretion by Staphylococcus A Cowan's-activated normal B cells suggesting that these T cell abnormalities may contribute to the pathogenesis of this syndrome.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1994

Clonal hematopoiesis and acquired thalassemia in common variable immunodeficiency.

BACKGROUND: Common variable immunodeficiency (CVID) is defined by hypogammaglobulinemia and increased susceptibility to infections. The gene defect responsible for CVID remains unknown. METHODS: During the course of their CVID disease, a female and three male patients developed microcytic anemia. The investigation of this anemia forms the basis for this report. RESULTS: Reticulocyte globin chain synthesis studies revealed the abnormal alpha/beta ratios that are pathognomonic of thalassemia. Through transcriptional analysis of the glucose-6-phosphate-dehydrogenase (G6PD) locus of the active X-chromosome in blood cells, we determined that the female patient has clonal reticulocytes, platelets, granulocytes, and B and T lymphocytes. CONCLUSIONS: The simultaneous presence of globin synthesis abnormalities and panhypogammaglobulinemia suggests that a common insult at the stem cell level could contribute to the development of CVID and acquired thalassemia.

Adolescent↗
PubMed1996

Analysis of a family containing three members with common variable immunodeficiency.

BACKGROUND: Common variable immunodeficiency (CVID), a diverse immunodeficiency syndrome characterized by low immune globulin levels and recurrent infections, has been observed in families with the HLA A1 B8 DR3 haplotype. METHODS: We report a two-generation family with three members affected by CVID. Immunoglobulin levels, antibody titers, lymphocyte marker analyses, T cell proliferation assays, and HLA typing were performed on the affected family members. RESULTS: Studies of the affected patients revealed low levels of immunoglobulin G and A; normal tetanus, rubella and rubeola antibody titers; low B cell numbers; normal T cell numbers; normal CD4/CD8 ratios and normal lymphocyte proliferation studies. HLA typing did not reveal the HLA A1 B8 DR3 haplotype previously associated with familial CVID. CONCLUSION: We report a family with a unique presentation of CVID involving possible genetic inheritance other than the HLA A1 B8 DR3 haplotype and possessing lymphocyte characteristics distinct from those usually seen in sporadic CVID.

Adolescent↗
PubMed1991

Expression of immunoglobulin genes in common variable immunodeficiency.

Five common variable immunodeficiency (CVI) patients were analyzed for expression of immunoglobulin (Ig) genes. In the pokeweed mitogen (PWM)-induced Ig-production assay, the combination of T and B cells showed that all patients' T cells had normal helper functions and all patients' B cells had profound defects. The defective B-cell maturation stages based on their Ig gene expression patterns were variable. One of five patients showed normal mu-chain gene expression and nearly normal IgM production, but neither IgG nor IgA production, which suggested that this patient's B-cell defects might lie on a mu- to gamma or mu- to alpha class-switch stage. B cells in another patient showed low mu-chain gene expression and low IgM production, but an Ig enhancer region, which is an important region for expression of Ig genes, was intact. Thus, this patient might have a transacting factor defect which interacts with the Ig enhancer region. The other three patients showed no mu-chain gene expression and no IgM production. Thus, their B-cell defects lay on the B-cell maturation stage, similar to X-linked agammaglobulinemia. These results showed that primary B-cell defects in CVI occurred at several B-cell differentiation stages, which could be recognized by expression of Ig genes.

Adult↗
PubMed1992

[Common variable immunodeficiency and sarcoidosis].

Variable Common Immunodeficiency (VCI) can course with non necrotizing epithelioid granulomatosis of sarcoid type. Although this entity is frequently referred, it is rare and its significance is not clear. The immunological study and response to treatment with corticoids and i.v. immunoglobulins of a patient is who suffered VIC with sarcoid granulomas on lymph node, liver and skin biopsies is here presented. The association between VCI and granulomatosis is discussed.

Adult↗
PubMed1993

Defective interleukin-2 and interferon-gamma gene expression in response to antigen in a subgroup of patients with common variable immunodeficiency.

Patients with common variable immunodeficiency (CVID) are heterogeneous in the clinical manifestations of the disease and in the underlying mechanisms leading to the immunodeficiency. The impairment of B-cell function can be due to an intrinsic defect of the B cells, a deficiency in the function of the antigen-presenting cell, or a dysfunction in the course of T-cell activation. In the present report we have focused our attention on T-lymphocyte activation in three patients with CVID. Numbers of T and B cells, as well as CD4 and CD8 T cell subsets, were within the normal range. The patients' B cells secreted IgM but did not secrete IgG and IgA in response to B-cell stimuli in vitro. Addition of allogeneic T cells was followed by an increase in IgM production but had no effect on the other immunoglobulin isotypes. Examination of T-cell function revealed impaired proliferative response, interleukin-2 (IL-2) and interferon-gamma gene expression and IL-2 release after antigenic stimulation, whereas T-cell proliferation, as well as IL-2 gene expression and release in response to stimulation via anti-CD3, were comparable to those of healthy control subjects. Anti-CD3-induced IFN-gamma gene activation in T cells from two patients was comparable to that of control subjects, whereas T cells from the third patient showed reduced expression of IFN-gamma mRNA. In contrast to the decreased IL-2 and IFN-gamma mRNA levels, IL-2R transcripts examined in parallel were normal in CVID T cells on stimulation with antigen. The defect in IL-2 and IFN-gamma mRNA expression after stimulation with antigen, but not with anti-CD3, suggests an abnormality confined to T-cell activation by the T-cell receptor.

Adult↗
PubMed1993

Defective calcium-dependent signal transduction in B lymphocytes of a certain common variable immunodeficiency.

Two different common variable immunodeficiency patients were studied. Patient 1 showed hypogammaglobulinemia in all major classes of gammaglobulins and slightly reduced percentages of circulating CD19+ cells, CD20+ cells and surface IgG-or IgA-bearing cells with a normal percentage of surface IgM-bearing cells. Patient 2 showed normal levels in IgM with IgG and IgA deficiencies and almost normal percentages of circulating CD19+ cells, CD20+ cells and surface IgM-, IgG- or IgA-bearing cells. The proliferative responses of peripheral blood mononuclear cells to B cell mitogen, Staphylococcus aureus Cowan I, were reduced in patient 1 but not in patient 2. The intracellular calcium concentrations in lymphoblastoid cell lines (LCLs) transformed by Epstein-Barr virus from patient 2 were increased after anti-mu stimulation. The concentrations were scarcely increased in LCLs from patient 1. These results suggest that B cells of patient 1 have a defective Ca(2+)-dependent signal transduction pathway, resulting in a failure of cell activation and cell proliferation. The defect in B cells of patient 2 may exist on immunoglobulin gene switching or expression rather than the Ca(2+)-dependent signal transduction pathway.

Agammaglobulinemia↗