In vivo modulation of cytokine synthesis by intravenous immunoglobulin. (1/340)

We examined the effects of intravenous immunoglobulin (IVIG) on cytokine regulation in vivo using samples taken before and after replacement-dose (200-400 mg/kg) IVIG in a group of patients with common variable immunodeficiency (CVID) and X-linked agammaglobulinaemia (XLA). The intracellular cytokine content of CD4+ and CD8+ lymphocytes, and their CD28+/- subsets, were measured following in vitro activation with phorbol myristate acetate (PMA) and ionomycin. The cytokines IL-2, interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha), and the early activation marker CD69, were assessed by four-colour flow cytometry of whole blood cultures taken before and after IVIG infusion. There was a significant increase in IL-2 expression in CD4+ (and CD4+28-) cells and an increase in TNF-alpha expression in CD8+28- cells following IVIG in CVID, but not in XLA patients. IFN-gamma and CD69 expression were not affected by IVIG infusion. This increase in TNF-alpha and IL-2, combined with unchanged IFN-gamma expression, is evidence against the putative 'anti-inflammatory' role of IVIG, and may explain the failure of resolution of granulomata in CVID patients treated with IVIG alone.  (+info)

HLA class II homozygosity confers susceptibility to common variable immunodeficiency (CVID). (2/340)

Most cases of CVID occur sporadically, but familial cases do also occur and 15% of the patients with the disease have first degree relatives with IgA deficiency (IgAD). Our purpose was to study CVID association with HLA class II alleles and to ascertain whether this disease shares a common genetic background with IgAD in our population. Patients with CVID (n = 42), were typed using gene amplification and sequence-specific oligonucleotide probing for HLA-DRB1, DRB3, DQA1 and DQB1 loci and their typing compared with that of 96 IgAD and 334 healthy controls. We observed a positive association between non-Asp residues at position 57 of the HLA-DQbeta chain and CVID, although much weaker than in IgAD. Further, we found an association between CVID and homozygosity for genes encoding HLA class II molecules, especially HLA-DQ, not seen in IgAD. The data support the hypothesis that a restricted diversity of HLA class II molecules may contribute to susceptibility to CVID.  (+info)

Gastric pathology in patients with common variable immunodeficiency. (3/340)

BACKGROUND/AIMS: Common variable immunodeficiency (CVID) is an immunological disorder characterised by defective antibody production. Patients with CVID have a high risk of gastric cancer. It has been suggested that gastric cancer results from an interaction between environmental factors and a genetic predisposition. The role of Helicobacter pylori as an environmental factor in gastric carcinogenesis is of current interest. Moreover, p53 gene mutations have been reported in gastric cancer. This study focuses on the gastric pathology of patients with CVID and correlation with H pylori infection. METHODS: Thirty four consecutive dyspeptic patients with CVID (mean age 49.6 years, range 14-72; 17 men) were included in the study. An upper gastrointestinal endoscopy was performed and biopsy specimens were taken from the antrum, incisura angularis, and gastric body. Biopsies were used for histological assessment, to identify the presence of H pylori, and to evaluate p53 overexpression. RESULTS: H pylori infection was detected in 14/34 (41%) patients. Chronic active gastritis involving both antrum and body was observed more frequently in H pylori positive (79%) than H pylori negative (20%) patients (p = 0.001). Similarly, a histological feature of multifocal atrophic gastritis was found more frequently in infected (50%) than uninfected patients (10%) (p = 0.012). In addition, one case of gastric adenocarcinoma and another of notable dysplasia were observed in the H pylori positive group. Overexpression of p53 was found in six (18%) patients, including one with normal gastric mucosa. CONCLUSIONS: It can be hypothesised that both H pylori and p53 alterations play a role in the gastric carcinogenesis of patients with CVID.  (+info)

Effect of IVIG on the hair regrowth in a common variable immune deficiency patient with alopecia universalis. (4/340)

Common variable immune deficiency (CVID) is associated with a variety of autoimmune diseases. Alopecia universalis (AU), believed to have an autoimmune basis, has been found in 1.6% of patients with CVID. Intravenous immunoglobulin (IVIG) therapy is used in various immunodeficiency disorders including CVID, and benefit has been shown in the therapy of autoimmune diseases. We report a patient with CVID and AU treated with IVIG who experienced significant hair regrowth. An 8-year-old girl with CVID and AU was treated with IVIG 400 mg/kg every 4 weeks. Since her second dose of IVIG, regrowth of eyelashes, eyebrows, body and scalp hair was observed in this patient. At present, about 1 year treat-meant of IVIG, significant hair regrowth is noted with 5-6 cm of scalp hair. We believe that IVIG may be beneficial in the treatment of AU, at least in patients with CVID.  (+info)

Identification of a subset of common variable immunodeficiency patients with impaired B-cell protein tyrosine phosphorylation. (5/340)

The mechanisms responsible for common variable immunodeficiency syndrome (CVID) are as yet unknown. In the present study, we show that the B-cell dysfunction in a subset of CVID patients is caused by defective protein tyrosine phosphorylation (PTP). We demonstrated that the PTP level and immunoglobulin (Ig) secretion malfunctions can be successfully repaired when normal plasma membrane components are implanted into these patients' B cells. Stimulation of CVID patients' peripheral blood mononucleated cells with anti-Ig antibody revealed that 7 of 11 patients had lower PTP levels than those found in the normal donor cells. Plasma membrane implantation to the cells of these patients resulted in elevated PTP levels which reached normal levels upon stimulation with anti-human Ig antibody. The results revealed two distinct groups of CVID patients. The first group included patients whose B cells expressed low PTP levels after Ig stimulation. In these patients the plasma membrane implantation restored the normal PTP level as well as the ability to secrete IgM and/or IgG after B-cell stimulation. In the second group, patients whose B cells expressed a normal PTP level after Ig stimulation, with no restoration of their ability to secrete Ig upon plasma membrane implantation and lipopolysaccharide stimulation. We conclude that the first group has an early signal transduction defect located in the B-cell plasma membrane, while in the second group the defect is located elsewhere.  (+info)

Up-regulation of IL-12 in monocytes: a fundamental defect in common variable immunodeficiency. (6/340)

We show that LPS-stimulated circulating CD14-positive monocytes from patients with common variable immunodeficiency (CVID) express a higher proportion of intracellular IL-12-positive cells than monocytes from patients with X-linked agammaglobulinemia or normal subjects. We used four-color flow cytometry and measured IL-12 with an Ab to the p40 subunit following stimulation with LPS. The raised IL-12 is associated with an increased frequency of IFN-gamma-positive T cells, but not of IFN-gamma-positive CD56+ NK cells. These increases in frequency of cytokine-positive cells are due to a decrease in the absolute numbers of circulating monocytes and T cells that are negative for IL-12 and IFN-gamma, respectively. The increased frequency of IL-12-positive monocytes appears to be selective because TNF-alpha was not increased, and is thus unlikely to reflect a general activation. Chronic infection is also unlikely to explain our data since cells from X-linked agammaglobulinemia patients with a similar Ig deficiency do not show these changes. Our data suggest a fundamental abnormality in the IL-12/IFN-gamma circuit in CVID, with up-regulation of IL-12 being the "primary" factor. This imbalance is likely to skew the immune response away from Ab production and also explains the failure of CVID T cells to make Ag-specific memory cells and the chronic inflammatory and granulomatous complications that are a feature of CVID. This disease appears to be a rare example of a polarized Th1-type response and may in part be due to a genetic defect in the control of IL-12 production.  (+info)

Lymphoid interstitial pneumonitis associated with common variable hypogammaglobulinaemia treated with cyclosporin A. (7/340)

Lymphoid interstitial pneumonitis (LIP) is a rare clinicopathological entity that may be associated with common variable immune deficiency (CVID) and may lead to respiratory failure and death. Some patients may respond to prolonged corticosteroid treatment. We hypothesised that, in view of the predominant T cell nature of LIP, cyclosporin A would be a more appropriate choice of immunosuppressive agent and report the first case of its successful use in a woman with LIP associated with CVID.  (+info)

Long-term outcome of chronic hepatitis C virus infection in primary hypogammaglobulinaemia. (8/340)

The clinical course of HCV infection in patients with primary hypogammaglobulinaemia appears to be more severe than in immunocompetent patients. We studied the long-term course of chronic HCV infection in 20 Norwegian hypogammaglobulinaemia patients with a 13-15 year known history of HCV infection. Twelve of 20 patients developed cirrhosis during the observation period (1984-1999), and the remaining eight also had chronic liver disease verified by liver biopsy in the majority of the cases. Eleven of the 20 patients are dead. Two died following liver transplantation for HCV cirrhosis. Five died due to terminal liver failure without receiving a liver allograft. Two patients died from other causes, but with advanced liver disease contributing to the outcome, while two deaths were unrelated to the HCV infection. Among patients with common variable immunodeficiency (CVI), five out of six are dead. Two patients cleared the hepatitis C virus 3 years following interferon monotherapy, while three patients achieved a sustained response to combination therapy with interferon and ribavirin. Viral load did not seem to have a major impact on disease progression. Our results emphasize the severity of hepatitis C virus infection in patients with hypogammaglobulinaemia. Patients with CVI appear to have the poorest prognosis.  (+info)

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