[Show abstract][Hide abstract] ABSTRACT: The European Common Variable Immunodeficiency Disorders registry was started in 1996 to define distinct clinical phenotypes and determine overlap within individual patients. A total of 7 centers contributed patient data, resulting in the largest cohort yet reported. Patients (334), validated for the diagnosis, were followed for an average of 25.6 years (9461 patient-years). Data were used to define 5 distinct clinical phenotypes: no complications, autoimmunity, polyclonal lymphocytic infiltration, enteropathy, and lymphoid malignancy. A total of 83% of patients had only one of these phenotypes. Analysis of mortality showed a considerable reduction in the last 15 years and that different phenotypes were associated with different survival times. Types of complications and clinical phenotypes varied significantly between countries, indicating the need for large, international registries. Ages at onset of symptoms and diagnosis were shown to have a Gaussian distribution, but were not useful predictors of phenotype. The only clinical predictor was polyclonal lymphocytic infiltration, which was associated with a 5-fold increased risk of lymphoid malignancy. There was widespread variation in the levels of serum immunoglobulin isotypes as well as in the percentages and absolute numbers of B cells, confirming the heterogeneity of these conditions. Higher serum IgM and lower circulating CD8 proportions were found to be predictive markers for polyclonal lymphocytic infiltration and autoimmunity, respectively.
[Show abstract][Hide abstract] ABSTRACT: Common variable immunodeficiency (CVID) is the most common primary antibody deficiency syndrome in humans, but it remains a diagnosis of exclusion in most cases. Several genetically defined primary immunodeficiencies mimic CVID. Among them is the X-linked lymphoproliferative syndrome (XLP) which was shown to be caused by either mutations in the gene SH2D1a/SAP or, more recently, in the BIRC4/XIAP gene.
We therefore analyzed a cohort of 28 male CVID patients and 2 patients with an IgG subclass deficiency for the prevalence of mutations in BIRC4, encoding for XIAP by direct sequencing.
All patients showed a wild-type sequence of BIRC4/XIAP. Two SNPs, rs5956583 (dbSNP126) located in exon 6 (P-->Q) and rs28382740 (dbSNP126) in the 3' untranslated region were observed at the same frequencies as reported in public databases.
We found no patient with a defect in the coding sequence of BIRC4/XIAP in our cohort of 30 hypogammaglobulinemic patients. We therefore estimate that XLP caused by XIAP deficiency may be a very rare differential diagnosis in male patients with CVID.
International Archives of Allergy and Immunology 06/2008; 147(2):147-51. DOI:10.1159/000135702 · 2.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A 77G allele of the gene encoding CD45, also known as the protein tyrosine phosphatase receptor-type C gene (PTPRC), has been associated with multiple sclerosis (MS). Here we determine allele frequencies in large numbers of MS patients, primary immunodeficiencies linked to major histocompatibility complex (MHC) locus and over 1,000 controls to assess whether aberrant splicing of PTPRC caused by the 77C-->G polymorphism results in increased susceptibility to these diseases. Our results show no difference in the frequency of the 77G allele in patients and controls and thus do not support a causative role for the polymorphism in the development of disorders with a strong autoimmune component in etiology.
[Show abstract][Hide abstract] ABSTRACT: Common variable immunodeficiency (CVID) is an heterogeneous syndrome characterized by decreased levels of serum Ig and recurrent bacterial infection. Here, we were interested to study whether a qualitative defect of the affinity Ab maturation process could be combined to the low level of serum Ig in a cohort of 38 CVID patients. For this, we designed a novel and rapid screening test for the detection of hypomutated V gene expressed by memory B cells. This test delineated a subset of 9/38 (23%) CVID patients with an abnormal pattern of Ig V gene mutation. The mean frequency of V gene mutation of this subset was significantly lower (1.74%) compared with other CVID patients (5.46%) and normal donors (6.5%) (p<0.0001). The mean age of this subgroup was significantly higher than other hypogammaglobulinemic patients with normal levels of V gene mutation (p<0.02), whereas no difference in the duration of symptoms was noted between the two groups. This suggests that hypomutation characterizes patients who began CVID late in life. Recently, it was shown that non-Ig sequences, such as the intronic BCL-6 gene, could be the target of the somatic hypermutation process in normal memory B cells. Our finding of a normal mutation frequency of the BCL-6 gene in two hypomutated CVID point to a defect of the Ig targeting of hypermutation machinery in these cases.
The Journal of Immunology 10/2000; 165(8):4725-30. DOI:10.4049/jimmunol.165.8.4725 · 4.92 Impact Factor