The EUROclass trial: defining subgroups in common variable immunodeficiency

Abstract

IntroductionCommon variable immunodeficiency (CVID) is the most common primary immunodeficiency in adults. 1 Recurrent bacterial infections of the respiratory tract are the clinical hallmark present in nearly all patients. 2 In addition, up to 40% of the patients show gastrointestinal disease, concomitant lymphoproliferative disorders, autoimmune phenomena, or granulomatous inflammation. 2 The pathogenic understanding of antibody deficiency in humans has always been hampered by the great heterogeneity of the syndrome. 3 In 1966, Rosen and Janeway started to group antibody deficiencies by their mode of inheritance. 4 In 1973, Cooper included the clinical course and serum immunoglobulin levels, thereby separating hyper-IgM syndromes and selective IgA deficiency. 5 The remaining group of still very heterogeneous antibody deficiencies was termed CVID. Consecutive attempts to subclassify CVID by B-cell function in vitro 6,7 failed to reach diagnostic acceptance because of laborious and poorly standardized procedures and a lack of clinical relevance.In 2002, we and others suggested a flow cytometric classification of CVID according to the B-cell phenotype. 8,9 The abnormalities of circulating B cells in patients with CVID had already been recognized earlier, 10 but only with the ease and the broad availability of flow cytometry was a widespread and systematic analysis of these aberrations possible. The Freiburg classification divided patients into 3 groups by analyzing the expression of IgM, IgD, CD27 and CD21. 8 Group 1 was characterized by a severe reduction of switched memory B cells (IgD Ϫ IgM Ϫ CD27 ϩ less than 0.4% of lymphocytes), while group 2 representing 25% of the analyzed CVID patients exhibited nearly normal numbers of class-switched memory B cells, suggesting a post germinal center defect. The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. Methods PatientsAll patients were diagnosed as having CVID based on the European Society for Immunodeficiencies/Pan-American Group for Immunodeficiency (ESID/PAGID) criteria, 11 including a marked decrease of IgG (at least 2 standard deviations [SDs] below the mean for age) and a marked decrease in at least one of the isotypes IgM or IgA, the onset of clinical significant immunodeficiency at greater than 2 years of age, and the exclusion of defined causes of hypogammaglobulinemia (see also www.esid.org). Not all patients have been evaluated for absent isohemagglutinins and/or poor response to vaccines. For the final evaluation of B-cell phenotyping, the following exclusion criteria were adopted: patients younger than 6 years of age at the time of flowcytometric evaluation, patients on immunosuppressive treatment, patients suffering currently from malignancies, and patients with less than 1% peripheral B cells. Altogether, 303 patients of origi...

Common variable immunodeficiency: Crossroads between infections, inflammation and autoimmunity

“…SMB develop in the germinal centers of lymph-nodes in a T-dependent manner, and their reduction may depend on functional defects in either B or T helper cells. Clinically, a severe reduction in SMB is associated with a higher risk of granulomatous disease and splenomegaly (39), suggesting that a most profound lack of B cell maturation is likely to be associated with the abnormal cellular or cytokine environment that supports granuloma formation (20). CVID patients had significantly fewer Treg than controls, and a low frequency of Treg is clinically associated with splenomegaly (46,47), granulomatous disease (48), and autoimmune cytopenia (49).…”

Autoimmune Manifestations in Common Variable Immunodeficiency

“…Brouet et al [7] were the first to recognize the potential lack of B cells bearing CD27 in CVID, and this was amplified by Agematsu and Ochs [8]. Subsequently, the lack of switched memory B cells (B cells of the CD27 + , IgM-IgDphenotype) were characteristic of a large proportion of subjects with CVID, and that there relative lack of these cells could be used to divide patients into two clinically and immunologically different groups [3,9,10]. The lack of switched memory B cells was also found related to a lack of antibody production to pneumococcal vaccine, and interestingly, in these and other studies, also to the presence of autoimmune disease [11,12].…”

Telomere‐dependent replicative senescence of B and T cells from patients with type 1a common variable immunodeficiency

“…Only a small proportion of CVID patients can be classified by the underlying genetic defect [2], and current classifications are mainly based on the B-cell phenotype [3,4]. A subset of CVID is hallmarked by the expansion of an unusual population of B cells with reduced expression of CD21 (CD21 low ); these patients are classified as CVID group 1a according to the Freiburg study [3].…”

“…A subset of CVID is hallmarked by the expansion of an unusual population of B cells with reduced expression of CD21 (CD21 low ); these patients are classified as CVID group 1a according to the Freiburg study [3]. Clinically, CVID 1a is characterized by a late onset, autoimmunity and benign polyclonal lymphoproliferation [3,4]. In addition, several T-cell abnormalities have been described in CVID 1a patients [5].…”