Autoimmunity in common variable immunodeficiency: Correlation with lymphocyte phenotype in the French DEFI study

Abstract

Common variable immunodeficiency (CVID) is the most frequent clinically expressed primary immunodeficiency in adults and is characterized by primary defective immunoglobulin production. Besides recurrent infectious manifestations, up to 20% of CVID patients develop autoimmune complications. In this study, we took advantages of the French DEFI database to investigate possible correlations between peripheral lymphocyte subpopulations and autoimmune clinical expression in CVID adult patients. In order to analyse homogeneous populations of patients with precise clinical phenotypes, we first focused on patients with autoimmune cytopenia because they represent prototypic autoantibody mediated diseases. In a secondary analysis, we have tested our conclusions including all “autoimmune” CVID patients. We describe one of the largest European studies with 311 CVID patients, including 55 patients with autoimmune cytopenia and 61 patients with clinical or serologic autoimmune expression, excluding autoimmune cytopenia. We clarify previous reports and we confirm a very significant correlation between an increased proportion of CD21^low B cells and CVID associated autoimmune cytopenia, but independently of the presence of other autoimmune disorders or of splenomegaly. Moreover, in CVID associated autoimmune cytopenia, T cells display an activated phenotype with an increase of HLA-DR and CD95 expression and a decrease in the naïve T cell numbers. Patients with other autoimmune manifestations do not harbour this “T and B cells phenotypic picture”. In view of recent findings on CD21^low B cells in CVID and RA, we suggest that both a restricted subset of B cells and a T cell help are required for a breakdown of B cell tolerance against membrane auto antigens in CVID.

Introduction

Common variable immunodeficiency (CVID) is the most frequent clinically expressed primary immunodeficiency in adults, and is characterized by low serum levels of IgG and usually of IgA or of IgM. As a consequence, patients can develop, often late in life, recurrent bacterial infections, mostly in the upper respiratory tract. This common clinical picture may result from multiple mechanisms. Although the vast majority of CVID patients do not have a defined genetic defect, failure of T cell/B cell-cooperation, primary T cell defects or primary B cell defects have been reported [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17].

Beside infectious manifestations, other clinical complications in CVID patients have been largely described as chronic enteropathy, benign or malignant lymphoproliferation, granulomatous disease and autoimmune disorders including autoimmune cytopenia [18], [19]. Thus, more than 20% of patients with common variable immune deficiency (CVID) have autoimmune complications which are poorly understood and in many cases difficult to manage on the clinical level [18], [20], [21], [22], [23]. The pathogenesis of autoimmunity in CVID has always been a paradox: autoantibodies or auto reactive B cells may be produced against some tissues whereas at the same time, few, if any, IgG are detected in the serum or after vaccinations. A way to address this paradox could be to identify in CVID patients lymphocyte sub-populations that could harbour auto reactive clones or reflect a pathway of abnormal activation of the immune system.

An European classification based on the main B cell abnormalities, which were the reduced percentages of B cells, of switched memory B cells (smB: CD27⁺IgD⁻) and an increase in the proportion of CD21^low cells (CD19^hiCD21⁻CD38⁻) helped to differentiate patients with the diagnosis of CVID [24]. In a previous work, patients with reduced smB (<0.4% of lymphocytes) and increased CD21^low (defined only on CD19⁺CD21⁻) B cells tended to have more autoimmune cytopenia and splenomegaly [[25], 40 CVID patients]; however, recently, the expansion of CD21^low B cells pointed only patients with splenomegaly [[23], the EURO class study, 303 CVID patients]. T cell abnormalities in CVID associated autoimmune manifestations have also been suggested as a more pronounced decrease in regulatory T cell numbers [12], [11] or a decrease in CD8T cell numbers [19]. The heterogeneity of the findings could be linked to the rarity of the pathology but one could also underline the difficulties in establishing homogeneous patient cohorts, considering the various potential manifestations of clinical or serologic autoimmunity.

In this study, we took advantage of the French DEFI database to investigate possible correlations between peripheral blood T and B cell subpopulations and autoimmune clinical expression in 311 adult patients with CVID [French DEFI study, [26]]. For each case, autoimmune manifestations have been recorded, and an extensive B and T lymphocytes immunophenotyping was centralized.

In order to analyse homogeneous populations of patients with precise clinical phenotypes, we first focused our analysis on patients with autoimmune cytopenia because they represent prototypic autoantibody mediated diseases and because they are the most frequent manifestations in CVID. In a secondary analysis, we have tested our conclusions including all “autoimmune” CVID patients.

The aims were to determine in the DEFI cohort clinical and immunologic phenotype of CVID patients with autoimmune manifestations 1) to test and possibly improve and unify previous data (see supra), 2) to test the hypothesis that common B and T cell abnormalities in different primary immunodeficiencies can be associated with autoimmunity.