Immune competence and switched memory B cells in common variable immunodeficiency

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Abstract

Common variable immunodeficiency (CVID) is presumed to be a heterogenous group of disorders with potentially separate etiologies. Memory B cell subsets, characterized by CD27 expression, have been suggested as a means to subclassify CVID patients. 53 patients were subdivided based on percentages of switched memory B cells (CD27+IgMIgD): 33 were placed in Group I (<0.4% CD27+IgMIgD cells/peripheral lymphocytes) and 20 in Group II (>0.4%). The median serum IgG for subjects in Group I was lower at 145 mg/dl vs. 329.5 mg/dl for Group II (P = 0.038). Post-pneumococcal vaccine IgG response was tested; the median protective response was 0.5 serotypes for Group I and 3 serotypes for Group II (P = 0.041). Autoimmune and granulomatous disease was found in higher rates in Group I. CVID patients with decreased percentages of switched memory B cells have lower levels of serum IgG, less effective pneumococcal vaccine antibody responses, and higher rates of autoimmune and granulomatous disease.

Introduction

Common variable immunodeficiency (CVID) is a primary immunodeficiency disease characterized by low levels of IgG and IgA and/or IgM, and documented antibody deficiency leading to recurrent infections, typically in the respiratory and gastrointestinal tract [1], [2], [3], [4]. The majority of the patients exhibit normal numbers of B and T cells. However, CVID is presumed to be a heterogenous group of disorders with separate etiologies as suggested by the fact that B cell defects, T cell defects, and defects in T cell costimulation have been demonstrated. In addition, clinical heterogeneity, such as the development of pulmonary or gastrointestinal disease [5], [6], autoimmune disease [7], [8], granulomas [9], and/or malignancy [10], also suggests other molecular and/or genetic differences between patients [11]. However, methods for classifying CVID patients into useful groups have proven elusive; this has contributed to the difficulty in determining the essential pathogenetic mechanisms responsible for CVID. An in vitro classification scheme developed by Bryant et al. [12], which separated patients by their B cells' ability to produce IgG, IgA, or IgM upon stimulation by S. aureus Cowan I plus IL-2 or anti-IgM plus IL-2, divides CVID patients into one of four groups; however, this method is difficult to perform routinely. In addition, the clinical relevance has been unclear.

Memory B cells, which have undergone somatic hypermutation and quickly generate immunoglobulins of all isotypes during secondary immune response, are characterized by CD27 surface antigen expression [13]. Class-switched CD27+IgMIgD memory B cells were initially found to be absent in patients with X-linked hyper-IgM syndrome [14]. Subsequently, Warnatz et al. analyzed the class-switched memory B cell compartment of CVID patients and developed a classification system correlating the numbers of class-switched memory B cells with Bryant's functional classification [15]. Warnatz et al. suggested that CVID patients can be separated into two groups: Group I with switched memory B cells less than 0.4% of all peripheral blood lymphocytes (PBLs) and Group II with switched memory B cells greater than 0.4% of PBLs. We have examined the biological relevance of this classification scheme by relating this to serum immunoglobulins, antibody production, age, and the clinical characteristics of patients in each of the two groups.

Section snippets

Patients and controls

Mount Sinai Medical Center has been a referral center for primary immunodeficiency patients, and 326 patients with CVID have been seen over the past 15 years. The 53 patients (ages 3–77) enrolled in this study were all new and follow-up CVID subjects seen at Mount Sinai between 2002 and 2004, and all had reduced serum IgG, IgA, and/or IgM two or more confidence intervals below the normal ranges for age. Antibody deficiency was verified by means of decreased antibody production to two or more

Switched memory B cells for Groups I and II

Thirty-three out of 53 patients (62%) were assigned to Group I (% CD27+IgMIgD/peripheral lymphocytes median = 0.12, range = 0.01–0.38) and 20 patients (38%) to Group II (% CD27+IgMIgD/peripheral lymphocytes median = 0.92, range = 0.41–6.5) (see Fig. 1 for example). Group I consisted of 12 males and 21 females; the median age was 40 (range 3–11). Group II contained 7 males and 13 females; the median age was 45.5 (range 10–67). When compared with 25 normal controls, all patients with CVID were found

Discussion

Previous attempts have been made to understand and classify CVID on the basis of in vitro B cell immunoglobulin production using a number of culture conditions and analyses of T cell function using various methods of stimulation. However, most classification schemes have used in vitro parameters and not in vivo laboratory or clinical correlations. After the demonstration that switched memory B cells were absent in the blood of patients with hyper IgM syndrome [14], several groups have examined

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    Funding Sources: NIH Grants AI-467370 and AI-48693.

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