Common variable immune deficiency in children--clinical characteristics varies depending on defect in peripheral B cell maturation

Abstract

Common variable immune deficiency (CVID) is a heterogeneous disease associated with ineffective production of antibodies. It is usually diagnosed in adulthood, but a variable proportion of children develop CVID. Early identification of patients with potentially worse prognosis may help to avoid serious complications. The goal of this study was to associate the clinical phenotype of patients with early onset CVID with peripheral B-cell maturation profile. Four color flow cytometry was used to define distribution of peripheral B-cell subsets in 49 children with early-onset CVID. All clinical data were extracted from medical records. A proportion of patients demonstrated diminishing with time total B-lymphocytes pool, beyond physiological age-related changes. Irrespective from duration of the follow-up period the B-cell maturation profile in individual patients remained unchanged. We identified six different aberrant peripheral B cell maturation profiles associated with different clinical characteristics. Patients with an early B-cell maturation block earlier required replacement therapy and were at significantly greater risk of enteropathy, granuloma formation, cytopenia, and lymphoproliferation. B-cell maturation inhibited at the natural effector stage was associated with higher risk of autoimmune manifestations other than autoimmune cytopenia. Prevalence of male patients was observed among patients with B-cell maturation inhibited at naïve B-cell stage. In conclusion, the diagnostic process in patients with suspected early-onset CVID shall include routine analysis of peripheral B-cell maturation to provide surrogate markers identifying patients at greater risk of developing certain complications.

Fig. 1

Immunophenotyping of peripheral B lymphocytes based on differential expression of CD19, IgD, IgM, CD21, CD27, CD38. B lymphocytes were identified as cells with positive expression of CD19 and low side scatter (1). Recent bone marrow emigrants (transitional B cells) have been defined as B lymphocytes demonstrating high surface expression of IgM and CD38 (2). B lymphocytes with positive surface expression of IgD, but lacking expression of CD27 were identified as naïve B cells (3). Natural effectors expressed both IgD and CD27 (4), while memory B lymphocytes expressed CD27, but did not express IgD (5). Plasmablasts were identified as B lymphocytes with positive expression of CD38, but lacking expression of IgM (6). B lymphocytes with low expression of CD21 and CD38 were considered as activated B lymphocytes (7)

Fig. 2

Despite lack of treatment with anti-CD-20 monoclonal antibody a proportion of patients demonstrated gradual decline in total B cell counts, beyond age-matched normal changes. Individual patients’ data are presented as dots on box-and-whisker plots of respective age groups, with the boxes representing the interquartile (25–75 percentiles) and the whiskers representing the 5–95 percentiles of the age-related normal range

Fig. 3

Patients from the study cohort were assigned into six groups reflecting the identified B-cell maturation blocks. Patients with reduced total B cell counts with poor ability to mature beyond naïve stage, were included in group I. Group II was composed of patients who accumulated transitional B cells. Patients from group III accumulated naïve B-cells, while in patients from group IV B lymphocytes where unable to mature beyond natural effector B-cells. Patient from group V demonstrated normal B-cell maturation profile, except for reduced proportions of plasmablasts. Patient assigned to group VI demonstrated normal B-cell maturation profile. Individual patients’ data are presented as dots on box-and-whisker plots of respective age groups, with the boxes representing the interquartile (25–75 percentiles) and the whiskers representing the 5–95 percentiles of the age-related normal range