Composition of the CD27+ Memory-B-Cell Compartment Delineates Immunoglobulin Deficiency Endotypes

Abstract

Abstract Abstract Purpose: The finding of reduced numbers of class-switched memory B cells (CSM) in peripheral blood is widely used to assist the diagnosis and subclassification of CVID. Limited data exists on this finding in relation to the entire class of PADs. In this study, consecutive 8-marker comprehensive B-cell panel results were analyzed to determine how reduced CSM quantities might inform the pathophysiology of CVID and other humoral immunodeficiencies. Methods: Subpopulations of CD27+ memory B cells from 64 consecutive subjects with or without humoral immunodeficiency were examined to identify associations with diagnosis and serum immunoglobulin level. Results: CD27+IgM-IgD- percentage (CSM%) was correlated with IgG level in a discontinuous manner with an estimated change point of 9.7% (95% CI: 4.7, 12.4). All subjects with a CSM% below 9.7% had substantially lower serum IgG and IgA levels compared with those above 9.7. CSM% below 9.7% is not associated with serum IgM level. Rather, the proportion of CD27+IgMonly B cells (IgMonly or IgMonly%) is correlated with serum IgM. Conclusion: Low CSM% may mark an endotype of humoral immune dysfunction defined by either loss of class switching or critical failure of the coordinated production of both memory cells and long-lived plasma cells responsible for adequate immunoglobulin levels in humans. In patients with low CSM%, maintenance or expansion of IgMonly cells and IgM production suggests the former explanation, while concomitant loss of IgMonly cells suggests the latter. These findings provide a simple endotypic stratification method for future studies on the failed coordinated B cell response in humans with PAD.