Abstract
ObjectiveSelective IgA deficiency (sIgAD) is the most common primary immunodeficiency in Western countries. Patients can suffer from recurrent infections and autoimmune diseases because of a largely unknown aetiology. To increase insights into the pathophysiology of the disease, we studied memory B and T cells and cytokine concentrations in peripheral blood.MethodsWe analysed 30 sIgAD patients (12 children, 18 adults) through detailed phenotyping of peripheral B‐cell, CD8+ T‐cell and CD4+ T‐cell subsets, sequence analysis of IGA and IGG transcripts, in vitro B‐cell activation and blood cytokine measurements.ResultsAll patients had significantly decreased numbers of T‐cell‐dependent (TD; CD27+) and T‐cell‐independent (TI; CD27−) IgA memory B cells and increased CD21low B‐cell numbers. IgM+IgD− memory B cells were decreased in children and normal in adult patients. IGA and IGG transcripts contained normal SHM levels. In sIgAD children, IGA transcripts more frequently used IGA2 than controls (58.5% vs. 25.1%), but not in adult patients. B‐cell activation after in vitro stimulation was normal. However, adult sIgAD patients exhibited increased blood levels of TGF‐β1, BAFF and APRIL, whereas they had decreased Th1 and Th17 cell numbers.ConclusionImpaired IgA memory formation in sIgAD patients is not due to a B‐cell activation defect. Instead, decreased Th1 and Th17 cell numbers and high blood levels of BAFF, APRIL and TGF‐β1 might reflect disturbed regulation of IgA responses in vivo.These insights into B‐cell extrinsic immune defects suggest the need for a broader immunological focus on genomics and functional analyses to unravel the pathogenesis of sIgAD.
Highlights
Selective IgA deficiency, the most common primary immunodeficiency in Western countries, is defined by very low to absent serum levels of IgA with normal IgG and IgM.[1]
This CD40Lindependent pathway involves the binding of the cytokine A proliferation-inducing ligand (APRIL) to its receptor transmembrane activator and CAML interactor (TACI), resulting in the expression of activation-induced cytidine deaminase (AID).[7,9]
We observed increased cytokine concentrations in B-cell activating factor (BAFF), APRIL and TGF-b1. These results show that SIgAD patients do not exhibit class switch abnormalities, but a defect in the formation of IgA memory B cells, and Th1 and Th17 cells
Summary
Selective IgA deficiency (sIgAD), the most common primary immunodeficiency in Western countries, is defined by very low to absent serum levels of IgA with normal IgG and IgM.[1]. CD27negative IgA memory B cells originate from TI responses in the intestinal tract and are characterised by high IgA2 usage and increased reactivity to intestinal bacteria.[8] This CD40Lindependent pathway involves the binding of the cytokine A proliferation-inducing ligand (APRIL) to its receptor transmembrane activator and CAML interactor (TACI), resulting in the expression of activation-induced cytidine deaminase (AID).[7,9] Additional cytokines, such as transforming growth factor-beta (TGF-b), vasoactive intestinal peptide (VIP) and IL-10, induce germline IGA transcripts leading to IGA class switching.[7,10,11] Previous studies described reduced numbers of Ig class-switched memory B cells and CD19+IgA+ B cells in sIgAD patients.[12,13,14] Recently, Blanco et al grouped sIgAD and other antibody deficiency patients based on the phenotyping of their B-cell compartment. To study underlying B-cell intrinsic and extrinsic defects in sIgAD, we performed immunophenotyping of the B-cell, CD8 T-cell and CD4 T-cell compartments, as well as genetic
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