Defective formation of IgA memory B cells, Th1 and Th17 cells in symptomatic patients with selective IgA deficiency.

Objective Selective 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. Methods We 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. Results All patients had significantly decreased numbers of T-cell-dependent (TD; CD27(+)) and T-cell-independent (TI; CD27(-)) IgA memory B cells and increased CD21(low) 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-beta 1, BAFF and APRIL, whereas they had decreased Th1 and Th17 cell numbers. Conclusion Impaired 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-beta 1 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.