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

Abstract

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 + Tcell 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 À ) IgA memory B cells and increased CD21 low B-cell numbers. IgM + IgD À 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-b1, 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-b1 might reflect disturbed regulation of IgA responses in vivo.These insights into B-cell extrinsic immune defects suggest the need for a broader ª immunological focus on genomics and functional analyses to unravel the pathogenesis of sIgAD.

The Epidemiology and Clinical Presentations of Atopic Diseases in Selective IgA Deficiency

“…They were increased in patients with severe SIgAD as compared to those with mild severity [166]. Increased level of CD21low was previously described but without correlation to clinical status [167].…”

A novel method to standardise serum IgA measurements shows an increased prevalence of IgA deficiency in young children with recurrent respiratory tract infections

“…Intrinsic B-cell defects, T cell, cytokine network abnormalities and environmental factors (including the microbiome composition) have all been associated with IgA deficiency. [25][26][27][28][29] While no clear inheritance pattern had been described, several monogenic mutations have been associated with IgA deficiency. 30 Also, multiple HLA and non-HLA genes have been described to be associated with disease phenotypes and development.…”

“…The aetiology of IgA deficiency represents a heterogeneous group of abnormalities. Intrinsic B‐cell defects, T cell, cytokine network abnormalities and environmental factors (including the microbiome composition) have all been associated with IgA deficiency 25–29 . While no clear inheritance pattern had been described, several monogenic mutations have been associated with IgA deficiency 30 .…”

Innate Mechanisms in Selective IgA Deficiency

“…In SIgAD patients a reduction in IgA+ memory B cells was found associated with no defect in class switching and affinity maturation. Therefore, it is suggested that SIgAD patients have defective regulation of the IgA response due to reduced Th1 and Th17 cells and increased blood concentrations of TGF-β1, BAFF and APRIL ( 137 ). In addition, increased numbers of CD27+IgA+ memory B cells were found in a cohort of children (n=729) having ever showed a food allergic reaction over the first 10 years of their life.…”