Transitional B Cells and TLR9 Responses Are Defective in Selective IgA Deficiency

Abstract

Selective IgA deficiency (IgAD) is the most common primary antibody deficiency in the western world with affected individuals suffering from an increased burden of autoimmunity, atopic diseases and infections. It has been shown that IgAD B cells can be induced with germinal center mimicking reactions to produce IgA. However, IgA is the most prevalent antibody in mucosal sites, where antigen-independent responses are important. Much interest has recently focused on the role of TLR9 in both naïve and mature B cell differentiation into IgA secreting plasma cells. Here, we analyze the phenotype and function of T and B cells in individuals with IgAD following IgA-inducing CpG-TLR9 stimulations. The IgAD individuals had significantly lower numbers of transitional B cells (CD19+CD24hiCD38hi) and class-switched memory B cells (CD20+CD27+IgD−) ex vivo. However, proportions of T cell populations ex vivo as well as in vitro induced T effector cells and T regulatory cells were comparable to healthy controls. After CpG stimulation, the transitional B cell defect was further enhanced, especially within its B regulatory subset expressing IL-10. Finally, CpG stimulation failed to induce IgA production in IgAD individuals. Collectively, our results demonstrate a defect of the TLR9 responses in IgAD that leads to B cell dysregulation and decreased IgA production.

The Heterogeneous Pathogenesis of Selective Immunoglobulin A Deficiency

“…Litzman et al [52] reported that there was no significant abnormality in the B-cell subsets of IgAD patients. However, further studies indicated decreased class-switched memory B cells in SIgAD patients [11, 12]. In this line, we indicated in one study that there are 2 subgroups of patients with IgAD (group I and II) based on switched memory B cells percentage [50].…”

“…Few studies have evaluated the measurement of B-lymphocyte subsets in SIgAD patients [11, 12, 50-52]. Litzman et al [52] reported that there was no significant abnormality in the B-cell subsets of IgAD patients.…”

“…However, in some studies, investigators have demonstrated no significant difference between SIgAD patients and healthy controls for any of the measured T-cell subpopulations (CD3 + , CD4 + , CD8 + , naïve, memory, and differentiated T cells) and the proliferation index and the percentage of divided cells [11, 12]. Moreover, Lemarquis et al [12] assessed effector T cell subpopulation functions and have shown that the activity of TH1, TH2, TH17, TH22, and T TFH cell are comparable in SIgAD patients compared to healthy controls. Only one study by our group has reflected a defect in regulatory T cells (Tregs) in SIgAD patients with autoimmunity [56].…”

“…B cell homing is mediated by specific adhesion molecules and chemokine receptors such as CCR9, CXCR4, and CCR10 that are important for homing to the small intestine and bone marrow by CCL25 ligand and CCL28 ligand, respectively [87]. A recent study showed that the proportion of the mucosal CXCR4, CCR10, and α4β7 homing receptors expression are comparable in SIgAD individuals and healthy controls [12]. Although some studies have shown that expression of homing receptors are normal in SIgAD patients but more broadly, research is also needed to prove these results.…”

“…Based on the several efforts to clarify the etiology and pathogenesis of SIgAD, the major problem is the failure of B lymphocyte to produce IgA [11, 12]. However, other abnormalities such as increased lymphocytic apoptosis, cytokine network, signaling pathway by costimulatory molecules and also the presence of predisposing major histocompatibility complex (MHC) alleles might be involved in the pathogenesis of SIgAD [13-15].…”