Increased expression of TACI on NOD B cells results in germinal centre reaction anomalies, enhanced plasma cell differentiation and immunoglobulin production

Abstract

B cells have an important pathogenic role in the development of type 1 diabetes in the non-obese diabetic (NOD) mouse. We have previously reported that NOD mice display an increased percentage of TACI -expressing B cells compared with C57BL/6 mice and this trait is linked to chromosomes 1 and 8. In this paper the genetic association of the transmembrane activator, calcium modulator and cyclophilin ligand interactor (TACI) trait was confirmed using double congenic NOD.B6C1/Idd22 mice. TACI ligation by a proliferation-inducing ligand (APRIL) has been shown to influence plasma cell differentiation, immunoglobulin production and isotype switch. Hence, the functional consequence of the up-regulation of TACI on NOD B cells was analysed both in vitro and in vivo. NOD B cells stimulated with APRIL showed an enhanced plasma cell differentiation and class switch to IgG and IgA compared with B cells from C57BL/6 mice. Moreover, flow cytometry analyses revealed that germinal centre B cells in NOD failed to down-regulate TACI. Availability of the TACI ligand B-cell activating factor (BAFF) has been shown to be a limiting factor in the germinal centre reaction. In line with this, upon immunization with 4-hydroxy-3-nitrophenylacetyl hapten-conjugated hen egg lysozyme, NOD mice produced higher titres of low-affinity antibodies compared with C57BL/6 mice. This observation was supported by the detection of increased levels of BAFF in NOD germinal centres after immunization compared with C57BL/6 by immunofluorescence. Our results support the hypothesis that increased TACI expression on NOD B cells contributes to the pathogenesis of type 1 diabetes in the NOD mouse.

Circulating B cells in type 1 diabetics exhibit fewer maturation-associated phenotypes

“…[47, 48] NOD mice exhibit increased TACI expression compared to B6 mice and this increase is accompanied by plasma cell differentiation and class switching to IgG and IgA. [49] In contrast, our analysis of human T1D subjects reveals a lower proportion of TACI-expressing mature B cells. The difference in these results could reflect anatomic compartment differences (most of the mouse work sampled splenic B cells) or differences between NOD and human T1D.…”

Regulation of type 1 diabetes development and B-cell activation in nonobese diabetic mice by early life exposure to a diabetogenic environment

“…NOD mice have impaired peripheral B cell tolerance at the transitional check point [ 74 ], which involves BAFF (also known as BLyS), a B-cell stimulating cytokine elevated in autoimmune conditions [ 75 ]. Moreover, genetic and phenotypic studies implicate TACI, one of the BAFF receptors, in type 1 diabetes development [ 76 ]. Given the elevated BAFF levels in NOD high sera, such mechanisms may raise T1D incidence in the NOD high environment.…”