IgA subclass switch recombination in human mucosal and systemic immune compartments

Abstract

Human immunoglobulin A (IgA) comprises two IgA subclasses, IgA1 and IgA2, whose distribution has been shown by immunohistochemistry to be different in various body compartments. In comparison with systemic immune compartments, we investigated the IgA switch profiles at the molecular level in salivary and lacrimal glands, nasal mucosa, and proximal and distal gut mucosa. Direct switching from IgM to IgA1 or IgA2 predominated in all immune compartments analyzed. Similar composition of the Sμ-Sα1 and Sμ-Sα2 junctions was observed, including microhomology usage, which suggested that there is no major difference in the actual recombination mechanism utilized during IgA subclass switching. The proportion of IgA1/IgA2 switch recombination events largely paralleled the previously published immunohistochemical representation of IgA1(+) and IgA2(+) plasma cells, implying that the local subclass distribution generally reflects precommitted memory/effector B cells that have undergone IgA subclass switching before extravasation at the effector site. The extremely low or undetectable levels of activation-induced cytidine deaminase (AID) and Iα-Cμ circle transcripts in intestinal lamina propria samples as compared with Peyer's patches suggest that the cellular IgA subclass distribution outside of organized gut-associated lymphoid tissue is only to a minor extent, if at all, influenced by in situ switching.

Synthetic Double-Stranded RNA Poly(I:C) Aggravates IgA Nephropathy by Triggering IgA Class Switching Recombination through the TLR3-BAFF Axis

“…The single diagnostic feature of IgAN is the finding of immune deposits predominantly containing polymeric IgA in the glomerular mesangium on renal biopsy [2] .…”

The efficacy of tonsillectomy on clinical remission and relapse in patients with IgA nephropathy: a randomized controlled trial

“…1 The single diagnostic feature of IgAN is the Ending of immune deposits predominantly containing polymeric IgA in the glomerular mesangium on renal biopsy. 2 Approximately 20-50% of IgAN patients would develop end-stage renal disease (ESRD) over the course of roughly 20 years, 3 thereby rekindling interest in the development of an effective, targeted therapy. The classical clinical picture in IgAN of recurrent episodes of visible hematuria coinciding with upper respiratory or intestinal tract infections indicating that infections induced abnormal mucosal immunity plays an important role in the pathogenesis of IgAN.…”

DNA-PKcs Is Involved in Ig Class Switch Recombination in Human B Cells

“…Of these, 55 fragments represented direct switching from IgM to IgA1 or IgA2 (Sm-Sa1 or Sm-Sa2), whereas the remaining one showed "footprints" of sequential switching from IgM to IgG1 and then to IgA2 and, finally, a trans-switching to IgA1 on the other allele (Sm-Sg1-Sa2-Sa1). This type of sequential switching (IgM-IgG-IgA) is occasionally observed in normal peripheral blood cells or mucosal tissues (41). The repair patterns at the CSR junctions were further characterized based on the putative recombination breakpoint sequences: if a clear boundary between the Sm and Sa sequences was observed at the breakpoint, the repair pattern was defined as direct end-joining; nucleotide(s) at the putative breakpoint, showing a perfect match with both the donor and acceptor S regions, was considered indicative of MH-mediated repair; in cases in which nontemplate nucleotides (usually 1-2 bp), not matching either the donor or acceptor S regions, were detected at the breakpoint, the repair pattern was defined as having an insertion.…”