Immunoregulatory roles for fc receptor-like molecules.
ABSTRACT Fc receptor-like (FCRL) molecules comprise a family of imunoregulatory transmembrane proteins that are preferentially, but not exclusively expressed on B lineage cells. A strong regulatory potential on B cell activation has been characterized for the different FCRL proteins, but their biological roles are just beginning to be elucidated. We review recent advances in the understanding of FCRL1-6 expression and function, and indicate their potential roles in the pathogenesis of immunodeficiencies, lymphoid malignancies and autoimmune diseases.
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ABSTRACT: FCRLA is an ER-resident B-cell specific protein. The exact function of this protein remains unclear although human FCRLA has been recently shown to interact with IgM, IgG and IgA. The retention of FCRLA in ER is mediated by the N-terminal domain. The major human FCRLA isoform is encoded by five exons, of which one encodes a short signal peptide (SSP) and the others code four protein domains. Here we show that human tissues also produce transcripts which contain an additional exon and encode proteins with signal peptide that is six residues longer (LSP). Transfection experiments demonstrated that the extension of the signal peptide had no visible effect on the topology and molecular mass of the processed four-domain FCRLA isoform. However, the length of the signal peptide was found to affect processing of two-domain FCRLA isoforms composed of the third and fourth domains (FCRLAd2). The signal peptide was not cleaved in the SSP-FCRLAd2 and this isoform was found to accumulate in the ER. In contrast, the LSP-containing FCRLAd2 isoform was processed, O-glycosylated and secreted. The secreted FCRLAd2 isoform did not interact with IgG- or IgM-immunosorbents.Immunology letters 06/2013; DOI:10.1016/j.imlet.2013.05.011 · 2.37 Impact Factor
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ABSTRACT: FcR-like (FCRL) 2 is a transmembrane protein with immunomodulatory potential that is preferentially expressed by memory B cells in humans. It has two consensus ITIMs in addition to a putative ITAM sequence in its cytoplasmic domain. We have confirmed the cellular distribution of FCRL2 and analyzed its functional potential to show that coligation with the BCR leads to tyrosine phosphorylation of its ITIM motifs and subsequent Src homology region 2 domain-containing phosphatase-1 recruitment to facilitate inhibition of BCR signaling. Mutational analysis indicates that the tyrosine residues in both inhibitory motifs of FCRL2 are required for complete inhibition of BCR signaling, whereas tyrosines in the putative activation motif are dispensable for signal modulation. These findings suggest a negative immunomodulatory function for FCRL2 in the regulation of memory B cells.The Journal of Immunology 11/2010; 185(12):7405-12. DOI:10.4049/jimmunol.1002305 · 5.36 Impact Factor
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ABSTRACT: Confirmation of clinical tolerance requires the cessation of immunosuppressive drugs, which evoke immune reactivation and allograft rejection in all but the rare individuals who successfully transition into a state of operational transplantation tolerance. Therefore, the safe conduct of trials in transplantation tolerance requires two conditions: a sensitive and reliable means to identify individuals still being maintained on immunosuppression who are most likely to exhibit tolerance after immunosuppression is withdrawn and a noninvasive means that assesses the quality or robustness of the tolerant (TOL) state. Two recent studies attempting to identify a gene signature in peripheral blood of spontaneously TOL kidney transplant recipients made the unexpected observation that TOL, but not immune-suppressed transplant recipients, exhibited enriched B cells and B-cell transcripts in their blood. In concert with the emerging appreciation of a specialized subset of regulatory B cells (Bregs) that possess immune-modulatory function, these observations raise the possibility that Bregs play a critical role in the maintenance of tolerance to renal allografts in transplant patients. This review summarizes these recent findings and speculates on the relationship of Bregs to the maintenance of transplantation tolerance.American Journal of Transplantation 10/2011; 11(12):2555-60. DOI:10.1111/j.1600-6143.2011.03773.x · 6.19 Impact Factor