Key Points Normal IgG and IgG2 differentially inhibit HIT antibody-dependent platelet activation according to the FcγRIIA H131R polymorphism. This variable effect of IgG and IgG2 probably explains the higher risk of thrombosis in patients homozygous for the FcγRIIA 131R allele.

FcγRIIIA/CD16A, the low-affinity receptor for the IgG Fc portion expressed on human CD56dim NK cells and involved in Ab-dependent cell cytotoxicity, is shed upon NK cell activation. We found that recombinant a disintegrin and metalloprotease (ADAM) 17 cleaved the ectodomain of FcγRIIIA/CD16A and a peptide for which the sequence encompasses aa 191–201 of the FcγRIIIA/CD16A stalk region but not ADAM10. MALDI-TOF analysis revealed that the peptide was cleaved between Ala195 and Val196 (i.e., 1 aa upstream of the expected position). This location of the cleavage site was confirmed by the finding that ADAM17 failed to cleave a peptide in which Ala and Val were reversed. ADAM17 was found to be expressed on NK cells, and stimulation with PMA or N-ethyl-maleimide resulted in the shedding of FcγRIIIA/CD16A and CD62L, a specific substrate of ADAM17. Selective inhibition of ADAM17 prevented the shedding of both molecules. Moreover, the shedding of FcγRIIIA/CD16A was strongly correlated with degranulation when a wide range of CD56dim NK cell activating receptors were stimulated, whereas both ADAM17-dependent shedding and internalization were involved in FcγRIIIA/CD16A downmodulation when the latter was engaged. Finally, the shedding of FcγRIIIA/CD16A was restricted to activated cells, suggesting that ADAM17 acts mainly, if not exclusively, in cis. Taken together, our results demonstrated for the first time, to our knowledge, at the molecular level that ADAM17 cleaves the stalk region of FcγRIIIA/CD16A and identified its cleavage site. The shedding of FcγRIIIA/CD16A was at least partially ADAM17 dependent, and it may be considered as a marker of FcγRIIIA/CD16A-independent NK cell activation highly correlated with degranulation.

BackgroundSignificant peripheral blood CD4+ T-cell depletion has been observed after a first cycle of rituximab, a monoclonal antibody directed against the CD20 antigen, which is currently used in rheumatoid arthritis. Of note, an absence of CD4+ T-cell decrease has been observed in non-responders. Herein, we describe CD4+ T-cell changes over repeated cycles of rituximab and their relationship with clinical outcomes.MethodsPatients with rheumatoid arthritis who started rituximab between July 2007 and July 2013 were analyzed up to November 2014. Lymphocyte phenotyping and clinical assessments were performed before, and 3 and 6 months after each cycle. Lymphocytes counts and disease activity were compared at each time point, using nonparametric tests.ResultsPatients received up to seven cycles of treatment during the study period. Mean CD4+ T-cell counts were above the upper limit of the reference range before each rituximab infusion and repeatedly reached the reference range at 6 months (and/or 3 months) post infusion. CD4+ T cells decreased concurrently with disease activity score.ConclusionsCD4+ T-cell counts could be a relevant biomarker of response to rituximab in rheumatoid arthritis and could be considered in making decisions about the timing of retreatment.

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