In the same study, and in contrast to these human ANCA data, F(ab

In the same study, and in contrast to these human ANCA data, F(ab)2 from a murine monoclonal antibody (mAb) had no activating capacity [38]. A PR3- and MPO-ANCA F(ab)2-induced respiratory burst was confirmed in another study [39], but not observed by other investigators [40–42]. The use of human versus murine antibodies, the strength of BGB324 cost the activation response, assaying intra- or extracellular oxidant generation and the antigen specificity of the antibodies that were employed

may, at least in part, explain some of the differences in the results. Williams et al. observed that ANCA F(ab)2 induced p21ras activation that was necessary, but not sufficient, for the respiratory burst [43]. Moreover, gene arrays showed that both ANCA F(ab)2 and ANCA BAY 57-1293 purchase immunoglobulin (Ig)G induce leucocyte gene transcription [44]. Interestingly, some of the transcribed genes were unique to intact ANCA IgG and some to the F(ab)2, whereas others were induced by both fragments. Thus, ANCA F(ab)2 bind to the neutrophil and trigger several neutrophil responses that do not depend on FcγR engagement. Few studies investigated this issue in monocytes. Weidner et al. showed that human ANCA also activated respiratory

burst in monocytes and that ANCA F(ab)2 triggered a similar response compared to the complete ANCA IgG [45]. In addition to the antigen-binding fragments, the Fc part of the ANCA molecule is also important. ANCA IgG bind to FcγRIIa (CD32A) and FcγRIIIb (CD16B). FcγRIIa blockade abrogated ANCA-induced activation, whereas the role of the FcγRIIIb blockade is somewhat more controversial [38,40–42,46]. The FcγRIIa has two allelic variants with either a histidine or an arginine at amino acid position 131, resulting

in a high-responder and low-responder receptor form. Neutrophils with the high-responder variant showed a stronger response to anti-PR3 and anti-MPO IgG1 mAbs in vitro[40]. This FcγRIIa also has high affinity to the IgG3 subclass, which is the dominant ANCA subclass in patients with active disease, and had the strongest capability to induce neutrophil adhesion in vitro[47,48]. Kocher et al. observed that ANCA IgG also bind to the FcγRIIIb on neutrophils Fenbendazole that is expressed approximately 10 times higher than the FcγRIIa [46]. Distinct patterns of CD11b increase and CD62L shedding suggested that FcγIIIb is involved in ANCA-induced neutrophil activation. FcγRIIIb has two common genetic variants named NA1 and NA2, the former triggering a stronger neutrophil activation than the latter. A recent study on a large cohort of patients with granulomatosis with polyangiitis (GPA, also known as Wegener’s granulomatosis) demonstrated a similar NA1 allele frequency in patients compared to controls. However, the presence of NA1 was associated with more severe renal disease [49].

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