Patients with anti-Jo1 antibodies display a characteristic IgG Fc-glycan profile which is further enhanced in anti-Jo1 autoantibodies

Abstract

IgG Fc-glycans affect IgG function and are altered in autoimmune diseases and autoantibodies. Anti-histidyl tRNA synthetase autoantibodies (anti-Jo1) are frequent in patients with idiopathic inflammatory myopathies (IIM) and anti-synthetase syndrome (ASS) with associated interstitial lung disease (ILD). Thus, we hypothesized that the total-IgG Fc-glycans from Jo1+ versus Jo1− patients and anti-Jo1-IgG would show characteristic differences, and that particular Fc-glycan features would be associated with specific clinical manifestations. By proteomics based mass spectrometry we observed a high abundance of agalactosylated IgG1 Fc-glycans in ASS/IIM patients (n = 44) compared to healthy age matched controls (n = 24). Using intra-individual normalization of the main agalactosylated glycan (FA2) of IgG1 vs FA2-IgG2, ASS/IIM and controls were distinguished with an area under the curve (AUC) of 79 ± 6%. For Jo1+ patients (n = 19) the AUCs went up to 88 ± 6%. Bisected and afucosylated Fc-glycans were significantly lower in Jo1+ compared to Jo1− patients. Anti-Jo1-IgG enriched from eleven patients contained even significantly lower abundances of bisected, afucosylated and galactosylated forms compared to matched total-IgG. ASS and ILD diagnosis, as well as lysozyme and thrombospondin correlated with Jo1+ characteristic Fc-glycan features. These results suggest that the anti-Jo1+ patient Fc-glycan profile contains phenotype specific features which may underlie the pathogenic role of Jo1 autoantibodies.

Roles of aminoacyl-tRNA synthetases in immune regulation and immune diseases

“…Moreover, infiltrating CD20 + CD27 + memory B cells were present in the muscle of anti-Jo-1 patients, indicating that B cell homeostasis was impaired in ASSD. Compared to Jo-1-negative patients, Jo-1-positive patients showed an Fc-glycan profile with less bisected and afucosylated glycans, which was further enhanced in anti-Jo-1 autoimmune IgG 80 . Importantly, the Fc-glycan profile features were correlated with certain clinical and diagnostic information of the patients, suggesting that the specific IgG Fc-glycans might be responsible for the pathogenicity of anti-Jo-1 autoantibodies.…”

Neutrophil dysregulation is pathogenic in idiopathic inflammatory myopathies

“…Isolation of MSAs. MSAs were isolated as previously reported (38). Plasma from 1 anti-Jo1-positive IIM subject (39-year-old female) and from 1 anti-MDA5-positive IIM subject (58-year-old male) were used to purify MSAs.…”

“…N-hydroxysuccinimide-activated prepacked sepharose columns (NHS columns, GE Healthcare) were coupled with 5 or 1 mg recombinant MDA5 and Jo1, respectively, and according to the manufacturer's instructions. Anti-MDA5 and anti-Jo1 IgG were isolated as previously reported (38). Briefly, plasma was centrifuged at 3000 g for 5 minutes, diluted 1:5 in PBS, and filtered using a 0.45-μM filter, before loading in the HiTrap Protein G HP columns (GE Healthcare) for IgG enrichment.…”

Serum-circulating His-tRNA synthetase inhibits organ-targeted immune responses

“…In a separate vein, we recently showed that anti-Jo-1 antibodies display an IgG Fc-glycan profile normally associated with anti-inflammatory properties. 43 Complement 5b-9 deposits were observed in capillaries located near the perimysium area in muscle biopsies of Jo-1+ patients. This may be an indication of immune activation with antibody and T-cell involvement.…”