Dataset Information

Longitudinal Pathogenic Properties and N-Glycosylation Profile of Antibodies from Patients with Pemphigus after Corticosteroid Treatment.

ABSTRACT: Pemphigus vulgaris is an autoimmune disease that occurs due to pathogenic autoantibodies that recognize the following epidermal adhesion proteins: desmogleins. Systemic corticosteroids usually decrease the titers of anti-desmoglein autoantibodies and improve patients' conditions. Since modifications of IgG N-glycosylation have been described in some autoimmune diseases, we hypothesized that changes in the pathogenic activity of pemphigus IgG could be related to changes in their N-glycosylation profile. The purpose of this study was to assess, longitudinally, the pathogenicity of pemphigus serum IgG and their N-glycosylation profile during phases of disease activity and clinical remission. The pathogenic activity of serum IgG was measured in vitro on immortalized keratinocytes, by immunofluorescence and dissociation assays, and IgG N-glycans were analyzed by mass spectrometry. We showed (i) a correlation between pemphigus clinical activity and the pathogenicity of serum IgG at baseline and at month 6, while the persistence of the in vitro pathogenic activity of IgG during its evolution, even in patients in clinical remission, seemed to be predictive of relapse; (ii) that modifications of the N-glycan structure were altered the in vitro pathogenicity of patients' autoantibodies; (iii) that the pathogenic properties of pemphigus IgG did not appear to be related to the disparity in IgG N-glycans during the course of pemphigus.

SUBMITTER: Petit M

PROVIDER: S-EPMC8533488 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Longitudinal Pathogenic Properties and N-Glycosylation Profile of Antibodies from Patients with Pemphigus after Corticosteroid Treatment.

Petit Marie M Walet-Balieu Marie-Laure ML Schapman Damien D Golinski Marie-Laure ML Burel Carole C Barray Marion M Drouot Laurent L Maho-Vaillant Maud M Hébert Vivien V Boyer Olivier O Bardor Muriel M Joly Pascal P Calbo Sébastien S

Biomedicines 20211008 10

Pemphigus vulgaris is an autoimmune disease that occurs due to pathogenic autoantibodies that recognize the following epidermal adhesion proteins: desmogleins. Systemic corticosteroids usually decrease the titers of anti-desmoglein autoantibodies and improve patients' conditions. Since modifications of IgG N-glycosylation have been described in some autoimmune diseases, we hypothesized that changes in the pathogenic activity of pemphigus IgG could be related to changes in their N-g ...[more]

PMID: 34680528

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Project description:Pemphigus Vulgaris is an autoimmune disease of the skin and mucous membranes, which is due to the production of pathogenic autoantibodies targeting desmoglein (DSG) 1 and 3, which are adhesion proteins of the keratinocytes. Rituximab is an anti-CD20 mAb which induces a prolonged depletion of blood B cells. We recently showed that rituximab was more effective than a standard oral corticosteroid (CS) treatment, allowing 90% of patients to achieve complete remission (CR). Additionally, we showed that DSG-specific-B (DSG positive) cells were still detectable during the B cell recovery which follows the initial rituximab-induced B cell depletion, even in patients in CR. In order to characterize DSG positive B cells in patients in CR after rituximab or CS treatment relative to those detectable at baseline in patients with an active pemphigus, we studied the expression profile of 31 genes of interest related to inflammatory cytokines, TNF receptors and activation markers. Using quantitative Polymerase Chain Reaction performed on one cell with a microfluidic technique, we found that patients' autoreactive B cells collected at baseline had a significantly higher expression of genes encoding for IL-1β, IL-23p19, and IL-12p35 pro-inflammatory cytokines and the IRF5 transcription factor, than non-autoreactive B cells. Surprisingly, the gene expression profile of DSG positive B cells collected after rituximab treatment in patients in CR was close to that of DSG positive B cells at baseline in patients with active pemphigus, except for the IL-1β and the CD27 memory marker genes, which were under-expressed after rituximab compared to baseline. Conversely, we observed a decreased expression of genes encoding for IL-1β and IL-23p19 in patients treated with CS relative to baseline. This study showed that: (i) DSG positive autoreactive B cells have a different gene expression profile than non-autoreactive B cells; (ii) rituximab and CS have different effects on the genes' expression in autoreactive DSG positive B cells from pemphigus patients.

Project description:ImportanceThe clinical relevance of antirituximab antibodies (ARAs) in patients with pemphigus who are treated with rituximab (RTX) is currently unknown.ObjectiveTo determine the prevalence of ARAs in patients with pemphigus who are treated with RTX and their association with complete remission (CR) and relapse.Design, setting, and participantsThis post hoc analysis of the Ritux3 trial was conducted from January 2010 to December 2015 in 25 dermatology departments in France and included 42 patients with moderate-to-severe pemphigus who were randomized to receive treatment with RTX. Five additional patients were recruited for an ancillary study. The proportions of patients who achieved CR or relapsed after an initial treatment cycle of RTX were compared depending on whether patients had ARAs.ExposuresPatients were treated with 1000 mg of RTX on days 1 and 15 and 2 maintenance infusions of 500 mg at months 12 and 18.Main outcomes and measuresRates of relapse and sustained CR at month 36. Levels of ARAs, antidesmoglein 1/3 antibodies, RTX serum concentrations, and peripheral blood CD19+ B-cell frequency were measured.ResultsOf 42 participants with vs without ARAs, the mean (SD) age was 55 (17) years and 56 (17) years, respectively; 25 (59.5%) were women. Antirituximab antibodies were detected in the serum samples of 13 of 42 patients (31%) during the first year. Nine patients who experienced relapse before month 12 were excluded because they received additional infusions and could not be further analyzed. Among the 33 remaining patients, 2 patients (6.1%) experienced relapse after month 12, and 31 (95.9%) maintained a sustained CR until month 36. The rate of sustained CR was not different whether patients had ARAs (11 of 13 [85%]) or not (20 of 20 [100%]) (P = .15). Both groups (ARA+ vs ARA-) also had similar CD19+ B-cell depletion and RTX levels, but patients with ARAs had higher anti-desmoglein 3 antibody (DSG3 Abs) levels compared with those without ARAs (mean [SD], 30.1 [50.9] AU/mL vs 4.0 [4.3] AU/mL; P = .03). The 2 patients with ARAs who experienced relapse after month 12 had an undetectable RTX level, incomplete B-cell depletion, and higher anti-DSG3 Abs level than the 11 patients who maintained a sustained CR with ARAs (RTX mean [SD] concentration, 0 ug/mL vs 12.5 [2.2] ug/mL; P = .03; incomplete B-cell depletion, 2 of 2 vs 4 of 11; P = .19; mean [SD] anti-DSG3 Abs levels, 103.5 [61.5] AU/mL vs 19.5 [11.0] AU/mL; P = .001) or patients without ARAs (mean [SD] RTX concentration, 0 ug/mL vs 13.5 [1.8] ug/mL; P = .02; incomplete B-cell depletion, 2 of 2 vs 5 of 20; P = .09; mean [SD] anti-DSG3 Abs level, 103.5 [61.5] AU/mL vs 4.0 [1.0] AU/mL; P < .001).Conclusions and relevanceThe results of this cohort study suggest that ARAs are frequently detected in patients with pemphigus who are treated with RTX and generally are not associated with patient outcomes. Only a few patients with the combination of ARAs, low RTX concentration, incomplete B-cell depletion, and persistent serum anti-DSG3 Abs seem at high risk of relapse.

Dataset Information

Longitudinal Pathogenic Properties and N-Glycosylation Profile of Antibodies from Patients with Pemphigus after Corticosteroid Treatment.

Publications

Longitudinal Pathogenic Properties and <i>N</i>-Glycosylation Profile of Antibodies from Patients with Pemphigus after Corticosteroid Treatment.

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