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The Diversity of Serum Anti-DSG3 IgG Subclasses Has a Major Impact on Pemphigus Activity and Is Predictive of Relapses After Treatment With Rituximab - PubMed

  • ️Sat Jan 01 2022

The Diversity of Serum Anti-DSG3 IgG Subclasses Has a Major Impact on Pemphigus Activity and Is Predictive of Relapses After Treatment With Rituximab

Marie-Laure Golinski et al. Front Immunol. 2022.

Abstract

Introduction: We studied the distribution and in vitro pathogenicity of anti-DSG3 IgG subclasses during the course of pemphigus vulgaris (PV).

Methods: We longitudinally studied the distribution of anti-DSG3 IgG subclasses (before versus after treatment) in sera from PV patients, using an addressable-laser bead immunoassay (ALBIA). The in vitro pathogenicity of corresponding sera was tested using keratinocyte dissociation and immunofluorescence assays.

Results: Sixty-five sera were assessed at baseline (33 from patients treated with rituximab and 32 with corticosteroids). Sixty-three percent of these baseline sera contained 2 or more anti-DSG3 IgG subclasses versus 35.7% of sera from patients in complete remission (CR) and 75.0% of sera from patients with persistent disease activity after treatment. IgG4 was the most frequently detected anti-DSG3 IgG subclass, both in patients with disease activity and in those in CR. The presence of three or more anti-DSG3 IgG subclasses was predictive of relapse, in particular when it included IgG3, with a positive predictive value of 62.5% and a negative predictive value of 92%. While anti-DSG3 IgG4 Abs from sera collected before treatment were most often pathogenic, anti-DSG3 IgG4 from sera collected after treatment were pathogenic only after adjusting their titer to the one measured before treatment. The IgG3 fraction containing anti-DSG3 Abs also had an in vitro pathogenic effect. The disappearance of the pathogenic effect of some sera after removal of anti-DSG3 IgG3 suggested an additional effect of this IgG subclass.

Conclusion: The serum levels and number of anti-DSG3 IgG subclasses drive the pathogenic effect of pemphigus sera and may predict the occurrence of relapses.

Keywords: desmoglein 3; immunoglobulin subclasses; pathogenicity; pemphigus; rituximab.

Copyright © 2022 Golinski, Lemieux, Maho-Vaillant, Barray, Drouot, Schapman, Petit, Hertl, Boyer, Calbo, Joly and Hébert.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1

Flowchart of the study. CS, corticosteroids; DSG3, desmoglein 3; RTX, rituximab.

Figure 2
Figure 2

Diagnostic value of ALBIA in comparison with ELISA anti-DSG3 results in pemphigus patients at baseline (n = 65). Correlation between ELISA anti-DSG3 IgG and ALBIA anti-DSG3 IgG1 (A) or IgG4 (B) values was assessed using Pearson’s rank correlation coefficient. ALBIA, addressable laser bead immunoassay; AU, arbitrary units; DSG3, desmoglein 3; ELISA, enzyme-linked immunosorbent assay; IU, international unit.

Figure 3
Figure 3

Distribution of anti-desmoglein 3 (DSG3) IgG subclasses from pemphigus patients with active disease (before treatment) and after treatment in patients with or without disease activity. (A) Distribution of anti-DSG3 IgG subclasses in the 65 pemphigus vulgaris (PV) patients with active disease at baseline. No anti-Dsg3 IgG subclasses were detected in 5 of these 65 patients (number shown outside). Among these 60 sera with positive ALBIA, 38 (63.3%) contained at least 2 or more anti-DSG3 IgG subclasses, while 22 (36.7%) sera contained only one anti-DSG3 IgG subclass (IgG4 in all cases). (B) Distribution of anti-DSG3 IgG subclasses in the 17 PV patients with persistent disease activity. No anti-Dsg3 IgG subclasses were detected in 1 of these 17 patients (number shown outside). Among these 16 sera with positive ALBIA, 12 sera (75.0%) still contained at least 2 or more anti-DSG3 IgG subclasses, while only 4 sera (25%) contained only one anti-DSG3 IgG subclass (IgG4 in all cases). (C) Distribution of anti-DSG3 IgG subclasses in the 16 PV patients in complete remission at Month 36. No anti-Dsg3 IgG subclasses were detected in 2 of these 16 patients (number shown outside). Among these 14 sera with positive ALBIA, only 5 sera (35.7%) still contained at least 2 or more anti-DSG3 IgG subclasses, while 9 sera (64.3%) contained only one anti-DSG3 IgG subclass (IgG4 in all but one case).

Figure 4
Figure 4

The number of anti-desmoglein 3 (DSG3) IgG subclasses as well as the presence of anti-DSG3 IgG3 in pemphigus vulgaris (PV) patients at baseline are associated with early relapse after rituximab (RTX) treatment. In the 33 PV patients treated by RTX, the distribution of anti-DSG3 IgG subclasses in the 26 non-relapsing (NR) (A) compared to the 7 early relapsing patients (RP) (B) show that RP have more IgG subclasses (p < 0.01) (C) and have a higher frequency of IgG3 than NR patients (71% vs. 12%; p = 0.004). No anti-Dsg3 IgG subclasses were detected in 2 of the 26 non-relapsing patients (number shown outside). Mean ± SEM were compared using unpaired t-test. Frequencies of anti-DSG3 subclasses were compared using Fisher’s exact test, **p < 0.01.

Figure 5
Figure 5

Pathogenicity of IgG3 and IgG4 anti-desmoglein 3 (DSG3) autoantibodies in pemphigus patients by keratinocyte dissociation and immunofluorescence assays. (A) IgG4 anti-DSG3 level (AU) were significantly decreased after remission (in RTX and CS groups) in pemphigus patients who had IgG4 only at baseline (n = 16) (p < 0.01). The four patients who still contained anti-DSG3 IgG4 after treatment are identified in red. The cutoff values are indicated as horizontal dotted lines and determined by the mean + 3 standard deviation (SD) of HD. Means were compared using paired t-test. (B) In patients whose sera contained exclusively anti-DSG3 IgG4 subclass after treatment, the mean anti-DSG3 IgG4 serum level in patients with persistent active disease was higher than in those in CR. Mean ± SEM were compared using unpaired t-test. (C) HaCaT cells pre-incubated for 24 h with positive control (AK23) or purified IgG of healthy donor (negative control) or PV patients with anti-DSG3 IgG4 only or (D) anti-DSG3 IgG3 and IgG4 were dissociated from the plate with dispase and the monolayers were mechanically disrupted. (E) HaCaT keratinocytes immunostaining incubated with purified IgG from a HD and from the patient’ IgG collected at the time of CR showed a linear labelling of DSG3 on the HaCaT cell plasma membrane. In contrast, the baseline purified IgG fraction induced the disappearance of the DSG3 labelling. Finally, removing the IgG3 fraction from the baseline patients’ serum led to the reappearance of the DSG3 staining, with a labelling close to that observed with control sera from HD, while the IgG3 fraction induced the disappearance of the DSG3 labelling. *p < 0.05; **p < 0.01.

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