Regulatory T Cells Increase After rh-MOG Stimulation in Non-Relapsing but Decrease in Relapsing MOG Antibody-Associated Disease at Onset in Children

Abstract

Background: Myelin oligodendrocytes glycoprotein (MOG) antibody-associated disease (MOGAD) represent 25% of pediatric acquired demyelinating syndrome (ADS); 40% of them may relapse, mimicking multiple sclerosis (MS), a recurrent and neurodegenerative ADS, which is MOG-Abs negative.

Aims: To identify MOG antigenic immunological response differences between MOGAD, MS and control patients, and between relapsing versus non-relapsing subgroups of MOGAD.

Methods: Three groups of patients were selected: MOGAD (n=12 among which 5 relapsing (MOGR) and 7 non-relapsing (MOGNR)), MS (n=10) and control patients (n=7). Peripheral blood mononuclear cells (PBMC) collected at the time of the first demyelinating event were cultured for 48 h with recombinant human (rh)-MOG protein (10 μg/ml) for a specific stimulation or without stimulation as a negative control. The T cells immunophenotypes were analyzed by flow cytometry. CD4⁺ T cells, T helper (Th) cells including Th1, Th2, and Th17 were analyzed by intracellular staining of cytokines. Regulatory T cells (T_regs, Foxp3⁺), CD45RA^-Foxp3⁺ T_regs and subpopulation naive T_regs (CD45RA⁺Foxp3^int), effector T_regs (CD45RA^-Foxp3^high) and non-suppressive T_regs (CD45RA^-Foxp3^int) proportions were determined.

Results: The mean onset age of each group, ranging from 9.9 to 13.8, and sex ratio, were similar between MOGR, MOGNR, MS and control patients as analyzed by one-way ANOVA and Chi-square test. When comparing unstimulated to rh-MOG stimulated T cells, a significant increase in the proportion of Th2 and Th17 cells was observed in MOGAD. Increase of Th17 cells was significant in MOGNR (means: 0.63 ± 0.15 vs. 1.36 ± 0.43; Wilcoxon-test p = 0.03) but not in MOGR. CD4⁺ T_regs were significantly increased in MOGNR (means: 3.51 ± 0.7 vs. 4.59 ± 1.33; Wilcoxon-test p = 0.046) while they decreased in MOGR. CD45RA^-Foxp3⁺ T_regs were significantly decreased in MOGR (means: 2.37 ± 0.23 vs. 1.99 ± 0.17; paired t-test p = 0.021), but not in MOGNR. MOGR showed the highest ratio of effector T_regs/non suppressive-T_regs, which was significantly higher than in MOGNR.

Conclusions: Our findings suggest that CD4⁺ Th2 and Th17 cells are involved in the pathophysiology of MOGAD in children. The opposite response of T_regs to rh-MOG in MOGNR, where CD4⁺ T_regs increased, and in MOGR, where CD45RA^-Foxp3⁺ T_regs decreased, suggests a probable loss of tolerance toward MOG autoantigen in MOGR which may explain relapses in this recurrent pediatric autoimmune disease.

Keywords: acquired demyelinating syndromes (ADS); auto-immune diseases; multiple sclerosis; myelin oligodendrocyte glycoprotein; neuroinflammation; regulatory T lymphocytes.