In‐depth peripheral CD4⁺ T profile correlates with myasthenic crisis

Abstract

Objective Myasthenia gravis (MG) is an autoimmune disease caused by autoantibodies against neuromuscular junctions. Myasthenic crisis (MC) represents the most severe state of MG with high in‐hospital mortality. We aimed to identify immune signatures using in‐depth profiling in MC, and to assess the correlations between immune biomarkers with clinical severity longitudinally. Methods We studied 181 participants including 57 healthy controls, 96 patients with MG who never experienced crisis and 28 MC patients from December 2018 through June 2020. Follow‐up visits occurred prospectively from crisis to 6 months off‐mechanical ventilation. The frequencies of 20 CD4+ T subpopulations and 18 serum cytokines were associated with clinical scores using correlations and principal component analysis. Results Patients in crisis exhibited a proinflammatory CD4+T response with elevated Th1 (P = 0.026), and Th17 cells (P = 0.032); decreased T follicular helper 2 (Tfh2) cells (P < 0.001), Tnaive in Tfh cells (P < 0.001), ICOS−Tfh cells (P = 0.017), and T central memory in Tfh (P = 0.022) compared with controls, and increased frequencies of Tregs (P = 0.026) and Tfh17 (P = 0.045) compared with non‐crisis MG. Cytokine cascade was identified in crisis including the ones associated with Th1 (IL‐1β/2/12p70/18/27/IFN‐γ/TNF‐α), Th2 (IL‐4/5/13), Th17 (IL‐6/17A/21/22/23/GM‐CSF), Th9 (IL‐9), and Treg (IL‐10). Longitudinally, seven immune biomarkers including Tregs, IL‐2/4/17A/IFN‐γ/TNF‐α/GM‐CSF had significant correlations with MG‐activities of daily living score. Interpretation Vigorous inflammatory CD4+ T signatures were identified in MC and are associated with clinical severity. Future research is needed to explore its potential candidacy for therapeutic intervention and predicting impending crisis.

Increased serum IL-2, IL-4, IL-5 and IL-12p70 levels in AChR subtype generalized myasthenia gravis

“…Although these cytokines were elevated in current selected cohort, IL-4 and IL-12p70 level were previously revealed to be decreased in non-crisis MG patients compared with healthy controls [ 8 ]. We have two explanations for this discrepancy: (1) non-crisis gMG selected in previous study were mainly comprised of MGFA II-IV who had never had a crisis but 25% have already been on immunotherapy, which may lower the peripheral inflammatory cytokines.…”

“…MG mimicking diseases including Lambert-Eaton myasthenic syndrome, peripheral neuropathy, myopathies, and motor neuron diseases were excluded before the recruiting. The patients who have already enrolled in previous study for 18 cytokine measurement have been excluded in current study [ 8 ]. The inclusion criteria from registration database for cytokine analysis were defined as: (1) onset symptoms and signs compatible with gMG; (2) immunotherapy naïve at baseline; (3) sero-positive for anti-AChR antibody; (4) MGFA clinical classification II to IV; (5) follow-up visits at 12 ± 6 months after baseline recruitment.…”

“…Cytokine measurement had been greatly facilitated by multiplex assay, which allows multiple analytes to be quantified simultaneously in a single biological matrix sample. With this assay, we had measured 18 inflammatory cytokines in two independent cohorts with myasthenic crisis and non-crisis gMG respectively [ 8 ]. However, the sample size for non-crisis gMG was relatively small and we included a certain proportion who have already been on immunotherapies.…”

Comorbid Autoimmune Diseases in Patients With Myasthenia Gravis: A Retrospective Cross-Sectional Study of a Chinese Cohort

“…Through our single-center registration database, we reviewed the records of all patients with MG who were admitted to Huashan Hospital Fudan University from August 2013 to August 2020. The diagnosis of MG was based on clinical symptoms and at least one of the following specific tests: objective clinical response to neostigmine test, seropositivity for anti-AChR/anti-MuSK antibody, or significant decremental response on 3 Hz repetitive nerve stimulation ( 12 , 13 ). Other diseases that mimic MG were excluded, including Lambert-Eaton syndrome, motor neuron disease, and congenital myasthenic syndrome.…”

Myasthenia Gravis: Epidemiology, Pathophysiology and Clinical Manifestations

“…On the other hand, T cell and cytokine profile may change during MG crisis. Huan et al demonstrated that patients with MG crisis had significantly elevated levels of Th17 as well as Th2-related cytokines IL-4 and IL-13 compared to 6 months post-ventilatory support [ 122 ]. Higher frequencies of Th1 and Th17 cytokines were also observed in MuSK-associated MG [ 123 ].…”