Molecular and clinical relationship between live‐attenuated Japanese encephalitis vaccination and childhood onset myasthenia gravis

Abstract

ObjectiveThe incidence of childhood onset myasthenia gravis (CMG) in China is higher than that in other countries; however, the reasons for this are unclear.MethodsWe investigated the clinical and immunological profiles of CMG, and assessed the potential precipitating factors. For the mouse studies, the possible implication of vaccination in the pathogenesis was explored.ResultsIn our retrospective study, 51.22% of the 4,219 cases of myasthenia gravis (MG) were of the childhood onset type. The cohort study uncovered that the pathophysiology of CMG was mediated by immune deviation, rather than through gene mutations or virus infections. The administration of the live‐attenuated Japanese encephalitis vaccine (LA‐JEV), but not the inactivated vaccine or other vaccines, in mice induced serum acetylcholine receptor (AChR) antibody production, reduced the AChR density at the endplates, and decreased both muscle strength and response to repetitive nerve stimulation. We found a peptide (containing 7 amino acids) of LA‐JEV similar to the AChR‐α subunit, and immunization with a synthesized protein containing this peptide reproduced the MG‐like phenotype in mice.InterpretationOur results describe the immunological profile of CMG. Immunization with LA‐JEV induced an autoimmune reaction against the AChR through molecular mimicry. These findings might explain the higher occurrence rate of CMG in China, where children are routinely vaccinated with LA‐JEV, compared with that in countries, where this vaccination is not as common. Efforts should be made to optimize immunization strategies and reduce the risk for developing autoimmune disorders among children. Ann Neurol 2018;84:386–400

Management of Juvenile Myasthenia Gravis

“…Annual influenza vaccination with inactivated vaccine is recommended. A recent study, suggested an association between a live-attenuated Japanese encephalitis vaccine and the high prevalence rate of JMG in China ( 36 ). The hypothesis was supported by a mouse model but has not been replicated by other groups and at this time, we would not contradict the use of live-attenuated vaccines where required.…”

Childhood-Onset Myasthenia Gravis, a Troublesome Clinical Entity with Heterogeneity in China

“…HLA DRw9 and DRw13 were strongly associated with Japanese MG [31], Bw46DR9 with Chinese [27,65], DQ8 and DR3 with Caucasian, and DR5 with African descents [66]. Besides, environmental factors may play as a trigger to activate the autoimmunity by way of molecular mimicry, supra-antigen or by-stander mechanism [17]. In all, CMG is a clinical entity with worldwide heterogeneity concerning the clinical presentations and the responses to therapy.…”

“…Unfortunately, the epidemiology of MG is generally lacking in China, and a survey in Yiyang county in Hunan Province in 1986 discovered 60 MG patients in 590,000 residents (incidence was 10/100,000), with CMG 48 cases (80%) [16]. The Chinese hospital-based reports stated that CMG patients were estimated to account for more than 50% of the MG population, with a peak of onset age before 10 years, mainly aged 2-5 years [4][5][6]17].…”

To Be or Not To Be Vaccinated: That Is a Question in Myasthenia Gravis

“…A recent investigation, exploring the molecular and clinical relationship between childhood-onset myasthenia gravis (CMG) and live-attenuated Japanese encephalitis vaccination (LA-JEV), implicated vaccinations in the development of MG, after excluding genetic factors and viral infection (60). Exposing BALB/c mice to a group of Chinese planned immunization programs, researchers found LA-JEV can cause MG-like symptoms in the mice (60).…”