Mycobacterium avium subsp. paratuberculosis Antigens Elicit a Strong IgG4 Response in Patients with Multiple Sclerosis and Exacerbate Experimental Autoimmune Encephalomyelitis

Davide Cossu; Yuji Tomizawa; Kazumasa Yokoyama; Tamami Sakanishi; Eiichi Momotani; Leonardo A Sechi; Nobutaka Hattori

doi:10.3390/life13071437

Mycobacterium avium subsp. paratuberculosis Antigens Elicit a Strong IgG4 Response in Patients with Multiple Sclerosis and Exacerbate Experimental Autoimmune Encephalomyelitis

Life (Basel). 2023 Jun 25;13(7):1437. doi: 10.3390/life13071437.

Authors

Davide Cossu^{1

2

3}, Yuji Tomizawa¹, Kazumasa Yokoyama^{1

4}, Tamami Sakanishi⁵, Eiichi Momotani^{1

6}, Leonardo A Sechi^{3

7}, Nobutaka Hattori^{1

8}

Affiliations

¹ Department of Neurology, Juntendo University, Tokyo 1138431, Japan.
² Biomedical Research Core Facilities, Juntendo University, Tokyo 1138431, Japan.
³ Department of Biomedical Sciences, Sassari University, 07100 Sassari, Italy.
⁴ Tosei Center for Neurological Diseases, Shizuoka 4180026, Japan.
⁵ Division of Cell Biology, Juntendo University, Tokyo 1138431, Japan.
⁶ Comparative Medical Research Institute, Tsukuba 3050856, Japan.
⁷ SC Microbiology, AOU Sassari, 07100 Sassari, Italy.
⁸ Neurodegenerative Disorders Collaborative Laboratory, RIKEN Center for Brain Science, Saitama 3510918, Japan.

Abstract

Neuroinflammation can be triggered by microbial products disrupting immune regulation. In this study, we investigated the levels of IgG1, IgG2, IgG3, and IgG4 subclasses against the heat shock protein (HSP)70_533-545 peptide and lipopentapeptide (MAP_Lp5) derived from Mycobacterium avium subsp. paratuberculosis (MAP) in the blood samples of Japanese and Italian individuals with relapsing remitting multiple sclerosis (MS). Additionally, we examined the impact of this peptide on MOG-induced experimental autoimmune encephalomyelitis (EAE). A total of 130 Japanese and 130 Italian subjects were retrospectively analyzed using the indirect ELISA method. Furthermore, a group of C57BL/6J mice received immunization with the MAP_HSP70_533-545 peptide two weeks prior to the active induction of MOG_35-55 EAE. The results revealed a significantly robust antibody response against MAP_HSP70_533-545 in serum of both Japanese and Italian MS patients compared to their respective control groups. Moreover, heightened levels of serum IgG4 antibodies specific to MAP antigens were correlated with the severity of the disease. Additionally, EAE mice that were immunized with MAP_HSP70_533-545 peptide exhibited more severe disease symptoms and increased reactivity of MOG_35-55-specific T-cell compared to untreated mice. These findings provide evidence suggesting a potential link between MAP and the development or exacerbation of MS, particularly in a subgroup of MS patients with elevated serum IgG4 levels.

Keywords: IgG4; experimental autoimmune encephalomyelitis; heath shock protein 70; multiple sclerosis; mycobacteria.

Abstract

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