Spinal fluid IgG antibodies from patients with demyelinating diseases bind multiple sclerosis-associated bacteria

Emily Eckman,John D Kriesel,Tom B Martins,Harry R Hill,Bert Lopansri,Kael F Fischer,Jon D Laman

doi:10.1007/s00109-021-02085-z

Abstract

A panel of 10 IgG enzyme-linked immunosorbent assays (ELISAs) were developed for the detection of anti-microbial immune responses in the cerebrospinal fluid (CSF) of patients with demyelinating diseases (DD). The anti-microbial ELISA assays follow on prior human brain tissue RNA sequencing studies that established multiple sclerosis (MS) microbial candidates. Lysates included in the ELISA panel were derived from Akkermansia muciniphila, Atopobium vaginae, Bacteroides fragilis, Lactobacillus paracasei, Odoribacter splanchnicus, Pseudomonas aeruginosa, Cutibacterium (Propionibacterium) acnes, Fusobacterium necrophorum, Porphyromonas gingivalis, and Streptococcus mutans. CSF responses from patients with demyelinating diseases (DD, N = 14) were compared to those with other neurological diseases (OND, N = 8) and controls (N = 13). Commercial positive and negative control CSF specimens were run with each assay. ELISA index values were derived for each specimen against each of the 10 bacterial lysates. CSF reactivity was significantly higher in the DD group compared to the controls against Akkermansia, Atopobium, Bacteroides, Lactobacillus, Odoribacter, and Fusobacterium. Four of the 11 tested DD group subjects had elevated antibody indexes against at least one of the 10 bacterial species, suggesting intrathecal antibody production. This CSF serological study supports the hypothesis that several of the previously identified MS candidate microbes contribute to demyelination in some patients.Key messagesA panel of 10 IgG enzyme-linked immunosorbent assays (ELISAs) were developed for the detection of anti-microbial immune responses in the cerebrospinal fluid (CSF) of patients with demyelinating diseases, including multiple sclerosis and acute disseminated encephalomyelitis.CSF reactivity was significantly higher in the demyelination group compared to the controls against the bacteria Akkermansia, Atopobium, Bacteroides, Lactobacillus, Odoribacter, and Fusobacterium.Several of the demyelination subjects had elevated antibody indexes against at least one of the 10 antigens, suggesting at least limited intrathecal production of anti-bacterial antibodies.This CSF serological study supports the hypothesis that several of the previously identified MS candidate microbes contribute to demyelination in some patients.

Highlights

A number of infections of the central nervous system (CNS) can lead to demyelination, including distemper, measles, JC virus, influenza, and possibly SARS-CoV-2 [1, 2]
Key messages & A panel of 10 immunoglobulin G (IgG) enzyme-linked immunosorbent assays (ELISAs) were developed for the detection of anti-microbial immune responses in the cerebrospinal fluid (CSF) of patients with demyelinating diseases, including multiple sclerosis and acute disseminated encephalomyelitis. & CSF reactivity was significantly higher in the demyelination group compared to the controls against the bacteria Akkermansia, Atopobium, Bacteroides, Lactobacillus, Odoribacter, and Fusobacterium. & Several of the demyelination subjects had elevated antibody indexes against at least one of the 10 antigens, suggesting at least limited intrathecal production of anti-bacterial antibodies. & This CSF serological study supports the hypothesis that several of the previously identified MS candidate microbes contribute to demyelination in some patients
We conducted a study of CSF reactivity against 10 MS microbial candidates previously identified by RNA sequencing of diseased brain tissue

Summary

Introduction

A number of infections of the central nervous system (CNS) can lead to demyelination, including distemper (dogs), measles (humans), JC virus (human), influenza (humans), and possibly SARS-CoV-2 [1, 2]. (MS), based on the epidemiology of the disease including geographic patterns, isolated outbreaks, and migration studies [3, 4] This field is contentious with much conflicting evidence. Researchers in the 1970s and 1980s made extensive efforts to find and isolate possible viral pathogens from fresh autopsy brain tissue [5] These efforts included inoculation of diseased human brain tissue into cell cultures, live animals, and even eggs, without any evidence of replicating viruses. Bacterial and fungal cultures were not performed, and ex vivo viral culture techniques included the use of antibiotics in the culture medium While these efforts to find viruses responsible for MS were certainly ambitious and laudable, this strategy likely would not have detected most bacteria, fungi, or protists within the affected brain tissue

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