Staphylococcal immune complexes and myelinolytic toxin in early acute multiple sclerosis lesions—An immunohistological study supported by multifactorial cluster analysis and antigen-imprint isoelectric focusing

Abstract

Highly significant clinical, epidemiological and pathogenetic similarities between multiple sclerosis (MS) and nasopharyngeal sinusitis has led to the hypothesis that MS is caused by the inadvertent incorporation of the lymphatic drainage of the nasopharynx into the extracellular fluid circulation of the CNS. It has been postulated that, in response to antigenic and toxic products generated by the mucosal nasopharygeal flora, the leptomeninges and CNS parenchyma acquire the characteristics of a persistently stimulated lymphoid organ. Using an extensive panel of bacterial antibodies, tissues from exceptionally early cases, identified and classified using multifactorial cluster analysis, were screened for bacterial antigens using immunohistological methods. Anti-staphylococcal antibodies detected antigen co-locating with IgG/C3d immune complexes in pre-demyelinating and in primary lesions. The distribution of the antigen in relation to the morphogenesis of early acute MS lesions is detailed. Evidence for the intrathecal processing of staphylococcal antigen was obtained using isoelectric focusing and antigen imprinting to identify antigen-specific oligoclonal bands. Employing a combination of isoelectric focusing, western blotting and mass spectrometric analysis, evidence for the intrathecal processing of staphylococcal β-haemolysin (sphingomyelinase) was obtained using CSF from MS cases. While a myelinolytic transportable toxin may be an important component in the pathogenesis of demyelination, in oligodendrocyte apoptosis, and in deviant immune responses within the CNS, the detection of other as yet unidentified staphylococcal-positive and negative oligoclonal bands points to the involvement of a cocktail of transportable antigens leaking in a similar manner into the CNS from the paranasal sinus mucosal tissues where these molecules are conserved by the resident flora to manipulate and subvert the normal processes of local and systemic immunity. Evidence for the access of other bacterial transportables to the CNS in MS should now be sought. The presence of 'high-output' toxigenic bacterial strains within the nasopharyngeal flora of MS patients should also be explored. The use of tracer molecules to detect and quantify nose-to-brain transport in MS patients is clearly apposite.

Cause and prevention of demyelination in a model multiple sclerosis lesion

“…In the LPS lesion, the demyelination results from the focal administration of a bacterial toxin, but although some have suggested that MS may arise from bacterial activity, there is no reason from our data to believe that other mechanisms that result in similar activation of the innate immune system, such as Epstein–Barr virus infection, would not also cause demyelination. If so, the precise identity of the infective agent may be less important than its ability in a particular person to induce a local environment toxic to oligodendrocytes, such as one characterized by hypoxia, nitric oxide, and superoxide.…”

“Smelling and Tasting” Parkinson's Disease: Using Senses to Improve the Knowledge of the Disease

“…Interestingly, some components of the respiratory microbial flora have been linked to neurodegenerative and neuroinflammatory diseases: (1) Chlamydia Pneumoniae infection is associated with a 5-fold increased incidence of Alzheimer Disease (AD) (Maheshwari and Eslick, 2015) and C. Pneumoniae DNA was found in 90% of brain tissue samples in AD in comparison with 5% in controls (Balin et al, 1998); 2Multiple Sclerosis (MS) has been linked to overrepresentation of nasal enterotoxin-A-producing S. Aureus (Brocke et al, 1993) and staphylococcal-specific oligoclonal bands (OCBs) are also identified in the cerebrospinal fluid of MS cases (Gay, 2013).…”

Invited Review: From nose to gut – the role of the microbiome in neurological disease

“…While the focus of research has primarily been on S. aureus toxins, this hypothesis proposes that a cocktail of bacterial toxins derived from the nasal microbiome are involved and may be responsible for the persistence of oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF) of MS cases. While some OCBs appear to represent reactivity to ubiquitous self‐epitopes , staphylococcal‐specific OCBs are also identified in the CSF of MS cases , suggesting a reactive intrathecal plasma cell clone. Further work is required to identify intrathecal IgG specific to other bacterial products of the nasal microbiome.…”

“…Specifically, S. aureus is a leading cause of chronic sinusitis and has also been independently associated with MS. The prevalence of nasal enterotoxin A‐producing S. aureus differs significantly between controls and people with active MS and staphylococcal syringomyelinase immune complexes are found throughout the CNS in individuals with MS .…”

“…In MS, the association with chronic sinusitis has led to speculation that a cocktail of transportable bacterial toxins produced by the nasal microbiome, particularly in the posterior paranasal sinuses, gains access to the ECF of the CNS via lymphatic drainage. Staphylococcal syringomyelinase immune complexes are found in the leptomeninges, the Virchow‐Robin spaces and the brain parenchyma of individuals with MS which suggests dispersion of S. aureus antigen throughout the ECF compartments of the CNS . In cell culture models, sphingomyelinase is able to induce oligodendrocyte apoptosis .…”