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Bacterial transportable toxins of the nasopharyngeal microbiota in multiple sclerosis. Nose-to-brain direct
NEUROL-2143; No. of Pages 6 revue neurologique xxx (2019) xxx–xxx
Available online at
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Environmental Neurology
Bacterial transportable toxins of the nasopharyngeal microbiota in multiple sclerosis. Nose-to-brain direct F. Gay * School of Biological Sciences, University of Essex, 68, coast road West Mersea, CO5 8LS Colchester, United Kingdom
info article
abstract
Article history:
Intranasal administration delivers molecules directly to the brain bypassing the blood-brain
Received 6 April 2019
barrier. Three distinct routes of access have been identified; olfactory, trigeminal and via the
Received in revised form
paranasal sub-mucosa of the posterior sinuses. Consequently, environmental toxins may
2 September 2019
access the CNS directly to induce inflammatory and degenerative disease. They may also
Accepted 2 September 2019
activate bacterial species of the nasal mucosal microbiome to release both immune-
Available online xxx
deviating cell wall antigens and transportable neurotoxins with local direct access to the CNS. Evidence is reviewed that toxins of the nasal bacterial microbiota may be directly implicated in the inflammatory and degenerative pathogenesis of multiple sclerosis. # 2019 Elsevier Masson SAS. All rights reserved.
1.
The blood-brain barrier bypassed
Delivery of therapeutic drugs to the central nervous system (CNS) from the systemic blood circulation is strictly limited by the blood-brain barrier (BBB) effectively excluding all but the smallest lipophilic molecules. However, delivery of therapeutically effective levels of macromolecules directly to the CNS, bypassing the BBB, has been achieved by intranasal delivery via the nasal mucosa. Numerous reports have recently described nose-to-brain transport of small proteins, peptides, and other neurotropic molecules in experimental animals and also in man [1–8]. Nose-to-brain as a direct route of entry to the CNS for air pollutants, that have the potential to cause or to alter the course of CNS diseases, is a rapidly emerging interest [9]. The clear association between smoking and solvent
inhalation in multiple sclerosis (MS) and in other degenerative CNS diseases has generated much speculation on the mechanisms involved [9–14]. It is generally assumed that toxins are absorbed via the lungs to induce deviant ‘autoimmune’ effects. However, inhaled toxins may access the CNS via the nasal mucosa, with the potential to act directly to induce inflammatory and degenerative neuronal and axonal damage [15,16]. Heroin inhalation is associated with both an indolent and a rapidly acute leukoencephalopathy resembling anoxic brain injury [17]. Inhaled toxins have the additional potential to activate species of the nasopharyngeal mucosal bacterial microbiome to release a profusion of neurotoxic and immune-deviant molecules. The pathogenic potential of nasal bacterial products in neurodegenerative diseases is now being considered [18–20]. The detection of the intrathecal synthesis of antibodies to Staphylococcal lipotechoic acid and peptido-
* School of Biological Sciences, University of Essex, 68, coast road West Mersea, CO5 8LS Colchester, United Kingdom. E-mail address: [email protected]. https://doi.org/10.1016/j.neurol.2019.09.004 0035-3787/# 2019 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Gay F. Bacterial transportable toxins of the nasopharyngeal microbiota in multiple sclerosis. Nose-to-brain direct. Revue neurologique (2019), https://doi.org/10.1016/j.neurol.2019.09.004
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glycan in MS patients [21] and direct evidence of antigen processing within lesions [22], has focused attention on Staphylococcus aureus as a source of significant gram-positive pro-inflammatory antigens accessing the CNS. More recently the detection of oligoclonal antibody in MS CSF to S. aureus beta toxin (neutral sphingomyelinase) and the location of the toxin within primary MS lesions [23] supports the nose-tobrain hypothesis. The clear evidence that MS is induced by unknown environmental factors in genetically susceptible individuals has led to numerous epidemiological studies to investigate particular occupational risks. An association with farming [24], and in particular exposure to livestock [25], has recently been further narrowed to dairy operators [26]. Considering the evidence relating to the nose-to-brain bacterial hypothesis, the acquisition by MS patients of specific toxigenic strains known to be dominant in cattle [27,28] needs to be tested in regions of high MS incidence, such as Orkney.
2.
The anatomy of nose-to-brain routes
Three distinct routes of direct nose-to-brain access have now been identified and are currently being researched. The olfactory route via the first cranial nerve passing through the cribriform plate of the ethmoid bone conveys viruses [29,30] and protozoans [31] directly to the meninges and to the olfactory bulb. It is now well established that a number of neurodegenerative diseases, including MS are associated with an impaired sense of smell [32–36], which may be transiently associated with the onset of acute MS attacks [37]. This has stimulated considerable interest in the hypothesis that the direct olfactory route to the CNS may account for the association of these conditions with environmental factors including cigarette smoke and exposure to various solvents [9–14]. A less familiar nose-to-brain route is the periaxonal lymphatic sheath of the fifth cranial nerve. The trigeminal nerve trunk has been shown to convey tracers from the mucosa of the maxillary sinus to the brain stem, cerebellum and spinal meninges [5]. The transport of bacterial transportable molecules centripetally along cranial and spinal nerve sheaths to access the meninges, with the subsequent induction of demyelination in the CNS, was originally demonstrated by Orr and Rose [38]. Dawson in his celebrated seminal monograph on MS [39], highlighted this work as an addendum, as it provided an explanation for the distinctive topographical distribution of both spinal and central lesions. Nerve trunk pathways of inflammation as a direct access of bacterial toxins to the CNS were later highlighted by Wright [40] and Brain [41], but were explored no further due to the growing presumption that MS was an immune-mediated demyelination, analogous to experimental allergic encephalomyelitis (EAE), and awaiting only the identification of an autoimmune target. The EAE hypothesis precluded any further enquiry into the pathogenic role of microbial toxins directly accessing the CNS via cranial and spinal nerve trunk routes. The failure to reproducibly identify any credible autoimmune target in MS after decades of meticulous searching, constitutes a considerable enigma [42]. This is all the more enigmatic in the face of some therapeutic
successes using disease modifying therapies to reduce intrathecal inflammation in relapsing-remitting MS. However, unremitting primary and secondary disease progression, despite effective control of inflammation, continues to raise the question of the primacy of unknown neurotoxic factors [43–46]. Involvement of the trigeminal nerve in MS involving facial sensory disturbance and occasionally trigeminal neuralgia is encountered between 1% and 6% of MS patients and with optic neuritis and is a frequent finding in Clinically Isolated Syndromes [47–49]. Using conventional MRI, signal abnormalities in the trans-cisternal nerve and in the pontine root entry zone were detected in approximately 3% of patients with a history of trigeminal neuralgia [50]. However, using high resolution MRI at 3T, Mills et al. [51] demonstrated trigeminal lesions in 11/47 (23%) of randomly chosen MS patients without any corresponding clinical association. High signals in the trigeminal nerve as it transits Meckel’s cave, in the absence of clinical effects, is suggestive of periaxonal inflammation as it was originally described by Orr and Rose [38]. In an MRI study of trigeminal nerve involvement in MS patients with trigeminal nerve symptoms (79% unilateral) Swinnen et al. [52] have reported a distinctive topography of the lesions within the intrapontine tract of the trigeminal nerve within the brainstem, a topography resembling the extension of herpes simplex virus via the periaxonal route [46]. These data are consistent with the hypothesis that the trigeminal nerve provides a direct route of ascending periaxonal lymphatic flow from its origins in the mucosa of the nasopharynx to the brainstem, to access the caudal CNS and the spinal cord. A third nose-to-brain route, which, for anatomical reasons is probably peculiar to homo sapiens [53,54], occurs in the walls of the sphenoidal and ethmoidal sinuses and in the optic canal. Here cancellous bone may be paper-thin and occasionally defective, so that sinus sub-mucosa lies directly on dura. This permits uninterrupted communication between the paranasal sinus sub-mucosa and the underlying meninges [55]. The recent detection of meningeal lymphatics [56] indicates an important direct connection between the circulation of CSF, the lymphatic drainage of the meninges and potential continuity of drainage with the paranasal sub-mucosal tissues [57–61]. The pathogenic significance of these findings to account for the distinctive topography of MS lesions, as originally described by Dawson [39], now appears to be re-emerging.
3.
Optic neuritis and sinusitis
The intimate anatomical proximity of the posterior nasal sinuses to the optic neural tracts led to a century of clinical speculation that optic neuritis (ON) could be caused by the extension of inflammation from an adjacent sinusitis. A large literature circa 1920–40 confidently claimed that surgical mucosal clearances rapidly restored optic nerve function [50]. It was only when it was realized that at least 75% of unilateral ON cases later developed into MS that the ‘beneficial response’ to surgical mucosal clearance was re-interpreted as the spontaneous remission characteristic of that relapsing and remitting disease. Rejection of surgical intervention in ON was therefore based on the presumption that MS was not caused by sinusitis and that no further enquiry was
Please cite this article in press as: Gay F. Bacterial transportable toxins of the nasopharyngeal microbiota in multiple sclerosis. Nose-to-brain direct. Revue neurologique (2019), https://doi.org/10.1016/j.neurol.2019.09.004
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warranted. In addition, the growing belief that MS was an immune-mediated demyelination awaiting only an autoimmune explanation also precluded any further inquiry into the idea that MS, ON and sinusitis could be related in a common pathological process. This idea however has been rejuvenated by epidemiological data showing that these conditions are significantly and closely associated in frequency, age of attack, season of attack and in the timing of attacks [62,63]. The detection of S. aureus neutral sphingomyelinase (beta toxin) in the primary MS lesion [23] has provided further credible support for the hypothesis that MS is caused by the leakage of bacterial pore-forming neurotoxin from foci within the nasal mucosa directly to the CNS (Fig. 1). In the light of these findings, the isolation of beta haemolytic S. aureus in pure culture from the inflamed ethmoidal submucosa in a classical case of acute unilateral optic neuritis [64] should now be regarded as potentially significant and requiring future bacteriological study of mucosal tissues from similar cases. The potential of sphingomyelinase to induce relevant and highly specific axonal, neuronal and immune damage has recently become evident. The toxin is classified [65] with a group of bacterial transportables inducing membrane ‘pores’ with an array of biologically significant consequences. Monocytes exposed to sphingomyelinase secrete IL-1beta and shed receptors for IL6 and LPS [66]. Permeability defects in monocyte membranes results in the
3
loss of potassium and sodium ion homeostasis leading to the activation of interleukin-converting enzyme [67]. The shedding of receptors for IL6 and LPS renders them soluble, presenting these to bystander cells, which then become sensitive to the respective ligands [68,69]. In multiple sclerosis there is both an increased immunoreactivity to the free LPS receptor and also intrathecal synthesis of antibody to the soluble Interleukin-6 receptor [69,70]. The removal of phosphate head groups from particular membrane lipids by sphingomyelinase shuts down the Kv1.3 channel, so that the electrical sensor cannot open the gate, deranging the immune response [71–73]. Oligodendroglia are highly susceptible to oxidative stress-induced damage. Primary multiple sclerosis lesions have been characterized by the apoptotic loss of oligodendrocytes [74], which can be induced by sphingomyelinase both in vitro and in vivo [75–77]. It is topographically significant that attacks of optic neuritis in MS are characteristically unilateral, and that recurrent attacks are significantly ipsilateral. [78] This is in marked contrast to the autoimmune demyelinating conditions, acute disseminated encephalomyelitis, (ADEM) neuromyelitis optica (NMO) and chronic relapsing inflammatory optic neuropathy (CRION) which are characteristically bilateral [78–81]. These frequently bilateral conditions caused by a systemic autoimmune attack across the BBB emphasize the topographical and significant difference from ON/MS. Moreo-
Fig. 1 – A and B. Detection of Staphylococcal sphingomyelinase (beta toxin in primary MS lesions [Gay F]) [23]. Cryostat sections of early acute MS spinal cord. Activated microglia with positive pinocytic vesicles applied to the surface of degenerate axons (arrows) positive for antigen. Rabbit anti-staphylococcal sphingomyelinase, with biotinylated antirabbit/streptavidin-HRP/DAB. C and D. Experimental lesion rat spinal cord, at 48 hours post injection of 2.5 nanogram Staphylococcal sphingomyelinase. Mild demyelination with marked axonal degeneration. Epoxy sections; toluidine blue (Spinal cord injections performed by Dr Andrew Davies, Dept of Neuroinflammation, IoN, UCL, UK). Please cite this article in press as: Gay F. Bacterial transportable toxins of the nasopharyngeal microbiota in multiple sclerosis. Nose-to-brain direct. Revue neurologique (2019), https://doi.org/10.1016/j.neurol.2019.09.004
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ver, histological evidence indicates that the primary attack in MS occurs internally and in tissues where the BBB is intact [74,82,83]. If these direct nose-to-brain findings are confirmed it would undoubtedly open up an almost totally new range of investigations and approaches to the diagnosis, treatment and prevention of MS. How might this be achieved? A recent study of patients with chronic sinusitis using automated perimetry, optical coherence tomography and CT scanning, have demonstrated and quantified optic nerve damage in these cases. The structural and functional optic nerve changes detected were significantly correlated with the severity and location of the indolent paranasal sinus disease. [84]. These neuro-ophthalmological findings closely resemble the optic nerve changes, including axonal loss, that have been described in MS [85–87]. Clearly similar neuro-ophthalmological studies combined with MRI and CT scanning in patients with unilateral ON should be employed to further investigate the nose-to-brain hypothesis and assess potential antimicrobial therapies. An understanding of the pathogenesis of MS in terms of the nose-to-brain access of bacterial toxins to the CNS should be further explored using cultural and PCR methods to detect high toxin producing strains within the nasal flora of MS patients. [23] Nasal delivery of disease modifying molecules linked to radiologically detectible tracers could be employed to assess the extent, location and clinical efficacy of nose-tobrain therapy in MS patients. The results of direct delivery of immune dysregulatory bacterial toxins, including the poreinducing transportables and sphingomyelinases (Fig. 1) in animal models should be explored.
Disclosure of interest The author declares that he has no competing interest.
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Please cite this article in press as: Gay F. Bacterial transportable toxins of the nasopharyngeal microbiota in multiple sclerosis. Nose-to-brain direct. Revue neurologique (2019), https://doi.org/10.1016/j.neurol.2019.09.004
Available online at
ScienceDirect www.sciencedirect.com
Environmental Neurology
Bacterial transportable toxins of the nasopharyngeal microbiota in multiple sclerosis. Nose-to-brain direct F. Gay * School of Biological Sciences, University of Essex, 68, coast road West Mersea, CO5 8LS Colchester, United Kingdom
info article
abstract
Article history:
Intranasal administration delivers molecules directly to the brain bypassing the blood-brain
Received 6 April 2019
barrier. Three distinct routes of access have been identified; olfactory, trigeminal and via the
Received in revised form
paranasal sub-mucosa of the posterior sinuses. Consequently, environmental toxins may
2 September 2019
access the CNS directly to induce inflammatory and degenerative disease. They may also
Accepted 2 September 2019
activate bacterial species of the nasal mucosal microbiome to release both immune-
Available online xxx
deviating cell wall antigens and transportable neurotoxins with local direct access to the CNS. Evidence is reviewed that toxins of the nasal bacterial microbiota may be directly implicated in the inflammatory and degenerative pathogenesis of multiple sclerosis. # 2019 Elsevier Masson SAS. All rights reserved.
1.
The blood-brain barrier bypassed
Delivery of therapeutic drugs to the central nervous system (CNS) from the systemic blood circulation is strictly limited by the blood-brain barrier (BBB) effectively excluding all but the smallest lipophilic molecules. However, delivery of therapeutically effective levels of macromolecules directly to the CNS, bypassing the BBB, has been achieved by intranasal delivery via the nasal mucosa. Numerous reports have recently described nose-to-brain transport of small proteins, peptides, and other neurotropic molecules in experimental animals and also in man [1–8]. Nose-to-brain as a direct route of entry to the CNS for air pollutants, that have the potential to cause or to alter the course of CNS diseases, is a rapidly emerging interest [9]. The clear association between smoking and solvent
inhalation in multiple sclerosis (MS) and in other degenerative CNS diseases has generated much speculation on the mechanisms involved [9–14]. It is generally assumed that toxins are absorbed via the lungs to induce deviant ‘autoimmune’ effects. However, inhaled toxins may access the CNS via the nasal mucosa, with the potential to act directly to induce inflammatory and degenerative neuronal and axonal damage [15,16]. Heroin inhalation is associated with both an indolent and a rapidly acute leukoencephalopathy resembling anoxic brain injury [17]. Inhaled toxins have the additional potential to activate species of the nasopharyngeal mucosal bacterial microbiome to release a profusion of neurotoxic and immune-deviant molecules. The pathogenic potential of nasal bacterial products in neurodegenerative diseases is now being considered [18–20]. The detection of the intrathecal synthesis of antibodies to Staphylococcal lipotechoic acid and peptido-
* School of Biological Sciences, University of Essex, 68, coast road West Mersea, CO5 8LS Colchester, United Kingdom. E-mail address: [email protected]. https://doi.org/10.1016/j.neurol.2019.09.004 0035-3787/# 2019 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Gay F. Bacterial transportable toxins of the nasopharyngeal microbiota in multiple sclerosis. Nose-to-brain direct. Revue neurologique (2019), https://doi.org/10.1016/j.neurol.2019.09.004
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glycan in MS patients [21] and direct evidence of antigen processing within lesions [22], has focused attention on Staphylococcus aureus as a source of significant gram-positive pro-inflammatory antigens accessing the CNS. More recently the detection of oligoclonal antibody in MS CSF to S. aureus beta toxin (neutral sphingomyelinase) and the location of the toxin within primary MS lesions [23] supports the nose-tobrain hypothesis. The clear evidence that MS is induced by unknown environmental factors in genetically susceptible individuals has led to numerous epidemiological studies to investigate particular occupational risks. An association with farming [24], and in particular exposure to livestock [25], has recently been further narrowed to dairy operators [26]. Considering the evidence relating to the nose-to-brain bacterial hypothesis, the acquisition by MS patients of specific toxigenic strains known to be dominant in cattle [27,28] needs to be tested in regions of high MS incidence, such as Orkney.
2.
The anatomy of nose-to-brain routes
Three distinct routes of direct nose-to-brain access have now been identified and are currently being researched. The olfactory route via the first cranial nerve passing through the cribriform plate of the ethmoid bone conveys viruses [29,30] and protozoans [31] directly to the meninges and to the olfactory bulb. It is now well established that a number of neurodegenerative diseases, including MS are associated with an impaired sense of smell [32–36], which may be transiently associated with the onset of acute MS attacks [37]. This has stimulated considerable interest in the hypothesis that the direct olfactory route to the CNS may account for the association of these conditions with environmental factors including cigarette smoke and exposure to various solvents [9–14]. A less familiar nose-to-brain route is the periaxonal lymphatic sheath of the fifth cranial nerve. The trigeminal nerve trunk has been shown to convey tracers from the mucosa of the maxillary sinus to the brain stem, cerebellum and spinal meninges [5]. The transport of bacterial transportable molecules centripetally along cranial and spinal nerve sheaths to access the meninges, with the subsequent induction of demyelination in the CNS, was originally demonstrated by Orr and Rose [38]. Dawson in his celebrated seminal monograph on MS [39], highlighted this work as an addendum, as it provided an explanation for the distinctive topographical distribution of both spinal and central lesions. Nerve trunk pathways of inflammation as a direct access of bacterial toxins to the CNS were later highlighted by Wright [40] and Brain [41], but were explored no further due to the growing presumption that MS was an immune-mediated demyelination, analogous to experimental allergic encephalomyelitis (EAE), and awaiting only the identification of an autoimmune target. The EAE hypothesis precluded any further enquiry into the pathogenic role of microbial toxins directly accessing the CNS via cranial and spinal nerve trunk routes. The failure to reproducibly identify any credible autoimmune target in MS after decades of meticulous searching, constitutes a considerable enigma [42]. This is all the more enigmatic in the face of some therapeutic
successes using disease modifying therapies to reduce intrathecal inflammation in relapsing-remitting MS. However, unremitting primary and secondary disease progression, despite effective control of inflammation, continues to raise the question of the primacy of unknown neurotoxic factors [43–46]. Involvement of the trigeminal nerve in MS involving facial sensory disturbance and occasionally trigeminal neuralgia is encountered between 1% and 6% of MS patients and with optic neuritis and is a frequent finding in Clinically Isolated Syndromes [47–49]. Using conventional MRI, signal abnormalities in the trans-cisternal nerve and in the pontine root entry zone were detected in approximately 3% of patients with a history of trigeminal neuralgia [50]. However, using high resolution MRI at 3T, Mills et al. [51] demonstrated trigeminal lesions in 11/47 (23%) of randomly chosen MS patients without any corresponding clinical association. High signals in the trigeminal nerve as it transits Meckel’s cave, in the absence of clinical effects, is suggestive of periaxonal inflammation as it was originally described by Orr and Rose [38]. In an MRI study of trigeminal nerve involvement in MS patients with trigeminal nerve symptoms (79% unilateral) Swinnen et al. [52] have reported a distinctive topography of the lesions within the intrapontine tract of the trigeminal nerve within the brainstem, a topography resembling the extension of herpes simplex virus via the periaxonal route [46]. These data are consistent with the hypothesis that the trigeminal nerve provides a direct route of ascending periaxonal lymphatic flow from its origins in the mucosa of the nasopharynx to the brainstem, to access the caudal CNS and the spinal cord. A third nose-to-brain route, which, for anatomical reasons is probably peculiar to homo sapiens [53,54], occurs in the walls of the sphenoidal and ethmoidal sinuses and in the optic canal. Here cancellous bone may be paper-thin and occasionally defective, so that sinus sub-mucosa lies directly on dura. This permits uninterrupted communication between the paranasal sinus sub-mucosa and the underlying meninges [55]. The recent detection of meningeal lymphatics [56] indicates an important direct connection between the circulation of CSF, the lymphatic drainage of the meninges and potential continuity of drainage with the paranasal sub-mucosal tissues [57–61]. The pathogenic significance of these findings to account for the distinctive topography of MS lesions, as originally described by Dawson [39], now appears to be re-emerging.
3.
Optic neuritis and sinusitis
The intimate anatomical proximity of the posterior nasal sinuses to the optic neural tracts led to a century of clinical speculation that optic neuritis (ON) could be caused by the extension of inflammation from an adjacent sinusitis. A large literature circa 1920–40 confidently claimed that surgical mucosal clearances rapidly restored optic nerve function [50]. It was only when it was realized that at least 75% of unilateral ON cases later developed into MS that the ‘beneficial response’ to surgical mucosal clearance was re-interpreted as the spontaneous remission characteristic of that relapsing and remitting disease. Rejection of surgical intervention in ON was therefore based on the presumption that MS was not caused by sinusitis and that no further enquiry was
Please cite this article in press as: Gay F. Bacterial transportable toxins of the nasopharyngeal microbiota in multiple sclerosis. Nose-to-brain direct. Revue neurologique (2019), https://doi.org/10.1016/j.neurol.2019.09.004
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warranted. In addition, the growing belief that MS was an immune-mediated demyelination awaiting only an autoimmune explanation also precluded any further inquiry into the idea that MS, ON and sinusitis could be related in a common pathological process. This idea however has been rejuvenated by epidemiological data showing that these conditions are significantly and closely associated in frequency, age of attack, season of attack and in the timing of attacks [62,63]. The detection of S. aureus neutral sphingomyelinase (beta toxin) in the primary MS lesion [23] has provided further credible support for the hypothesis that MS is caused by the leakage of bacterial pore-forming neurotoxin from foci within the nasal mucosa directly to the CNS (Fig. 1). In the light of these findings, the isolation of beta haemolytic S. aureus in pure culture from the inflamed ethmoidal submucosa in a classical case of acute unilateral optic neuritis [64] should now be regarded as potentially significant and requiring future bacteriological study of mucosal tissues from similar cases. The potential of sphingomyelinase to induce relevant and highly specific axonal, neuronal and immune damage has recently become evident. The toxin is classified [65] with a group of bacterial transportables inducing membrane ‘pores’ with an array of biologically significant consequences. Monocytes exposed to sphingomyelinase secrete IL-1beta and shed receptors for IL6 and LPS [66]. Permeability defects in monocyte membranes results in the
3
loss of potassium and sodium ion homeostasis leading to the activation of interleukin-converting enzyme [67]. The shedding of receptors for IL6 and LPS renders them soluble, presenting these to bystander cells, which then become sensitive to the respective ligands [68,69]. In multiple sclerosis there is both an increased immunoreactivity to the free LPS receptor and also intrathecal synthesis of antibody to the soluble Interleukin-6 receptor [69,70]. The removal of phosphate head groups from particular membrane lipids by sphingomyelinase shuts down the Kv1.3 channel, so that the electrical sensor cannot open the gate, deranging the immune response [71–73]. Oligodendroglia are highly susceptible to oxidative stress-induced damage. Primary multiple sclerosis lesions have been characterized by the apoptotic loss of oligodendrocytes [74], which can be induced by sphingomyelinase both in vitro and in vivo [75–77]. It is topographically significant that attacks of optic neuritis in MS are characteristically unilateral, and that recurrent attacks are significantly ipsilateral. [78] This is in marked contrast to the autoimmune demyelinating conditions, acute disseminated encephalomyelitis, (ADEM) neuromyelitis optica (NMO) and chronic relapsing inflammatory optic neuropathy (CRION) which are characteristically bilateral [78–81]. These frequently bilateral conditions caused by a systemic autoimmune attack across the BBB emphasize the topographical and significant difference from ON/MS. Moreo-
Fig. 1 – A and B. Detection of Staphylococcal sphingomyelinase (beta toxin in primary MS lesions [Gay F]) [23]. Cryostat sections of early acute MS spinal cord. Activated microglia with positive pinocytic vesicles applied to the surface of degenerate axons (arrows) positive for antigen. Rabbit anti-staphylococcal sphingomyelinase, with biotinylated antirabbit/streptavidin-HRP/DAB. C and D. Experimental lesion rat spinal cord, at 48 hours post injection of 2.5 nanogram Staphylococcal sphingomyelinase. Mild demyelination with marked axonal degeneration. Epoxy sections; toluidine blue (Spinal cord injections performed by Dr Andrew Davies, Dept of Neuroinflammation, IoN, UCL, UK). Please cite this article in press as: Gay F. Bacterial transportable toxins of the nasopharyngeal microbiota in multiple sclerosis. Nose-to-brain direct. Revue neurologique (2019), https://doi.org/10.1016/j.neurol.2019.09.004
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ver, histological evidence indicates that the primary attack in MS occurs internally and in tissues where the BBB is intact [74,82,83]. If these direct nose-to-brain findings are confirmed it would undoubtedly open up an almost totally new range of investigations and approaches to the diagnosis, treatment and prevention of MS. How might this be achieved? A recent study of patients with chronic sinusitis using automated perimetry, optical coherence tomography and CT scanning, have demonstrated and quantified optic nerve damage in these cases. The structural and functional optic nerve changes detected were significantly correlated with the severity and location of the indolent paranasal sinus disease. [84]. These neuro-ophthalmological findings closely resemble the optic nerve changes, including axonal loss, that have been described in MS [85–87]. Clearly similar neuro-ophthalmological studies combined with MRI and CT scanning in patients with unilateral ON should be employed to further investigate the nose-to-brain hypothesis and assess potential antimicrobial therapies. An understanding of the pathogenesis of MS in terms of the nose-to-brain access of bacterial toxins to the CNS should be further explored using cultural and PCR methods to detect high toxin producing strains within the nasal flora of MS patients. [23] Nasal delivery of disease modifying molecules linked to radiologically detectible tracers could be employed to assess the extent, location and clinical efficacy of nose-tobrain therapy in MS patients. The results of direct delivery of immune dysregulatory bacterial toxins, including the poreinducing transportables and sphingomyelinases (Fig. 1) in animal models should be explored.
Disclosure of interest The author declares that he has no competing interest.
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Please cite this article in press as: Gay F. Bacterial transportable toxins of the nasopharyngeal microbiota in multiple sclerosis. Nose-to-brain direct. Revue neurologique (2019), https://doi.org/10.1016/j.neurol.2019.09.004