NEUROLOGICAL REVIEW SECTION EDITOR: DAVID E. PLEASURE, MD Acinetobacter Immune Responses in Multiple Sclerosis Etiopathogenetic Role and Its Possible Use as a Diagnostic Marker Alan Ebringer, MD; Lucy Hughes, PhD; Taha Rashid, MBChB; Clyde Wilson, PhD ultiple sclerosis (MS) is the most common cause of neurologic disability among young people. The etiology of MS is controversial, but immune responses are considered to somehow be involved. The diagnosis of MS depends on a combination of various clinical and laboratory features, but apart from some myelin-neuronal autoantibody Mprofiles or oligoclonal bands in the cerebrospinal fluid no other serologic diagnostic test or marker has yet been discovered. However, the presence of antibodies to Acinetobacter species in MS patients opens the possibility of developing a composite laboratory diagnostic marker, the myelin-Acinetobacter- neurofilament index. Whether Acinetobacter is the triggering agent of MS remains to be determined, but the measurement of anti-Acinetobacter antibodies could be used as a marker of disease activity. To evaluate this, prospective randomized controlled studies should be performed with MS patients, especially in the early stages of the disease. Arch Neurol. 2005;62:33-36 Multiple sclerosis (MS) is a common de- screening studies performed in outbred myelinating disease of the central nervous populations of Northern European origin system, usually affecting young people and was successful in identifying genetic mark- characterized pathologically by scattered ers that show statistically significant link- areas of inflammation with or without axo- age with the disease. It has been suggested nal damage, involving particularly the white that many different chromosomal regions matter. Multiple sclerosis has a world- are likely to be involved in MS.4 wide distribution, and as many as 1 mil- lion people are affected by the disease. The prevalence of MS shows a latitudinal effect Evidence of Environmental Factors in that it is higher in Scandinavian coun- 1 tries than in the tropics. The reverse is ob- Various studies have supported the role of served in the Southern hemisphere, where environmental or microbial factors in the MS is 7 times more common in Tasmania pathogenesis of MS: (1) a relatively low and Southern New Zealand than in tropi- 2 concordance rate for monozygotic twins cal Queensland in populations coming pre- (approximately 25%), dizygotic twins (ap- dominantly from Anglo-Celtic stock. This proximately 5%), and siblings (approxi- latitudinal effect could be linked to greater mately 3%) of patients with MS5; (2) re- prevalence of respiratory infections dur- ports of an outbreak of MS in the Faroe ing autumn and winter. Islands, which occurred after the start of World War II6; (3) increase in the prob- ETIOPATHOGENESIS ability of developing MS with migration rate from low- to high-risk areas, espe- Evidence of Genetic Factors cially among those in younger age groups7; 3 and (4) the occurrence of remissions and In a recent review, none of the 3 large exacerbations in MS as a common hall- mark of the disease and a possible result Author Affiliations: Division of Life Sciences, Infection and Immunity Group, of fluctuations in the exposure to certain Waterloo Campus, King’s College, London, England. triggering environmental factors. (REPRINTED) ARCH NEUROL / VOL 62, JAN 2005 WWW.ARCHNEUROL.COM 33 ©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Microorganisms Possibly Involved in the in patients with Alzheimer disease and dementia, when com- Etiopathogenesis of MS pared with controls. Various microbial agents have been implicated in the etio- UPPER RESPIRATORY TRACT AND PARANASAL pathogenesis of MS. The role of viruses8 has been exten- SINUSES AS THE SOURCE OF INFECTIONS IN MS sively studied, but no clear consensus has emerged from these investigations. Viruses such as Epstein-Barr virus The most likely source for the entry of any triggering mi- and human herpesvirus 6, which have been implicated crobial factor in MS is through the upper respiratory tract in MS, are ubiquitous in the environment, but others have (URT). Several lines of evidence support this possibility. failed to confirm a link between human herpesvirus 6 and First, sinusitis is present in many MS patients, and the rate MS.9 Some researchers have found a link between the of MS exacerbations during the sinusitis attacks was found gram-negative Chlamydia pneumoniae bacteria and MS,10 to be doubled.17 Furthermore, using magnetic resonance but others have failed to confirm these associations.11 The imaging of the nasal sinuses, 53% of MS patients had evi- role of other bacteria, such as Acinetobacter species and dence of sinusitis.18 Second, in one study,19 the main caus- Pseudomonas aeruginosa, has only been studied recently ative agents involved in sinusitis were found to be Aci- but with some encouraging results. netobacter, Pseudomonas, and Staphylococcus aureus.Ina subsequent study involving antral tap and endoscopi- Acinetobacter and MS cally directed tissue culture performed on acute sinusitis patients, 37% and 33% of the isolates from the antral tap Myelin sequences known to produce experimental aller- and the endoscopically directed tissue culture, respec- gic encephalomyelitis in guinea pigs, an animal model tively, were Acinetobacter bacteria.20 Third, in another ret- of MS,12 were examined using the GenBank (NCBI, rospective study,21 more than 50% of MS patients had a Bethesda, Md) and SwissProt (TrEMBL, Geneva, Swit- history of repeated respiratory tract infections during their zerland) databases for molecular mimicry between brain childhood. Fourth, clinically manifest infections predomi- tissues and microbes. The ubiquitous saprophytic mi- nantly of the URT were observed to be followed by more crobe, Acinetobacter, was found to possess such a se- attacks of exacerbations in patients with MS.22 quence.13 These results suggest that MS could be triggered and Antibody levels against 5 strains of Acinetobacter sp, perpetuated following repeated attacks of subclinical or P aeruginosa, and Escherichia coli were investigated in 26 overt infections in the URT or paranasal sinuses. Further- English patients with MS and compared with 20 pa- more, viral infections of the URT and paranasal sinuses, tients with cerebrovascular accidents and 25 healthy con- which occur more frequently in autumn and winter, could trol. There were significant elevations in the levels of an- provide a suitable biological milieu for the secondary tibodies of IgM, IgG, and IgA classes against all bacterial growth of a saprophytic microbe such as Acinetobacter. agents except E coli in patients with MS when compared with those with cerebrovascular accidents and healthy MOLECULAR MIMICRY AND MS controls.14 The elevations in these antibodies were found to be more prominent against Acinetobacter calcoaceti- Molecular mimicry or cross-reactivity has been pro- cus, Acinetobacter 11171, and Acinetobacter lwoffii strains, posed as the main pathogenetic mechanism for develop- and in some cases their levels were reaching titers of up ment of autoimmune diseases, such as rheumatic fever, to 1:6400. Sydenham chorea, rheumatoid arthritis, and ankylosing In a more recent study15 performed on serum samples spondylitis.23 The molecular mimicry hypothesis is based taken from the same group of patients and controls in- on the demonstration of autoimmunity, involving mo- cluded in the previous study, antibody levels against mim- lecular and/or immunologic cross-reactivity between the icking peptide from Acinetobacter (PϽ.001), Pseudomo- putatively causative microbes and autoantigens, in- nas (PϽ.001), myelin basic protein (MBP) (PϽ.001), and creased antibodies against these microbial and autoan- myelin oligodendrocyte glycoprotein (MOG) (PϽ.001) tigenic molecules, and the binding of these microbial were found to be elevated in patients with MS when com- cross-reactive antibodies to the targeted tissues with re- pared with those with cerebrovascular accidents or healthy sultant immune-mediated cytotoxic tissue damage.24 controls. Antiserum raised in mice against Acinetobacter- mimicking peptides were found to be significantly in- Evidence of Autoimmunity in MS hibited by peptides from the MBP or Pseudomonas mi- crobe. Furthermore, MOG peptides were found to inhibit Autoantibodies to many myelin-neuronal antigens have antibodies against the mimicking sequences present in been found in patients with MS. For example, the levels Acinetobacter, but no inhibition was observed when hu- of antibodies to MBP,25 MOG,26 and neurofilament14,27 were man papillomavirus peptides were used as controls. found to be elevated in patients with MS when com- In another study,16 serum samples from Austrian pa- pared with control groups. Some of these antibodies were tients with MS or other neurologic diseases and healthy con- even found to be predictive of the development of clini- trols were screened against 3 strains of Acinetobacter spp. cally definite MS after a first demyelinating event.28 Fur- There were significant elevations of total antibodies against thermore, levels of anti-MBP or anti-MOG antibodies were A calcoaceticus, A lwoffii, and A 11171 bacterial strains in reported to be elevated in the cerebrospinal fluid and/or patients with MS and those with some other neurologic dis- isolated from the plaque lesions in the central nervous eases, such as sporadic Creutzfeldt-Jakob disease,