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Figure 1.
Schematic molecular similarities between Acinetobacter and Pseudomonas bacterial enzymes and brain antigens. 4-CMLD indicates 4-carboxy-muconolactone decarboxylase; 3-OACT, 3-oxoadipate coenzyme A transferase; and γ-CMLD, γ-carboxy-muconolactone decarboxylase. Amino acids and their locations are also shown: Leu indicates leucine; Tyr, tyrosine; Arg, arginine; Ala, alanine; Gly, glycine; Lys, lysine; Asp, asparagine; Ser, serine; Phe, phenylalanine; Try, tryptophan; Thr, threonine; and His, histidine.

Schematic molecular similarities between Acinetobacter and Pseudomonas bacterial enzymes and brain antigens. 4-CMLD indicates 4-carboxy-muconolactone decarboxylase; 3-OACT, 3-oxoadipate coenzyme A transferase; and γ-CMLD, γ-carboxy-muconolactone decarboxylase. Amino acids and their locations are also shown: Leu indicates leucine; Tyr, tyrosine; Arg, arginine; Ala, alanine; Gly, glycine; Lys, lysine; Asp, asparagine; Ser, serine; Phe, phenylalanine; Try, tryptophan; Thr, threonine; and His, histidine.

Figure 2.
Proposed sequential pathogenetic events in the development of multiple sclerosis. MBP indicates myelin basic protein; MOG, myelin oligodendrocyte glycoprotein.

Proposed sequential pathogenetic events in the development of multiple sclerosis. MBP indicates myelin basic protein; MOG, myelin oligodendrocyte glycoprotein.

1.
Kurtzke  JF Multiple sclerosis: changing times. Neuroepidemiology 1991;101- 8
PubMedArticle
2.
Miller  DHHammond  SRMcLeod  JGPurdie  GSkegg  DC Multiple sclerosis in Australia and New Zealand. J Neurol Neurosurg Psychiatry 1990;53903- 905
PubMedArticle
3.
Hensiek  AESawcer  SJCompston  DA Searching for needles in haystacks. Brain Res Bull 2003;61229- 234
PubMedArticle
4.
Kenealy  SJPericak-Vance  MAHaines  JL The genetic epidemiology of multiple sclerosis. J Neuroimmunol 2003;1437- 12
PubMedArticle
5.
Willer  CJDyment  DARisch  NJSadovnick  ADEbers  GC Twin concordance and sibling recurrence rates in multiple sclerosis. Proc Natl Acad Sci U S A 2003;10012877- 12882
PubMedArticle
6.
Kurtzke  JFHyllested  K Multiple sclerosis in the Faroe Islands, III: an alternative assessment of the three epidemics. Acta Neurol Scand 1987;76317- 339
PubMedArticle
7.
Dean  GElian  M Age at immigration to England of Asian and Caribbean immigrants and the risk of developing multiple sclerosis. J Neurol Neurosurg Psychiatry 1997;63565- 568
PubMedArticle
8.
Gilden  DH Viruses and multiple sclerosis. JAMA 2001;2863127- 3129
PubMedArticle
9.
Enbom  MWang  FZFredrikson  SMartin  CDahl  HLinde  A Similar humoral and cellular immunological reactivities to human herpesvirus 6 in patients with multiple sclerosis and controls. Clin Diagn Lab Immunol 1999;6545- 549
10.
Layh-Schmitt  GBendl  CHildt  U  et al.  Evidence for infection with Chlamydia pneumoniae in a subgroup of patients with multiple sclerosis. Ann Neurol 2000;47652- 655
PubMedArticle
11.
Chatzipanagiotou  STsakanikas  CAnagnostouli  MRentzos  MIoannidis  ANicolaou  C Detection of Chlamydia pneumoniae in the cerebrospinal fluid of patients with multiple sclerosis by combination of cell culture and PCR: no evidence for possible association. Mol Diagn 2003;741- 43
PubMed
12.
Eylar  EHCaccam  JJackson  JJWestall  FCRobinson  AB Experimental allergic encephalomyelitis. Science 1970;1681220- 1223
PubMedArticle
13.
Ebringer  APirt  SJWilson  CCunningham  PThorpe  CEttelaie  C Bovine spongiform encephalopathy. Environ Health Perspect 1997;1051172- 1174
PubMedArticle
14.
Hughes  LEBonell  SNatt  RS  et al.  Antibody responses to Acinetobacter spp. and Pseudomonas aeruginosa in multiple sclerosis. Clin Diagn Lab Immunol 2001;81181- 1188
PubMed
15.
Hughes  LSmith  PABonell  S  et al.  Cross-reactivity between related sequences found in Acinetobacter spp., Pseudomonas aeruginosa, myelin basic protein and myelin oligodendrocyte glycoprotein in multiple sclerosis. J Neuroimmunol 2003;144105- 115
PubMedArticle
16.
Allerberger  FBerger  TReindl  M  et al Anti-Acinetobacter and anti-neuronal antibodies in Austrian patients with multiple sclerosis and other neurological diseases. Ann Neurol In press
17.
Gay  DDick  GUpton  G Multiple sclerosis associated with sinusitis: case-controlled study in general practice. Lancet 1986;1815- 819
PubMedArticle
18.
Jones  RLCrowe  PChavda  SVPahor  AL The incidence of sinusitis in patients with multiple sclerosis. Rhinology 1997;35118- 119
PubMed
19.
Bert  FLambert-Zechovsky  N Sinusitis in mechanically ventilated patients and its role in the pathogenesis of nosocomial pneumonia. Eur J Clin Microbiol Infect Dis 1996;15533- 544
PubMedArticle
20.
Casiano  RRCohn  SVillasuso  E  et al.  Comparison of antral tap with endoscopically directed nasal culture. Laryngoscope 2001;1111333- 1337
PubMedArticle
21.
Lamoureux  GLapierre  YDucharme  G Past infectious events and disease evolution in multiple sclerosis. J Neurol 1983;23081- 90
PubMedArticle
22.
Buljevac  DFlach  HZHop  WCJ  et al.  Prospective study on the relationship between infections and multiple sclerosis exacerbations. Brain 2002;125952- 960
PubMedArticle
23.
Ebringer  AWilson  C HLA molecules, bacteria and autoimmunity. J Med Microbiol 2000;49305- 311
PubMed
24.
Wilson  CRashid  TTiwana  H  et al.  Cytotoxicity responses to peptide antigens in rheumatoid arthritis and ankylosing spondylitis. J Rheumatol 2003;30972- 978
PubMed
25.
Warren  KGCatz  I A correlation between cerebrospinal fluid myelin basic protein and anti-myelin basic protein in multiple sclerosis. Ann Neurol 1987;21183- 189
PubMedArticle
26.
Reindl  MLinington  CBrehm  U  et al.  Antibodies against the myelin oligodendrocyte glycoprotein and the myelin basic protein in multiple sclerosis and other neurological diseases: a comparative study. Brain 1999;1222047- 2056
PubMedArticle
27.
Silber  ESemra  YKGregson  NASharief  MK Patients with progressive multiple sclerosis have elevated antibodies to neurofilament subunit. Neurology 2002;581372- 1381
PubMedArticle
28.
Berger  TRubner  PSchautzer  F  et al.  Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event. N Engl J Med 2003;349139- 145
PubMedArticle
29.
Cross  AHTrotter  JLLyons  J B cells and antibodies in CNS demyelinating disease. J Neuroimmunol 2001;1121- 14
PubMedArticle
30.
Bernard  CCAMandel  TMackay  IR Experimental models of human autoimmune disease: overview and prototypes.  In: Rose  NR, Mackay  IR, eds. The Autoimmune Diseases. San Diego, Calif: Academic Press; 1992:47-106
31.
Revel  M Interferon-β in the treatment of relapsing-remitting multiple sclerosis. Pharmacol Ther 2003;10049- 62
PubMedArticle
32.
Tiwana  HWilson  CPirt  JCartmell  WEbringer  A Autoantibodies to brain components and antibodies to Acinetobacter calcoaceticus are present in bovine spongiform encephalopathy. Infect Immun 1999;676591- 6595
PubMed
33.
Kirvan  CASwedo  SEHeuser  JSCunningham  MW Mimicry and autoantibody-mediated neuronal cell signalling in Sydenham chorea. Nat Med 2003;9914- 920
PubMedArticle
34.
Poser  CMPaty  DWScheinberg  L  et al.  New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13227- 231
PubMedArticle
35.
McDonald  WICompston  AEdan  G  et al.  Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50121- 127
PubMedArticle
36.
Noseworthy  JH Management of multiple sclerosis: current trials and future options. Curr Opin Neurol 2003;16289- 297
PubMedArticle
Neurological Review
January 2005

Acinetobacter Immune Responses in Multiple SclerosisEtiopathogenetic Role and Its Possible Use as a Diagnostic Marker

Author Affiliations

Author Affiliations: Division of Life Sciences, Infection and Immunity Group, Waterloo Campus, King’s College, London, England.

 

DAVID E.PLEASUREMD

Arch Neurol. 2005;62(1):33-36. doi:10.1001/archneur.62.1.33
Abstract

Multiple 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 profiles 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.

Multiple sclerosis (MS) is a common demyelinating disease of the central nervous system, usually affecting young people and characterized pathologically by scattered areas of inflammation with or without axonal damage, involving particularly the white matter. Multiple sclerosis has a worldwide distribution, and as many as 1 million people are affected by the disease. The prevalence of MS shows a latitudinal effect in that it is higher in Scandinavian countries than in the tropics.1 The reverse is observed in the Southern hemisphere, where MS is 7 times more common in Tasmania and Southern New Zealand than in tropical Queensland2 in populations coming predominantly from Anglo-Celtic stock. This latitudinal effect could be linked to greater prevalence of respiratory infections during autumn and winter.

ETIOPATHOGENESIS
Evidence of Genetic Factors

In a recent review,3 none of the 3 large screening studies performed in outbred populations of Northern European origin was successful in identifying genetic markers that show statistically significant linkage with the disease. It has been suggested that many different chromosomal regions are likely to be involved in MS.4

Evidence of Environmental Factors

Various studies have supported the role of environmental or microbial factors in the pathogenesis of MS: (1) a relatively low concordance rate for monozygotic twins (approximately 25%), dizygotic twins (approximately 5%), and siblings (approximately 3%) of patients with MS5 ; (2) reports of an outbreak of MS in the Faroe Islands, which occurred after the start of World War II6 ; (3) increase in the probability of developing MS with migration rate from low- to high-risk areas, especially among those in younger age groups7 ; and (4) the occurrence of remissions and exacerbations in MS as a common hallmark of the disease and a possible result of fluctuations in the exposure to certain triggering environmental factors.

Microorganisms Possibly Involved in the Etiopathogenesis of MS

Various microbial agents have been implicated in the etiopathogenesis of MS. The role of viruses8 has been extensively studied, but no clear consensus has emerged from these investigations. Viruses such as Epstein-Barr virus and human herpesvirus 6, which have been implicated in MS, are ubiquitous in the environment, but others have failed to confirm a link between human herpesvirus 6 and MS.9 Some researchers have found a link between the gram-negative Chlamydia pneumoniae bacteria and MS,10 but others have failed to confirm these associations.11 The role of other bacteria, such as Acinetobacter species and Pseudomonas aeruginosa, has only been studied recently but with some encouraging results.

Acinetobacter and MS

Myelin sequences known to produce experimental allergic encephalomyelitis in guinea pigs, an animal model of MS,12 were examined using the GenBank (NCBI, Bethesda, Md) and SwissProt (TrEMBL, Geneva, Switzerland) databases for molecular mimicry between brain tissues and microbes. The ubiquitous saprophytic microbe, Acinetobacter, was found to possess such a sequence.13

Antibody levels against 5 strains of Acinetobacter sp, P aeruginosa, and Escherichia coli were investigated in 26 English patients with MS and compared with 20 patients with cerebrovascular accidents and 25 healthy control. There were significant elevations in the levels of antibodies of IgM, IgG, and IgA classes against all bacterial agents except E coli in patients with MS when compared with those with cerebrovascular accidents and healthy controls.14 The elevations in these antibodies were found to be more prominent against Acinetobactercalcoaceticus, Acinetobacter 11171, and Acinetobacterlwoffii strains, and in some cases their levels were reaching titers of up to 1:6400.

In a more recent study15 performed on serum samples taken from the same group of patients and controls included in the previous study, antibody levels against mimicking peptide from Acinetobacter (P<.001), Pseudomonas (P<.001), myelin basic protein (MBP) (P<.001), and myelin oligodendrocyte glycoprotein (MOG) (P<.001) were found to be elevated in patients with MS when compared with those with cerebrovascular accidents or healthy controls. Antiserum raised in mice against Acinetobacter-mimicking peptides were found to be significantly inhibited by peptides from the MBP or Pseudomonas microbe. Furthermore, MOG peptides were found to inhibit antibodies against the mimicking sequences present in Acinetobacter, but no inhibition was observed when human papillomavirus peptides were used as controls.

In another study,16 serum samples from Austrian patients with MS or other neurologic diseases and healthy controls were screened against 3 strains of Acinetobacter spp. There were significant elevations of total antibodies against Acalcoaceticus, A lwoffii, and A 11171 bacterial strains in patients with MS and those with some other neurologic diseases, such as sporadic Creutzfeldt-Jakob disease, but not in patients with Alzheimer disease and dementia, when compared with controls.

UPPER RESPIRATORY TRACT AND PARANASAL SINUSES AS THE SOURCE OF INFECTIONS IN MS

The most likely source for the entry of any triggering microbial factor in MS is through the upper respiratory tract (URT). Several lines of evidence support this possibility. First, sinusitis is present in many MS patients, and the rate of MS exacerbations during the sinusitis attacks was found to be doubled.17 Furthermore, using magnetic resonance imaging of the nasal sinuses, 53% of MS patients had evidence of sinusitis.18 Second, in one study,19 the main causative agents involved in sinusitis were found to be Acinetobacter, Pseudomonas, and Staphylococcus aureus. In a subsequent study involving antral tap and endoscopically directed tissue culture performed on acute sinusitis patients, 37% and 33% of the isolates from the antral tap and the endoscopically directed tissue culture, respectively, were Acinetobacter bacteria.20 Third, in another retrospective study,21 more than 50% of MS patients had a history of repeated respiratory tract infections during their childhood. Fourth, clinically manifest infections predominantly of the URT were observed to be followed by more attacks of exacerbations in patients with MS.22

These results suggest that MS could be triggered and perpetuated following repeated attacks of subclinical or overt infections in the URT or paranasal sinuses. Furthermore, viral infections of the URT and paranasal sinuses, which occur more frequently in autumn and winter, could provide a suitable biological milieu for the secondary growth of a saprophytic microbe such as Acinetobacter.

MOLECULAR MIMICRY AND MS

Molecular mimicry or cross-reactivity has been proposed as the main pathogenetic mechanism for development of autoimmune diseases, such as rheumatic fever, Sydenham chorea, rheumatoid arthritis, and ankylosing spondylitis.23 The molecular mimicry hypothesis is based on the demonstration of autoimmunity, involving molecular and/or immunologic cross-reactivity between the putatively causative microbes and autoantigens, increased antibodies against these microbial and autoantigenic molecules, and the binding of these microbial cross-reactive antibodies to the targeted tissues with resultant immune-mediated cytotoxic tissue damage.24

Evidence of Autoimmunity in MS

Autoantibodies to many myelin-neuronal antigens have been found in patients with MS. For example, the levels of antibodies to MBP,25 MOG,26 and neurofilament14,27 were found to be elevated in patients with MS when compared with control groups. Some of these antibodies were even found to be predictive of the development of clinically definite MS after a first demyelinating event.28 Furthermore, levels of anti-MBP or anti-MOG antibodies were reported to be elevated in the cerebrospinal fluid and/or isolated from the plaque lesions in the central nervous system of MS patients.29 In studies30 that involved animal models of MS, such as experimental allergic encephalomyelitis, MS-like lesions were detected and characterized by local infiltrations of immune-mediated cells and products, when these animals were inoculated with the myelin-neuronal antigens. Patients with MS have reportedly responded to the currently used immunomodulatory and anti-inflammatory therapeutic agents, especially interferon beta 1 products31 and corticosteroids.

Evidence of Molecular Similarities Between Acinetobacter and Pseudomonas Bacteria and Brain Antigens

Acinetobacter and Pseudomonas enzymes show molecular similarities to certain brain antigens (Figure 1). The enzyme 4-carboxy-muconolactone decarboxylase possesses an amino acid sequence that is similar to MBP,13 and protocatechuate 3,4-dioxygenase has a sequence homologous to neurofilament.32 The 3-oxoadipate coenzyme A transferase enzyme of the same bacteria possesses amino acid sequences that are similar to those present in the MOG brain tissue antigens.15 In this latter study, it was also shown that the enzyme γ-carboxy-muconolactone decarboxylase of the Pseudomonas microbes possesses amino acid residues that are homologous to those present in the MBP molecules.

Possible Pathogenetic Pathway in MS Involving Acinetobacter Species

It is proposed that antibodies against Acinetobacter and possibly Pseudomonas microorganisms are produced as the result of URT or paranasal sinus infections by these microbes (Figure 2). In view of the existing molecular similarities between microbes and brain antigens, these cross-reactive antibodies, which are mostly of the IgG isotype, could cross the blood-brain barrier. The binding of these antibodies to the myelin-neuronal antigens, such as MBP, MOG, and neurofilaments, when present in high titers would activate complement and other inflammatory cascades, thereby producing demyelination through the process of antibody-dependent, cell-mediated cytotoxicity in the same way that has been shown in patients with Sydenham (rheumatic) chorea.33 These events could eventually result in multiple sites of demyelinations with or without axonal degenerations.

PROPOSAL FOR A NEW LABORATORY DIAGNOSTIC MARKER IN MS

Apart from the criteria for the diagnosis of MS by Poser et al,34 other diagnostic criteria, which have been recommended by neurologists from the United States and Europe, are all based on a combination of clinical and paraclinical features.35 The main clinical evidence is based on the objective findings of dissemination in time (relapses) and space (different locality) of the clinical presentations typical of MS, whereas the nonclinical criteria are mainly based on the following: (1) magnetic resonance imaging evidence of multiple neurologic lesions of different sizes and locations; (2) identification of IgG oligoclonal bands in the cerebrospinal fluid; and (3) delayed but well-preserved visual evoked potentials.

These paraclinical criteria are helpful in aiding the diagnosis of clinically probable cases of MS, but they require expensive facilities. Furthermore, these diagnostic criteria cannot identify all cases of MS because of the clinical variability of the disease. Hence, the search for the development of a less invasive and reproducible test is of crucial importance.

We propose that a combination of elevated titers of antibodies against Acinetobacter, MBP, and neurofilament could be used for such a diagnostic test. The myelin-Acinetobacter-neurofilament (MAN) index, which has been described previously,14 was calculated using the optical density (OD) readings from the IgG antibody determined by enzyme-linked immunosorbent assay. The formula used was as follows: MAN Index = (MBP OD × 10) (Acinetobacter OD × 10) (Neurofilament OD × 10).

The MAN index is calibrated by determining scores in MS patients and healthy controls. For an active MS patient, the MAN index is expected to be above the 95% confidence intervals of the healthy controls. Further research is needed to elaborate and modify this particular diagnostic marker. For example, instead of using whole bacteria, Acinetobacter peptides, which carry the cross-reactive brain antigens, may give a clearer separation when compared with controls.15

MONITORING TREATMENT IN MS

The current therapeutic strategy in the management of MS involves the use of immunomodulatory and immunosuppressive drugs. These modalities have been found to be effective mainly in cases of relapsing-remitting forms but less so in the progressive forms of MS.36 The evidence of the bacterial (Acinetobacter and Pseudomonas) involvements in the etiopathogenesis of MS suggests the possibility of using antimicrobial therapy, and its use should be evaluated in prospective, longitudinal randomized controlled studies.

In conclusion, the demonstration of the cross-reactivity between Acinetobacter and Pseudomonas bacteria and brain antigens has raised the possibility of developing a disease marker, the MAN index, which could predict the occurrence of relapses in patients with MS and/or monitor response to therapy. However, further studies need to be performed on greater numbers of MS patients to establish the sensitivity and specificity profiles and the degree of the reproducibility of the MAN index.

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Article Information

Correspondence: Alan Ebringer, MD, Division of Life Sciences, Infection and Immunity Group, King’s College London, 150 Stamford St, London SE1, England (alan.ebringer@kcl.ac.uk).

Accepted for Publication: January 28, 2004.

Author Contributions:Acquisition of data: Ebringer, Hughes, Rashid, and Wilson. Analysis and interpretation of data: Ebringer, Hughes, Rashid, and Wilson. Critical revision of the manuscript for important intellectual content: Ebringer, Hughes, Rashid, and Wilson. Statistical analysis: Ebringer, Hughes, Rashid, and Wilson.

Funding/Support: This work was supported by the American Friends of King’s College, London, England.

References
1.
Kurtzke  JF Multiple sclerosis: changing times. Neuroepidemiology 1991;101- 8
PubMedArticle
2.
Miller  DHHammond  SRMcLeod  JGPurdie  GSkegg  DC Multiple sclerosis in Australia and New Zealand. J Neurol Neurosurg Psychiatry 1990;53903- 905
PubMedArticle
3.
Hensiek  AESawcer  SJCompston  DA Searching for needles in haystacks. Brain Res Bull 2003;61229- 234
PubMedArticle
4.
Kenealy  SJPericak-Vance  MAHaines  JL The genetic epidemiology of multiple sclerosis. J Neuroimmunol 2003;1437- 12
PubMedArticle
5.
Willer  CJDyment  DARisch  NJSadovnick  ADEbers  GC Twin concordance and sibling recurrence rates in multiple sclerosis. Proc Natl Acad Sci U S A 2003;10012877- 12882
PubMedArticle
6.
Kurtzke  JFHyllested  K Multiple sclerosis in the Faroe Islands, III: an alternative assessment of the three epidemics. Acta Neurol Scand 1987;76317- 339
PubMedArticle
7.
Dean  GElian  M Age at immigration to England of Asian and Caribbean immigrants and the risk of developing multiple sclerosis. J Neurol Neurosurg Psychiatry 1997;63565- 568
PubMedArticle
8.
Gilden  DH Viruses and multiple sclerosis. JAMA 2001;2863127- 3129
PubMedArticle
9.
Enbom  MWang  FZFredrikson  SMartin  CDahl  HLinde  A Similar humoral and cellular immunological reactivities to human herpesvirus 6 in patients with multiple sclerosis and controls. Clin Diagn Lab Immunol 1999;6545- 549
10.
Layh-Schmitt  GBendl  CHildt  U  et al.  Evidence for infection with Chlamydia pneumoniae in a subgroup of patients with multiple sclerosis. Ann Neurol 2000;47652- 655
PubMedArticle
11.
Chatzipanagiotou  STsakanikas  CAnagnostouli  MRentzos  MIoannidis  ANicolaou  C Detection of Chlamydia pneumoniae in the cerebrospinal fluid of patients with multiple sclerosis by combination of cell culture and PCR: no evidence for possible association. Mol Diagn 2003;741- 43
PubMed
12.
Eylar  EHCaccam  JJackson  JJWestall  FCRobinson  AB Experimental allergic encephalomyelitis. Science 1970;1681220- 1223
PubMedArticle
13.
Ebringer  APirt  SJWilson  CCunningham  PThorpe  CEttelaie  C Bovine spongiform encephalopathy. Environ Health Perspect 1997;1051172- 1174
PubMedArticle
14.
Hughes  LEBonell  SNatt  RS  et al.  Antibody responses to Acinetobacter spp. and Pseudomonas aeruginosa in multiple sclerosis. Clin Diagn Lab Immunol 2001;81181- 1188
PubMed
15.
Hughes  LSmith  PABonell  S  et al.  Cross-reactivity between related sequences found in Acinetobacter spp., Pseudomonas aeruginosa, myelin basic protein and myelin oligodendrocyte glycoprotein in multiple sclerosis. J Neuroimmunol 2003;144105- 115
PubMedArticle
16.
Allerberger  FBerger  TReindl  M  et al Anti-Acinetobacter and anti-neuronal antibodies in Austrian patients with multiple sclerosis and other neurological diseases. Ann Neurol In press
17.
Gay  DDick  GUpton  G Multiple sclerosis associated with sinusitis: case-controlled study in general practice. Lancet 1986;1815- 819
PubMedArticle
18.
Jones  RLCrowe  PChavda  SVPahor  AL The incidence of sinusitis in patients with multiple sclerosis. Rhinology 1997;35118- 119
PubMed
19.
Bert  FLambert-Zechovsky  N Sinusitis in mechanically ventilated patients and its role in the pathogenesis of nosocomial pneumonia. Eur J Clin Microbiol Infect Dis 1996;15533- 544
PubMedArticle
20.
Casiano  RRCohn  SVillasuso  E  et al.  Comparison of antral tap with endoscopically directed nasal culture. Laryngoscope 2001;1111333- 1337
PubMedArticle
21.
Lamoureux  GLapierre  YDucharme  G Past infectious events and disease evolution in multiple sclerosis. J Neurol 1983;23081- 90
PubMedArticle
22.
Buljevac  DFlach  HZHop  WCJ  et al.  Prospective study on the relationship between infections and multiple sclerosis exacerbations. Brain 2002;125952- 960
PubMedArticle
23.
Ebringer  AWilson  C HLA molecules, bacteria and autoimmunity. J Med Microbiol 2000;49305- 311
PubMed
24.
Wilson  CRashid  TTiwana  H  et al.  Cytotoxicity responses to peptide antigens in rheumatoid arthritis and ankylosing spondylitis. J Rheumatol 2003;30972- 978
PubMed
25.
Warren  KGCatz  I A correlation between cerebrospinal fluid myelin basic protein and anti-myelin basic protein in multiple sclerosis. Ann Neurol 1987;21183- 189
PubMedArticle
26.
Reindl  MLinington  CBrehm  U  et al.  Antibodies against the myelin oligodendrocyte glycoprotein and the myelin basic protein in multiple sclerosis and other neurological diseases: a comparative study. Brain 1999;1222047- 2056
PubMedArticle
27.
Silber  ESemra  YKGregson  NASharief  MK Patients with progressive multiple sclerosis have elevated antibodies to neurofilament subunit. Neurology 2002;581372- 1381
PubMedArticle
28.
Berger  TRubner  PSchautzer  F  et al.  Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event. N Engl J Med 2003;349139- 145
PubMedArticle
29.
Cross  AHTrotter  JLLyons  J B cells and antibodies in CNS demyelinating disease. J Neuroimmunol 2001;1121- 14
PubMedArticle
30.
Bernard  CCAMandel  TMackay  IR Experimental models of human autoimmune disease: overview and prototypes.  In: Rose  NR, Mackay  IR, eds. The Autoimmune Diseases. San Diego, Calif: Academic Press; 1992:47-106
31.
Revel  M Interferon-β in the treatment of relapsing-remitting multiple sclerosis. Pharmacol Ther 2003;10049- 62
PubMedArticle
32.
Tiwana  HWilson  CPirt  JCartmell  WEbringer  A Autoantibodies to brain components and antibodies to Acinetobacter calcoaceticus are present in bovine spongiform encephalopathy. Infect Immun 1999;676591- 6595
PubMed
33.
Kirvan  CASwedo  SEHeuser  JSCunningham  MW Mimicry and autoantibody-mediated neuronal cell signalling in Sydenham chorea. Nat Med 2003;9914- 920
PubMedArticle
34.
Poser  CMPaty  DWScheinberg  L  et al.  New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13227- 231
PubMedArticle
35.
McDonald  WICompston  AEdan  G  et al.  Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50121- 127
PubMedArticle
36.
Noseworthy  JH Management of multiple sclerosis: current trials and future options. Curr Opin Neurol 2003;16289- 297
PubMedArticle
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