Impact of Helicobacter pylori on multiple sclerosis-related clinically isolated syndrome.

OBJECTIVES: There are no data regarding the relationship between Helicobacter pylori infection (Hp-I) and clinically isolated syndrome (CIS) suggestive of multiple sclerosis. The purpose of this pilot study was to investigate the association between active Hp-I, confirmed by histology, and CIS and to evaluate the impact of Hp eradication on the CIS clinical course. MATERIAL AND METHODS: We conducted a study on 48 patients with CIS and 20 matched controls. At baseline, apart from histology, serum anti-Hp-specific IgG titer, inflammatory mediators, and HLA-A, HLA-B, HLA-DR genetic polymorphisms were estimated. Hp-positive patients received standard triple eradication regimen, and all patients were followed up for 2 years. RESULTS: The prevalence of Hp-I was significantly higher in patients with CIS (43/48, 89.6%) than in control (10/20, 50%) (P < 0.001, OR: 8.6, 95% CI: 2.4-30.8). When compared with controls, patients with CIS also showed significantly higher serum anti-Hp IgG titer and HLA-A26, HLA-A30, and HLA-B57 frequencies. Hp-positive patients also showed higher serum concentrations of inflammatory cytokines and homocysteine. At 2-year clinical endpoint, in the subgroup of CIS patients with successful Hp eradication, the number of patients who presented with a second episode was significantly lower accompanied by significant improvement in mean Expanded Disability Status Scale score. CONCLUSIONS: Hp-I seems more frequent in a Greek CIS cohort and its eradication might delay CIS progression, suggesting a possible link between Hp-I and CIS.

Polyautoimmunity in a Greek cohort of multiple sclerosis.

OBJECTIVES: The aim of this study was to assess the existence of polyautoimmunity in a Greek cohort of multiple sclerosis (MS), particularly multiple autoimmune syndrome (MAS), i.e., the presence of three or more distinct autoimmune disorders (ADs) in the same individual. METHODS: Cross-sectional control study. RESULTS: The overall prevalence of polyautoimmunity in 2140 MS patients (female to male ratio: 2.1:1) was 8.3% (vs 6.07% in 1580 matched control participants, P = 0.008) mainly due to differences in autoimmune thyroid disorders (AITD) and vitiligo. The prevalence of MAS was 1.0%. The most frequent diseases encountered in MS were organ-specific ADs. There was no statistical difference in the total rates of ADs between female and male MS patients. There were higher rates of AITD in women (P = 0.004) and higher rates of iritis (P = 0.039) and ankylosing spondylitis (P = 0.003) in men. MS was diagnosed in the same year with AD in 7.4% of patients with additional ADs, earlier than AD in 42.0% and later than AD in 50.6%. CONCLUSION: Polyautoimmunity and particularly MAS occur more frequently in MS patients than in control participants indicating that MS may be part of a generalized susceptibility to autoimmunity. Therefore, polyautoimmunity may be implicated in the etiopathogenesis of MS-related ADs, with a potential impact on relative therapeutic strategies.

Pseudo-quadriceps sparing in multiple sclerosis.

BACKGROUND: Sparing of the quadriceps muscle has been reported in various myopathies. In multiple sclerosis (MS) and pyramidal syndromes, in general, such a differential involvement of distinct muscle groups has not been described. METHODS: Muscle power was evaluated in 127 patients with chronic pyramidal syndrome caused by MS and 37 patients with acute or chronic paraparesis from other etiologies (mainly cerebro-vascular events). RESULTS: A striking difference in muscle power of the quadriceps (spared) and the iliopsoas (significantly weakened) was found in the patients suffering from chronic pyramidal syndrome caused by MS. The mean muscle power of the iliopsoas was 1.68±1.1 and that of the quadriceps 4.06±1.4 (P<0.00005). In the control group, the mean muscle power was 2±1.2 and 2.4±1.4 (difference not significant), for the iliopsoas and the quadriceps, respectively. CONCLUSIONS: Quadriceps muscle remains relatively spared in patients with MS, even with severe and long-standing paraparesis. Various neuroanatomical, neurophysiological, and rehabilitational mechanisms may be involved and explain this phenomenon. This observation may contribute to the building of more reliable and linear scales for the assessment of motor disability and disease progression in MS.

The Emerging Role of Helicobacter Pylori-Induced Metabolic Gastrointestinal Dysmotility and Neurodegeneration.

Helicobacter pylori infection (Hp-I) is a prevalent disorder identified in the majority of the population in many countries around the world and is responsible for substantial gastrointestinal morbidity. Likewise, neurodegenerative diseases such as Alzheimer's disease, Parkinson's diseases, multiple sclerosis or glaucoma defined as ocular Alzheimer's disease, are associated with a large public health burden and are among the leading causes of disability. Emerging evidences suggest that Hp-I may be associated with neurodegenerative conditions. Moreover, Hp-I could be a predictor of metabolic syndrome (MetS). Hp-I and its related MetS may induce gastrointestinal tract dys-motility disorders with systemic complications possibly including central nervous system neurodegenerative pathologies. We hereby explore the emerging role of Hprelated metabolic gastrointestinal dys-motilities on the molecular pathophysiology of Hprelated neurodegenerative and gastrointestinal disorders. Improving understanding of such Hp-I pathophysiology in brain pathologies may offer benefits by application of new relative therapeutic strategies including novel opportunities toward enhancing Hp eradication.

Rolipram suppresses experimental autoimmune neuritis and prevents relapses in Lewis rats.

Rolipram, a phosphodiesterase type 4 inhibitor, can markedly down-regulate antigen-driven T cell proliferation and suppress TNF-alpha production in vitro and in vivo. Here we report the effects of Rolipram on experimental autoimmune neuritis (EAN), which can be induced by immunization with myelin components of the peripheral nervous system (PNS) combined with Freund's complete adjuvant (FCA), and which represents a CD4+ T cell-mediated animal model for human Guillain-Barré syndrome. EAN induced in Lewis rats by inoculation with the PNS P2 protein peptide 57-81 and FCA was strongly suppressed by Rolipram administered twice daily intraperitoneally from day 9 post immunization (p.i.), i.e. after onset of clinical EAN. Suppression of EAN was associated with down-regulated myelin antigen-induced T cell responses as well as down-regulated IFN-gamma and TNF-alpha production. A relapse of clinical EAN occurred upon treatment of a short duration (7 days), while prolongation of treatment resulted in the prevention of clinical EAN relapse. There was no relationship between clinical EAN relapse and high levels of TNF-alpha. The immunomodulatory effects of Rolipram call for further research into the potential role of drugs acting on the immune system in the treatment of autoimmune diseases.

IL-10 and IFN-gamma in Guillain-Barré syndrome. Network Members of the Swedish Epidemiological Study Group.

Guillain-Barré syndrome (GBS) is an acute inflammatory disease affecting myelin and axons of the peripheral nervous system (PNS). GBS is considered to be caused by breakdown of tolerance to autoantigens of the PNS. The involvement of cytokines in GBS and in relation to treatment with high dose intravenous immunoglobulin (IvIg) is incompletely known. We studied the temporal profiles of IL-10 and IFN-gamma-secreting blood mononuclear cells (MNC) over the course of GBS, using enzyme-linked immunospot (ELISPOT) assays. Pretreatment levels of blood MNC spontaneously secreting IL-10 were higher in the acute phase of GBS than in control patients with aseptic meningitis, other neurological diseases, diabetic neuropathy and healthy subjects. Levels of IFN-gamma-secreting blood MNC were not increased over the course of GBS. Patients treated with IvIg had lower numbers of IL-10-secreting MNC compared to untreated patients. High levels of IL-10-secreting MNC correlated with serum anti-ganglioside IgM antibody levels, and with neurophysiological signs of axonal damage. The present data suggests that IFN-gamma is not involved in GBS pathogenesis, and IL-10 being up-regulated in the early phase of GBS and associated with axonal damage, may have a pathogenetic role in GBS.

P0 glycoprotein peptides 56-71 and 180-199 dose-dependently induce acute and chronic experimental autoimmune neuritis in Lewis rats associated with epitope spreading.

Two synthetic peripheral nerve myelin P0 protein peptides, an immunodominant (amino acids 180-199) and a cryptic (amino acids 56-71) one, induced an acute or chronic course of experimental autoimmune neuritis (EAN) in Lewis rats, when given at low dose (50-100 microg/rat) or high dose (250 microg/rat), respectively. Corresponding to the different clinical course, pathological changes and immune responses were found: (1) Onset of clinical signs of P0 peptide 56-71 (P0 56-71) induced EAN was 1-3 days later than in P0 peptide 180-199 (P0 180-199) induced EAN at all immunizing doses, whereas the peak of the disease occurred at a similar time point post immunization (p.i.), i.e. at days 14-16 p.i. in P0 56-71 induced EAN and at day 16 p.i. in P0 180-199 induced EAN. (2) Intramolecular epitope spreading as assessed by delayed type hypersensitivity response occurred in P0 56-71 induced EAN at both low and high antigen doses and in P0 180-199 induced EAN at high antigen dose (250 microg/rat) only. (3) P0 180-199 stimulated higher levels of interferon-gamma production in P0 180-199 induced EAN than in P0 56-71 induced EAN and vice versa. (4) Histopathologic evaluation revealed a similar grade of mononuclear cell infiltration in the sciatic nerves of both types of EAN, but more severe demyelination was found in P0 180-199 induced EAN compared to P0 56-71 induced EAN. The results support the hypothesis that high dose autoantigen immunization induces extensive determinant spreading and chronic course of autoimmune diseases.

Dynamics of production of MIP-1alpha, MCP-1 and MIP-2 and potential role of neutralization of these chemokines in the regulation of immune responses during experimental autoimmune neuritis in Lewis rats.

Experimental autoimmune neuritis (EAN) is an inflammatory autoimmune demyelinating disease of the peripheral nervous system (PNS) and represents an animal model of Guillain-Barré syndrome (GBS), which is a major inflammatory demyelinating disease of the PNS in humans. In the present study, the dynamics of the expression of the chemokines macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-2 and monocyte chemotactic protein-1 (MCP-1) were determined in the sciatic nerves of EAN rats. Additionally, the effect of neutralizing antibodies against MIP-1alpha, MIP-2 and MCP-1 on the clinical course of EAN and the chemokine expression was investigated. The maximum of MIP-1alpha positive cells in the sciatic nerves was seen on day 14 post immunization (p.i.) correlating with the development of severe clinical signs. Administration of an anti-MIP-1alpha antibody suppressed the clinical signs of EAN and inhibited inflammation and demyelination in the sciatic nerve. Peak numbers of MCP-1 positive cells in the sciatic nerves were detected on day 7 p.i. Administration of an anti-MCP-1 antibody caused a delay of onset of EAN. However, 4 of the 6 EAN rats receiving the anti-MCP-antibody showed the same degree of inflammatory cell infiltration and demyelination in the sciatic nerves as sham-treated EAN rats, whereas only 2 EAN rats had less inflammation and demyelination. The numbers of MIP-2 positive cells reached a maximum on day 21 p.i. Anti-MIP-2 antibody failed to suppress the clinical signs of EAN and the inflammation and demyelination in the sciatic nerves. Only administration of the anti-MIP-1alpha antibody resulted in a significant reduction in the number of chemokine (MIP-1alpha)-positive cells and ED1-positive macrophages in the sciatic nerves. The present results demonstrate that MIP-1alpha and MCP-1 may play a role in the immunopathogenesis of EAN, and that MIP-1alpha induced trafficking of inflammatory cells can be inhibited by immunoneutralization. Further elucidation of the regulation and coordination of MIP-1alpha and MCP-1 production may lead to new therapeutic approaches to GBS in humans.

The emerging role of endocrine disruptors in pathogenesis of insulin resistance: a concept implicating nonalcoholic fatty liver disease.

Endocrine disruptors or endocrine-disrupting chemicals (EDCs) represent a highly heterogeneous group of molecules found in the environment or in consumer products. Toxicology and epidemiology studies have suggested the involvement of diverse EDCs in an increasing number of metabolic disorders, including insulin resistance (IR) and IR-related co morbidities, such as obesity, type 2 diabetes mellitus (T2DM) and polycystic ovary syndrome. Nonalcoholic fatty liver disease (NAFLD), another IR related condition, is emerging as a significant public health concern, affecting 30-45% of the general population in the Western world. To evaluate whether EDCs may also play a role in the pathogenesis of NAFLD, we reviewed the literature on well-studied EDCs, such as dioxins, bisphenol A, phthalates and other persistent organic pollutants, in relation to pathways that might contribute to the pathogenesis of fatty liver / NAFDL. Certain EDCs may be responsible for inducing alterations similar to those encountered in NAFLD either directly through a hepatotoxic effect and/or indirectly by triggering hepatic and systematic IR. Considering these effects, which act in concert with the effects of the epidemics of obesity and T2DM, EDCs may play a significant role in the pathogenesis of fatty liver, thereby increasing the prevalence of NAFLD worldwide. Translational studies and clinical trials investigating the association between EDCs and NAFLD are required to confirm and extent these studies.

Gastrointestinal immune system and brain dialogue implicated in neuroinflammatory and neurodegenerative diseases.

A common characteristic of the central nervous system (CNS) neurodegenerative disorders is neuroinflammation, marked by augmented numbers of activated and primed microglia, increased inflammatory cytokines and decreased anti-inflammatory molecules. CNS neuroinflammation is a critical component in the progression of several neurodegenerative diseases which sensitize the brain to produce an exaggerated response to immune stimuli in the periphery. Neuroinflammation might initiate from the periphery and peripheral conditions through disrupted blood-brain barrier powerfully influence various brain pathologies. Gastrointestinal tract (GIT) represents a vulnerable area through which pathogens influence the brain and induce CNS neuroinflammation. The pathogens may access the CNS through blood, the nasal olfactory pathways and the GIT. Potential GI pathogens, such as Helicobacter pylori, induce humoral and cellular immune responses that, owing to the sharing of homologous epitopes (molecular mimicry), cross-react with CNS components thereby contributing and possibly perpetuating neural tissue damage. GIT is strictly connected to the CNS and a bi-directional communication exists between them. The brain is involved in regulating the immune and gut system. Conversely, limited attention has been paid on the GIT role in the development and regulation of the CNS autoimmune diseases. The GIT is the primary immune organ with specialized immunoregulatory and anti-inflammatory functions, represented by the gastrointestinal immune system (GIS). This review focuses on the potential GIS and brain dialogue implicated in neurodegenerative diseases. Gaining a better understanding of the relationship between GIS and CNS could provide an insight on the pathogenesis and therapeutic strategies of these disorders.