Multiple Sclerosis Infection Research Articles

Parasite Infections in Multiple Sclerosis Modulate Immune Responses through a Retinoic Acid–Dependent Pathway

We recently demonstrated better outcomes in helminth-infected multiple sclerosis (MS) patients, compared with uninfected ones. The present study evaluates the role of TLR2 and retinoic acid (RA) in parasite-driven protection in MS patients. RA serum levels were significantly higher in helminth-infected MS patients than in uninfected MS subjects or healthy controls. Genes involved in RA biosynthesis and metabolism, such as Adh1 and Raldh2, as well as RA receptors and IL-10, were induced in dendritic cells (DCs) via TLR2-dependent ERK signaling. This programmed DCs to induce FOXP3(+) T regulatory cells and suppressed production of proinflammatory cytokines (IL-6, IL-12, IL-23, and TNF-α) via induction of suppressor of cytokine signaling 3 (SOCS3), an effect mediated by soluble egg Ag (SEA) obtained from Schistosoma mansoni, and by RA. SEA-activated DCs also inhibited IL-17 and IFN-γ production through autoreactive T cells. These inhibitory effects were abrogated when SOCS3 gene expression was silenced, indicating that SEA-mediated signaling inhibited production of these cytokines by T cells, through a SOCS3-dependent pathway. Overall, helminth-related immunomodulation observed in MS patients was mediated by TLR2- and RA-dependent pathways, through two different mechanisms, as follows: 1) induction of IL-10 and FOXP3(+) T regulatory cells, and 2) suppression of proinflammatory cytokine production mediated by SOCS3.

Epstein–Barr Virus and Autoimmunity: The Role of a Latent Viral Infection in Multiple Sclerosis and Systemic Lupus Erythematosus Pathogenesis

Multiple sclerosis (MS) and systemic lupus erythematosus (SLE) are both chronic autoimmune diseases with unknown etiology. To date, EBV is the most closely implicated infectious agent to be associated with both MS and SLE. Epidemiological findings show a strong correlation between EBV infection and the risk of developing these diseases. The type and magnitude of both EBV-specific antibodies and T-cell responses produced by MS or SLE patients are dysregulated when compared with healthy cohorts. Despite all these findings, it is still not clear if and how EBV triggers autoimmunity. EBV infects and establishes latency mainly in B cells, but it can also infect other cell types and indirectly influence the activation status of the immune system by stimulating the production of proinflammatory mediators. This could play a role in both MS and SLE pathogenesis. In this review we will summarize recent literature that links EBV infection to SLE and MS, and discuss possible new mechanisms that explain how EBV drives autoimmunity.

Urinary tract infection in multiple sclerosis: a practical algorithm for a common problem

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Altered natural killer cells' response to herpes virus infection in multiple sclerosis involves KIR2DL2 expression

The role of herpes viruses as potential triggers of multiple sclerosis (MS) is still debated. Peripheral blood mononuclear cells from MS patients and controls were treated with CpG sequences and infected in vitro with HSV-1. Samples were analyzed for viral yield, TLR9 pathways, cytokine secretion, NK cell activation and killer immunoglobulin-like receptor (KIR) expression. CpG treatment promoted an unexpected sensitivity to herpes virus infection in a subset of MS patients: TLR9 pathways did not show defects while NK cells presented decreased degranulation and cytotoxicity and up-regulated the inhibitory KIR2DL2 receptor. CpG treatment of purified NK cells affected directly KIR2DL2 modulation and cell activation. These data suggest potential implications for viral pathogenesis of MS.

HHV‐6 infection in multiple sclerosis. A clinical and laboratory analysis

To elucidate the role of human herpesvirus-6 (HHV-6) in the development of multiple sclerosis (MS). Nine patients with MS and with acute or chronic HHV-6 infection were evaluated. Intrathecal antibody production to HHV-6 and oligoclonal IgG bands in the cerebrospinal fluid (CSF) was observed in two patients with a clinically definite MS and chronic HHV-6 infection (based on the presence of HHV-6 specific antibodies in the CSF). A temporal association between the symptoms of clinically possible MS and acute primary HHV-6A infection (based on avidity of HHV-6 specific antibodies) was observed in two patients. Human herpesvirus-6 infection may be an associated agent in some MS cases. Viral studies are needed to identify a possible viral etiology and give specific therapy.

Helminth infections associated with multiple sclerosis induce regulatory B cells

To assess the importance of B-cell control during parasite infections in multiple sclerosis (MS) patients. Peripheral blood CD19+ B cells from 12 helminth-infected MS patients, 12 MS patients without infection, 10 patients infected with Trypanosoma cruzi, 8 subjects infected with Paracoccidioides brasiliensis, and 12 healthy control subjects were purified using magnetic cell sorting. Interleukin (IL)-4, IL-6, IL-10, tumor necrosis factor-alpha, lymphotoxin, transforming growth factor-beta, brain-derived neurotrophic factor, and nerve growth factor secretion were evaluated after stimulation with CDw32 L cells and CD40 antibody using enzyme-linked immunosorbent assays. The production of anti-myelin oligodendrocyte glycoprotein IgG and IgM antibodies was evaluated by enzyme-linked immunosorbent spot assays. Cell phenotype was assessed by flow cytometry. Helminth infections in MS patients created a B-cell population producing high levels of IL-10, dampening harmful immune responses through a mechanism mediated, at least in part, by the ICOS-B7RP-1 pathway. The IL-10-producing B-cell phenotype detected expressed high levels of CD1d and was similar to the one observed in mature naive B2 cells (namely, CD11b(-), CD5(-), CD27(-), and IgD+). Moreover, B cells isolated from helminth-infected MS patients also produced greater amounts of brain-derived neurotrophic factor and nerve growth factor compared with those of normal subjects, T. cruzi-infected subjects, P. brasiliensis-infected subjects, or uninfected MS patients, raising the possibility that these cells may exert a neuroprotective effect on the central nervous system. Increased production of B-cell-derived IL-10 and of neurotrophic factors are part of the parasite's regulation of host immunity and can alter the course of MS, potentially explaining environmental-related MS suppression observed in areas with low disease prevalence.

Herpesviruses and human endogenous retroviral sequences in the cerebrospinal fluid of multiple sclerosis patients

Objective To analyze the possible role of human herpesvirus (HHVs) and human endogenous retroviruses (HERVs) infection in multiple sclerosis (MS) pathogenesis. Methods A total of 92 cerebrospinal fluid (CSF) samples were collected: 48 from MS patients at the first clinically evident demyelinating event, 23 from patients with other inflammatory neurological diseases (OINDs) and 21 from patients with other non-inflammatory neurological diseases (ONINDs). Total DNA and RNA were isolated, and the prevalences and viral loads of herpes simplex virus (HSV), varicella-zoster virus (VZV), Epstein–Barr virus (EBV), cytomegalovirus (CMV), HHV-6, HERV-H and HERV-W in the CSF of MS patients and controls were evaluated using a quantitative real-time polymerase chain reaction assay. Results (i) For HSV, 1/48 (2.1%, 86 copies/ml of CSF) MS patients and 1/23 (4.3%, 115.2 copies/ml of CSF) OIND patients (a myelitis case) had HSV sequences in the CSF; (ii) for EBV, only 1/48 (2.1%, 72 copies/ml of CSF) MS patients was positive for EBV; (iii) for HHV-6, only 5/48 (10.4%) MS patients had HHV-6 genomes in their CSF (128.1 copies/ml of CSF); (iv) we did not find any positive cases for VZV, CMV, HERV-H and HERV-W among MS patients or controls; (v) no cases of co-infections were found; (vi) the whole prevalence of HHVs was 7/48 (14.6%) for MS patients and 1/44 (2.3%) for controls (p = 0.038). Conclusion The findings described here show that HHV infection is more frequent in the CSF of MS patients than in patients with other neurological diseases; however, only HHV-6 seems to be involved in the pathogenesis of MS in a subset of patients.

A role of late Epstein-Barr virus infection in multiple sclerosis.

To assess Epstein-Barr virus (EBV) seroconversion in a high multiple sclerosis (MS) prevalence area and to evaluate the recall of diagnosed infectious mononucleosis in MS patients. The study was based on information or blood samples, or both, from schoolchildren, young MS patients and matched controls. EBV serology was performed on 1154 blood samples. We demonstrate that more than one third of the population in a high MS prevalence area is seronegative to EBV at puberty. This is in contrast to the virtually complete seroconversion to EBV early in life in individuals from areas with a low prevalence of MS. Furthermore, we demonstrate that recall of diagnosed infectious mononucleosis (IM), but not recall of common childhood diseases, is significantly more frequent among MS patients than healthy controls. All MS patients, including patients without prior immunosuppressive treatment, were EBV seropositive. During or after puberty, EBV is transmitted to a major proportion of the population in an MS high-prevalence area. Together with our previous documentation of an association between late infection with EBV and an increased risk of developing MS, these data support a role of EBV infection in MS.

Human Herpesvirus-6 (HHV-6) infection in multiple sclerosis: a preliminary report.

We examined cerebral spinal fluid (CSF) from multiple sclerosis (MS) patients and patients with other neurological diseases (OND) for antibody specific for Human Herpesvirus-6 (HHV-6) and for HHV-6 DNA detectable by PCR. CSF from MS patients had a higher frequency of IgG antibody to HHV-6 late antigens (39.4%) compared with CSF from OND (7.4%). In contrast, the frequency of detectable IgG antibody in CSF from MS patients specific for Epstein-Barr Virus (EBV) (12.1%) and Human Cytomegalovirus (HCMV) (6.1%) was much lower. Two of 12 MS CSFs (16.7%) also contained HHV-6 DNA detected by PCR. None of four OND CSF were positive for HHV-6 DNA. Plasma from 16 patients with MS, eight with OND and 72 healthy donors were tested for antibodies by ELISA to HHV-6 early (p41/38) and late (gp110) proteins. Although no differences in anti-gp110 IgG antibody were detected between MS patients, patients with other neurological diseases, and normals, IgG antibody to early protein p41/38 was detected in > 68% of the plasma from MS patients, 12.5% from OND patients and 27.8% of the controls. IgM antibody to p41/38 was present in > 56% of MS patients, 12.5% of OND patients, and 19% of controls. These data suggest that more than half of the MS patients had active, ongoing HHV-6 infections. HHV-6 was also isolated from peripheral blood mononuclear cells (PBMC) from 3/5 MS patients who were in relapse or had progressive disease and was identified as HHV-6 Variant B. These preliminary results support the hypothesis that HHV-6 may be a co-factor in the pathogenesis of some cases of MS.

Clinical relapses and disease activity on magnetic resonance imaging associated with viral upper respiratory tract infections in multiple sclerosis

BACKGROUNDAlthough the risk of clinical attacks of multiple sclerosis seems to be significantly increased with viral upper respiratory tract infections (URTI), serological evidence for the reported association remains controversial. In...

Human Herpesvirus-6 (HHV-6) infection in multiple sclerosis: a preliminary report

Human Herpesvirus-6 (HHV-6) infection in multiple sclerosis: a preliminary report

Therapy with antibody against leukocyte integrin VLA-4 (CD49d) is effective and safe in virus-facilitated experimental allergic encephalomyelitis

Experimental allerigic encephalomyelitis (EAE) is facilitated in resistant BALB/c mice by intraperitoneal infection with an avirulent Semliki Forest virus (SFV-A7). Viral infection increases the incidence of EAE from 15–30% to 60–90% and speeds up appearance of paralysis from 24 to 14 days. In this paper, we describe treatment of virus-facilitated EAE with monoclonal antibodies (mAbs) against leukocyte and/or endothelial cell adhesion molecules. Therapy with mAb against ICAM-1 (intercellular adhesion molecule-1) had a modest effect, but caused hemorrhagic brain and spinal cord lesions. Therapy with mAb against Mac-1 ( α M β 2-integrin) was well tolerated but had no effect. Therapy with mAb against VLA-4 α 4 β 1-integrin) was safe, diminished both clinical and histopathological signs of EAE, decreased induction of VCAM-1 (vascular cell adhesion molecule-1) on brain vessels and diminished infiltration of VLA-4 + cells into the brain. The amount of viral antigen in the brain was not altered. We conclude that facilitation of leukocyte entry into the brain is a major mechanism for viral facilitation of EAE in the BALB/c mouse, and that facilitation can be inhibited by anti-adhesion therapy. This may have implications for treatment of relapses triggered by viral infections in multiple sclerosis.

Dorsal root ganglia may be reservoirs of viral infection in multiple sclerosis

There are presently two competitive theories that attempt to explain the etiology of multiple sclerosis (MS). Briefly summarized, they are: 1. An infection, probably of viral type, may attack the oligodendroglia of the central nervous system; or, 2. An autoimmune process may begin with an infection of the peripheral lymphatic immune system, producing antibodies that cross the blood-brain barrier, leading to myelinoclasia. Since 1935, research has been directed toward myelin of the central nervous system and the myelin sheaths of peripheral nerve; however, dorsal root and cranial sensory ganglia (DRG) have apparently not been studied. The present hypothesis states that an infectious agent (probably viral) finds privileged sanctuary in the dorsal root and cranial sensory ganglia (DRG): thereafter periodically invading the spinal cord, brain, or peripheral nerve. Previously reported erratic spinal fluid viral titers and cultures can be explained by differences in the anatomy of the DRG in which there is a variable and limited contact of spinal fluid with sensory ganglia. Clues to this hypothesis were noted by the author during routine neurological examinations of patients with MS, in which sensory signs and symptoms were frequently encountered. This clinical observation has also been reported by others who found such symptoms in 75% of MS patients, ranking second only to incoordination.

Failure to detect measles virus sequences in lymphocytes of patients with multiple sclerosis

A role for measles virus (MV) infection in multiple sclerosis (MS) has been suggested by the finding that antibodies to MV are present in the cerebrospinal fluid of patients with MS. Our results do not support a role for MV infection of lymphocytes in MS.

Childhood Infections in Multiple Sclerosis: A Study of North African-Born Patients Who Migrated to France

We conducted a study on 152 patients with multiple sclerosis (MS) who were born in North Africa and migrated to France. Information was obtained from patients on common childhood infections. We found that, in most cases, common childhood illnesses occurred before migration, but these infections occurred at later ages when the patients were in France: the mean differences were equal to 3 years for measles, 2.1 years for chickenpox, and 4.5 years for mumps. In comparison with data available for the general populations of Algeria and France, the mean ages of childhood infections, and particularly measles, were higher in MS patients. Data confirm that, wherever they live, MS patients tend to have childhood infections at a relatively late age and suggest that migration delays the age of viral infections. This might be one of the possible explanations for the effect of migration on the risk of MS.

Treatment of neurogenic bladder dysfunction in multiple sclerosis by ultrasound-controlled bladder training.

Neurogenic bladder dysfunction, the main cause of chronic urinary tract infections in multiple sclerosis (MS), is efficiently treated by bladder training with ultrasound control of the residual urine. However, the beneficial effects of bladder training in the hospital are often lost within a short time when the patient returns to his home. Reexamination at home of 97 MS patients with increased residual urine and/or chronic urinary tract infections showed that the group which claimed to continue bladder training at home had significantly less residual urine at home than the group which did not continue bladder training at home. The residual urine decreased from 210 ml on average to almost normal while the patients did bladder training in the hospital, but the volume nearly doubled within a short time at home. Thus, more decentralized rehabilitation by family members, volunteer personnel or local nurses is necessary. Decentralized symptomatic therapy is the most efficient treatment of MS at present. Family members. volunteers, and local nurses, however, need training. Without these improvements in decentralized rehabilitation the hospital treatment of MS is of little benefit because urinary tract infection quickly recurs at home. For efficient bladder training the patient needs feedback regarding the residual urine; this can be provided with minimum risk by ultrasound sonocystography. In those rare cases in which bladder training does not work, intermittent catheterization must be carried out by the patients or their families, volunteer personnel or a local nurse. A continuous indwelling catheter should not be used. antibiotic treatment should be applied only on the basis of a precise bacteriological diagnosis.

Persistent measles virus infection in vitro and in man

The characteristics of cell lines persistently infected with measles virus are described. Molecular mechanisms for measles virus-persistence in vitro as well as in human disease include defective interfering particles, mutant virus strains, proviral DNA, and nonpermissive cell types. The role of measles virus in subacute sclerosing panencephalitis and evidence for measles virus infection in multiple sclerosis, Paget's disease, and systemic lupus erythematosus are discussed.