The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease.

Multiple sclerosis is a demyelinating disease, characterized by inflammation in the brain and spinal cord, possibly due to autoimmunity. Large-scale sequencing of cDNA libraries, derived from plaques dissected from brains of patients with multiple sclerosis (MS), indicated an abundance of transcripts for osteopontin (OPN). Microarray analysis of spinal cords from rats paralyzed by experimental autoimmune encephalomyelitis (EAE), a model of MS, also revealed increased OPN transcripts. Osteopontin-deficient mice were resistant to progressive EAE and had frequent remissions, and myelin-reactive T cells in OPN-/- mice produced more interleukin 10 and less interferon-gamma than in OPN+/+ mice. Osteopontin thus appears to regulate T helper cell-1 (TH1)-mediated demyelinating disease, and it may offer a potential target in blocking development of progressive MS.

[Recent advances in the immunology of multiple sclerosis]. / Progrès récents concernant les mécanismes immunitaires de la sclérose en plaques.

INTRODUCTION: Multiple sclerosis (MS) is a heterogeneous disease. From an immunological point of view, it is considered an inflammatory TH1-mediated autoimmune disease of unknown origin, targeting myelin proteins. STATE OF ART: Neuropathological analysis of MS lesions classified different clinical MS types according to the preponderance of different subsets of immune cells in the lesions (clinico-pathological correlation). Ex vivo analysis of various immunological parameters (like cytokines, antigenic targets) and MRI findings suggest a heterogeneous process leading to the autoimmune destruction of the myelin sheath. Clinical therapeutic trials, especially those using monoclonal antibodies, have recently improved our understanding of the immunology of MS, by focusing our interest on molecules modulating the reactivity of T or B cells, and on the influence of adhesion molecules on relapsing remititing MS. Finally, large scale transcriptional analysis of MS and EAE lesions gave a large amount of information about molecules that are up or down regulated during the disease process, and identified new candidates like osteopontin, which ended up being a key proinflammatory molecule influencing the course of the disease and a therapeutic target for EAE. PERSPECTIVES: Investigating the numerous MS and EAE large scale transcriptional profiles will allow new hypotheses to arise, especially in the immunological field of MS. The relationship between inflammation and axonal loss is one of the key questions raised by researchers, and whether these two processes are directly related or not is still debated today. CONCLUSION: A better understanding of the immunology of MS would lead to the discovery of new therapeutic and biological tools, allowing practical improvement of MS patient care.

Comparison of risk factors in vasospastic angina without significant fixed coronary narrowing to significant fixed coronary narrowing and no vasospastic angina.

To determine the importance of usual risk factors of coronary artery disease (CAD) in patients with coronary artery spasm, 40 patients with vasospastic angina (VA), normal or nearly normal coronary arteries and without previous myocardial infarction were compared with 2 control groups of 40 patients each, matched for age and sex: 1 group with CAD and 1 without heart disease. Ninety percent of patients with VA were cigarette smokers and 70% were heavy smokers (more than 20 cigarettes daily), compared with 53% and 33% in patients with CAD (p less than 0.001) and 30% and 15% in those without heart disease (p less than 0.001). Except for cigarette smoking, the risk factor profile of patients with VA appeared more like the profile of patients without heart disease than that of patients with CAD. The results suggest that cigarette smoking may play a role in CAD independent of atherosclerosis and possibly favoring coronary artery spasm.

Common viruses associated with lower pediatric multiple sclerosis risk.

BACKGROUND: Because common viruses are encountered during childhood, pediatric multiple sclerosis (MS) offers a unique opportunity to investigate the influence of these viruses on disease susceptibility and the interactions between seroprevalence and select HLA genotypes. We studied seroprevalence for Epstein-Barr virus (EBV), cytomegalovirus (CMV), and herpes simplex virus (HSV) type 1 and HLA-DRB1*1501/1503 status as predictors of pediatric MS. METHODS: This was a retrospective analysis of prospectively collected demographic, clinical, and biologic data in subjects up to 18 years of age with early MS, control subjects seen at the same regional referral pediatric MS clinics, and additional healthy pediatric control subjects. RESULTS: Patients with early pediatric MS (n=189) and pediatric control subjects (n=66) were tested. Epstein-Barr nuclear antigen-1 seropositivity was associated with an increased odds of MS (odds ratio [OR] 3.78, 95% confidence interval [CI] 1.52-9.38, p=0.004) in analyses adjusted for age, sex, race, ethnicity, and HLA-DRB1*1501/1503 status. In multivariate analyses including EBV status, a remote infection with CMV (OR 0.27, 95% CI 0.11-0.67, p=0.004) was associated with a lower risk of developing MS. Although a remote infection with HSV-1 was not associated with an increased odds of MS, a strong interaction was found between HSV-1 status and HLA-DRB1 in predicting MS (p<0.001). HSV-1 was associated with an increased risk of MS in those without a DRB1*15 allele (OR 4.11, 95% CI 1.17-14.37, p=0.03), whereas the effect was reversed in those who were DRB1*15-positive (OR 0.07, 95% CI 0.02-0.32, p=0.001). CONCLUSIONS: These findings suggest that some infections with common viruses may in fact lower MS susceptibility. If this is confirmed, the pathways for risk modification remain to be elucidated.

Younger children with MS have a distinct CSF inflammatory profile at disease onset.

BACKGROUND: The clinical and MRI presentation differs between earlier- and later-onset pediatric multiple sclerosis (MS), whereas the effect of age on the CSF inflammatory profile is unknown and may contribute to delayed diagnosis. OBJECTIVES: To compare the CSF cellular and immunoglobulin G (IgG) profiles between earlier- and later-onset pediatric MS. METHODS: We queried the databases of 6 pediatric MS centers for earlier-onset (onset <11 years) and later-onset (> or = 11 and <18 years) patients with MS or clinically isolated syndrome who underwent CSF analysis within the first 3 months of presentation (observational study). We compared CSF white blood cell (WBC) differential count, IgG index, and IgG oligoclonal bands between age groups. RESULTS: We identified 40 earlier-onset (mean age at onset = 7.2 +/- 2.7 years, 60% females) and 67 later-onset pediatric MS patients (15.1 +/- 1.7 years, 63% females). Although WBC count tended to be higher in earlier-onset patients (median = 9/mm(3) [0-343] vs 6 [0-140], p = 0.15), they had a lower proportion of lymphocytes (70% [0-100] vs 93% [0-100] of WBCs, p = 0.0085; difference = +3% per 1-year increase of age, p = 0.0011) and higher proportion of neutrophils than later-onset patients (0.5% [0-75] vs 0% [0-50] of WBCs, p = 0.16; difference = -1% per 1-year increase of age, p = 0.033). In earlier-onset disease, fewer patients had an elevated IgG index than in the later-onset group (35% vs 68% of patients, p = 0.031). CONCLUSION: Age modifies the CSF profile at pediatric multiple sclerosis (MS) onset, which may mislead the diagnosis. Our findings suggest an activation of the innate rather than the adaptive immune system in the earlier stages of MS or an immature immune response.

Vanishing MS T2-bright lesions before puberty: a distinct MRI phenotype?

BACKGROUND: Multiple sclerosis (MS) onset before puberty may have a distinct clinical presentation. Pediatric patients with MS may less often meet MRI diagnostic criteria for adults. Whether initial MRI presentation is distinct in prepubertal patients is unknown. METHODS: We queried the UCSF MS database for pediatric patients with MS (onset or=11 years) pediatric MS. The next available brain MRI scan was used to evaluate lesion resolution. RESULTS: Thirteen children with EOPMS (median age 8.90 years, range [3.58-10.98], 38% girls) and 18 with LOPMS (median age 14.47 years, range [11.78-18.00], 61% girls) were identified. While the overall number of T2-bright lesions was similar in the two groups, patients with EOPMS had fewer well-defined ovoid T2-bright lesions (median = 7, range [0-29] vs 21.5, [4-100]; p = 0.004) and more often had confluent lesions (31% of patients vs 0%; p = 0.02) on their first MRI compared with patients with LOPMS. Ninety-two percent of patients with EOPMS had a reduction in the number of T2-bright lesions on the second scan compared to 29% of patients with LOPMS (p = 0.002). CONCLUSIONS: The distinct prepubertal multiple sclerosis (MS) MRI phenotype suggests that underlying biologic processes may differ in earlier-onset pediatric MS compared to later-onset pediatric MS. These findings may delay diagnosis in that age range. MRI criteria for MS diagnosis may need to be revised before puberty.

Clinical features of children and adolescents with multiple sclerosis.

There is increasing appreciation that multiple sclerosis (MS) can begin in childhood or adolescence, but pediatric MS continues to be a rare entity, with an estimated 2 to 5% of patients with MS experiencing their first clinical symptoms before age 16. A prompt diagnosis of pediatric MS is important to optimize overall management of both the physical and social impact of the disease. The widespread use of disease-modifying therapies (DMT) for MS in adults, as early as following an initial isolated episode, has led to the use of DMT in children and adolescents with MS. However, it is imperative to distinguish pediatric MS from other childhood CNS inflammatory demyelinating disorders such as acute disseminated encephalomyelitis. Although increasing evidence suggests a slower disease course in children with MS compared to adults, significant disability can still accumulate by early adulthood. Furthermore, associated neurocognitive deficits can impair both academic and psychosocial function at a critical juncture in a young person's life. This article reviews the clinical characteristics, neuroimaging, paraclinical findings, disease course, epidemiology, genetics, and pathophysiology of pediatric MS vis-à-vis adult MS. Further research of pediatric MS may advance our understanding of MS pathophysiology in general, as well as improve the long-term health care outcomes of children and adolescents diagnosed with MS.

Treatment of pediatric multiple sclerosis and variants.

Studies in adult patients with multiple sclerosis (MS) suggest significant benefit of early treatment initiation. However, there are no approved therapies for children and adolescents with MS. For adult MS, tolerability and efficacy of several immunomodulatory and immunosuppressive drugs have been demonstrated. Guidelines for the use of these MS therapies in children do not exist. Several small cohort studies of the safety and tolerability of disease-modifying therapies (DMT) in children and adolescents with MS have been recently reported. The side effects of interferon beta (IFNB) and glatiramer acetate (GA) appear to be similar to those reported by adults. The long-term tolerability and safety have yet to be established and efficacy data have yet to be studied. In view of the potential for significant long-term physical and cognitive disability in children with MS, and recent evidence that initiation of immunomodulatory therapy early in the course of MS improves long-term prognosis, an increasing number of children and adolescents with MS are being offered the DMT approved for adults. This review summarizes current knowledge of DMT in pediatric MS and experience in several centers treating pediatric MS and MS variants such as neuromyelitis optica or Devic disease, Balo concentric sclerosis, Marburg acute MS, and Schilder disease (myelinoclastic diffuse sclerosis). Finally, an overview of symptomatic MS therapies and experiences with these treatments in pediatric patients is provided.

[Role of autoimmunity in multiple sclerosis]. / Rôle de l'auto-immunité dans la sclérose en plaques.

A number of evidences indicate that an antigen-specific immune reaction is responsible for the formation and/or the maintenance of multiple sclerosis (MS) lesions. This disease is characterized by the following: 1), an infiltration of the white matter of the brain and spinal cord by inflammatory cells; 2), the T and B lymphocytes, present in the lesions or in the cerebrospinal fluid of patients, show signs of activation; i.e., the classic IgG oligoclonal bands of the cerebrospinal fluid (activation of B lymphocytes) and the presence of activation markers on the surface of the T lymphocytes; 3), the presence of an association, and a linkage between the disease and the genes of the HLA complex. The HLA molecules are implicated in the presentation of the antigen to the T lymphocytes; 4), finally, it should be noted that the therapeutic approaches aimed at reducing (immunosuppressants) or at modulating (beta-interferon, copolymer 1) the immune responses have a positive effect on this disease, whereas those treatments which activate the immune system (gamma-interferon) have a negative effect.

[Supertransformation of a human lymphoblastoid cell line by chemical carcinogens]. / Surtransformation d'une lignée lymphoblastique humaine par des cancérogènes chimiques.

We have studied the in vitro malignant progression of human lymphoid cells by the combined effect of genetic, viral and mutagenic factors. A lymphoblastoid cell line immortalized by Epstein-Barr virus was used; it was derived from a patient suffering from ataxia-telangiectasia, a genetic disease linked to a deficiency in DNA repair. Cells were treated by sub-toxic doses of two potent mutagens (carcinogens), NQO (4-nitroquinolein-oxid) and R 7 000 (2-nitro-7-methoxy-naphto-furan). The treated cells showed an increased ability to form colonies in soft agarose, among which some compact colonies appeared, different from the diffuse colonies formed by untreated control cells. Sub-clones derived from these compact colonies differ also from the original cells by their behavior in liquid culture medium, by their increased tumorigenicity in Nude Mice and by their capacity to form nodules on Chicken chorioallantoic membrane. Some of the sub-clones produce non-regressing large tumors in Nude Mice with a cell inoculum lower than that required for Burkitt lymphoma cells while being less invasive than the latter. However, by their morphology, the malignant cells of the sub-clones remain similar to the original lymphoblastoid cells. Thus, such a malignant progression obtained in vitro cannot be considered as identical to that which leads to Burkitt lymphoma in African children.

T cell receptor V beta 5 and V beta 17 clonal diversity in cerebrospinal fluid and peripheral blood lymphocytes of multiple sclerosis patients.

To better characterize the cellular immune response taking place in the MS central nervous system, we investigated the blood and CSF T cell receptor (TCR) V beta 5 and V beta 17 repertoire in HLA-typed patients with recently diagnosed MS or other neurological diseases (OND). Using a RT-PCR based technique, we analysed directly ex vivo the CDR3 size of TCR beta chains utilizing V beta 5 (eight patients with MS and one with OND) or V beta 17 (eight patients with MS and six with OND) gene segments on paired blood-CSF samples. Globally, the analysis of V beta 5-J beta and V beta 17-J beta repertoire showed a less diverse pattern in the CSF samples than in the corresponding peripheral blood lymphocytes both in MS and in OND patients. However, we did not detect any recurrent clonal expansion within the V beta 5+ T cells in MS patients, underlining the potential limits of V beta 5-based immunotherapy in MS. We found an expanded T cell population using the same V beta 17-J beta 1.6 combination with identical CDR3 length in the CSF of three MS patients and none of the control patients. These results suggest selective expansion of T cells expressing this segment gene in the MS central nervous system.

Antagonistic action of IFN-beta and IFN-gamma on high affinity Fc gamma receptor expression in healthy controls and multiple sclerosis patients.

Monocyte-macrophage activation by IFN-gamma is characterized by a pronounced increase of high affinity Fc receptors for IgG (Fc gamma RI), capable of triggering respiratory burst, phagocytosis, Ab-dependent cytotoxicity, and release of proinflammatory cytokines. In view of the antagonism of IFN-beta on IFN-gamma action, of interest in the chronic inflammatory disorder multiple sclerosis, we examined the possible effect of IFN-beta on IFN-gamma induction of Fc gamma RI gene expression. We found that IFN-beta significantly down-regulated IFN-gamma-induced Fc gamma RI surface expression in peripheral blood monocytes from healthy donors, in a dose- and time-dependent manner. This down-regulation of Fc gamma RI surface levels did not correspond to a decrease in Fc gamma RI mRNA, suggesting a posttranscriptional effect of IFN-beta. Down-regulation of Fc gamma RI surface expression correlated with diminished cellular signaling through Fc gamma RI, since the IFN-gamma-induced increase in Fc gamma receptor-triggered respiratory burst was nearly completely abrogated by simultaneous addition of IFN-beta. Finally, the same antagonism between both IFNs on Fc gamma RI surface expression was observed in peripheral blood monocytes derived from multiple sclerosis patients; inhibition by IFN-beta was even increased (82+/-11%), as compared with healthy controls (67+/-4%). These results may partially help explain the beneficial effect of IFN-beta in multiple sclerosis.

An unexpected version of horror autotoxicus: anaphylactic shock to a self-peptide.

EAE can refer either to experimental autoimmune encephalomyelitis or experimental allergic encephalomyelitis. Although EAE is classically a prototypic T helper 1 (TH1) cell-mediated autoimmune disease, it can also be induced by TH2 cells. Characteristically, the most severe manifestation of allergy, anaphylaxis, is associated with exposure to a foreign antigen that is often derived from medication, insect venom or food. We report here that, after self-tolerance to myelin is destroyed, anaphylaxis may be triggered by a self-antigen, in this case a myelin peptide. "Horror autotoxicus", which was initially described by Ehrlich, may not only include autoimmunity to self, it may also encompass immediate hypersensitivity to self, which leads to shock and rapid death.