Neuregulin-1 beta 1 is implicated in pathogenesis of multiple sclerosis.

Multiple sclerosis is characterized by immune mediated neurodegeneration that results in progressive, life-long neurological and cognitive impairments. Yet, the endogenous mechanisms underlying multiple sclerosis pathophysiology are not fully understood. Here, we provide compelling evidence that associates dysregulation of neuregulin-1 beta 1 (Nrg-1ß1) with multiple sclerosis pathogenesis and progression. In the experimental autoimmune encephalomyelitis model of multiple sclerosis, we demonstrate that Nrg-1ß1 levels are abated within spinal cord lesions and peripherally in the plasma and spleen during presymptomatic, onset and progressive course of the disease. We demonstrate that plasma levels of Nrg-1ß1 are also significantly reduced in individuals with early multiple sclerosis and is positively associated with progression to relapsing-remitting multiple sclerosis. The functional impact of Nrg-1ß1 downregulation preceded disease onset and progression, and its systemic restoration was sufficient to delay experimental autoimmune encephalomyelitis symptoms and alleviate disease burden. Intriguingly, Nrg-1ß1 therapy exhibited a desirable and extended therapeutic time window of efficacy when administered prophylactically, symptomatically, acutely or chronically. Using in vivo and in vitro assessments, we identified that Nrg-1ß1 treatment mediates its beneficial effects in EAE by providing a more balanced immune response. Mechanistically, Nrg-1ß1 moderated monocyte infiltration at the blood-CNS interface by attenuating chondroitin sulphate proteoglycans and MMP9. Moreover, Nrg-1ß1 fostered a regulatory and reparative phenotype in macrophages, T helper type 1 (Th1) cells and microglia in the spinal cord lesions of EAE mice. Taken together, our new findings in multiple sclerosis and experimental autoimmune encephalomyelitis have uncovered a novel regulatory role for Nrg-1ß1 early in the disease course and suggest its potential as a specific therapeutic target to ameliorate disease progression and severity.

Poly(ADP-ribose) polymerase 2 contributes to neuroinflammation and neurological dysfunction in mouse experimental autoimmune encephalomyelitis.

BACKGROUND: Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis characterized by entry of activated T cells and antigen presenting cells into the central nervous system and subsequent autoimmune destruction of nerve myelin. Previous studies revealed that non-selective inhibition of poly(ADP-ribose) polymerases (PARPs) 1 and 2 protect against neuroinflammation and motor dysfunction associated with EAE, but the role of the PARP-2 isoform has not yet been investigated selectively. RESULTS: EAE was induced in mice lacking PARP-2, and neurological EAE signs, blood-spine barrier (BSB) permeability, demyelination and inflammatory infiltration were monitored for 35 days after immunization. Mice lacking PARP-2 exhibited significantly reduced overall disease burden and peak neurological dysfunction. PARP-2 deletion also significantly delayed EAE onset and reduced BSB permeability, demyelination and central nervous system (CNS) markers of proinflammatory Th1 and Th17 T helper lymphocytes. CONCLUSIONS: This study represents the first description of a significant role for PARP-2 in neuroinflammation and neurological dysfunction in EAE.

Is microglial apoptosis an early pathogenic change in cerebral X-linked adrenoleukodystrophy?

OBJECTIVE: Mutations in the X-linked adrenoleukodystrophy (X-ALD) protein cause accumulation of unbranched saturated very-long-chain fatty acids, particularly in brain and adrenal cortex. In humans, the genetic defect causes progressive inflammatory demyelination in the brain, where very-long-chain fatty acids accumulate within phospholipid fractions such as lysophosphatidylcholine. METHODS: To address mechanisms of inflammation, we studied microglial activation in human ALD (10 autopsies) and lysophosphatidylcholine (C24:0) injection into the parietal cortex of mice. RESULTS: Unexpectedly, we found a zone lacking microglia within perilesional white matter, immediately beyond the actively demyelinating lesion edge. Surrounding this zone we observed clusters of activated and apoptotic microglia within subcortical white matter. Lysophosphatidylcholine (C24:0) injection in mice led to widespread microglial activation and apoptosis. INTERPRETATION: Our data suggest that the distinct mononuclear phagocytic cell response seen in cerebral X-ALD results, at least in part, from aberrant signaling to cognate receptors on microglia. Our findings support a hypothesis that microglial apoptosis in perilesional white matter represents an early stage in lesion evolution and may be an appropriate target for intervention in X-ALD patients with evidence of cerebral demyelination.

The expression and function of chemokines involved in CNS inflammation.

Chemokines and their receptors have principal roles in leukocyte trafficking under normal physiological and pathological conditions. The differential expression of the chemokine system in different parts of the CNS provides insights into the processes that are required for normal immune surveillance and pathological immune-mediated effector processes. Insights derived from studying multiple sclerosis, an inflammatory disorder of the CNS in humans, and experimental autoimmune encephalomyelitis, an animal model of this disorder, aid in further understanding the complexities of chemokine-mediated inflammation. Knowledge of the molecular biology of chemokines and their receptors, and the roles of specific chemokine ligands and receptors in the CNS in health and in disease have made these proteins targets for therapeutic intervention in neuroinflammation. We also discuss currently proposed and potentially useful chemokine receptor antagonists.

Effect of comorbidity on mortality in multiple sclerosis.

OBJECTIVE: We aimed to compare survival in the multiple sclerosis (MS) population with a matched cohort from the general population, and to evaluate the association of comorbidity with survival in both populations. METHODS: Using population-based administrative data, we identified 5,797 persons with MS and 28,807 controls matched on sex, year of birth, and region. We estimated annual mortality rates. Using Cox proportional hazards regression, we evaluated the association between comorbidity status and mortality, stratifying by birth cohort, and adjusting for sex, socioeconomic status, and region. We compared causes of death between populations. RESULTS: Median survival from birth in the MS population was 75.9 years vs 83.4 years in the matched population. MS was associated with a 2-fold increased risk of death (adjusted hazard ratio 2.40; 95% confidence interval: 2.24-2.58). Several comorbidities were associated with increased hazard of death in both populations, including diabetes, ischemic heart disease, depression, anxiety, and chronic lung disease. The magnitude of the associations of mortality with chronic lung disease, diabetes, hypertension, and ischemic heart disease was lower in the MS population than the matched population. The most common causes of death in the MS population were diseases of the nervous system and diseases of the circulatory system. Mortality rates due to infectious diseases and diseases of the respiratory system were higher in the MS population. CONCLUSION: In the MS population, survival remained shorter than expected. Within the MS population, comorbidity was associated with increased mortality risk. However, comorbidity did not preferentially increase mortality risk in the MS population as compared with controls.

Comorbidity increases the risk of hospitalizations in multiple sclerosis.

OBJECTIVE: We aimed to evaluate the association between comorbidity and rates of hospitalization in the multiple sclerosis (MS) population as compared to a matched cohort from the general population. METHODS: Using population-based administrative data from the Canadian province of Manitoba, we identified 4,875 persons with MS and a matched general population cohort of 24,533 persons. We identified all acute care hospitalizations in the period 2007-2011. Using general linear models, we evaluated the association between comorbidity status and hospitalization rates (all-cause, non-MS-related, MS-related) in the 2 populations, adjusting for age, sex, and socioeconomic status. RESULTS: Comorbidity was common in both cohorts. Over the 5-year study period, the MS population had a 1.5-fold higher hospitalization rate (adjusted rate ratio [aRR] 1.56; 95% confidence interval [CI] 1.44-1.68) than the matched population. Any comorbidity was associated with a 2-fold increased risk of non-MS-related hospitalization rates (aRR 2.21; 95% CI 1.73-2.82) in the MS population, but a nearly 4-fold increase in hospitalization rates in the matched population (aRR 3.85; 95% CI 3.40-4.35). Comorbidity was not associated with rates of hospitalization for MS-related reasons, regardless of how comorbidity status was defined. CONCLUSIONS: In the MS population, comorbidity is associated with an increased risk of all-cause hospitalizations, suggesting that the prevention and management of comorbidity may reduce hospitalizations.

Dramatically changing rates and reasons for hospitalization in multiple sclerosis.

OBJECTIVE: We aimed to describe hospitalizations in the multiple sclerosis (MS) population, and to evaluate temporal trends in hospitalizations in the MS population compared to the general population. METHODS: Using population-based administrative data, we identified 5,797 persons with MS and a matched general population cohort of 28,769 persons. Using general linear models, we evaluated temporal trends in hospitalization rates and length of stay in the 2 populations over the period 1984-2011. RESULTS: In 1984 the hospitalization rate was 35 per 100 person-years in the MS population and 10.5 in the matched population (relative risk [RR] 3.33; 95% confidence interval: 1.67-6.64). Over the study period hospitalizations declined 75% in the MS population but only 41% in the matched population. The proportion of hospitalizations due to MS declined substantially from 43.4% in 1984 to 7.8% in 2011. The 3 most common non-MS-related reasons for admission in the MS population were diseases of the digestive, genitourinary, and circulatory systems. Admissions for bacterial pneumonia, influenza, urinary tract infections, and pressure ulcers occurred more often in the MS population than in the general population, while admissions for circulatory system disease and neoplasms occurred less often. Older age, male sex, and lower socioeconomic status were associated with increased hospitalization rates for non-MS-related reasons. CONCLUSIONS: Although hospitalization rates have declined dramatically in the MS population over the last quarter century, they remain higher than in the general population. Admissions for MS-related reasons now constitute only a small proportion of the reasons for hospitalization.

Imaging correlates of leukocyte accumulation and CXCR4/CXCL12 in multiple sclerosis.

OBJECTIVE: To compare leukocyte accumulation and expression of the chemokine receptor/ligand pair CXCR4/CXCL12 in magnetic resonance imaging-defined regions of interest (ROIs) in brains from patients with chronic multiple sclerosis. We studied the following ROIs: normal-appearing white matter (NAWM); regions abnormal only on T2-weighted images (T2 only); and regions abnormal on T2- and T1-weighted images with an abnormal magnetization transfer ratio (T2/T1/MTR). DESIGN: Case-control study. SETTING: Cleveland Clinic. PATIENTS: Brain tissue was acquired from 5 patients with secondary progressive multiple sclerosis (MS) and 5 nonneurological controls. INTERVENTION: Magnetic resonance imaging pathological correlations were performed on the 5 cases. Based on imaging characteristics, 30 ROIs were excised. MAIN OUTCOME MEASURE: Using immunohistochemical analysis, we evaluated myelin status, leukocyte accumulation, and CXCR4/CXCL12 expression in the MS ROIs and white matter regions from the 5 nonneurological controls. RESULTS: Eight of 10 T2/T1/MTR regions were chronic active or chronic inactive demyelinated lesions, whereas only 2 of 10 T2-only regions were demyelinated and characterized as active or chronic active lesions. Equivalent numbers of CD68+ leukocytes (the predominant cell type) were present in myelinated T2-only regions as compared with NAWM. Parenchymal T cells were significantly increased in T2/T1/MTR ROIs as compared with T2-only regions and NAWM. Expression of CXCR4 and phospho-CXCR4 were found on reactive microglia and macrophages in T2-only and T2/T1/MTR lesions. CXCL12 immunoreactivity was detected in astrocytes, astrocytic processes, and vascular elements in inflamed MS lesions. CONCLUSIONS: Inflammatory leukocyte accumulation was not increased in myelinated MS ROIs with abnormal T2 signal as compared with NAWM. Robust expression of CXCR4/CXCL12 on inflammatory elements in MS lesions highlights a role of this chemokine/receptor pair in central nervous system inflammation.

Inflammatory progressive multifocal leukoencephalopathy in human immunodeficiency virus-negative patients.

OBJECTIVE: Inflammatory progressive multifocal leukoencephalopathy (iPML) with enhancing magnetic resonance imaging (MRI) lesions and leukocyte infiltration occurs in human immunodeficiency virus (HIV)-infected individuals after highly active antiretroviral therapy (HAART) treatment. MRI diagnostic criteria for PML suggest that iPML does not occur in HIV-negative individuals. METHODS: We studied pathologically proved PML (12 by biopsy, 9 with MRI, 32 at autopsy). RESULTS: HIV-negative (2/5) and -positive (2/4) PML patients had enhancing MRI lesions, correlated with CD3(+) lymphocyte infiltration. Inflammatory infiltrates occurred in the majority of HIV-negative (7/8) and HIV-positive/HAART (17/20) cases (p > 0.2), but in only 2 of 16 HIV-positive/non-HAART cases (p < 0.001). INTERPRETATION: iPML showed radiographic and pathological similarity in HIV-positive/HAART and HIV-negative patients. HIV-negative iPML necessitates further consideration of MRI criteria for PML.