Excessive axoplasmic Ca++accumulation causes a vicious cycle of impaired mitochondrial function, reduced energy production and compromised axonal transport that further propagates damage (Mahad et al., 2008). interact and/or interfere with its pathology. Understanding the putative mechanisms that drive disease pathogenesis will be key in helping to develop effective therapeutic strategies to prevent, mitigate, and treat the diverse morbidities associated with multiple sclerosis. Keywords:Neuroimmunology, Multiple sclerosis, Inflammation, Demyelination, Regeneration, Immune modulation == 1. Introduction == Multiple sclerosis (MS) is an inflammatory demyelinating disease of the human central nervous system (CNS) (Compston and Coles, 2002,2008). Recently, the International Advisory Committee on clinical trials in MS refined the two different MS phenotypes (i.e. relapsing and progressive) on the basis of both (i) disease activity and (ii) disease progression (Lublin et al., 2014) (Table 1). == Table 1. == Major characteristics of MS forms as classified by (Lublin et al., 2014). Clinical isolated syndrome (CIS), which was not included in the initial clinical descriptors (Lublin and Reingold, 1996), is now recognized as the inceptive clinical presentation of a disease that displays the characteristics of an inflammatory demyelinating disorder that has yet to fulfill the criteria necessary to diagnose MS (Miller et al., 2005a,b). CIS may be either active or inactive [as defined by the clinical assessment of relapse occurrence and/or magnetic resonance imaging (MRI) activity] (Lublin et Rabbit Polyclonal to EDG3 al., 2014) and typically involves the optic nerve, brainstem/cerebellum, spinal cord, or cerebral hemispheres Idasanutlin (RG7388) (Polman et al., 2011). If CIS is usually active and fulfills current MS diagnostic criteria, the syndrome transitions to relapsing-remitting (RR) MS (Polman et al., 2011). RR MS may also be active or inactive, and is characterized by discrete episodes of acute neurological deficits and/or worsening of a given neurological function (i.e. relapse), followed by a complete or partial recovery (i.e. remission) (Lublin and Reingold, 1996). RR MS is the most common phenotype of MS (accounting for ~85% of total cases), it displays a clear association with sex (female to male prevalence is usually between 2:1 and Idasanutlin (RG7388) 3:1), and develops in young adults between the ages of 20 and 30 years (Confavreux et al., 1980). Progressive MS includes secondary progressive (SP) and primary progressive (PP) MS, both of which can be either active or inactive (as per the above) and the disease course may develop with or without progression Idasanutlin (RG7388) (measured by clinical evaluation which is usually assessed at a minimum annually) (Lublin et al., 2014). Recent data estimate that within 5 and 15 years of an initial diagnosis of MS, 25 and 75% of patients respectively, will go on to develop SP MS (Scalfari et al., 2014). Thus the probability of disease progression increases in accordance with time after initial disease onset (Scalfari et al., 2014). Unfortunately, to date there are no clinical, imaging, immunological or pathological criteria that determine the conversion from RR MS to SP MS. PP MS is usually Idasanutlin (RG7388) characterized by the progressive accumulation of disability from the onset of the disease without identifiable acute relapses, affects ~15% of total MS patients, does not have a clear increase in female prevalence, and has a delayed onset as compared to RR MS (by ~10 years) (Ebers, 2004). The reasons underlying the prodigious variability of MS clinical presentation and concordant course of disease are still under investigation, but it has been hypothesized that the different clinical patterns of MS may represent different phases of the same pathologic process (Lucchinetti et al., 2000). As such, progressive forms of MS may emerge when compensatory mechanisms of repair fail to cope with the accumulation of the axonal and neuronal damage induced by the inflammatory reaction (Franklin, 2002). Therefore, the different processes that drive demyelination at the level of white matter (WM), as well as damage of the gray matter (GM), should be interpreted as major determinants of disease heterogeneity in MS patients (Lassmann.