multiple sclerosis ( ms ) is a chronic inflammatory disease of the central nervous system , which leads to the development of focal inflammatory lesions with secondary axonal damage . this concept has recently been challenged by several observations , suggesting that in ms neurodegeneration may occur independently of inflammation . more radical view suggests that the primary process in ms is neurodegeneration augmented by a secondary inflammatory reaction . are there any arguments for this concept ? in contrast to white matter lesions , very little inflammation is seen in cortical ms plaques ( lassmann 2010 ) . however , it is also evident that cortical demyelination occurs in association with profound meningeal inflammation ( kutzeinigg et al . soluble inflammatory factors from these cells can diffuse into the cortical tissue and destroy myelin . another presented argument for the independence of neurodegeneration from inflammation is that treatments targeting inflammation are only effective in relapsing type of the disease , being largely ineffective in progressive forms of ms . inflammation in multiple sclerosis appears as a crucial multi - step process beginning with peripheral immune reactions creating autoreactive t cells , transmigration of immune cells through blood brain barrier , followed by demyelination , degeneration and axonal damage in the white and gray matter . the exact factors that initiate inflammation in ms are unknown , but it is generally accepted that environmental factors play an important role in genetically susceptible individuals triggering t cell mediated response against cns . myelin - specific activated autoreactive t cells are found in the peripheral blood of ms patients . molecular mimicry mechanism in which t cells generated against non self , viral or microbial epitopes , cross react with self myelin epitopes of the similar sequence has been postulated as a potential autoimmune mechanism ( comabella and khoury 2012 ) . there are several genes that confer susceptibility to ms . among the most important are genes of the major histocompatibility complex like hladrb1 * 1501 allele , hla dqa1 * 0102 allele or hla dqb1 * 0602 allele , responsible for about 50  % genetic risk for ms . it has also been found that hla drb1 1501 allele is linked to disease severity . other genes , which have been identified code for receptors of interleukin 2 and interleukin 7 . the leukocyte trafficking to the brain of ms patients is a complex process ( rubenko - moll et al . it is initiated by tethering and rolling of the leukocytes on endothelial surfaces , mediated by endothelial selectins which interact with glycosylated ligands on the leukocytes . a significant increase in soluble forms of selectins has been found in the sera of patients with relapsing  remitting ms and correlated with disease activity ( losy 1999 ; kuenz et al . 2005 ) . the rolling leukocytes interact with chemokines , which are immobilized on endothelium , and bind to their receptors on leukocytes . the chemokine receptors activation results in g - protein signal and the activation of leukocyte integrins changing their state from low to high affinity / avidity . the activated integrins interact with their endothelial counter - receptors of the immunoglobulin superfamily . among the most important are : the 2 integrin leukocyte function associated antigen ( lfa-1 ) binding to icam-1 and the 41 integrin very late antigen-4 ( vla-4 ) binding to vcam-1 . increased soluble icam-1 levels have been found in the csf and sera of ms patients and correlated with disease activity ( hartung et al . elevated concentrations of svcam-1 in the csf and sera have also been found in ms patients ( droogan and mcmillan 1996 ) . the correlation between svcam-1 and gadolinium enhancement in mri has been shown ( hartung et al . 1995 ) . another important adhesion molecule is the platelet endothelial cell adhesion molecule-1 ( pecam-1 ) ( woodfin et al . pecam-1 binds to itself and also to leukocyte v3 integrin , an adhesion molecule found on endothelial cells and nk cells . the process of migration through intercellular junctions of vascular endothelial cells is mediated by homophilic adhesive interactions that take place between leukocyte and endothelial cell junctional pecam-1 molecules . increased levels of specam-1 have been detected in serum and csf of patients with active , gadolinium enhancing ms lesions on mri ( losy et al . following leukocyte arrest , in the locomotion phase of the process the leukocytes travel across endothelial surfaces in search of interendothelial junctions . after protrusion , transmigration occurs in response to the abluminal chemokines according to the chemotactic gradient . entry into the brain parenchyma needs a transversing of the glia limitans and its associated basement membrane which requires the action of matrix matalloproteases . the association between specific mmp serum levels , clinical and mri activity has been observed in ms patients ( helgeland and gilhus 2012 ) . chemokines stimulate integrin activation , mediate leukocyte locomotion on endothelial cells and participate in transendothelial migration according to chemoattractant gradients . the cxcr3 receptor is expressed on the majority of t cells in the csf of patients with ms . cxcl9 and cxcl10 , cxcr3 receptor ligands were elevated in the csf of patients with ms during relapse . both chemokines have been found to be elevated in the csf of patients with ms and demyelinating lesions ( krumbholtz et al . it has been shown that these cells correlate with disease activity in ms patients ( infante - duarte et al . inflammatory pathogenic t cells , which enter the cns initiate a complex immunological cascade consisting of epitope spreading , which triggers new attacks and activation of the innate immune system consisting of microglia , dendritic cells , astrocytes and b cells which leads to chronic cns inflammation ( weiner 2009 ) . infiltrating cells secrete proinflammatory cytokines like ifn- , tnf- , il-2 . another important cytokine playing a significant role in ms is il-18 , stimulating the release of ifn- ( losy and niezgoda 2001 ) . proinflammatory cytokines stimulate the release of chemokines , expression of adhesion molecules and can be factors damaging both myelin sheath and axons . the regulatory t cells ( cd4 + cd25 + treg ) are a small subset of cd4 + t cells . defects in functional suppression by these cells in ms patients has been described ( viglietta et al . it has been shown that il 23 produced by macrophages and dendritic cells is important for the expansion of th17 cells ( korn et al . th 17 cells in the csf of ms patients are significantly increased during exacerbations in comparison with remission periods ( brucklacher - waldert et al . cd8 + cells are also involved in inflammatory reaction and correlate better with axon destruction in demyelinating lesions than cd4 + cells ( bitsch et al . cd8 + cells can directly damage axons or this damage can follow the destruction of the myelin sheath and oligodendrocytes ( melzer et al . 2009).these cells may transect neuritis in an mhc class i / peptide - restricted fashion . the mechanism of axonal damage is multifactorial and includes also action of proteases and free radicals released during cns inflammation as well as lack of neurotrophic factors provided to axons ( comabella and khoury 2012 ) . b cells stimulated by il-4 , il-6 and il-10 are involved in the production of antibodies which can participate in demyelination in the form of immune complexes which activate complement or participate in antibody dependent cell cytotoxicity . b cells have also the capacity to function as antigen presenting cells and contribute to t cell activation ( barun and bar - or 2012 ) . neuroinflammation is not only present in relapsing  remitting multiple sclerosis but also in the secondary and primary progressive forms of the disease . t and b cell infiltrates correlate well with the activity of demyelinating lesions , while plasma cells seem to be most pronounced in patients with secondary and primary progressive ms . a highly significant association between inflammation consisting of t cells , b cells , plasma cells and macrophages and axonal injury exists in ms patients including progressive forms of the disease alone ( frischer et al . natalizumab which is a monoclonal antibody against vla-4 integrin , interfering with the process of leukocytes adhesion to endothelium , reduces significantly the relapse rate , the risk of disability progression and mri activity ( polman et al . alemtuzumab causing prolonged depletion of peripheral blood lymphocytes shows better results in comparison with ifn- 1a in the reduction of the relapse rate and the risk for sustained disability . rituximab a chimeric antibody against cd20 on b cells has shown a reduction in mri activity and a reduction of the relapse rate ( hauser et al . 2009 ) . another monoclonal antibody , daclizumab , directed against the  subunit ( cd25 ) of il-2 receptor it can also cause an expansion of the subset of nk cells , cd56 bright cells , which lyse autologous t cells . added to treatment with interferon  1a reduced significantly the mri activity of ms patients ( wynn et al . several oral new dugs have also anti - inflammatory properties and affect clinical and mri activity in ms patients . fingolimod , sphingosine-1-phosphate receptor modulator reversibly sequesters lymphocytes mainly in the lymph nodes , reducing their recirculation to the cns and abrogating the neuroinflammatory process ( kappos et al . it has been also shown to suppress the generation of th17 cells in vitro ( liao et al . triflunomide blocks lymphocyte t and b proliferation by inhibiting dehydroorotate dehydrogenase ( dhodh ) , a key enzyme needed for pyrimidine synthesis ( o  connor et al . dimethyl fumarate ( bg-12 ) induces a shift from th1 ( proinflammatory ) to th2 ( anti - inflammatory ) cytokine response . it decreases also the expression of icam-1 and vcam-1 ( de - hyung lee et al . it is now established that anti - inflammatory and immunomodulatory treatment is beneficial in the early relapsing stage of ms , but these treatments are ineffective in secondary progressive and particularly in primary progressive ms . in such a situation current immunomodulatory , immunosuppressive or anti - inflammatory treatments might not reach this inflammatory process in concentrations which are sufficient to exert a beneficial effect . neurodegeneration caused by inflammation in earlier stages of the disease is dominant in later stages of ms and requires neuroprotective and neuroregeneration treatment strategies .
multiple sclerosis ( ms ) is characterized by multiple areas of inflammation , demyelination and neurodegeneration . 
 multiple molecular and cellular components mediate neuroinflammation in ms . 
 they involve : adhesion molecules , chemokines , cytokines , matalloproteases and the following cells : cd4 + t cells , cd8 + t cells , b cells , microglia and macrophages . infiltrating th1 
 cd4 + t cells secrete proinflammatory cytokines . 
 they stimulate the release of chemokines , expression of adhesion molecules and can be factors that cause damage to the myelin sheath and axons . 
 chemokines stimulate integrin activation , mediate leukocyte locomotion on endothelial cells and participate in transendothelial migration . 
 cd8 + cells can directly damage axons . 
 b cells are involved in the production of antibodies which can participate in demyelination . 
 b cells can also function as antigen presenting cells and contribute to t cell activation . 
 neuroinflammation is not only present in relapsing  remitting ms , but also in the secondary and primary progressive forms of the disease . 
 the association between inflammation consisting of t cells , b cells , plasma cells and macrophages and axonal injury exists in ms patients including the progressive forms of the disease . 
 the above association does not exclude the possibility that neurodegeneration can exist independently from inflammation . 
 very little inflammation is seen in cortical ms plaques . 
 anti - inflammatory therapies with different mode of action change the course of ms . 
 anti - inflammatory and immunomodulatory treatments are beneficial in the early relapsing stage of ms , but these treatments are ineffective in secondary progressive and primary progressive ms . in the stage of progressive 
 ms , inflammation becomes trapped behind a closed or repaired blood  brain barrier . 
 in such a situation current immunomodulatory , immunosuppressive or anti - inflammatory treatments might not reach this inflammatory process to exert a beneficial effect .