this phenomenon was defined as a complete inaccessibility for the immune cells and immune mediators , mainly due to the impermeability of the blood - brain barrier ( bbb ) . in the light of relatively recently obtained results from multiple studies , brain now , it is considered that this term is mainly related to the specific bbb architecture , brain - resident cells immunoregulatory function , and their microenvironment , which results in restricted access of immune system elements to the central nervous system ( cns ) [ 2 , 3 ] . it has been proposed that specific morphological architecture of cns borders is crucial for maintaining its immune privilege . the bbb and the blood - cerebrospinal fluid barrier ( bcsfb ) , as an outer element of cns borders , may be breached by activated immune cells . after migration through the brain barriers , immune cells target the cerebrospinal fluid - drained leptomeningeal and perivascular spaces . the inner elements of the cns border are glia limitans , built of astrocytic foot processes and parenchymal basement membrane . within the csf - drained leptomeningeal and perivascular spaces , macrophages are present , which can act as antigen presenting cells ( apcs ) for the activated t cells . after recognizing specific antigens , t cells become reactivated and result in accumulation of additional immune cells . in this stage , the inner barrier may be disturbed , and immune cells and various mediators act inside the brain . thus , in physiological conditions , cns homeostasis is ensured by permission for immune cells migration through the bbb and bcsfb only to the csf space , where in the absence of antigens , they patrol cns barriers . other features related to brain immune privilege include absence of the lymphatic vessels in the parenchyma , which allow in other organs for draining antibodies and immune cells to peripheral lymph nodes , low expression of mhc class ii on cns resident cells , and deficiency of dendritic cells ( dcs ) in the parenchyma [ 810 ] . the immune privilege of the brain is also connected with specific cns - driven mechanisms regulating t cells functions within cns . brain resident cells , namely , neurons and glia , may actively regulate macrophage and lymphocyte responses [ 11 , 12 ] . it is important to notice that immune privilege is not applied for all brain regions . other regions of cns , the ventricles , meninges and subarachnoid spaces , demonstrate immune reactivity similar to that seen on the periphery . in pathological conditions , such immune privilege is disrupted leading to the development of inflammation and/or neurodegeneration , which are hallmarks of various cns diseases , for example , alzheimer 's disease , parkinson 's disease , and multiple sclerosis ( ms ) . multiple sclerosis is a chronic inflammatory , neurodegenerative disorder characterized by cns infiltration of autoreactive immune cells , demyelination , acute astrogliosis , and axonal loss . the aetiology of ms is still not known , but it is widely appreciated that the disease is a result of complex interplay between genetic and environmental factors [ 14 , 15 ] . progression of this disorder leads to many neurological dysfunctions , such as loss of vision , loss of sensation , and problems with walking . about 80% of ms patients develop relapsing - remitting form of disease , while 1015% presents primary progressive form . however , after about 10 years , roughly half of relapsing - remitting patients develop a secondary progressive stage of disease . the presence of various forms of disease and differential immunopathology points toward the important role of various subsets of t - helper cells and their relative proportion present at the site of inflammation . it was considered for a long period of time that t - helper type 1 ( th1 ) cells were the major effectors in ms pathophysiology . th1 cells are characterized by the expression of the transcription factor t - bet and the ifn- production . however , more recently , a new subset of t - helper cells have been identified , namely , th17 cells . this subpopulation is characterized by expression of the retinoic acid receptor - related orphan receptor alpha and gamma t ( ror- and ror-t ) and by the production of il-17 . it was reported that th17 cells better attach to brain endothelium than th1 cells , in part due to the presence of cd146 on their surface , and they are more effective in migration through the bbb , as they express high levels of ccr6 and cd6 . this cytokine is also a potent inducer of neutrophil infiltration to the site of inflammation . recruited neutrophils activate various enzymes such as matrix metalloproteinases ( mmps ) , proteases , and gelatinases participating in further bbb disruption [ 23 , 24 ] . studies conducted on experimental autoimmune encephalomyelitis ( eae ) , an animal model of ms , shows , however , that th17 cells are not sufficient for disease induction . these results suggest that th17 subset together with th1 cells is responsible for disease development . t - helper type 2 ( th2 ) cells  is also important for ms pathology , as it was reported that their response results in disease amelioration . regulatory t cells ( tregs ) also fulfilled protective function , which has been manifested in the control of autoimmune diseases and prevention of their progression . however , in multiple sclerosis , the function but not their frequency is impaired , leading to disease progression . cd8 + t cells are also implicated in ms pathology , as the clonal and oligoclonal expansion of myelin antigen - reactive cd8 + subset was observed within ms plaques . activated t cells express on their surface high levels of molecules , like very late antigen-4 ( vla-4 ) and leukocyte - function - associated antigen-1 ( lfa-1 ) , which has improved their adhesion to the brain endothelium and subsequent migration across bbb [ 2931 ] . after such migration t cells undergo antigen restimulation , resulting in their accumulation and proliferation . reactivated t cells release proinflammatory molecules , which cns resident cells , macrophages , and b cells [ 32 , 33 ] . b cells and plasma cells contribute to ms pathology , as they were detected in brain and csf of ms patients . what is more , antibodies directed against myelin antigens have been reported in the serum of ms patients [ 3436 ] . , they display a quiescent phenotype that is characterized by a cd45 phenotype and lowered expression of mhc class ii , b 7.2 , and cd40 . in stress condition they undergo morphological changes , develop phagocytic abilities , and upregulate mhc class ii , b7.2 , and cd40 expression becoming highly activated [ 3739 ] . microglia play important role in response to pathological stimuli affecting cns , as it was shown that the overproduction of their secreted factors , such as tnf- , contributed to the development and progression of ms . astrocytes react to pathogen / danger signals by cytoskeletal rearrangements associated with an increase in glial fibrillary acidic protein ( gfap ) and process extension , which are the hallmark of a reactive astrogliosis , process seen in ms patients [ 41 , 42 ] . they secrete interferons , thought to be crucial in the cns defense mechanism against diverse inflammatory factors . however , prolonged unopposed proinflammatory cytokine signaling could have harmful consequences leading to pathological inflammation and neurodegeneration . recruitment of myd88 to the toll - il-1 receptor ( tir ) domain of the il-1 receptor is essential in the cell signaling pathways underlying astrocyte - mediated inflammation and neurotoxicity [ 41 , 42 ] . however , in ms pathology , they are not the only class ii positive cells as the monocytes , dcs , microglia , and astrocytes could also act as an antigen presenting cells . members of the toll - like receptor ( tlr ) family are thought to be the primary evolutionarily conserved sensors of pathogen - associated molecular patterns . binding of the appropriate ligand to tlrs initiates molecular cascade leading to phagocytosis , production of a variety of cytokines , and subsequently regulation of inflammatory reaction and adaptive immune response . in neuroinflammation the increase in tlrs expression was observed in ms brain lesions , csf mononuclear cells , and also eae [ 47 , 48 ] . microrna ( mir ) is a relatively novel class of small noncoding rna , demonstrating regulatory function to mrna translation . mirs are approximately 22  nt long single - stranded molecules , encoded in intergenic regions , introns , exons , exon overlaps , or utr regions . they may be present as single genes , or they are arranged in clusters . mirs may be expressed as independent genes with their own transcriptional regulatory elements or from intronic sequences of protein - coding genes . the presence of mir clusters may be evidence of their structural or functional ( targeting mrnas of proteins involved in the same cellular pathway ) similarity between encoded mirs . most of micrornas are transcribed by the rna polymerase ii , whereas some of them are results of rna polymerase iii activity . they are usually transcribed as a primary transcript ( pri - mirna ) , which is usually several kilobases long , and contain stem - loop structures . pri - mirna is processed in the nucleus by the microprocessor complex composed of a processing enzyme drosha and rna binding protein , dgcr8/pasha . this enzymatic complex performs asymmetric cleavage which generate about 70  nt long pre - mirna containing a two nt 3 overhang , essential for nuclear export [ 56 , 57 ] . pre - mirna is transported to the cytoplasm by exportin 5 and ran gtpase for final processing by the rnase iii enzyme dicer , specialized to bind rna ends , especially with short 3 overhangs . dicer release an approximately 22  nt double - stranded mir with a 5 phosphate end . next , duplex rna is incorporated into a protein complex named rna - induced silencing complex ( risc ) , unwound by a helicase and separated to two ssrnas . the key protein players of risc are rna binding protein argonaute ( ago ) and its rna binding partner , trbp . the guide strand is thermodynamically favored for incorporation to the ago complex as it has a less stable 5 end than passenger strand , which mostly undergoes degradation . micrornas fine - tune the production of proteins within cells through repression or activation of mrna translation . they act through the interaction of their seed region mainly with the 3 untranslated region ( utr ) of the given mrna , as it was recently shown that they can interact also with 5 utr or protein coding region [ 61 , 62 ] . mature mir altered mrna expression by either inhibiting translation or signaling for mrna degradation , depending on the degree of sequence complementarity between seed region located on the 5 end of mir ( between 2 and 8  nt ) and binding site of mrna , although sequences outside the seed region are also important for recognizing targets and optimizing mrna regulation . the seed area may be supplemented by nucleotide 8 of mir , by adenine from nucleotide 1 of mir , or by both of them . the newly discovered microrna 's seed region comprises of nucleotides 3 to 8 [ 6466 ] . mirs are universal regulators of protein expression , as a single molecule can regulate translation of hundreds of targeted mrnas and single mrna 's 3 utr may have multiple binding sites for various micrornas . mirs may function in two ways to enhance their regulatory capacity , by targeting multiple binding sites present within 3 utr of mrna or by targeting multiple genes from the same cellular pathway . it is estimated that in mammals , mirs may regulate more than 60% of protein - coding genes . moreover , micrornas may function not only in cytoplasm , as they were also identified in the nucleus [ 68 , 69 ] , where they may act as an epigenetic regulators of gene expression . micrornas play crucial role in the regulation of diverse biological processes , like tissue development and homeostasis , cell proliferation and differentiation , apoptosis , and immune system function . they are crucial for system 's ability to coping with external and internal perturbations , as they regulate the mrna expression profile by reinforcing transcription , reducing defective and overabundant transcript copy number . altered biogenesis and/or function of mir is implicated in the various pathological processes such as autoimmunity , viral infections , neurodegeneration , and inflammation . dysregulated mirs contribute to the development of various diseases , for example , cancer , cardiovascular , or neurological diseases [ 71 , 74 , 75 ] . tlr ligands , antigens , or cytokines can alter mir expression level through specific transcription factors regulation [ 7678 ] . it was also reported that cytokines may lead to deregulation of dicer expression resulting in aberrant pre - microrna processing . there are various processes , except for the impact of inflammatory factors , contributing to such regulation such as mutations , epigenetic inactivation , or gene amplification . in the light of rapidly accumulating data from various studies , it has been concluded that mirnas are crucial regulators of immune cell development and function . diverse alterations in their biogenesis and regulatory role have been observed in inflammatory diseases such as rheumatoid arthritis , psoriasis , and multiple sclerosis . as multiple sclerosis is one of the most common neurological debilitating disease of as yet unknown etiology , we want to review in this section current knowledge regarding the role of these small noncoding rnas in the ms inflammation ( table 1 ) . multiple sclerosis is considered as a t - cell - mediated disorder , so it is not surprising that researchers attention is directed toward the role of mirs deregulation in t - cell maturation , activation , and function . expression of this mir has been linked to t cells activation following tcr stimulation [ 81 , 82 ] . mice deficient in this mir have demonstrated normal lymphocyte development , but altered th1/th2 ratio with presence of increased th2 polarization and elevated levels of th2 cytokine production [ 8385 ] . studies conducted by cox et al . on ms patients identified significant downregulation of hsa - mir-17 and hsa - mir-20a . using knock - in and knock - down approaches foxo1 , belonging to forkhead family transcription factors , is a suppressor of t - cell proliferation , activation , and differentiation . downregulation of foxo1 expression , in part by hsa - mir-182 - 5p , is crucial for the t - cell clonal expansion . it has been suggested that mir-146a expression may play a role in cell fate determination . studies conducted on mouse lymphocytes have shown that the level of mir-146a is increased in th1 cells and decreased in th2 cells , when compared to its expression in naive t cells . the polarization of th1 cells may be in part regulated also by mir-21 , as il-12p35 is one of its potential targets . il-12p35 is a subunit of il-12 , cytokine which controls th1 differentiation and ifn- secretion by the synergistic action with il-18 . du et al . indicated , in the studies conducted on ms chinese patients , that mir-326 is a regulator of th17 cells differentiation . it was shown that in vivo silencing of mir-326 caused reduced number of th17 subset and mild eae , whereas its overexpression resulted in elevated level of th17 cells and more severe eae . it was concluded that mir-326 acts on ets-1 , a negative regulator of th17 differentiation . reported significant upregulation of another mir , namely , mir-301a in t - helper cells in response to mog antigen . mir-301a regulates th17 differentiation through inhibition of pias3 , a negative regulator of the stat3 activation pathway . inhibition of mir-301a results also in decreased secretion of il-17 and downregulation of ror- and ror-t expression . o'connell et al . have revealed in ms animal model the positive role of mir-155 in autoimmunity as this mir drives th17 differentiation of t cells . as mentioned earlier however , it was reported that this microrna is also expressed due to cd8 + t cells activation , where it may function as a regulator of cd69 expression . micrornas play important roles in regulatory t cells ( tregs ) that are important protective cells preventing development and progression of autoimmune diseases . mir-155 was shown to regulate treg development , as mir-155-deficient mice have reduced numbers of tregs , whereas mir-146 and mir-17 - 92 cluster regulate treg function . mir-146a , when highly expressed in this t cell subset , selectively controls treg - mediated inhibition of ifn--dependent th1 response and inflammation by activating stat1 expression . it was also reported that in human tregs mir-21 functions as a positive indirect regulator of foxp3 expression , while mir-31 acts as its negative regulator . recently , it was shown that foxp3 represses mir-142 - 3p expression , leading to exacerbation in camp production and suppressor function of treg cells . development of bone marrow - derived b cells is partially regulated by mir-181a expression . during b - cell development from the pro - b to the pre - b - cell stage , the expression level of mir-181a decreases . mir-181a is also considered as a positive regulator of b cells differentiation , as its expression in hematopoietic stem and progenitor cells leads to an increase in fraction of b - lineage cells and decrease in t cells or myeloid cells . conditional deletion of dicer in mouse b cells also results in complete b cell development blockage . inhibition of mir-17 - 92 expression results in elevated levels of proapoptotic protein bim and inhibition of b cell development at the pro - b to pre - b stage . it was shown that its constitutive expression may lead to similar results as seen for dicer- and mir-17 - 92-deficient mouse . c - myb .   as observed for the first time in t cells , mir-155 is crucial also for b - cell functions . it has been reported that mir-155 is important in b - cell responses to thymus - dependent and- independent antigens . elevated expression of pu.1 , a target for mir-155 , leads to the reduced production of igg1 cells . this suggests that mir-155 regulation of pu.1 may be in part responsible for proper generation of immunoglobulin class - switched plasma cells . mir-155 also represses activation - induced cytidine deaminase , enzyme essential for immunoglobulin gene diversification [ 106 , 107 ] . moreover , mir-155-deficient b cells generated reduced extrafollicular and germinal center responses . recently , immunoglobulin class switch recombination was also connected with the function of mir-181b . it was reported that mir-223 negatively regulates both the proliferation and activation of neutrophils by targeting mef2c , a transcription factor promoting myeloid progenitor proliferation . moreover , neutrophils deficient in this mir are hypermature and hypersensitive to activating stimuli and that they display aberrant pattern of lineage - specific marker expression . however , there are contradictory results from different study indicating that mir-223 is a positive regulator of granulocytopoiesis . additionally , mir-223 modulates the nf-b pathway leading to alterations in immune inflammatory responses . it was reported that another mir , namely , mir-9 , is similarly upregulated in human peripheral monocytes and neutrophils . this upregulation is mediated by proinflammatory signals conveyed in a myd88- and nf-b - dependent manner . results obtained from numerous studies have shown that expression of toll - like receptors ( tlrs ) may be regulated by mir-146a . expression of mir-146a was significantly upregulated by tnf- and il-1 and blocked by its receptor antagonist . interestingly , mir-146a acts through suppression of proinflammatory proteins such as interleukin-1 receptor - associated kinase 1/2 ( irak1/2 ) and tnf receptor - associated factor ( traf ) as well as il-1 in a negative feedback loop . it may also directly interacts with complement factor h ( cfh ) , a repressor of the inflammatory reaction , leading to exacerbation of inflammation [ 114 , 115 ] . provided evidence that mir-124 has crucial role in maintaining quiescent phenotype of microglia in mouse eae  experimental model of ms . expression of mir-124 was significantly downregulated in activated microglia , resulting in subsequent upregulation of ccaat enhancer - binding proteins ( c / ebpalpha ) and pu.1 expression . expression of brain - specific mir-124 was observed only in microglia , suggesting that this small noncoding rna participates in the resting phenotype of these cells through the regulation of c / ebpalpha / pu.1 pathway . mir-155 decreases expression level of suppressor of cytokine signaling 1 ( socs-1 ) leading to elevated cytokine and no production . recently , studies conducted by iyer et al . reported regulatory role of mir-146a in astrocyte - mediated inflammatory response . in addition , it was reported that in multiple sclerosis lesions mir-155 is highly expressed in reactive astrocytes . by the application of mir-155 inhibitor oligonucleotide , tarassishin et al . that monocytopoiesis is partially controlled by three mirnas : mir-17 - 5p , mir-20a , and mir-106a . however , aml1 binds to and transcriptionally inhibits expression of those three mirs in a negative feedback loop . studies by junker et al . conducted in active ms lesions identified three upregulated mirnas : mir-155 , mir-326 , and mir-34a that target the same transcript the interaction of cd47 with signal regulatory protein- present on macrophages inhibits igg or complement - induced phagocytosis . downregulation of cd47 expression results in promotion of myelin phagocytosis by macrophages during ms course [ 123 , 124 ] . it was also reported that mir-155 knockdown results in increase in the proinflammatory cytokine il-1 expression . they were reported to play important role in myeloid - derived dc differentiation through regulation of jagged1 and wnt1 mrna translation . the induction of central tolerance is regulated during t - cell maturation to maintain proper immune system functioning . there is evidence for strong correlation between the sensitivity of the t cells to antigen and levels of mir-181a . a decrease in tcr sensitivity may result in self - tolerance breakdown and subsequent autoimmunity development . the high levels of mir-181a may contribute to the decreased activation threshold of autoreactive t cells , while inhibition of mir-181a expression in the immature t cells lowers their sensitivity . the function of mir-181a is mainly mediated by downregulation of several protein tyrosine phosphatases , such as shp-2 , dusp5 , and dusp6 . the process of immune cells recruitment into the brain parenchyma is also regulated by micrornas . it was revealed that mir-17 and mir-126 targeted icam1 and vcam1 mrna , respectively [ 130 , 131 ] . moreover , it was shown that mir-124 and -126 have regulated expression of ccl2 , a chemokine responsible for monocytes recruitment to brain parenchyma . hence , mirnas associated with inflammatory response may also act as a potential neuroprotectants [ 132 , 133 ] . inflammation is an extremely important and complex biological process of the immune system activated in response to harmful stimuli such as diverse pathogens or cell damage . its main physiological function is manifested in removal of pathogens and damaged cells or healing process . however , in some circumstances , inflammatory response may be unleashed from the biological control leading to tissue damage . dysregulated inflammatory reaction can result in development of autoimmune disorders such as rheumatoid arthritis , psoriasis , or multiple sclerosis [ 135 , 136 ] . multiple sclerosis is a multifactorial neurological disease characterized by the presence of inflammatory brain infiltrates and subsequent neurodegeneration . it is stated that ms develops in genetic susceptibility individuals , which are exposed for action of various predisposing environmental factors . although multiple sclerosis has been studied for many years , exact factors underlying its pathogenesis remain still unknown . it has been recently shown that less than 2% of human genome undergoes translation into proteins . however , more than half of the human genome is transcribed , suggesting that most of the transcripts account for noncoding rnas ( ncrnas ) . it has now become obvious that such rna molecules are not the  junk sequences  as it was thought before . noncoding rnas may be divided into two groups : long and short ncrnas . within each of these groups these small rnas are crucial posttranscriptional regulators altering diverse cellular processes . it was reported that they are important fine - tuners of immune responses . both the induction and repression of mirna expression mediated by various inflammatory stimuli may lead to alteration in immune cells differentiation and function , thus leading to the development of neuroinflammatory , autoimmune diseases ( table 1 ) . recently , researchers attention is pointed toward the function of ncrnas as an another level of genetic regulation , which may contribute to ms pathogenesis . as it was shown in multiple studies , micrornas play diverse roles in immune system , indicating that interplay between mirs and their targets is rather complex and multifactorial . what further complicates the issue , mirs are not functioning only inside particular cell types but also they act as a signal - carrying paracrine elements contributing to cell - cell communication [ 138 , 139 ] . further studies should be conducted to reveal the role of micrornas and other ncrnas as they compose complex and crucial regulatory machinery , being also potential and promising targets for novel therapies .
micrornas are relatively recently discovered class of small noncoding rnas , which function as important regulators of gene expression . 
 they fine - tune protein expression either by translational inhibition or mrna degradation . 
 micrornas act as regulators of diverse cellular processes , such as cell differentiation , proliferation , and apoptosis . 
 their defective biogenesis or function has been identified in various pathological conditions , like inflammation , neurodegeneration , or autoimmunity . 
 multiple sclerosis is one of the predominated debilitating neurological diseases affecting mainly young adults . 
 it is a multifactorial disorder of as yet unknown aetiology . as far 
 , it is suggested that interplay between genetic and environmental factors is responsible for ms pathogenesis . 
 the role of micrornas in this pathology is now extensively studied . here 
 , we want to review the current knowledge of micrornas role in multiple sclerosis .