Multiple Sclerosis (MS) represents a chronic inflammatory autoimmune condition like other autoimmune ones such as rheumatoid arthritis (RA), Psoariasis, Endometriosis, etc. MS results in continuous depletion of axonal myelin in various regions of the central nervous System (CNS) & influences the occurrence of a variety of clinical symptoms like muscle spasms, optic neuritis as well as paralysis. Over a decade advances made in research conducted in animal models of MS to get better insight of pathophysiology of MS disease corroborated that MS is an autoimmune inflammatory disorder secondary to recruitment of self-reactive lymphocytes, basically CD4+T cells in the CNS. Actually high concentrations of T helper cells (Th) cell subsets as well as associated cytokines as well as chemokines have been observed in the CNS lesions as well as cerebrospinal; fluid (CSF) of MS patients ,along with breakdown of blood brain barrier (BBB), as well as consequent activation of resident astrocytes as well as microglia and ultimately neuroinflammation. Thus we decided to do a systematic review utilizing the Pubmed Engine, Google Scholar Web of Science utilizing the MeSH terms like Th cell kinds like Th1; Th 17; Th22; Th9 and others from 1980 till date on 31st July 2020. We found over 25,000 articles out of which we selected 154 articles for this review to study the influence of the variety of Th like cells involved in the aetiopathogenesis. No meta-analysis was conducted. Till date various kinds of Th cells have been discovered and named as per the liberated lineage defining cytokines. Significantly Th 1, Th17, Th22, Th9 as well as Th1 like Th17 have been correlated with MS. Thus we have detailed the crosstalk of various Th cell subpopulations as well as their lineage defining cytokines in manipulating the inflammatory responses in MS along with how the innovative drugs that have received FDA approval interact which target T lymphocytes for the therapy of the disease.

Multiple Sclerosis (MS) represents a chronic inflammatory autoimmune condition of the central nervous System (CNS) that influences roughly 2-3 million people worldwide which gets initiated by both environmental as well as genetic factors [1]. Roughly 15-30% of cases with MS present with relapse-remitting (RR) clinical course, that has the properties of acute episodes of neurological abnormalities like optic neuritis, sensory alterations or motor dysfunction, that is mostly followed by times of remission or recovery [2,3]. Following different time courses, roughly 50% of RRMS patients propagate to a chronic secondary progressive (SP) clinical stage, having the properties of gradually declining condition. In approximately 15% of patients, MS is propagating right from its initiation, known as primary progressive (PP) MS, a clinical course that has the properties of a slow and continuous deterioration in the neurological function’s [4]. Basic etiopathological typical property is the breaking of the blood brain barrier (BBB), loss of oligodendrocytes, demyelination, and astrocytes gliosis along with axonal degeneration [5]. Inflammation exists in all stages, with key role of pro inflammatory cytokines as well as chemokines in the etiopathology of MS by compromise of blood brain barrier (BBB), immune cell recruitition via the periphery as well as activation of resident microglia. Microglial activation is believed to be one of the initial processes in the formation of MS lesions. Activated Microglial, actually is believed to add to the disease propagation by liberating inflammatory cytokines as well as chemokines along with reactive oxygen species (ROS) as well as glutamate [6]. MS getting converted from RR to the progressive phase has also been associated with continued chronic Inflammation in the CNS. Furthermore both SPMS as well as PPMS patients present with generalized Inflammation in the total brain that is associated with cortical demyelination as well as diffuse damage of the white matter [7]. Despite every cell kind of the innate as well as adaptive immune system might bring about the inflammatory response among the CNS, an essential aid is through the autoreactive CD4⁺T cells. Autoreactive T cells most probably activated in the peripheral lymph node migrate into the CNS [8], where they get reactivated as well as liberate cytokines as well as chemokines which manipulate the inflammatory lesions that are classical of MS [9]. Like, the robust genetic risk factor for MS is the human leukocyte antigen(HLA)-DRB^*15:01, a major histocompatibility complex (MHC)class II allele that is implicated in the presentation of self-peptides to CD4⁺T cells [10]. This review has the objective of giving a detailed part of various CD4⁺T helper cells (Th) cell subsets in the etiopathophysiology of MS along with present treatment methods which target T cell-mediated responses. The part of regulatory T (Treg) cells in repressing the function of autoreactive Th cell in MS is further detailed.

Subsets of Th cell

CD4⁺T cells represent the central controllers of the adaptive immune response that works opposite to a lot of microbes utilizing the aiding B lymphocytes to generate antibodies (Ab) by liberating particular cytokines which offer efficacious protection from pathogens. Separate Th cell Subsets, generating 1 or greater lineage defining cytokines as well as expressing master transcription factors as well as homing receptors, differentiate from naive CD4⁺T cells after provocation by a particular class of pathogenic microorganisms along with to the cytokines surroundings. Naive CD4⁺T cells get activated inside the peripheral Lymph Nodes through mature dendritic cells (DC’s) which present pathogen derived peptides correlated with MHC as well as costimulatory molecules facilitate T cells proliferation along with forming polarising cytokines that then stimulate T cells differentiation into separate Th cell Subsets, like Th 1, Th2, Th17, Th22 as well as Th9 [11]. Additionally to this protective aspect from pathogens, Separate Th cell Subsets display a key part in the pathogenesis as described.

Th 1 cells

Th 1 Cells got isolated in the late 80’s [12]. Being a subset of CD4⁺T cells which bring about effective adaptive immune response from intracellular pathogens by liberating Interferon (IFN) which activates macrophages for killing intracellular microbes along with facilitating the generation of opsonising Ab [11]. Th 1 can get isolated through surface expression of the CXC chemokine Receptor Type 3(CXCR3) as well as interleukin (IL)-12 Receptor (IL-12 R) chains , in addition to the intracytoplasmic expression of the master transcription factor T-bet [13]. IL)-12 as well as IFN work together for the induction of the expression of T-bet, hence escalating the Th 1 polarization [14]. Earlier studies conducted in an experimental autoimmune encephalomyelitis (EAE) aimal model of MS showed a key part of Th 1 Cells in the pathogenesis of MS. Actually IFN librerating Th 1 Cells were identified as the most common Th 1 Cells subset in the central nervous system (CNS) as well as EAE animals [15]. Plenty of IFN was identified in the CNS lesions of EAE [16] along with the active lesions of MS patients [17], as well as the adoptive transfer of Th 1 Cells was enough to generate EAE in the mice receiving it [18], These results along with initial observations that delivery of IFN to MS patients augmented the disease [19], that is further corroborated by the significant part of IL-12/ IFN axis as well as Th 1 Cells in both EAE as well as MS pathogenesis. Despite the neuropathological part of infiltrated Th 1 Cells into the CNS is not known properly, there are different proofs pointing that microglia is the main cell target of Th 1 Cells. Microglia represent the resident macrophages of CNS, based on the type of external stimuli , might differentiate into inflammatory M1 like or anti- inflammatory M2 like phenotype [20]. Th 1 Cells generate various effector molecules which activate resident microglia along with initiating their differentiation into the inflammatory as well as neurotoxic M1 like phenotype [21]. Further Th 1 Cells promote the upregulation of class II MHC as well as costimulatory molecules present on microglia, hence facilitating the reactivation of the infiltrated Th Cells along with their differentiation further [22]. Nevertheless , more research regarding mice deficient in IL-12p35 subunits [23] or IL-12R2 chain [24] or IFN [25] were prone to EAE in addition to the results demonstrating that delivery of IL-12 at the time of initial phases, the disease repressed EAE in an IFN dependent way [23], reduced the significance of this concept that Th 1 Cells were the major pathogenic Cells subset in EAE as well as MS. Ultimately the invention that IL-23 shares the p40 subunits with IL-12 [26] as well as IL-23R comprises or IL-12R1 chain [27], explained these conflicting results as well as explained the part of IL-23 in facilitating EAE by initiating as well as stimulating the expansion of Th 17 Cells, that is a subset of Th Cells that generates IL-17 [28,29].

Th 17 cells

Th 17 Cells got isolated by 2005 [28], being a significant subset of CD4⁺T cells which bring about effective immune response against extracellular bacteria as well as fungi [30]. Th 17 Cells might be isolated depending on the particular surface markers like CD161. The chemokine receptor CCR6 as well as CCR4, thecytokine receptors IL-23R as well as IL-1R [31], the intracytoplamic expression of retinoic acid as well as receptor-associated orphan nuclear receptor (ROR  ) as well as the generation of particular cytokines like IL-17A-, IL-21 as well as IL-22 [32]. Especially IL-17A as well as IL-17F work on various cell kinds, like macrophages, epithetlial as well as endothelial cells by stimulating the expression of inflammatory cytokines as well as chemokines as well as facilitating the recruitment of neutrophils in inflammatory zones [33]. IL-21 gives a positive feedback loop for good expansion of the Th 17 Cells subsets [34], while IL-22 works on epithelial cells facilitating the generation of anti-microbial peptides along with mucus [35]. Besides these roles of facilitating the host defense against pathogens, tissue damage might also result ending in chronic inflammatory diseases [36]. Noticeably Th 17 Cells are implicated in the pathogenesis of various autoimmune diseases that includes MS [37], where they have a key part in disrupting the blood brain barrier (BBB) [38] Along with targeting resident astrocytes as well as microglia within the CNS & hence facilitate their activation as well as neuroinflammation in EAE [21,39,40] (Figure 1). Especially Th 17 Cells are markedly efficacious in controlling astrocytes instead of microglia. Astrocytes represent resident CNS cells having particular anatomical positions along with morphological as well as functional properties. Their location is at the border between the BBB as well as neurons and control the motion of molecules as well as cells among circulation as well as CNS. Furthermore by generating neutrotrophic factors (NF’s) they also control neurogenesis along with tissue repair. Secondary to CNS damage, astrocytes go through significant morphological as well as functional alterations, a process known a astrogliosis [41]. Astrocytes express a functional IL-17 receptor A which is upregulated more in EAE [42]. IL-17 is known to upregulate the generation of inflammatory cytokines as well as chemokines [43] along with IL-17 signaling once dysfunctional in astrocytes abrogates EAE [44]. Th 17 Cells along with aid of Th 1 have been demonstrated to control the function of astrocytes via stimulating the downregulation of NF’s as well as the upregulation of inflammatory cytokines as well as chemokines [39,45]. Other posited pathological function of Th 17 as well as IL-17 is the inhibition of maturation along with survival of oligodendrocytes (OL’s) [46], besides their apoptosis [47]. OL’s represent myelinating giant cells of the CNS at the time of formation and right through adulthood. In case of MS constant demyelination as well as neurodegeneration get correlated with impairment as well as apoptosis of OL’s resulting from direct cytotoxicity from Antigen specific T cells along with autoantibodies along with T cells modulated pro inflammatory cytokines which activate resident microglia [48]. In the last decade, various studies conducted in EAE mice [9,28,49], in addition to the immunological examination of MS cases proved a key part of Th 17 Cells in the etiopathogenesis of MS [29,50]. High amounts of IL-17 generating CD4⁺T cells have been observed in the peripheral blood or CSF of RRMS patients at the time of relapses [50] as well as in MS patients having active disease [51]. Further the preferential expansion of Th 17 Cells has been associated with the total amount of active plaques on magnetic resonance imaging (MRI) [52], along with disease propagation [53]. IL-17A, together with IL-6, has further been illustrated to facilitate the breakdown of BBB in RRMS patients [54], by changing the expression of adhesion molecules on endothelial cells [55] as well as promoting the depolymerisation of the actin cytoskeleton near tight junctions [56]. Like human Th 17 Cells display an enhanced migratory ability in RRMS patients with greater disease severity as well as inflammatory lesions [57]. Various transcription factors, of which most dependable ROR [58] as well as STAT3 [59], along with cytokines like IL-6, transforming growth factor beta (TGF-), interleukin 21(IL-21), IL-1- as well as IL-23 have been detailed to facilitate IL-17 expression as well as Th 17 Cells differentiation in both human as well as mouse [60,61]. In case of mouse system, the differentiation of Th 17 Cells is facilitated by TGF-, along with IL-6, IL-21, IL-1- [62]. In the human system, certain GRPS pointed that IL-1- as well as IL-23 can provide for TGF- functions by stimulating human Th cell differentiation [63,64]. Rest of researchers saw a key role of TGF- along with IL-6, IL-21, IL-1-, IL-23 for stimulating the expression of ROR as well as Th 17 Cells differentiation [65]. In human but not in mouse [66], CD28, a significant costimulatory molecule expressed on T cells [67], as well as implicated in the control of both tolerance as well as autoimmunity [68], has further been implicated to stimulate CD4⁺T cells to generate inflammatory cytokines as well as chemokines associated with Th 17 Cells phenotype [69] as well as to escalate the inflammatory response in MS by reprogramming T cells metabolism as well as promoting the expression of Th 17 Cells-related cytokines [70]. Th 17 Cells show tremendous plasticity along with utilize various functional profiles, based on the inflammatory or anti inflammatory surroundings [71]. Th 17 Cells have the ability to differentiate into markedly pathogenic Th 1 like Th 17 as well as Treg Cells, and actually have certain similar features, like the expression of CD49b as well as the transcription factor aryl hydrocarbon receptor (AhR) possibly in view of a shared TGF-need for their differentiation [72]. Regarding this Gigliani et al. demonstrated in mice that at the time of resolution of inflammation, Th 17 Cells go through a reprogramming of transcription, resulting in their differentiation into T reg Cells in TGF- presence that is AhR dependent [73]. Recently Capone et al. encountered the great plasticity of Th 17 Cells in cases of MS, who demonstrated that human Th 17 Cells polarized from the naive CD4⁺T cells along with from peripheral blood Th 17 Cells of RRMS patients upregulated the expression of IL-1R as well as generated greater amounts of IL-21, IL-2 as well as tumor nacrosis factor (TNF)- hence resulting in acquiring a greater pathogenic profile [74]. Constantly escalated expression of IFN as well as CXCR3 along with decreased expression of anti-inflammatory IL-10 was observed in Th 17 Cells from clinically active MS patients [75]. Th 17 Cells further generate GM-CSF, that is another cytokine which has been pointed to have a key part in the pathogenicity of Th 17 Cells in EAE models [37]. Further the percentage of IL-17 as well as granulocyte-macrophages colony stimulating factor (GM-CSF) cogenerating cells were enriched with the cerebro spinal fluid (CSF) of RRMS [76] and they escalated at the time of relapse [77]. Th 17 Cells have been implicated to generate IL-22 [24], a cytokine which enhances pro inflammatory innate defense modes in epithelial cells [78], which along with other cytokines having the Th 17 signature have been implicated in various inflammatory as well as autoimmune diseases [79].

Th 1 like Th 17 cells

A novel Th 1 l subset known as Th 1 like Th 17 cells which generate both IFN as well as IL-17 have been isolated in both human as well as mice recently [80]. They express IL-23 as well as coexpress CXCR3 as well as T-bet along with CCR6 as well as ROR, generate lesser quantities of IL-17 A as compared to classical Th 17 cells but greater amount of IFN [32], The origin of Th 1 like Th 17 cells is not fully clear but various studies corroborate the belief that these cells originate from Th 17 cells in IL-12. TNF- as well as /or IL-1 presence [81,82]. In mice the greater pathogenicity of Th 1 like Th 17 cells as compared to Th 17 cells correlated with the generation of various inflammatory cytokines as well as chemokines like GM-CSF, IL-22, CC chemokine Ligand 4(CCL4), and CCXCR3 [83]. These results got corroborated in human system by the evaluation of the transcriptional profile of peripheral blood Th 17 cells as well as Th 1 like Th 17 cells in MS [75]. These data got further extended utilizing data from single cell transcriptome evaluation conducted in experimental autoimmune wncephalitis (EAE), by demonstrating that the differentiation of Th 17 cells in the CNS from precursors in the Lymph Nodes was determined by four particular genes, Gpr65. Toso, Plzp, as well as Cd51 that were also implicated in disease proneness [84]. This Th 1 like Th 17 cells participating in neuroinflammation has been examined in studies in both EAE as well as MS patients [85]. Like Th 1 like Th 17 cells had the capacity to cross the BBB as well as collect in the CNS of acute EAE as well as were observed in brain tissues from MS patients [86], as well as upregulated in RRMS patients during relapse [87]. Myelin-particular Th 1 like Th 17 cells escalated in both peripheral blood CSF of patients with MS [88], as well as Th17.1 cells, a Th 1 like Th 17 subpopulation expressing raised amounts of IF, GM-CSF, very late antigen 4(VLA4), as well as low amounts of IL-17, have been correlated with the disease activity in case of RRMS patients [89]. The neuropathic actions of Th 1 like Th 17 cells within CNS are still getting studied but have a chance to overlap with those observed in Th 1 as well as Th 17 cells (Figure 1).

Th22 Cells

IL-22 is generated by Th 17 cells as well as by a unique CD4⁺T cells subset , that got discovered in 2000[90] known as Th22 [91]. Other cellular resources for IL22 are natural killer (NK) cells [92]. ILC3subset of innate lymphoid cells as well as as well as to a lesser degree, other leukocytes that are macrophages [93]. IL-22 represents being a, member of the IL-10 family with its main actions being exerted on non haemopoietic cells like epithelial cells. IL-22, actually stimulates the regeneration as well as proliferation of epithelial cells as well as facilitates the generation of antimicrobial peptides needed for epithelial barrier functions as well as protection against extra cellular (EC) pathogens [94]. Despite the part of IL-22 in MS has not been fully investigated, proof that is coming out points to the involvement of IL-22 in MS immunopathogenesis. Earlier studies by Kabir et al., observed the upregulation of IL-22R in the brains of MS patients as well as the part of IL-22 in synergism with IL-17A in disruption of the integrity of BBB tight junctions by decreasing the expression of occludin in epithelial cells [94,95]. Data that has been more recent, demonstrated greater amounts of IL-22 in serum of relapsing MS as compared to healthy donors [77,20-22], as well as a decrease of IL-22 was seen during the recovery phase of acute EAE [96]. The number of IL-22 generating cells also escalated in both peripheral blood [97] as well as CSF [76] of RRMS patients that were resistant to IFN therapy [97]. In view of great amounts expression of CCR6, that is needed for the movement into the CNS, myelin particular IL-22 generating cells can act synergistically with Th 17 cells, and hence result in breaking of the BBB as well as start the autoimmune response against constituents of the CNS myelin [54]. Like myelin particular IL-17 as well as IL-22 generating CD4⁺T cells resistant to corticoids has been correlated with active brain lesions in the MS patients, especially in the plaques and mainly in the astrocytes [95], that might enhance the permeability of the BBB by liberating matrix metallo proteinases (MMPs) [41]. Significantly recent studies point a part of IL-22 as well as IL-22 generating cells in controlling the survival as well as action of both OLs as well as astrocytes in MS [95,98] (Figure 1). Lastly, the isolation of single nucleotide polymorphism (SNP) of IL-22 binding protein (IL-22BP, also known as IL-2RA), an antagonist of IL-22, as MS risk gene [99], agrees with the part of IL-22 generating cells in the immunopathogenesis of MS.

Figure 1: Courtesy ref no 40-Pathogenic T helper (Th) cell subsets in multiple sclerosis (MS). Self-reactive Th1, Th22 cell, and Th1-like Th17 subsets activated in peripheral lymph nodes cross the blood–brain barrier (BBB) and migrate into the central nervous system (CNS). In the CNS, T cells are reactivated and, by producing their lineage-defining cytokines, regulate the functions of CNS-resident cells (microglia, astrocytes, oligodendrocytes) by enhancing inflammatory cytokine production, antigen-presenting cell (APC) functions, and apoptosis, thus contributing to axonal damage and demyelination.

Th9 cells

In the last 10yrs a separate subset of effector CD4⁺T cells subset, having the properties of generating IL-9 got identified. Despite initial correlation of IL-9 in the start with a Th-2 response, studies done more recently gave a newer definition to the IL-9 generating CD4⁺T cells as Th 9 cells [100]. In MS the part of Th 9 Cells have mainly been evaluated in a mouse model of EAE. The initial study contrasted the encephalitogenic activity of myelin oligodendrocyte glycoprotein (MOG)-particular Th 9, Th 17, as well as Th 1 cells in an EAE model of adoptive transfer. It was shown that Th 9 cells receiving mice had lesser infiltrates of lymphocytes in the meninges as compared to EAE formed by Th 1 as well as Th 17 cells, hence pointing that the mode of EAE induced via Th 9 cells was separate from the mode of Th 1 as well as Th 17 cells [101]. More studies conducted in knockout mice showed contradictory outcomes. Actually mice where IL-9R was absent displayed a course of greater severity, pointing to a controlling part of the cytokine in regulating pathogenic modes of immune responses [102]. Constantly, in EAE, IL-9 was documented to be an anti-inflammatory cytokine generated by non-pathogenic Th 17 cells in conjunction to IL-10 [103]. Conversely, rest of groups observed that IL-9 neutralization as well as IL-9R deficiency ameliorared EAE [104]. Ruocco et al. evaluated the action of IL-9 in MS by associating the amounts of IL-9 in the cerebrospinal fluid (CSF) of 107 RRMS patients on diagnosis along with at the time of course of disease. Intriguingly they observed that IL-9 amounts in the CSF of RRMS patients inversely associated with indices of inflammatory activity, neurodegeneration, as well as propagation of MS –correlated disability [105]. An earlier study in MS patients demonstrated that IL-9 amounts were less at the time of clinical relapses as well as escalated after prednisonole therapy , hence pointing the existence of Th-9 cells in the CSF of MS patients, in which IL-9 could have a protective part in MS disease by decreasing the amounts of IL-17 generated by Th 17 cells [106] as well as the expression of the mitochondrial apoptotic pro-apoptotic factor Bax [107], hence escalating neuronal survival in organotypic human brain slice cultures [108]. In view of the contradictory outcomes documented on the aid of Th-9 cells as well as IL-9 in either MS or EAE, more studies are needed for clarification of the part of Th-9 cells in MS pathogenesis.

Treg cells

The formation of autoimmunity gets finely controlled by particular subsets of Tcells which manipulate immune responses by checking pathogenic Th-cells under regulation. Initially isolated in 1995 by Sagakuchi et al, Treg Cells were a subset of CD4⁺CD25⁺T cell subset having the capacity of repressing effector inflammatory Tcells as well as sustain self-tolerance [109]. In the past two decades, work has been done regarding further characterizing Treg Cells in relation to autoimmune diseases with a minimum of 2 major subsets of CD4⁺ Treg Cells have been isolated –natural n Treg Cells which form in the thymus after the recalling of self-antigens as well as express the transcription factor forkhead box P3(Fox P3) [110] as well as inducible iTreg cells, which get produced from the naive CD4⁺ T Cells under particular situations of antigen stimulation as well as in the existence of specific cytokine milieu. iTreg cells is made up of various subsets that are Fox P3Treg cells, type1 regulatory (Tr1) Tcells generating large amounts of IL-10 as well as Th3 generating TGF [111]. In humans, circulating iTreg further show large amounts of phenotypic heterogeneity strictly associated with their differentiation status as well as immunosuppressive functions [112]. Changes in both amount as well as repressive functions of separate Treg subsets have been documented in MS, particularly in RRMS patients [113], as well as exert disease actions on Treg cells [112].

T cell targeting treatment

The role of autoreactive inflammatory Tcell subsets in the MS pathogenesis gets corroborated by knowing that maximum of the approved disease-manipulating treatments target T cells. Glatiramate acetate (GA), a mixture of synthetic polypeptides, having only 4 amino acids’s glutamate, lysine, alanine, as well as tyrosine got approval through FDA for therapy of RRMS in 1996. Despite the mode of action of GA are not clear, various studies point to a key part of GA on various antigen presenting cells (APC), by facilitating the differentiation of microglia, IFN-, an antiviral cytokine, having immunosuppressive as well as antiproliferative actions , has been the 1^st line drug approved via FDA for the therapy of RRMS in 1993. The maximum significant action of IFN- on Tcells are the inhibition of Tcell activation as well as liberation of cytokines [114], the shift of Th cells from an inflammatory Th1 to an anti-inflammatory Th2 cell phenotype, the decrease of both Th 17 as well as IL-17 amounts , as well as an escalation of suppressive Treg [115]. A massive reduction of IL-22 in the serum of RRMS patients following 6 as well as 12 mths of therapy with IFN-, has also been recently documented as well as corroborated the reduction of MS severity [116]. macrophages as well as dendritic cells (DCs) into the suppressive M2 phenotype generating anti- inflammatory cytokines like TGF- as well as IL-10 [117]. The outcomes of these actions on T cells involve the shift of reactive T cells from Th1 to Th2 [118] as well as the enhancement of Treg [119], which repress the action of all autoreactive inflammatory Th cell subsets. Regarding this Spadaro etal., showed that in GA-responder of RRMS patients, anti- inflammatory Treg cells remain for greater than 10yrs following GA therapy [120]. Akin to IFN-, GA is not efficacious in decreasing the disability of propagating MS [121], however, due to its long term effectiveness as well as safety it is the commonest 1^st line therapy registered all over the world for RRMS [122]. Dimethyl fumarate (DMF), a fumaric acid ester having anti- inflammatory action got approval for therapy of RRMS patients in 2013 [123]. It causes both direct as well as indirect actions on Tcells [124]. DMD decreases the generation of inflammatory cytokines like IL-1  tumor nacrosis factor (TNF) as well as IL-6 in microglia [125], as well as inhibits inflammatory cytokines generation in human peripheral blood mononuclear cells (PBMC) [126], possibly by influencing the activation of nuclear factor (NF)-B family of transcription factors [127]. Besides a total decrease in peripheral T cell numbers seen in RRMS patients given therapy with DMF [128], marked alterations in circulating Th cell subsets were further seen [129], with a special decrease of memory CD4⁺ T Cells [128], DMF therapy further stimulates a shift of the balance various Th cell subsets, with a decrease of IFN- generating Th1 as well as IL-17 generating Th-17 cells as well as an escalation of IL-4 generating Th2 cells [130]. Lastly an ideal response to DMF therapy also correlated with an enhancement of Treg cells in the peripheral blood of RRMS patients [129,131]. Fingolimod, that is a 1^st oral treatment molecule that got approval for RRMS [132,133], works as an antagonist of sphingosine-1-phosphate receptor(SIPR), which is necessary for the exit of T lymphocytes from Lymph Nodes [134]. Via binding of SIPR as well as stimulating its internalization, Fingolimod modulates the naive as well as effector memory T lymphocytes are set apart from the lymphoid organs [135]. A detailed evaluation of effectiveness of Fingolimod on various T cell subsets in RRMS patients who received therapy with Fingolimod showed a selective decrease in the frequency of both IFN- as well as IL-17 generating cells [136]. Dominuguez-Villar et al, demonstrated that Fingolimod therapy robustly decreased central memory Th1, Th17, as well as Th 1 like Th 17 cells while effector memory Th1, as well as Th 1 like Th 17 cells subsets were not that much influenced. The evaluation of Fingolimod actions on T cells at the time of 12 mths of also experienced a manipulation of phenotype of Th 17 cells as well as Treg cells. Effector Th Cells displayed a reduction of the exhaustion markers like programmed death1 (PD1) as well as Tcell immunoglobin as well as mucin domain containing 3(TIMS) [137]. Further, the repressive functions of Treg in Fingolimod therapy receiving RRMS patients were further upregulated, hence pointing to another part of Fingolimod in restoring peripheral tolerance, apart from the retention of T lymphocytes in Lymph Nodes [137,138]. Natalizumab is a disease manipulating drug which influences the movement of T cells was approved in 2004. It represents a monoclonal Ab (mAb) which targets VLA4 expressed by activa.ted T as well as B lymphocytes [115] as well as inhibits VLA4 interaction with the vascular cellular adhesion molecule1(VCAM1) expressed on endothelial cells [139], hence blocking T cells penetration of the BBB [91-94], especially the Th 1 like Th 17.1 subset [89]. Inspite of the effectiveness of both Fingolimod as well as Natalizumab in peripheral setting apart of inflammatory T cells as well as avoiding their migration across BBB, respectively, aberrant inflammatory actions as well as recurrence along with clinical relapses have been seen following cessation of Fingolimod [140], as well as Natalizumab therapy in case of MS patients [141]. Furthermore continued therapy with Natalizumab been correlated with the reactivation of latent John Cunningham virus, hence facilitating propagating multifocal leukoencephalopathy [142]. Two humanized mAb targeting T cells for RRMS got approved by food and drug administration (FDA) as well as EMA. Alemtuzumab, got approval in 2013, which targets CD52 which is expressed at great amounts on B as well as T cells [143], hence resulting in depletion of both CD4⁺ T Cells as well as CD8⁺Tcells by Ab dependent (ADCC) as well as complement dependent cytotoxicity(CDC). Daclizumab that got approval in 2016, represent a mAb that targets CD25, the high affinity subunit of IL-2 receptor (IL-2R), that gets expressed on activated T Cells as well as Treg [144]. In comparison to Alemtuzumab, Daclizumab does not bring about T cells by ADCC or CDC however, by neutralizing IL2 binding to CD25, as well as the high affinity IL-2R, like NK cells as well as resting T cells [145]. In view of high risk of serious as well as potentially fatal immune responses like encephalitis as well as meningomyelitis, in May 2018, the marketing authority of Daclizumab was stopped by EMA [146]. In November 2019 EMA further recommended a restrictive utilization of Alemtuzumab (lemtrada) for RRMS patients with markedly active disease inspite of therapy with one of the disease manipulating therapy [147]. Intriguingly, Gingele et al. ocumented recently that ocrelizumab, a humanized mAb targeting CD20, that got approval in 2017 for relapsing MS as well as PPMS as well as believed to particularly targeting B [148], was further efficacious in removing a markedly activated CD20⁺Tcell subset generating inflammatory cytokines [149]. As CD20⁺ inflammatory Tcells are located in the peripheral blood as well as brain of MS patients [149] their removal might explain the effectiveness of ocrelizumab therapy. Besides the approved T cells targeting therapies, various therapeutic methods with the objective of inhibition of autoreactive inflammatory Tcells are getting evaluated currently in various clinical trials of MS [150]. Of the lot, maximum effectiveness offered by mAb targeting Th17-associated cytokines, especially IL-17A that are undergoing trials for MS. Especially, Sekukinumab, a totally humanized anti IL-17A mAb with the objective of repressing pathogenic Th17, as well as Th 1 like Th 17 cell subset, got approval in 2005 as 1stline treatment for psoariasis [151]. The significant decrease (67%) of new magnetic resonance imaging(MRI) lesions seen in 73 treatment naive RRMS patients foll 24 wks of therapy with Sekukinumab [152] resulted in a placebo controlled randomized phase II clinical trial(NCT01874340). Nevertheles, this trial was ended by the sponsor on the basis of formation of another anti IL-17A mAb, Ixekizumab, having better action act Sekukinumab for psoariasis [153] as well as better potential for therapy of MS. Clinical trials are still ongoing. Besides that trials are on regarding utilization of adipose derived stem cells in refractory MS (reviewed by us) [154]. The diagnosis of multiple sclerosis in children, like in adults, needs proof of dissemination of inflammatory activity in > than one region in the CNS (dissemination in space) and recurrent disease over time (dissemination in time). The identification of myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) and aquaporin-A antibodies (AQP4-Ab), and the consequent discovery of their pathogenic mechanisms, have led to a shift in the classification of relapsing demyelinating syndromes. This is reflec ted in the 2017 revised criteria for the diagnosis of multiple sclerosis, which emphasizes the exclusion of multiple sclerosis mimics and aims to enable earlier diagnosis and thus treatment initiation. The long-term efficacy of individual therapies initiated in children with multiple sclerosis is hard to evaluate, owing to the small numbers of patients who have the disease, the relatively high number of patients who switch therapy, and the need for long follow-up studies. Nevertheless, an improvement in prognosis with a globally reduced annual relapse rate in children with multiple sclerosis is now observed compared with the pretreatment era, indicating a possible long-term effect of therapies. Given the higher relapse rate in children compared with adults, and the impact MS has on cognition in the developing brain, there is a query whether rapid enhancement or potent agents should be used in children, while the short- and long-term safety profiles of these drugs are being established. With the results of the first randomized controlled trial (RCT) of fingolimod versus interferon-1a in paediatric MS published in 2018 and several clinical trials underway, there is hope for further progress in the field of paediatric multiple sclerosis. Thus early and precise diagnosis of MS is crucial. The discovery of antibody-mediated demyelination has changed the diagnosis and management of relapsing demyelination syndromes. Traditional escalation therapy is being challenged by induction therapy [155].

Over the past 2 decades our insight on the immunopathogenetic modes in MS has robustly escalated, hence observing a basic part of encephalotigenic Th cells, especially Th 1 like Th 17, Th 17, Th 22, as well as GMCSF generating CD4⁺ T Cells, in starting as well as continuation of the inflammatory responses as well as the subsequent neurodegeneration in MS. Hence, most of the treatment protocols that have received approval aim to ameliorate the inflammatory T helper cells as well as emerging T cell-based therapies having greater selectivity are the currently ongoing Clinical trials for MS. The differences in adult and paediatric MS has been touched along with slow escalation of drugs with provisional damage to growing brain and subsequent influence in cognition.

1. Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, et al. Diagnosis of multiple sclerosis: 2017 versions of McDonald criteria. Lancet Neurol. 2018; 17: 162-173.
2. Brownlee WJ, Hanly TA, Fazekas F, Miller DH. Diagnosis of multiple sclerosis: Progresses and challenges. Lancet. 2017; 389: 1336-346.
3. Lorscheider J, Buzzard K, Jokubaitis V, Spelman T, Havrdova E, Horakova D, et al. Defining secondary progressive multiple sclerosis. Brain. 2016; 139: 2395-2405.
4. Lassmann H, Van Horssen J, Mahad D. Progressive Multiple Sclerosis: Pathology and pathogenesis. Nat Rev Neurol. 2012; 8: 647-656.
5. Baecher-Allan C, Kaskow BJ, Weiner HL. Multiple Sclerosis: Mechanisms and immunotherapy. Neuron. 2018; 97: 747-768.
6. Thompson AJ, Baranzini SE, Guerts J, Hemmer B, Ciccarelli O. Multiple Sclerosis. Lancet. 2018; 391: 1622-1636.
7. Frischer JM, Bramow S, Dal-BiancoA, Lucchinetti CF, Rauschka H, Schmidbauer M, et al. The relation between inflammation and neurodifferentiation in multiple sclerosis brains. Brain. 2009; 132: 1175-1189.
8. Zhang J, Markovic-Plese S, Lacet B, Raus J, Weiner HL, Hafler DA. Increased frequency of interleukin 2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid in patients with Multiple Sclerosis. J Exp Med. 1994; 179: 973-984.
9. Batoulis H, Addicks K, Kuerten S. Emerging concepts in autoimmune encephalomyelitis beyond the CD4/TH1 paradigm. Ann Anat. 2010; 192: 179-193.
10. Sawcer S, Hellenthal G, Pirinen M, Spencer CC, Patsopoulos NA, Moutsianas L, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011; 476: 214-219.
11. Sallusto F. Heterogeneity of human CD4⁺T cells against microbes. Annu Rev Immunol. 2016; 34: 317-334.
12. Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989; 7: 145-173.
13. Annunziato F, Cosmi L, Liotta F, Maggi E, Romagnani S. Human T helper type 1 dichotomy: origin, phenotype and biological activities. Immunology. 2014; 144: 343-351.
14. Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell. 2000; 100: 655-669.
15. Voskuhl RR, Martin R, Bergman C, Dalal M, Ruddle NH, Mcfarland HF. T helper 1 (Th1) functional phenotype of human myelin basic protein-specific T lymphocytes. Autoimmunity. 1993; 15: 137-143.
16. Merrill JE, Kono DH, Clayton J, Ando DG, Hinton DR, Hofman FM. Inflammatory leukocytes and cytokines in the peptide-induced disease of experimental allergic encephalomyelitis in SJL and B10. PL mice. Proc Natl Acad Sci USA. 1992; 89: 574-578.
17. Lock C, Hermans G, Pedotti R, Brendolan A, Schadt E, Garren H, Langer-Gould A, et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med. 2002; 8: 500-508.
18. Segal BM, Shevach EM. IL-12 unmasks latent autoimmune disease in resistant mice. J Exp Med. 1996; 184: 771-75.
19. Panitch H, Haley A, Hirsch R, Johnson K. Exacerbations of multiple sclerosis in patients treated with gamma interferon. The Lancet. 1987; 1: 893-895.
20. Aguzzi A, Barres BA, Bennett ML. Microglia: scapegoat, saboteur, or something else. Science. 2013; 339: 156-161.
21. Murphy ÁC, Lalor SJ, Lynch MA, Mills KH. Infiltration of Th1 and Th17 cells and activation of microglia in the CNS during the course of experimental autoimmune encephalomyelitis. Brain Behav Immu. 2010; 24: 641-651.
22. Prajeeth CK, Löhr K, Floess S, Zimmermann J, Ulrich R, Gudi V, et al. Effector molecules released by Th1 but not Th17 cells drive an M1 response in microglia. Brain Behav Immun. 2014; 37: 248-259.
23. Gran B, Chu N, Zhang GX, Yu S, Li Y, Chen XH, et al. Early administration of IL-12 suppresses EAE through induction of interferon-. J Neuroimmunol. 2004; 156: 123-131.
24. Zhang GX, Gran B, Yu S, Li J, Siglienti I, Chen X, et al. Induction of experimental autoimmune encephalomyelitis in IL-12 receptor-2-deficient mice: IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the central nervous system. J Immunol. 2003; 170: 2153-2160.
25. Ferber IA, Brocke S, Taylor-Edwards C, Ridgway W, Dinisco C, Steinman L, et al. Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J Immunol. 1996; 156: 5-7.
26. Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000; 13: 715-725.
27. Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J, et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12R1 and a novel cytokine receptor subunit, IL-23R. J Immunol 2002; 168: 5699-5708.
28. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005; 201: 233-240.
29. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2006; 6: 1123-1132.
30. Stockinger B, Veldhoen M. Differentiation and function of Th17 T cells. Curr Opin Immunol. 2007; 19: 281-286.
31. Annunziato F, Cosmi L, Liotta F, Maggi E, Romagnani S. Defining the human T helper 17 cell phenotype. Trends Immunol. 2012; 33: 505-512.
32. Kolls JK, Lindén A. Interleukin-17 family members and inflammation. Immunity. 2004; 21: 467-476.
33. Pelletier M, Maggi L, Micheletti A, Lazzeri E, Tamassia N, Costantini C, et al. Evidence for a cross-talk between human neutrophils and Th17 cells. Blood. 2010; 115: 335-343.
34. Nurieva R, Yang XO, Martinez G, Zhang Y, Panopoulos AD, Ma L, et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature. 2007; 448: 480-483.
35. Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, Collins M, et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med. 2006; 203: 2271-279.
36. Stadhouders R, Lubberts E, Hendriks RW. A cellular and molecular view of T helper 17 cell plasticity in autoimmunity. J Autoimmun. 2018; 87: 1-15.
37. Volpe E, Battistini L, Borsellino G. Advances in T helper 17 cell biology: pathogenic role and potential therapy in multiple sclerosis. Mediators Inflamm. 2015; 2015: 475158.
38. Tahmasebinia F, Pourgholaminejad A. The role of Th17 cells in auto-inflammatory neurological disorders. Prog Neuropsychopharmacol Biol Psychaitry. 2017; 14: 2014.
39. Prajeeth CK, Kronisch J, Khorooshi R, Knier B, Toft-Hansen H, Gudi V, et al. Effectors of Th1 and Th17 cells act on astrocytes and augment their neuroinflammatory properties. J Neuroinflammation. 2017; 14: 204.
40. Kunkl M, Frascolla S, Amormino C, Volpe E, Tuosto L. T Helper Cells: The modulators of inflammation in multiple sclerosis. Cells. 2020; 9: 482.  
41. Brambilla R. The contribution of astrocytes to the neuroinflammatory response in multiple sclerosis and experimental autoimmune encephalomyelitis. Acta Neuropathol. 2019.
42. Sarma JD, Ciric B, Marek R, Sadhukhan S, Caruso ML, Shafagh J, et al. Functional interleukin-17 receptor A is expressed in central nervous system glia and upregulated in experimental autoimmune encephalomyelitis. Acta Neuropathol. 2019.
43. Elain G, Jeanneau R, Rutkowska A, Mir AK, Dev KK. The selective anti-IL-17 monoclonal antibody sekukinumab (AIN457) attenuates IL-17-A induced levels of IL-6 in human astrocytes. Glia. 2014; 62: 725-735.
44. Kang Z, Altuntas CZ, Gulen MF, Liu C, Giltiay N, Qin H, et al. Astrocyte-restricted ablation of interleukin-17-induced Act1-mediated signaling ameliorates autoimmune encephalomyelitis. Immunity. 2010; 32: 414-425.
45. Prajeeth CK, Dittrich-Breiholz O, Talbot SR, Robert PA, Huehn J, Stangel M. IFN- Producing Th1 Cells induce different transcriptional profiles in microglia and astrocytes. Front Cell Neurosci. 2018; 12: 352.
46. Kang Z, Wang C, Zepp J, Wu L, Sun K, Zhao J, et al. Act1 mediates IL-17–induced EAE pathogenesis selectively in NG2+ glial cells. Nat Neurosci. 2013; 16: 1401-408.
47. Paintlia MK, Paintlia AS, Singh AK, Singh I. Synergistic activity of interleukin-17 and tumor necrosis factor-enhances oxidative stress-mediated oligodendrocyte apoptosis. J Neurochem. 2011; 116: 508-521.
48. Dulamea AO. Role of oligodendrocyte dysfunction in demyelination, remyelination and neurodegeneration in multiple sclerosis. Adv Exp Med Biol. 2017; 958: 91-127.
49. Stromnes IM, Cerretti LM, Liggitt D, Harris RA, Goverman JM. Differential regulation of central nervous system autoimmunity by TH 1 and TH 17 cells. Nat Med. 2008; 14: 337-342.
50. Brucklacher-Waldert V, Stuerner K, Kolster M, Wolthausen J, Tolosa E. Phenotypical and functional characterization of T helper 17 cells in multiple sclerosis. Brain. 2009; 132: 3329-3341.
51. Tzartos JS, Friese MA, Craner MJ, Palace J, Newcombe J, Esiri MM, et al. Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol. 2008; 172: 146-155.
52. Hedegaard CJ, Krakauer M, Bendtzen K, Lund H, Sellebjerg F, Nielsen CH. T helper cell type 1 (Th1), Th2 and Th17 responses to myelin basic protein and disease activity in multiple sclerosis. Immunology. 2008; 125: 161-169.
53. Arellano G, Acuña E, Reyes LI, Ottum PA, De Sarno P, Villarroel L, et al. Th1 and Th17 cells and associated cytokines discriminate among clinically isolated syndrome and multiple sclerosis phenotypes. Front Immunol. 2017; 8: 753.
54. Kebir H, Kreymborg K, Ifergan I, Dodelet-Devillers A, Cayrol R, Bernard M, et al. Human TH 17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med. 2007; 13: 1173-1175.
55. Setiadi AF, Abbas AR, Jeet S, Wong K, Bischof A, Peng I, et al. IL-17A is associated with the breakdown of the blood-brain barrier in relapsing-remitting multiple sclerosis. J Neuroimmunol. 2019; 332: 147-154.
56. Rahman MT, Ghosh C, Hossain M, Linfield D, Rezaee F, Janigro D, Marchi N, et al. IFN- IL-17A, or zonulin rapidly increase the permeability of the blood-brain and small intestinal epithelial barriers: Relevance for neuro-inflammatory diseases. Biochem Biophys Res Commun. 2018; 507: 274-279.
57. Colamatteo A, Maggioli E, Loiola RA, Sheikh MH, Calì G, Bruzzese D, et al. Reduced annexin A1 expression associates with disease severity and inflammation in multiple sclerosis patients. J Immunol. 2019; 203: 1753-1765.
58. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, et al. The orphan nuclear receptor RORt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006; 126: 1121-1133.
59. Whitley SK, Balasubramani A, Zindl C, Sen R, Shibata Y, Crawford GE, et al. IL-1R signalling promotes STAT3 and NF- B factor recruitment to distal cis-regulatory elements that regulate IL-17A/F transcription. J Biol Chem. 2018; 293: 15790-15800.
60. Hirahara K, Ghoreschi K, Laurence A, Yang XP, Kanno Y, O’Shea JJ, et al. Signal transduction pathways and regulation in Th17 cell differentiation. Cytokine Growth Factor Rev. 2010; 21: 425-434.
61. Annuziato F, Cosmi L, Liotta F, Maggi F, Romagnani S. Human Th17 cells: are they different from murine Th17 cells. Eur J Immunol. 2009; 39: 637-640.
62. Yang XO, Pappu BP, Nurieva R, Akimzzhanova A, Kang HS, Chung Y, et al. T helper lineage differentiation is programmed by orphan nuclear receptor ROR alpha and ROR gamma. Immunity. 2008; 28: 29-39.
63. Basu R, Whitley SK, Bhaumik S, Zindl CL, Schoeb TR, Benveniste EN, et al. IL-1 signaling modulates activation of STAT transcription factors to antagonize retinoic acid signaling and control the TH 17 cell–iT reg cell balance. Nat Immunol. 2015; 16: 286-295.
64. Mailer RK, Joly AL, Liu S, Elias S, Tegner J, Andersson J. IL-1 promotes Th17 differentiation by inducing alternative splicing of FOXP3. Sci Rep. 2015; 5: 14674.
65. Yang L, Anderson DE, Baecher-Allan C, Hastings WD, Bettelli E, Oukka M, et al. IL-21 and TGF- are required for differentiation of human TH 17 cells. Nature. 2008; 454: 350-352.
66. Porciello N, Grazioli P, Campese AF, Kunkl M, Caristi S, Mastrogiovanni M, et al. A non-conserved amino acid variant regulates differential signalling between human and mouse CD28. Nat Commun. 2018; 9: 1080.
67. Porciello N, Tuosto L. CD28 costimulatory signals in T lymphocyte activation: emerging functions beyond a qualitative and quantitative support to TCR signalling. Cytokine Growth Factor Rev. 2016; 28: 11-19.
68. Porciello N, Kunkl M, Tuosto L. CD28 between tolerance and autoimmunity: the side effects of animal models. F1000Research. 2018; 7.
69. Kunkl M, Porciello N, Mastrogiovanni M, Capuano C, Lucantoni F, Moretti C, et al. isa-2011B, a Phosphatidylinositol 4-Phosphate 5-Kinase  inhibitor, impairs cD28-Dependent costimulatory and Pro-inflammatory signals in human T lymphocytes. Front Immunol. 2017; 8: 5-12.
70. Kunkl M, Sambucci M, Ruggieri S, Amormino C, Tortorella C, Gasperini C, et al. CD28 autonomous signaling up-regulates c-myc expression and promotes glycolysis enabling inflammatory T cell responses in multiple sclerosis. Cells. 2019; 8: 575.
71. Cosmi L, Santarlasci V, Maggi F, Liotta F, Annuziato F. Th17 plasticity: Pathophysiology and treatment of chronic inflammatory disorders. Curr Opin Pharmacol. 2014; 17: 12-16.
72. Gagliani N, Magnani CF, Huber S, Gianolini ME, Pala M, Licona-Lemon P, et al. Coexpression of CD49b and LAG-3 identifies Human and mouse T regulatory type 1 cells. Nat Med. 2013; 19: 739-746.
73. Gagliani N, Vesely MC, Iseppon A, Brockmann L, Xu H, Palm NW, et al. T H 17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature. 2015; 523: 221-225.
74. Capone A, Bianco M, Ruocco G, De Bardi M, Battistini L, Ruggieri S, et al. Distinct expression of inflammatory features in T helper 17 cells from multiple sclerosis patients. Cells. 2019; 8: 533.
75. Hu D, Notarbartolo S, Croonenborghs T, Patel B, Cialic R, Yang TH, et al. Transcriptional signature of human pro-inflammatory TH 17 cells identifies reduced IL10 gene expression in multiple sclerosis. Nat Commun. 2017; 8: 1600.
76. Ghezzi L, Cantoni C, Cignarella F, Bollman B, Cross AH, Salter A, et al. T cells producing GM-CSF and IL-13 are enriched in the cerebro spinal fluid of relapsing MS patients. Mult Scler. 2019; 1: 1352458519852092.
77. Muls N, Nasr Z, Dang HA, Sindic C, Van Pesch V. IL-22, GM-CSF and IL-17 in peripheral CD4+ T cell subpopulations during multiple sclerosis relapses and remission. Impact of corticosteroid therapy. PloS one. 2017; 12: e017373780.
78. Trifari S, Spits H. IL-22, producing CD24⁺T cells: middlemen between the immune system and its environment. Eur J Immunol. 2010; 40: 2369-2237.
79. Shabgah AG, Navashenaq JG, Shabgah OG, Mohammadi H, Sahebkar A. Interleukin-22 in human inflammatory diseases and viral infections. Autoimmun Rev. 2017; 16: 1209-1218.
80. Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, Lanzavecchia A, et al. Surface phenotype and antigenic specificity of human interleukin 17–producing T helper memory cells. Nat Immunol. 2007; 8: 639-646.
81. Duhen T, Campbell DJ. IL-1 promotes the differentiation of polyfunctional human CCR6+ CXCR3+ Th1/17 cells that are specific for pathogenic and commensal microbes. J Immunol. 2014; 193: 120-129.
82. Maggi L, Cimaz R, Capone M, Santarlasci V, Querci V, Simonini G, et al. Brief Report: Etanercept Inhibits the Tumor Necrosis Factor –Driven Shift of Th17 Lymphocytes Toward a Nonclassic Th1 Phenotype in Juvenile Idiopathic Arthritis. Arthritis Rheumatol. 2014; 66: 1372-377.
83. Lee Y, Awasthi A, Yosef N, Quintana FJ, Xiao S, Peters A, et al. Induction and molecular signature of pathogenic TH 17 cells. Nat Immunol. 2012; 13: 991-999.
84. Gaublomme JT, Yosef N, Lee Y, Gertner RS, Yang LV, Wu C, et al. Single-cell genomics unveils critical regulators of Th17 cell pathogenicity. Cell. 2015; 163: 1400-1412.
85. Becher B, Segal M. Th17 cytokines in autoimmune inflammation. Curr Opin Immunol. 2011; 23: 707-712.
86. Kebir H, Ifergan I, Alvarez JI, Bernard M, Poirier J, Arbour N, et al. Preferential recruitment of interferon-–expressing TH17 cells in multiple sclerosis. Ann Neurol. 2009; 66: 390-402.
87. Edwards LJ, Robins RA, Constantinescu CS. Th17/Th1 phenotype in demyelinating disease. Cytokine. 2010; 50: 19-23.
88. Cao Y, Goods BA, Raddassi K, Nepom GT, Kwok WW, Love JC, Hafler DA. Functional inflammatory profiles distinguish myelin-reactive T cells from patients with multiple sclerosis. Sci Transl Med. 2015; 7: 287ra274.
89. Van Langelaar J, van der Vuurst de Vries RM, Janssen M, Wierenga-Wolf AF, Spilt IM, Siepman TA, et al. T helper 17.1 cells associate with multiple sclerosis disease activity: perspectives for early intervention. Brain; 2018; 141: 1334-1349.
90. Dumoutier L, Van Roost E, Ameye G, Michaux L, Renauld JC. IL-TIF/IL-22: genomic organization and mapping of the human and mouse genes. Genes Immun. 2000; 1: 488-494.
91. Duhen T, Geiger R, Jarrossay D, Lanzavecchia A, Sallusto F. Production of Interleukin-22 but not Interleukin-17 by a subset of human skin-homing memory T cells. Nat Immunol. 2009; 10: 857-863.
92. Witte E, Witte K, Warszaska K, Sabat R, Wolk K. Interleukin-22: A cytokine produced by T,NK and NKT cell subsets ,with importance in the innate immune defense and tissue production. Cytokine Growth Factor Rev. 2010; 21: 365-379.
93. Dudakov JA, Hanash AM, van den Brink MR. Interleukin-22: immunobiology and pathology. Annu Rev Immunol. 2015; 33: 747-785.
94. Schreiber F, Arasteh JM, Lawley TD. Pathogen resistance mediated by IL-22 signaling at the epithelial–microbiota interface. J Mol Biol. 2015; 427: 3676-3682.
95. Perriard G, Mathias A, Enz L, Canales M, Schluep M, Gentner M, et al. Interleukin-22 is increased in multiple sclerosis patients and targets astrocytes. J Neuroinflammation. 2015; 12: 119.
96. Almoda B, Costa M, Montoya M, Gonzelez B, Catellano B. Increase in Th17 and Treg lymphocytes and decrease in IL-22 corelate with the recovery phase of acute EAE in rat. PLoS One. 2011; 6: e27473.
97. Rolla S, Bardina V, De Mercanti S, Quaglino P, De Palma R, Gned D, et al. Th22 cells are expanded in multiple sclerosis and are resistant to IFN-. J Leukocyt Biol. 2014; 96: 1155-1164.
98. Zhen J, Yuan J, FuY, Zhu R, Wang M, Chang H, et al. IL-22 promotes fas expression expression in oligodendrogliocytes and inhibits FOXP3 expression in Tcells by activating the NF-kappa B pathway in Multiple Sclerosis. Mol Immunol. 2017; 82: 84-93.
99. Laaksonen H, Guerreiro-Cacais AO, Adzemovic MZ, Parsa R, Zeitelhofer M, Jagodic M, et al. The Multiple Sclerosis risk gene IL22 RA2 contributes to a more severe murine autoimmune neuroinflammation. Genes Immun. 2014; 15: 457-465.
100. Dardalhon V, Awasthi A, Kwon H, Galtileos G, Gao W, Sobel RA, et al. IL-4 inhibits TGF –beta induced FOXP3 +Tcells ,and together with TGF-beta generate IL-9+IL10+ FOXP3(-)effector Tcells. Nat Immunol. 2008; 9: 1347-1355.
101. Jager A, Dardolhon V, Sobel RA, Bettwlli E, Kuchroo VK. Th1, Th17, and Th9 effector cells induce Experimental autoimmune encephalomyelitis with different pathological phenotypes. J Immunol. 2009; 183: 7169-7177.
102. Elyaman W, Bradshaw EM, Uyttenhove C, Dardolhon V, Awasthi A, Imitolla J, et al. IL-9 induces differentiation of Th17, cells and enhance s function of FOXP3 + natural regulatory Tcells. Proc Natl Acad Sci USA. 2009; 106: 12885-12890.
103. Ghoreschi K, Laurence A, YangXP, Tato CM, McGeachy MJ, Konkel JE, et al. Generation of pathogenic T(h)17 cells in the absence of TGF-beta signalling. Nature. 2010; 467: 967-971.
104. Li H, Nourbaksksh B, Ciric B, Zhang GX, Rostami A. Neutralization of IL9 ameliorates experimental autoimmune encephalomyelitis by decreasing the effector Tcell population. J Immunol. 2010; 185: 4095-4100.
105. Ruocco G, Rossi S, Motta C, Macchiaro G, Barberi F, DeBardi M, et al. T helper 9cells induced by plasmacytoid dendritic cells regulate Interleukin-17 in Multiple Sclerosis. Clin Sci. 2015; 129: 291-303.
106. Matsushita T, Tateishi T, Isobe N, Yonekawa T, Yamasaki R, Matsuse D, et al. Characteristic cerebro spinal fluid cytokine/chemokine profiles of neuromyelitis optica, with relapsing -remitting primary progressive Multiple Sclerosis. PLoS One. 2013; 8: e61835.
107. Fontaine RH, Cases O, Lelievre V, Meeples B, Renault JC, Loron G, et al. IL9/ IL9 receptor signalling selectively protect cortical neurons against developmental apoptosis. Cells Death Differ. 2008; 15: 1542-1552.
108. Bsibsi M, Persoon-Deen C, Verwer RW, Meeuwsen S, Ravid R, Van Noort J, et al. Toll like receptor3 on adult human astrocyte triggers production of neuroprotective mediators. Glia. 2006; 53: 688-695.
109. Sagakuchi S, Sagakuchi N, Asano M, Itoh M, Tato CM. Immunologic self-tolerance maintained by activated Tcells expressing IL2 receptor alpha chain (CD25): Breakdown of a single mechanism of selftolerance causes various autoimmune diseases. J Immunol. 1995; 155: 1151-1164.
110. Fontenot JD, Gavin MA, Rudensky AV. FOXP3 programs the developmental function of CD4+CD25+ regulatory Tcells. Nat Immunol 2003; 4: 330-336.
111. Povoleri GA, Scotta C, Nova-Lamprti EA, John S, Lombardi G, Afzali B. Thymic versus induced regulatory Tcells-who regulate the regulators. Front Immunol. 2013; 4: 169.
112. Sambucci M, Gargano F, Guerrera G, Battistini L, Borsellino G. One, no one and one hundred thousand: T regulatory cells’ multiple identities in neuroimmunity. Front Immunol. 2019; 10: 2947.
113. DeRosa V, Galgani M, Porcellini A, Colamatteo A, Santopaolo M, Zuchegna C, et al. Glycolysis controls the induction of human regulatory Tcells by modulating the expression of FOXP3 exon 2 splicing variants. Nat Immunol. 2015; 16:1174.
114. Mirandola SR, Hallal DE, Farias AS, Oliviera EC, Brandao CO, Ruocco HH, et al. Interferon beta modifies the peripheral blood cell cytokine secretion in patients with Multiple Sclerosis. Int Immunopharmacol. 2009; 9: 824-830.
115. Rommet PS, Milo R, Han MH, Satyanarayan S, Shelner J, Hauer L, et al. Immunological aspects of approved MS therapeutics. Front Immunol. 2019; 10: 1564.
116. Abdel-Dayem MA, Shaker ME, Gameim NM. Impact of Interferon beta 1b, Interferon beta 1a and fingolimod therapies on serum Interleukin-22, 32 alpha and 34 concentrations in patients with relapsing- remitting Multiple Sclerosis. J NeuroImmunol. 2019; 337: 577062.
117. Weber MS, Starck M, Wagenpfeil S, Meinl E, Hohlfeld R, Farina C. Multiple Sclerosis: Glatiramate acetate inhibits monocyte reactivity in vitro and in vivo. Brain. 2004; 127: 1370-1378.
118. Chen M, Gran B, Costello K, Johnson K, Martin R, Dhib-Jaiput S. Glatiramate acetate induces a Th2 -biased response and crossrectivity with myelin basic protein in patients with MS. Mult Scler. 2001; 7: 209-219.
119. Hong J, LiN, Zhang X, Zheng JB, Zhang JZ. Induction of CD4+CD25+ regulatory Tcells by copolymer -1 through activation of transcription factor FOXP3. Proc Natl Acad Sci USA. 2005; 102: 6449-6454.
120. Sparado M, MontaroloF, Perga S, Martire S, Brescia F, Malucchi S, et al. Biological activity of Glatiramate acetate on Treg and anti-inflammatory monocytes persists for more than 10yrs in responder Multiple Sclerosis patients. Clin Immunol. 2017; 181: 83-88.
121. Correale J, Gaitan MI, Ysrraelit MC, Fiol MP. Progessive Multiple Sclerosis: from pathogen nic mechanisms to treatment. Brain. 2017; 140: 527-546.
122. Ford C, Goodman AD, Johnson K, Kachuck N, Lindsey JW, Lisak R, et al. Continuous long-term immunomodulatory therapy in relapsing Multiple Sclerosis: Results from 15 year analysis of the us prospective open label study of Glatiramate acetate. Mult Scler. 2010; 16: 342-350.
123. Dubey D, Kieseier BC, Hartung HP, Hemmer B, Warnke C, Menge T, et al. Dimethyl fumarate in relapsing remitting Multiple Sclerosis: Rationale, mechanisms of action, pharmokinetic efficacy and safety. Exp Rev Neurother. 2015; 15: 339-346.
124. Mills EA, Ogrodnik MA, Plave A, MaoDraayer Y. Emerging understanding of the mechanisms of action of Dimethyl fumarate in the treatment of. Front Neurol. 2018; 9: 5.
125. Wilms H, Sievers J, Rickert U, Rostami-Yazdi M, Mrowietz U, Lucius R. Dimethyl fumarate inhibits microglial and astrocvtic inflammation by suppressing the synthesis of nitric oxide, IL-1 beta,TNF-alpha and IL-6 in an in vitro model of brain inflammation. J Neuro inflammation. 2010; 7: 30.
126. Li R, Rezk A, Ghadiri M, Luessi F, Zipp F, Li H, et al. Dimethyl fumarate treatment mediates an anti-inflammatory shift in B cell subsets in patients of Multiple Sclerosis. J Immunol. 2017; 198: 691-698.
127. Gillard GO, Collette B, Anderson J, Chao J, Scannevin RH, Huss DJ, Fontenot JD. Dmf, but not other fumarates, inhibits NF-kappa B activity in vitro in an NRF2 –independent manner. J Neuro Immunol. 2015; 283: 74-85.
128. Ghadiri M, Rezk A, LiR, Evans A, Luessi F, Zipp F, et al. Dimethyl fumarate-induced lymphopenia in MS due to differential T cell-subset apoptosis. Neurol Neuro Immunol Neuro Inflamm. 2017; 4: e340.
129. Gross CC, Schuttle –Mecklenbeck A, Linsing S, Posevitz-Fejfar A, Wiendl H, Klotz L. Dimethyl fumarate treatment alters circulating T helper cell subsets in Multiple Sclerosis. Neurol Neuro Immunol Neuro Inflamm. 2016; 3: e183.
130. Wu Q, Wang Q, Mao G, Dowling CA, Lundy SK, Mao-Draayer Y. Dimethyl fumarate selectively reduces memory T cells and shifts the balance between Th1/Th17 and Th2 in Multiple Sclerosis patients. J Immunol. 2017; 198: 3069-3080.
131. Medina S, Villarubia N, Sainz De la Maza S, Lifante J, Costa Frossard L, et al. Optimal responses to Dimethyl fumarate associates in MS with a shift from an anti-inflammatory to a tolerogenic blood cell profile. Mult Scler. 2018; 24: 1317-1327.
132. Kappos L, Pollman C, Pozilli C, Thompson A, Beckmann K, Dahlke F. Final analysis of the European multicenter trial on IFN-beta 1b to secondary progressive MS. Neurology. 2001; 57: 1969-975.
133. Kappos L, Radue EW, O’Connor P, Pollman C, Hohlfeld R, Calabresi P, Selmaj K, et al. A placebo controlled trial of oral Fingolimod in relapsing Multiple Sclerosis. N Engl J Med. 2010; 362: 387-401.
134. Pappu R, Schwab SR, Cornelissen I, Pereira JP, Regard JP, Xu Y, et al. Promotion of lymphocytes egress into blood and lymph node by distinct source of sphingosine-1 –phosphate. Science. 2007; 316: 295-298.
135. Pelletier D, Hafler FA. Fingolimod for Multiple Sclerosis. N Engl J Med. 2012; 366: 339-347.
136. Serpero ld, Filaci G, Parodi A, Battaglia F, Kalli F, Brogi D, et al. Fingolimod modulates peripheral effector and regulatory Tcells in MS patients. J Neuroimmune Pharmacol. 2013; 8: 1106-1113.
137. Dominiquez –Villar M, Raddassi K, Danielsen AC, Guarnaccia J, Haffer DA. Fingolimod modulates Tcell phenotype and regulatory Tcells plasticity in vivo. J Autoimmun. 2019; 96: 40-49.
138. Engelhardt B, Kappos L. Natalizumab: Targeting alpha 4 beta 1integrins in Multiple Sclerosis, Neurodegener Dis. 2008; 5: 16-22.
139. Coisne C, Mao W, Engelhardt B. Cutting edge: Natalizumab blocks adhesion but not initial contact of human Tcells to the blood brain barrier in vivo in an animal model of Multiple Sclerosis. J Immunol. 2009; 182: 5909-5913.
140. Hatcher SE, Waubant E, Nourbaksksh B, Crabtree-Hartman E, Graves JS. Rebound syndrome in patients with Multiple Sclerosis after cessation of Fingolimod treatment. JAMA Neurol. 2016; 73: 790-794.
141. Guegen A, Roux P, Deschamps R, Moulignier A, Bansa C, Savatovsky J, et al. Abnormal inflammatory activity returns after Natalizumab cessation in Multiple Sclerosis. J Neurol Neurosurg Psychiatry. 2014; 85: 1038-1040.
142. Campagnolo D, Dong Q, Lee L, Ho PR, Amarante D, KoengdenH. Statistical analysis of pml indices of Natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012; 366: 1870-880.
143. Ruck T, Bittner S, Wiendl H, Meuth SG. Alemtuzumab in Multiple Sclerosis: mechanisms of action and beyond. Int J Mol Sci. 2015; 16: 16414-16439.
144. Milo R. The efficacy and safety of Daclizumab and its potential in the treatment of Multiple Sclerosis. Ther Adv Neurol Disord 2014;7:7-21.
145. Wiendl HH, Gross CC. Modulation of IL-2 r alpha with Daclizumab in the treatment of Multiple Sclerosis. Nat Rev Neurol. 2013; 9: 394-404.
146. European Medical Agency. 2018.
147. European Medical Agency. 2020.
148. Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, et al. Ocrelizumab versus Interferon beta 1a in relapsing Multiple Sclerosis. N Engl J Med. 2017; 376: 221-234.
149. Gingele S, Jacobus TL, Konen EF, Hummert MW, Suhs KW, Schwenkenbecher, et al. Ocrelizumab depletes CD20(⁺)T cells in Multiple Sclerosis patients. Cells. 2018; 8: 12.
150. Bittner S, Wiendl HH. Neuroimmunotherapies targeting T cells: from pathology to therapeutic applications. Neurotherapeutics. 2016; 13: 4-19.
151. McInnes IB, Mease PJ, Kirkham B, Kavanaugh A, Richlin CT, Rahman P, et al. Sekukinumab,a human anti IL-17A monoclonal antibody in patrients with psoariatic arthritis(FUTURE 2): A randomized, double blind, placebo controlled, phase 3 trial. Lancet. 2015; 386: 1137-1146.
152. Fernandez O, Alvarez-Cermano JC, Arnal Garcia C, Arroyo Gonzalez R, Breva L, Hernandez C, et al. Review of the novelties presented in the 29^th congress of the European committee for treatment and research in Multiple Sclerosis(ECTRIMS). Rev Neurol. 2014; 59: 371-379.
153. van der Heijde D, Wei JC, Dougados M, Mease P, Deodhar A, Maksymowych WP, et al. Ixekizumab, an interleukin-17A antagonist in the treatment of ankylosing spondylitis or radiographic axial spondyloarthritis in patients previously untreated with biological disease-modifying anti-rheumatic drugs (COAST-V): 16 week results of a phase 3 randomised, double-blind, active-controlled and placebo-controlled trial. Lancet. 2018; 392: 2441-2451.
154. Kaur KK, Allahbadia GN, Singh M. Regenerative therapies utilizing adipose derived stem cells (adsc’s)-edge over bone marrow - mesenchymal stem cells and umbilical cord- mesenchymal stem cells in -a systematic review. 2020.
155. Duignan S, Brownlee W, Wassmer E, Hemingway C, Lam M, Cicarelli O, et al. Paediatric multiple sclerosis: a new era in diagnosis and treatment. Dev Med Child Neuro. 2019; 61: 1039-1049.