TLR7 signaling exacerbates CNS autoimmunity through downregulation of Foxp3+ Treg cells

The innate Toll‐like receptor 7 (TLR7) detects infections by recognizing viral and bacterial single‐stranded RNA. In addition to pathogen‐derived RNA, immune cells expressing high levels of TLR7, such as B cells and dendritic cells (DCs), can be activated by self‐RNA. During myelin‐induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, TLR7 expression is increased within the central nervous system (CNS). To define the contribution of TLR7 to the development of EAE, we evaluated the course of the disease in C57BL/6‐Tlr7‐deficient mice compared with that in WT mice and found that TLR7‐deficient mice had decreased disease severity. This protection was associated with decreased myelin oligodendrocyte glycoprotein‐specific T‐cell activation by primed DCs, decreased circulating autoantibodies, attenuated inflammation within the CNS, and increased Foxp3⁺ regulatory T cells in the periphery and in the CNS. In conclusion, we show that TLR7 is involved in the maintenance of autoimmunity in the pathogenesis of EAE.     

Induction of experimental autoimmune encephalomyelitis in transgenic mice expressing ovalbumin in oligodendrocytes

We have used the 5' flanking sequence of the myelin basic protein gene known to include the core promoter and a strong oligodendrocyte (ODC)-specific enhancer to target expression of the well-studied model antigen ovalbumin (OVA) to ODC in transgenic mice. OVA protein was detected in a tissue- and cell-specific manner in these "ODC-OVA" mice. Without immunization, CD4 T cells and B cells remained ignorant of the neo-self antigen expressed in the central nervous system (CNS), as indicated by unimpaired development and lack of activation of OVA/IA(b)-specific TCR transgenic T cells in these mice, and the ability to mount normal OVA-specific recall and antibody responses. Upon immunization with OVA in complete Freund's adjuvant, about half of the transgenic mice developed neurological symptoms characteristic of experimental autoimmune encephalomyelitis (EAE). Mononuclear infiltrates in the brain and spinal cord contained both macrophages and T cells, similar to classical models of EAE induced by immunization with CNS antigens in adjuvant. The wealth of immunological reagents available to study and manipulate the OVA-specific response should make this new model useful for the investigation of components and mechanisms involved in CNS-specific autoimmunity.     

A central role for peripheral dendritic cells in the induction of acquired thymic tolerance

Despite extensive negative selection in the thymus, numerous clones of self-reactive T cells are normally exported to the periphery. In most instances, autoimmunity is prevented by regulatory T (Tr) cells, many of which are also of recent thymic origin. We have demonstrated recently that natural killer (NK) Tr thymocytes (THYr) can be induced by the injection of antigen into the eye, an immunologically privileged site; and that the intravenous infusion of antigen-presenting cells (APCs) from such animals also induces NKT THYr. Furthermore, we have also observed that some of these APCs migrate to the thymus as CD11c(+) dendritic cells (DCs). Other authors have correlated the migration of DCs to the thymus with the generation of CD4(+)CD25(+) THYr. We therefore propose a novel tolerance induction pathway by which tolerogenic DCs routinely transport antigen (both self and nonself) from the periphery to the thymus, where they positively select THYr. We also propose that the ability of tolerogenic DCs to induce acquired thymic tolerance on demand might have important implications for the immunotherapy of autoimmunity and allotransplantation.     

The central nervous system environment controls effector CD4+ T cell cytokine profile in experimental allergic encephalomyelitis

In experimental allergic encephalomyelitis (EAE), CD4⁺ T cells infiltrate the central nervous system (CNS). We derived CD4⁺ T cell lines from SJL/J mice that were specific for encephalitogenic myelin basic protein (MBP) peptides and produced both Th1 and Th2 cytokines. These lines transferred EAE to naive mice. Peptide-specific cells re-isolated from the CNS only produced Th1 cytokines, whereas T cells in the lymph nodes produced both Th1 and Th2 cytokines. Mononuclear cells isolated from the CNS, the majority of which were microglia, presented antigen to and stimulated MBP-specific T cell lines in vitro. Although CNS antigen-presenting cells (APC) supported increased production of interferon (IFN)-γ mRNA by these T cells, there was no increase in the interleukin (IL)-4 signal, whereas splenic APC induced increases in both IFN-γ and IL-4. mRNA for IL-12 (p40 subunit) was up-regulated in both infiltrating macrophages and resident microglia from mice with EAE. We have thus shown that a Th1 cytokine bias within the CNS can be induced by CNS APC, and that IL-12 is up-regulated in microglial cells within the CNS of mice with EAE. Microglia may therefore control Th1 cytokine responses within the CNS.     

The critical role of antigen-presentation-induced cytokine crosstalk in the central nervous system in multiple sclerosis and experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is a debilitating disease of the central nervous system (CNS) that has been extensively studied using the animal model experimental autoimmune encephalomyelitis (EAE). It is believed that CD4(+) T lymphocytes play an important role in the pathogenesis of this disease by mediating the demyelination of neuronal axons via secretion of proinflammatory cytokines resulting in the clinical manifestations. Although a great deal of information has been gained in the last several decades about the cells involved in the inflammatory and disease mediating process, important questions have remained unanswered. It has long been held that initial neuroantigen presentation and T cell activation events occur in the immune periphery and then translocate to the CNS. However, an increasing body of evidence suggests that antigen (Ag) presentation might initiate within the CNS itself. Importantly, it has remained unresolved which antigen presenting cells (APCs) in the CNS are the first to acquire and present neuroantigens during EAE/MS to T cells, and what the conditions are under which this takes place, ie, whether this occurs in the healthy CNS or only during inflammatory conditions and what the related cytokine microenvironment is comprised of. In particular, the central role of interferon-γ as a primary mediator of CNS pathology during EAE has been challenged by the emergence of Th17 cells producing interleukin-17. This review describes our current understanding of potential APCs in the CNS and the contribution of these and other CNS-resident cells to disease pathology. Additionally, we discuss the question of where Ag presentation is initiated and under what conditions neuroantigens are made available to APCs with special emphasis on which cytokines may be important in this process.     

Role of MHC class II expressing CD4+ T cells in proteolipid protein(91-110)-induced EAE in HLA-DR3 transgenic mice

MHC class II molecules play a central role in the control of adaptive immune responses through selection of the CD4(+) T cell repertoire in the thymus and antigen presentation in the periphery. Inherited susceptibility to autoimmune disorders such as multiple sclerosis, rheumatoid arthritis and IDDM are associated with particular MHC class II alleles. Advent of HLA transgenic mice has helped us in deciphering the role of particular HLA DR and DQ class II molecules in human autoimmune diseases. In mice, the expression of class II is restricted to professional antigen-presenting cells (APC). However, in humans, class II is also expressed on T cells, unlike murine T cells. We have developed new humanized HLA class II transgenic mice expressing class II molecules not only on APC but also on a subset of CD4(+) T cells. The expression of class II on CD4(+) T cells is inducible, and class II(+) CD4(+) T cells can present antigen in the absence of APC. Further, using EAE, a well-established animal model of MS, we tested the functional significance of these class II(+) CD4(+) T cells. DR3.AEo transgenic mice were susceptible to proteolipid protein(91-110)-induced EAE and showed CNS pathology accompanied by widespread inflammation and demyelination seen in human MS patients, suggesting a role for class II(+) CD4(+) T cells in the pathogenesis.     

Antigen-presenting cell diversity for T cell reactivation in central nervous system autoimmunity

Autoreactive T cells are considered the major culprits in the pathogenesis of many autoimmune diseases like multiple sclerosis (MS). Upon activation in the lymphoid organs, autoreactive T cells migrate towards the central nervous system (CNS) and target the myelin sheath-forming oligodendrocytes, resulting in detrimental neurological symptoms. Despite the availability of extensively studied systems like the experimental autoimmune encephalomyelitis (EAE) model, our understanding of this disease and the underlying pathogenesis is still elusive. One vividly discussed subject represents the T cell reactivation in the CNS. In order to exert their effector functions in the CNS, autoreactive T cells must encounter antigen-presenting cells (APCs). This interaction provides an antigen-restricted stimulus in the context of major histocompatibility complex class II (MHC-II) and other co-stimulatory molecules. Peripherally derived dendritic cells (DCs), B cells, border-associated macrophages (BAM), CNS-resident microglia, and astrocytes have the capacity to express molecules required for antigen presentation under inflammatory conditions. Also, endothelial cells can fulfill these prerequisites in certain situations. Which of these cells in fact act as APCs for T cell reactivation and to which extent they can exert this function has been studied intensively, but unfortunately with no firm conclusion. In this review, we will summarize the findings that support or question the antigen presenting capacities of the mentioned cell types of CNS-localized T cell reactivation.     

Epicutaneous immunization with autoantigenic peptides induces T suppressor cells that prevent experimental allergic encephalomyelitis

Information on how suppressor/regulatory T cells can be generated directly in vivo and prevent autoimmunity remains fragmentary. We show here that epicutaneous immunization (ECi) with the immunodominant peptide of myelin basic protein (MBP), Ac1-11, protects mice that are transgenic for an Ac1-11-specific T cell receptor against both the induced and spontaneous forms of experimental allergic encephalomyelitis (EAE). This protection was antigen specific and antigen dose dependent, and was mediated by CD4(+)/CD25(-) T cells whose suppressive activity required cell-cell contact and could transfer protection to naive recipients. These ECi-induced suppressor T cells controlled naive MBP-specific CD4 T cells by inhibiting both their activation and their capacity to secrete IFN-gamma. There was no CD4 T cell infiltration in the brain of protected mice. Finally, ECi with autoantigenic peptides protected two nontransgenic models from relapsing-remitting EAE in an antigen-specific and antigen dose-dependent manner.     

Immunological cell type characterization and Th1-Th17 cytokine production in a mouse model of Gaucher disease

Gaucher disease is a lysosomal storage disease resulting from insufficient acid β-glucosidase (glucocerebrosidase, GCase, EC 4.2.1.25) activity and the resultant accumulation of glucosylceramide. Macrophage (M?) lineage cells are thought to be the major disease effectors because of their secretion of numerous cytokines and chemokines that influence other poorly defined immunological cell populations. Increases in several such populations were identified in a Gba1 mouse model (D409V/null; 9V/null) of Gaucher disease including antigen presenting cells (APCs), i.e., M?, dendritic cells (DCs), neutrophils (PMNs), and CD4(+) T cells. FACS analyses showed increases in these cell types in 9V/null liver, spleen lung, and bone marrow. T-cells or APCs enhanced activations were evident by positivity of CD40L, CD69, as well as CD40, CD80, CD86, and MHCII on the respective cells. M?, and, unexpectedly, DCs, PMNs, and T cells, from 9V/null mice showed excess glucosylceramides as potential bases for activation of APCs and T cells to induce Th1 (IFNγ, IL12, TNFα,) and Th17 (IL17A/F) cytokine production. These data imply that excess glucosylceramides in these cells are pivotal for activation of APCs and T cell induction of Th1 and Th17 responses and PMN recruitment in multiple organs of this model of Gaucher disease.     

EAE mediated by a non‐IFN‐γ/non‐IL‐17 pathway

Previous studies have shown that EAE can be elicited by the adoptive transfer of either IFN‐γ‐producing (Th1) or IL‐17‐producing (Th17) myelin‐specific CD4⁺ T‐cell lines. Paradoxically, mice deficient in either IFN‐γ or IL‐17 remain susceptible to EAE following immunization with myelin antigens in CFA. These observations raise questions about the redundancy of IFN‐γ and IL‐17 in autoimmune demyelinating disease mediated by a diverse, polyclonal population of autoreactive T cells. In this study, we show that an atypical form of EAE, induced in C57BL/6 mice by the adoptive transfer of IFN‐γ‐deficient effector T cells, required IL‐17 signaling for the development of brainstem infiltrates. In contrast, classical EAE, characterized by predominant spinal cord inflammation, occurred in the combined absence of IFN‐γ and IL‐17 signaling, but was dependent on GM‐CSF and CXCR2. Our findings contribute to a growing body of data, indicating that individual cytokines vary in their importance across different models of CNS autoimmunity.     

Dendritic Cells Ameliorate Autoimmunity in the CNS by Controlling the Homeostasis of PD-1 Receptor(+) Regulatory T Cells

Mature dendritic cells (DCs) are established as unrivaled antigen-presenting cells (APCs) in the initiation of immune responses, whereas steady-state DCs induce peripheral T?cell tolerance. Using various genetic approaches, we depleted CD11c(+) DCs in mice and induced autoimmune CNS inflammation. Unexpectedly, mice lacking DCs developed aggravated disease compared to control mice. Furthermore, when we engineered DCs to present a CNS-associated autoantigen in an induced manner, we found robust tolerance that prevented disease, which coincided with an upregulation of the PD-1 receptor on antigen-specific T?cells. Additionally, we showed that PD-1 was necessary for DC-mediated induction of regulatory T?cells. Our results show that a reduction of DCs interferes with tolerance, resulting in a stronger inflammatory response, and that other APC populations could compensate for the loss of immunogenic APC function in DC-depleted mice.     

IL-10 is involved in the suppression of experimental autoimmune encephalomyelitis by CD25+CD4+ regulatory T cells

CD25(+)CD4(+) regulatory T cells inhibit the activation of autoreactive T cells in vitro and in vivo, and suppress organ-specific autoimmune diseases. The mechanism of CD25(+)CD4(+) T cells in the regulation of experimental autoimmune encephalomyelitis (EAE) is poorly understood. To assess the role of CD25(+)CD4(+) T cells in EAE, SJL mice were immunized with myelin proteolipid protein (PLP)(139-151) to develop EAE and were treated with anti-CD25 mAb. Treatment with anti-CD25 antibody following immunization resulted in a significant enhancement of EAE disease severity and mortality. There was increased inflammation in the central nervous system (CNS) of anti-CD25 mAb-treated mice. Anti-CD25 antibody treatment caused a decrease in the percentage of CD25(+)CD4(+) T cells in blood, peripheral lymph node (LN) and spleen associated with increased production of IFN-gamma and a decrease in IL-10 production by LN cells stimulated with PLP(130-151) in vitro. In addition, transfer of CD25(+)CD4(+) regulatory T cells from naive SJL mice decreased the severity of active EAE. In vitro, anti-CD3-stimulated CD25(+)CD4(+) T cells from naive SJL mice secreted IL-10 and IL-10 soluble receptor (sR) partially reversed the in vitro suppressive activity of CD25(+)CD4(+) T cells. CD25(+)CD4(+) T cells from IL-10-deficient mice were unable to suppress active EAE. These findings demonstrate that CD25(+)CD4(+) T cells suppress pathogenic autoreactive T cells in actively induced EAE and suggest they may play an important natural regulatory function in controlling CNS autoimmune disease through a mechanism that involves IL-10.     

Infection with Mycobacterium bovis BCG diverts traffic of myelin oligodendroglial glycoprotein autoantigen-specific T cells away from the central nervous system and ameliorates experimental autoimmune encephalomyelitis

Infectious agents have been proposed to influence susceptibility to autoimmune diseases such as multiple sclerosis. We induced a Th1-mediated central nervous system (CNS) autoimmune disease, experimental autoimmune encephalomyelitis (EAE) in mice with an ongoing infection with Mycobacterium bovis strain bacillus Calmette-Guérin (BCG) to study this possibility. C57BL/6 mice infected with live BCG for 6 weeks were immunized with myelin oligodendroglial glycoprotein peptide (MOG(35-55)) to induce EAE. The clinical severity of EAE was reduced in BCG-infected mice in a BCG dose-dependent manner. Inflammatory-cell infiltration and demyelination of the spinal cord were significantly lessened in BCG-infected animals compared with uninfected EAE controls. ELISPOT and gamma interferon intracellular cytokine analysis of the frequency of antigen-specific CD4(+) T cells in the CNS and in BCG-induced granulomas and adoptive transfer of MOG(35-55)-specific green fluorescent protein-expressing cells into BCG-infected animals indicated that nervous tissue-specific (MOG(35-55)) CD4(+) T cells accumulate in the BCG-induced granuloma sites. These data suggest a novel mechanism for infection-mediated modulation of autoimmunity. We demonstrate that redirected trafficking of activated CNS antigen-specific CD4(+) T cells to local inflammatory sites induced by BCG infection modulates the initiation and progression of a Th1-mediated CNS autoimmune disease.     

Evidence that Fas and FasL contribute to the pathogenesis of experimental autoimmune encephalomyelitis

The well established and characterized animal model for the human demyelinating autoimmune disease multiple sclerosis (MS) is known as experimental autoimmune encephalomyelitis (EAE). EAE is clinically characterized by focal areas of inflammation and demyelination and an infiltrate composed of large numbers of lymphocytes and macrophages, often found in a perivascular localization but also throughout the central nervous system (CNS). Active immunization of mice with several different protein components of myelin, including myelin basic protein (MBP), proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG), are capable of eliciting an immune response resulting in the quintessential symptoms of EAE: ascending paralysis involving the tail and then the limbs. Depending on the mouse strain and myelin antigen utilized, the disease course can be acute or chronic relapsing, characterized by a rapid onset of hind limb weakness that commonly progresses to paralysis, followed by spontaneous remission starting 7-10 days after the initial appearance of symptoms. EAE can also be induced passively by the adoptive transfer of in vitro activated CD4+ T cell clones or lines, typically of the Th1 phenotype, into irradiated susceptible recipients. The mechanisms involved in the cellular pathogenesis leading to paralysis and demyelination have been extensively studied and are primarily mediated by CD4+ T cells of the Th1 phenotype, with specificity for myelin antigens. Following activation, Th1 CD4 T cells produce in abundance the inflammatory cytokines TNF-alpha, IFN-gamma and lymphotoxin alpha (LT-alpha, also know as TNF-beta). IFN-gamma production is highly correlated with encephalitogenicity and may contribute to disease by up-regulation of adhesion molecules on endothelial cells, facilitating migration of lymphocytes into the CNS; by induction of major histocompatibility complex (MHC) class I and MHC class II molecules on astrocytes, microglial cells and brain endothelium, facilitating antigen (Ag) presentation in the CNS; and by activation of macrophages, leading to production of nitric oxide, a potent cytotoxic molecule. TNF-alpha and LT-alpha are both members of the TNF family of molecules and cause cell death by apoptosis following interaction with their counter-receptors, the TNFR1 and TNFR2, leading to a cascade of proteolytic events culminating in the blebbing of the cytoplasmic membrane, nuclear condensation and DNA fragmentation. Consequently, the production of TNF-alpha and LT-alpha by Th1 clones has been correlated with encephalitogenic potential and antibodies (Abs) to both prevents EAE upon transfer of encephalitogenic clones. Even though substantial evidence exists for the role of inflammatory cytokines in the pathogenesis of EAE, other mechanisms of myelin destruction are thought to exist. To date, many reports have implicated a role for the cell death-inducing ligand pair Fas and Fas-ligand (FasL).     

Experimental autoimmune encephalomyelitis in mice expressing the autoantigen MBP 1-10 covalently bound to the MHC class II molecule I-Au

Most autoantigens implicated in multiple sclerosis (MS) are expressed not only in the central nervous system (CNS) but also in the thymus and the periphery. Nevertheless, these autoantigens might induce a strong autoimmune response leading to severe destruction within the CNS. To investigate the influence of a dominantly presented autoantigen on experimental autoimmune encephalomyelitis (EAE), we generated transgenic mice expressing the autoantigenic peptide MBP 1-10 covalently bound to the MHC class II molecule I-Au. These mice were crossed either with B10.PL or with TCR-transgenic Tg4 mice, specific for the transgenic peptide-MHC combination. In double transgenic mice we found strong thymic deletion and residual peripheral T cells were refractory to antigen stimulation in vitro. Residual peripheral CD4+ T cells expressed activation markers and a high proportion was CD25 positive. Transfer of both CD25-negative and CD25-positive CD4+ T cells from double transgenic animals into B10.PL mice strongly inhibited the progression of EAE. Despite this thorough tolerance induction, some double transgenic mice developed severe signs of EAE after an extended period of time. Our data show that in the circumstances where autoantigenic priming persists, and where the number of antigen-specific T cells is high enough, autoimmunity may prevail over very potent tolerance-inducing mechanisms.     

The role of CD8 suppressors versus destructors in autoimmune central nervous system inflammation

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) of putative autoimmune origin. Recent evidence indicates that MS autoimmunity is linked to defects in regulatory T-cell function, which normally regulates immune responses to self-antigens and prevents autoimmune diseases. MS and its animal model, experimental autoimmune encephalomyelitis (EAE), have long been regarded as a CD4(+) T-cell-mediated autoimmune disease. Studies addressing the role of CD8(+) T cells, however, have only recently begun to emerge. Pathogenic function was attributed to CD8(+) T cells because of their abundant presence or oligoclonal repertoire within MS lesions. However, CD8(+) T cells appeared to have important regulatory functions, as demonstrated in EAE or human MS studies. We here review the contribution of CD8(+) T cells to inflammation and immune regulation in CNS autoimmunity. The knowledge of distinct CD8(+) T-cell populations exerting destructive versus beneficial functions is summarized. The long-term goal is to delineate the exact phenotypic and functional characteristics of regulatory CD8(+) T-cell populations (natural as well as inducible) in humans. This knowledge may help to further develop concepts of reconstituting or enhancing endogenous mechanisms of immune tolerance in future therapeutic concepts for MS.     

Density of CD163+ CD11c+ dendritic cells increases and CD103+ dendritic cells decreases in the coeliac lesion

Coeliac disease is a chronic inflammation of the intestinal mucosa controlled by gluten-specific T cells restricted by disease-associated HLA-DQ molecules. We have previously reported that mucosal CD11c(+) dendritic cells (DCs) are responsible for activation of gluten-reactive T cells within the coeliac lesion. In mice, intestinal CD11c(+) DCs comprise several functionally distinct subsets. Here, we report that HLA-DQ(+) antigen-presenting cells (APCs) in normal human duodenal mucosa can be divided into four subsets with striking similarities to those described in mice: CD163(+) CD11c(-) macrophages (74%), and CD11c(+) cells expressing either CD163 (7%), CD103 (11%) or CD1c (13%). CD103(+) and CD1c(+) DCs belonged to partly overlapping populations, whereas CD163(+) CD11c(+) APCs appeared to be a distinct population. In the coeliac lesion, we found increased density of CD163(+) CD11c(+) APCs, whereas the density of CD103(+) and CD1c(+) DCs was decreased, suggesting that distinct subpopulations of APCs in coeliac disease may exert different functions in the pathogenesis.     

PD-1 ligands expressed on myeloid-derived APC in the CNS regulate T-cell responses in EAE

Disease progression in experimental autoimmune encephalomyelitis (EAE) is regulated by programmed death receptor 1 (PD-1) and its ligands, B7-H1 (programmed death ligand 1 (PD-L1)) and B7-DC (PD-L2). B7-H1 and B7-DC have negative regulatory effects upon binding PD-1 on activated T cells and B7-H1 deficiency increases severity of both diabetes and EAE. However, the role of PD-L expression on different APC in the CNS in regulating local T-cell function during relapsing EAE has not been examined. Our data show that the majority of CNS CD4+ T cells isolated during acute EAE are PD-1+, and T cells specific for relapse-associated epitopes express PD-1 upon antigen stimulation in the CNS. B7-H1 and B7-DC are differentially expressed on discrete APC populations in the inflamed CNS. B7-H1 and PD-1 have mainly inhibitory functions on CNS T cells. B7-H1 negatively regulates the stimulation of activated PD-1+ T(H) cells, in co-cultures with microglia and different CNS-infiltrating APC presenting endogenously processed peptides. The preponderance of IFN-gamma+ versus IL-17+ T cells in the CNS of B7-H1(-/-) mice suggests that B7-H1 more selectively suppresses T(H)-1 than T(H)-17 responses in vivo. In contrast, blockade of B7-DC has less pronounced regulatory effects. Overall, the results demonstrate that B7-H1 expressed by CNS myeloid APC negatively regulates T-cell activation during acute relapsing EAE.     

Blockade of tumour necrosis factor‐α in experimental autoimmune encephalomyelitis reveals differential effects on the antigen‐specific immune response and central nervous system histopathology

In various autoimmune diseases, anti‐tumour necrosis factor (TNF)‐α treatment has been shown to reduce both clinical disease severity and T helper type 1 (Th1)1/Th17 responses. In experimental autoimmune encephalomyelitis (EAE), however, the role of TNF‐α has remained unclear. Here, C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein (MOG) peptide 35–55 and treated with anti‐TNF‐α, control antibody or vehicle. The clinical disease course, incidence and severity were assessed. On day 20 after immunization the antigen‐specific Th1/Th17 response was evaluated by enzyme‐linked immunospot (ELISPOT) in spleen and central nervous system (CNS). Also, the extent of spinal cord histopathology was analysed on semi‐ and ultrathin sections. Our results demonstrate that anti‐TNF‐α treatment reduced the incidence and delayed the onset of EAE, but had no effect on disease severity once EAE had been established. Whereas anti‐TNF‐α treatment induced an increase in splenic Th1/Th17 responses, there was no effect on the number of antigen‐specific Th1/Th17 cells in the spinal cord. Accordingly, the degree of CNS histopathology was comparable in control and anti‐TNF‐α‐treated mice. In conclusion, while the anti‐TNF‐α treatment had neither immunosuppressive effects on the Th1/Th17 response in the CNS nor histoprotective properties in EAE, it enhanced the myelin‐specific T cell response in the immune periphery.     

Developmental maturation of innate immune cell function correlates with susceptibility to central nervous system autoimmunity

MS is an inflammatory CNS disorder, which typically occurs in early adulthood and rarely in children. Here we tested whether functional maturation of innate immune cells may determine susceptibility to CNS autoimmune disease in EAE. Two‐week‐old mice were resistant to active EAE, which causes fulminant paralysis in adult mice; this resistance was associated with an impaired development of Th1 and Th17 cells. Resistant, young mice had higher frequencies of myeloid‐derived suppressor cells and plasma‐cytoid DCs. Furthermore, myeloid APCs and B cells from young mice expressed lower levels of MHC class II and CD40, produced decreased amounts of proinflammatory cytokines, and released enhanced levels of anti‐inflammatory IL‐10. When used as APCs, splenocytes from 2‐week‐old mice failed to differentiate naive T cells into Th1 and Th17 cells irrespective of the T‐cell donor's age, and promoted development of Treg cells and Th2 cells instead. Adoptive transfer of adult APCs restored the ability of 2‐week‐old mice to generate encephalitogenic T cells and develop EAE. Collectively, these findings indicate that the innate immune compartment functionally matures during development, which may be a prerequisite for development of T‐cell‐mediated CNS autoimmune disease.