Blood-Brain Barrier Disruption And Lesion Localisation In Experimental Autoimmune Encephalomyelitis With Predominant Cerebellar And Brainstem Involvement

The role of the blood-brain barrier (BBB) in determining lesion distribution was assessed in an atypical model of experimental autoimmune encephalomyelitis (EAE) induced in C3H/HeJ mice by immunisation with peptide 190-209 of myelin proteolipid protein, which can result in two distinct types of EAE, each with distinct lesion distribution. Areas of the BBB showing constitutively greater permeability in naive mice did not correlate with the lesion distribution in EAE. BBB disruption occurred only in sites of inflammatory cell infiltration. Irrespective of the clinical type, the BBB was disrupted in the cerebellum and brainstem. Pertussis toxin had no effect on lesion distribution. Thus, lesion distribution is not influenced solely by BBB permeability

NF-kB, a potential therapeutic target for the treatment of multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) that afflicts over 2 million people worldwide. On the basis of the temporal course of disease, MS can be subdivided into three clinical groups: relapsing remitting MS (RR-MS), secondary progressive MS and primary progressive MS. There is a high degree of clinical diversity within these subgroups. The pathogenesis of MS in most patients is likely to result from autoreactive, activated CD4(+) T cells moving from the periphery across the blood brain barrier into the CNS. Most therapeutic agents used in MS (e.g. immunosuppressive and immunomodulatory drugs and cell cycle interruption drugs) are only used for RR-MS. These treatments show some efficiency in lessening the relapse rate in RR-MS and time to progression, but cannot cure MS. Thus, there is a need for new efficient treatments for all types of MS. An increasing number of studies indicate that nuclear factor-kappa B plays an important role in controlling expression of genes relevant to the pathogenesis of autoimmunity. Genetic factors related to NF-kappa B may also be determinants of MS susceptibility, as polymorphisms in the molecules involved in regulation of the NF-kappa B signal transduction pathway differ between RRMS and progressive MS. Herein, the role of NF-kappa B in MS will be reviewed and its potential as a new therapeutic target in MS will be considered and compared with existing treatments

Chemokines and Chemokine Receptors: Potential Therapeutic Targets in Multiple Sclerosis

Multiple sclerosis (MS) is a common inflammatory and demyelinating disease of the central nervous system (CNS), which causes progressive neurological disability. The disease is characterised pathologically by destruction of the myelin sheaths, which surround nerve fibres in the CNS. It is believed that this tissue damage in the brain and spinal cord of MS patients is caused by an inflammatory response that is initiated when autoreactive T cells, specific for myelin antigens, cross the blood-brain barrier and detect their antigen within the CNS. As a result, most therapies to date have been immunosuppressive and/or anti-inflammatory in nature, targeting the process involved in activation and migration of leukocytes and promotion of the immune response. Over the last decade, a family of chemotactic cytokines called chemokines, have been found to be involved in the trafficking of leukocytes in both the normal and pathological states. The expression of these chemokines and their receptors is increased during the acute phase of MS and also in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). As a result, these chemokines have become an emerging focus for research into novel therapeutics for EAE and ultimately MS. This review will briefly describe the structure and function of chemokines and their receptors, before discussing the latest advances in developing pharmacological agents to block the effects of chemokines involved in promoting the inflammatory response in EAE and MS

Predicting the effects of potentially therapeutic modified peptides on polyclonal T cell populations in a mouse model of multiple sclerosis

Altered peptide ligands (APLs) have routinely been studied in clonal populations of Th cells that express a single T cell receptor (TCR), but results generated in this manner poorly predict the effects of APLs on polyclonal Th cells in vivo, contributing to the failure of phase II clinical trials of APLs in autoimmune diseases such as multiple sclerosis (MS). We have used a panel of APLs derived from an encephalitogenic epitope of myelin proteolipid protein to investigate the relationship between antigen cross-reactivity in a polyclonal environment, encephalitogenicity, and the capacity of an APL to provide protection against experimental autoimmune encephalomyelitis (EAE) in SJL mice. In general, polyclonal Th cell lines specific for encephalitogenic APLs cross-reacted with other encephalitogenic APLs, but not with non-encephalitogenic APLs, and vice versa. This, alongside analysis of TCR V beta usage, suggested that encephalitogenic and non-encephalitogenic subgroups of APIs expand largely non-cross-reactive Th cell populations. As an exception to the rule, one non-encephalitogenic APL, L188, induced proliferation in polyclonal CD4(+) T cells specific for the native encephalitogen, with minimal induction of cytokine production. Co-immunization of L188 alongside the native encephalitogen slightly enhanced disease development. In contrast, another APL, A188, which induced 1L-10 production without proliferation in CD4+ T cells specific for the native encephalitogen, was able to protect against development of EAE in a dose-dependent fashion when co-immunized alongside the native encephalitogen. These results suggest that testing against polyclonal Th cell lines in vitro may be an effective strategy for distinguishing between potentially therapeutic and non-therapeutic APLs. (C) 2017 Elsevier B.V. All rights reserved

Thiopalmitoylation of altered peptide ligands enhances their protective effects in an animal model of multiple sclerosis

Previously, we have shown that conjugation of a palmitic chain via a thioester bond to a cysteine residue in weakly or nonencephalitogenic or neuritogenic peptides markedly enhances their ability to induce autoimmune disease in an MHC class II–restricted manner. From those studies, however, it was not clear whether thiopalmitoylation of the peptides was merely enhancing their disease-inducing potential or whether the lipid was itself playing a pathogenic role. To investigate this further, we have now tested the effects of thiopalmitoylation on MHC class II–restricted altered peptide ligands (APLs), which are normally protective in experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis. We hypothesized that if thiopalmitoylation of a peptide merely enhances its innate potential, then thiopalmitoylated APLs (S-palmAPLs) should show enhanced protective effects. Alternatively, if thiopalmitoylation itself can make a peptide pathogenic, then S-palmAPLs should have decreased therapeutic potential. We synthesized APLs and corresponding S-palmAPLs and showed that the S-palmAPLs were much more effective than the nonconjugated APL at inhibiting the development of experimental autoimmune encephalomyelitis. This was due to several features of the S-palmAPL:S-palmAPL–primed cells show an enhanced ability to proliferate and produce the anti-inflammatory cytokine, IL-10, in vitro. Furthermore, the bioavailability of S-palmAPL was greatly enhanced, compared with the nonpalmitoylated APL, and S-palm APL was taken up more rapidly into dendritic cells and channeled into the MHC class II processing pathway. These results show that thiopalmitoylation of MHC class II–restricted peptides is a simple way to enhance their effects in vivo and could have wide therapeutic application

The effect of ageing on human lymphocyte subsets: comparison of males and females

There is reported to be a decline in immune function and an alteration in the frequency of circulating lymphocytes with advancing age. There are also differences in ageing and lifespan between males and females. We performed this study to see if there were differences between males and females in the frequency of the different lymphocyte subsets with age.Using flow cytometry we have examined different populations of peripheral blood leukocytes purified from healthy subjects with age ranging from the third to the tenth decade. We used linear regression analysis to determine if there is a linear relationship between age and cell frequencies. For the whole group, we find that with age there is a significant decline in the percentage of naïve T cells and CD8(+) T cells, and an increase in the percentage of effector memory cells, CD4(+)foxp3(+) T cells and NK cells. For all cells where there was an effect of ageing, the slope of the curve was greater for men than for women and this was statistically significant for CD8(+)alphabeta(+) T cells and CD3(+)CD45RA(-)CCR7(-) effector memory cells. There was also a difference for naïve cells but this was not significant.The cause of the change in percentage of lymphocyte subsets with age, and the different effects on males and females is not fully understood but warrants further study

Reactivity to Novel Autoantigens in Patients with Coexisting Central Nervous System Demyelinating Disease and Autoimmune Thyroid Disease

Several lines of evidence suggest a definite and unique link between CNS demyelinating diseases and autoimmune thyroid disease (AITD). The aim of the current study was to systematically compare the clinical and laboratory features of patients with coexistent AITD and CNS demyelinating disease with those of patients with just CNS demyelinating disease. Forty-four patients with coexisting CNS demyelinating disease and AITD were identified and their clinical and radiological features were recorded. Blood and DNA were collected and tested for HLA type and for the response of T cells and antibodies to a variety of antigens. Patients with multiple sclerosis (MS) without AITD and healthy individuals were included as controls. Patients with coexisting AITD and CNS demyelinating disease were almost exclusively female (43/44) and had prominent spinal cord involvement as the main neurological finding. The HLA molecules carried by individuals with CNS demyelinating disease and AITD differed from both other MS patients and healthy individuals. Furthermore, patients with both CNS disease and AITD showed less T cell reactivity than patients with MS alone to myelin proteolipid protein, but, compared to other groups, showed elevated levels of T cell reactivity to the calcitonin gene-related peptide, which is present in both the CNS and the thyroid, and elevated levels of T cell and antibody to the leucine-rich repeat-containing G-protein coupled receptor 4 (LGR4), a molecule that is expressed in the brainstem and spinal cord, and which is a homolog of the thyroid-stimulating hormone receptor. We suggest that reactivity of autoreactive immune cells in these patients against antigens present in both the thyroid and the spinal cord is a potential mechanism underlying the pattern of lesion development in the CNS in patients with coexisting AITD and MS and might indicate a novel mechanism of disease pathogenesis in these patients

Increased circulating T cell reactivity to GM3 and GQ1b gangliosides in primary progressive multiple sclerosis

We have previously shown that patients with primary progressive multiple sclerosis (MS) have significantly elevated plasma levels of antibody to GM3 ganglioside compared to patients with relapsing-remitting MS, healthy subjects and patients with other neurological diseases. Anti-GM3 antibody levels were elevated also in patients with secondary progressive MS but to a lesser extent than in primary progressive MS. As gangliosides are particularly enriched in the axonal membrane, these findings suggested that antiganglioside immune responses might contribute to the axonal damage in progressive forms of MS. The present study was performed to determine whether peripheral blood T cell responses to GM3 are also increased in progressive MS. Blood was collected from 98 untreated patients with MS (40 with relapsing-remitting, 27 with secondary progressive and 31 with primary progressive MS), 50 healthy subjects and 24 patients with other disorders of the CNS, and reactivity to GM1, GM3, GD1a, GD1b, GD3, GT1b, GQ1b and sulphatide was assessed by 6-day T cell proliferation assays. Increased T cell reactivity to GM3 and GQ1b occurred significantly more often in patients with primary progressive MS than in healthy subjects and patients with other CNS diseases. These findings suggest that ganglioside-specific T cells may contribute to the axonal damage in primary progressive MS. (C) 2002 Elsevier Science Ltd. All rights reserved

Immunology of multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) leading to demyelination, axonal damage, and progressive neurologic disability. The development of MS is influenced by environmental factors, particularly the Epstein-Barr virus (EBV), and genetic factors, which include specific HLA types, particularly DRB1*1501-DQA1*0102-DQB1*0602, and a predisposition to autoimmunity in general. MS patients have increased circulating T-cell and antibody reactivity to myelin proteins and gangliosides. It is proposed that the role of EBV is to infect autoreactive B cells that then seed the CNS and promote the survival of autoreactive T cells there. It is also proposed that the clinical attacks of relapsing-remitting MS are orchestrated by myelin-reactive T cells entering the white matter of the CNS from the blood, and that the progressive disability in primary and secondary progressive MS is caused by the action of autoantibodies produced in the CNS by ­meningeal lymphoid follicles with germinal centers