Increased immunoreactivity to two overlapping peptides of myelin proteolipid protein in multiple sclerosis

2000

Acta Neuropathologica

Experimental autoimmune encephalomyelitis (EAE) is an autoimmune demyelinating disease that can be induced in a variety of animal species and which is commonly used as an animal model of multiple sclerosis. In rodent EAE models, the clinical disease is typified by ascending paralysis; however, other clinical patterns can also be observed by inducing disease with particular peptides of myelin proteolipid protein (PLP) or myelin oligodendrocyte glycoprotein. Here we describe EAE induced in C3H/HeJ mice by inoculation with residues 190-209 of PLP. This form of EAE is manifested clinically by a movement disorder, with axial rotation of the head and trunk. Histologically, this form of EAE is characterized by predominant cerebellar or brain stem involvement, depending on whether EAE is induced by active immunization with the PLP peptide, or by passive transfer of T cells specific for the peptide. The inflammatory cell infiltrate is composed of polymorphonuclear cells and mononuclear cells. This rotatory form of EAE may be a useful model for studying the neuropathological characteristics of multiple sclerosis affecting the brain stem and cerebellum.

Section: Discussionmentioning

confidence: 99%

A neuropathological analysis of experimental autoimmune encephalomyelitis with predominant brain stem and cerebellar involvement and differences between active and passive induction

Muller

Pender

2000

Acta Neuropathologica

“…Since MS patients in Group 1 and Group 2 represented two distinct patient sets, we investigated possible reasons for the reduced responses in Group 2. We have previously reported that the proportion of MS patients making increased T-cell responses to PLP184-199 and PLP190-209 is low in the early stages of MS (duration <6 years) and in patients who have had MS for more than 20 years, whereas more patients who have had MS for between 6-20 years have increased reactivity to these PLP peptides [20]. When the groups were analyzed according to disease duration, the highest percentages of responders were found in the groups of patients who had had MS for 10-20 years, and the lowest percentages of responders were those individuals who had had MS for <2 years or >20 years ( Fig.…”

Section: Reactivity To Plp Peptides Is Increased In Ms Patients Compamentioning

confidence: 97%

“…The T-cell proliferation assays were performed using established techniques on fresh peripheral blood mononuclear cells (PBMC), as previously described [20]. Briefly, PBMC were separated from heparinized blood by centrifugation through histopaque (Sigma Chemical Co, St Louis, USA) and washed twice.…”

Section: T-cell Proliferationmentioning

confidence: 99%

Effect of gender on T-cell proliferative responses to myelin proteolipid protein antigens in patients with multiple sclerosis and controls

Journal of Autoimmunity

Csurhes

Pender

et al. 2004

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system. Gender influences both susceptibility to MS, with the disease being more common in women, and the clinical course of disease, with an increased proportion of males developing the primary progressive form of the disease. The basis for these differences may include genetic and immunological factors, and the immunological differences between men and women may be influenced by the effects of the sex hormones. Over several years we have collected blood from MS patients and controls, and measured T-cell responses to myelin proteolipid protein (PLP) and myelin basic protein (MBP) and have shown increased responses to PLP in MS patients compared to healthy controls and patients with other neurological diseases. In the present study we analyzed data from over 500 individuals, to determine whether there are differences between males and females in their responses to PLP and MBP. We found that there was higher frequency of increased T-cell reactivity to immunodominant PLP peptides in women than in men, particularly in non-MS individuals. We suggest that this may be relevant to the higher prevalence of MS in women.

“…The acylation sites Cys 108 and Cys 140 are within the encephalitogenic PLP epitopes PLP 104 -117 and PLP 139 -151 , respectively (1,4,9,10). Reactivity to these epitopes is also found in some patients with multiple sclerosis (MS) (11)(12)(13)(14)(15). However, the contribution that the thioacyl side chains make to the immunogenicity and encephalitogenicity of PLP has not been studied.…”

mentioning

confidence: 99%

Thiopalmitoylation of Myelin Proteolipid Protein Epitopes Enhances Immunogenicity and Encephalitogenicity

The Journal of Immunology

Denis

Sobel

et al. 2001

Proteolipid protein (PLP) is the most abundant protein of CNS myelin, and is posttranslationally acylated by covalent attachment of long chain fatty acids to cysteine residues via a thioester linkage. Two of the acylation sites are within epitopes of PLP that are encephalitogenic in SJL/J mice (PLP104–117 and PLP139–151) and against which increased immune responses have been detected in some multiple sclerosis patients. It is known that attachment of certain types of lipid side chains to peptides can result in their enhanced immunogenicity. The aim of this study was to determine whether thioacylated PLP peptides, as occur in the native protein, are more immunogenic than their nonacylated counterparts, and whether thioacylation influences the development of autoreactivity and experimental autoimmune encephalomyelitis. The results show that in comparison with nonacylated peptides, thioacylated PLP lipopeptides can induce greater T cell and Ab responses to both the acylated and nonacylated peptides. They also enhanced the development and chronicity of experimental autoimmune encephalomyelitis. Synthetic peptides in which the fatty acid was attached via an amide linkage at the N terminus were not encephalitogenic, and they induced greater proportions of CD8+ cells in initial in vitro stimulation. Therefore, the lability and the site of the linkage between the peptide and fatty acid may be important for induction of encephalitogenic CD4+ T cells. These results suggest that immune responses induced by endogenous thioacylated lipopeptides may contribute to the immunopathogenesis of chronic experimental demyelinating diseases and multiple sclerosis.