Multiple Sclerosis and Central Nervous System Demyelination

Pouly, Sandrine; Antel, Jack P.

doi:10.1006/jaut.1999.0321

Cited by 41 publications

(27 citation statements)

References 125 publications

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“…Moreover, oligodendrocytes are sensitive to granzyme/perforin-mediated killing, whereas other neural cells are less sensitive to granzyme-mediated effects (43). Our finding that granzyme A is not upregulated in HC is in concordance with a previous report (44).…”

Section: Discussionsupporting

confidence: 93%

The IL-7Rα Pathway Is Quantitatively and Functionally Altered in CD8 T Cells in Multiple Sclerosis

Kreft

Verbraak

Wierenga‐Wolf

et al. 2012

The Journal of Immunology

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The IL-7Rα single nucleotide polymorphism rs6897932 is associated with an increased risk for multiple sclerosis (MS). IL-7Rα is a promising candidate to be involved in autoimmunity, because it regulates T cell homeostasis, proliferation, and antiapoptotic signaling. However, the exact underlying mechanisms in the pathogenesis of MS are poorly understood. We investigated whether CD4 and CD8 lymphocyte subsets differed in IL-7Rα expression and functionality in 78 MS patients compared with 59 healthy controls (HC). A significantly higher frequency of IL-7Rα+ CD8 effector memory (CD8EM) was found in MS. Moreover, IL-7Rα membrane expression was significantly increased in MS in naive and memory CD8 (all p < 0.05) with a similar trend in CD8EM (p = 0.055). No correlation was found between the expression level or frequency of IL-7Rα+CD8+ and rs6897932 risk allele carriership. Upon IL-7 stimulation, MS patients had stronger STAT5 activation in CD8EM compared with HC. IL-7 stimulation had a differential effect on both mRNA and protein expression of granzyme A and granzyme B between MS and HC. Stainings of different lesions in postmortem MS brain material showed expression of IL-7 and CD8+IL-7Rα+ in preactive, but not in active, demyelinating MS lesions, indicating involvement of IL-7Rα+ lymphocytes in lesion development. The intralesional production of IL-7 in combination with the lower threshold for IL-7–induced cytotoxicity in MS may enhance the pathogenicity of these CD8 T cells. This is of special interest in light of the established demyelinating and cytotoxic actions of granzyme A.

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Section: Discussionsupporting

confidence: 93%

The IL-7Rα Pathway Is Quantitatively and Functionally Altered in CD8 T Cells in Multiple Sclerosis

Kreft

Verbraak

Wierenga‐Wolf

et al. 2012

The Journal of Immunology

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“…185 There have been several studies reporting an intracellular pro-apoptotic role for GrB in MS. As oligodendrocytes and neurons express MHC-I, GrB-expressing CTLs may be responsible for the induction of cytotoxicity resulting in axonal damage and demyelination. 197 In addition, neurons expressing MHC-1 resist Fas-mediated killing but are susceptible to granule-mediated apoptosis. 198 gd T cells have also been suggested to direct cytotoxicity to the myelin-oligodendrocyte unit; however, inhibition of GrB in these cells only partially reduced cytolysis.…”

Section: Rasmussen's Encephalitismentioning

confidence: 99%

Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma

Boivin

Cooper

Hiebert

et al. 2009

Laboratory Investigation

256

290

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“…Recentemente, vários grupos sugerem participação direta desses autoanticorpos na manutenção da resposta inflamatória no SNC, afetando o controle da rede idiotípica e/ou promovendo via FcR a ativação de leucócitos e secreção de quimiocinas 10,26 . O reconhecimento de que as respostas imunes são fortemente controladas em diversos níveis por genes específicos tem engendrado estudos com o objetivo de estabelecer loci específicos entre susceptibilidade à EM 27,28 . Uma forte associação suscetibilidade à EM e presença do alelo DQB1*0602 tem sido descrita em diferentes populações étnicas, como caucasianos do norte da Europa, afro-caribenhos e chineses 3,8,29,30 .…”

Section: Discussionunclassified

Determinação de autoanticorpos para antígenos da mielina no soro de pacientes HLA - DQB1*0602 com esclerose múltipla

Carvalho

Sant'anna

Santos

et al. 2003

Arq. Neuro-Psiquiatr.

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RESUMO -Esclerose múltipla (EM) é doença inflamatória desmielinizante do sistema nervoso central (SNC) de natureza autoimune, mediada por linfócitos Th1. A produção de autoanticorpos séricos para proteína básica da mielina (MBP), proteolipídeo PLP e sequência da glicoproteína de oligodendrócito MOG 92-106, foi determinada em 54 indivíduos saudáveis e 26 pacientes com EM expressando ou não o alelo de suscetibilidade HLA-DQB1*0602. Independentemente da expressão do alelo DQB1*0602, todos os pacientes apresentaram produção marcante (p< 0,0001) de autoanticorpos isotipo IgG para MBP e MOG 92-106, e do isotipo IgA para PLP e MOG 92-106. Os resultados sugerem que outros alelos HLA da classe II exerçam influência na suscetibilidade à EM e no reconhecimento imunológico dos antígenos encefalitogênicos, determinando o padrão de resposta autoimune e contribuindo na manutenção e/ou controle da inflamação no SNC.PALAVRAS-CHAVE: esclerose múltipla, desmielinização, autoimunidade, antígenos da mielina, HLA DQB1*0602. Determination of autoantibody for myelin antigens in the serum of patients HLA -DQB1*0602 with multiple sclerosisABSTRACT -Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the human central nervous system (CNS) mediated by autoimmune Th1 lymphocytes. We determined the serum levels of autoantibodies for myelin basic protein (MBP), proteolipid (PLP) and myelin oligodendrocyte glycoprotein sequence MOG 92-106 in a group of 54 healthy individuals and 26 MS patients expressing or not HLA DQB1*0602. Regardless expression of the susceptibility alelle DQB1*0602, MS patients presented marked (p<0.0001) IgG antibody production for MBP and MOG92-106. Yet, significant (p<0.0001) IgA antibody levels were mainly observed for PLP and MOG antigens. Our results suggest that other HLA class II alleles may be conferring susceptibility to MS in this population and influencing the pattern of immune recognition of encephalitogen antigens. Furthermore, distinct IgG and/or IgA autoantibody production may be contributing to the control or maintenance of the CNS inflammatory reaction.KEY WORDS: multiple sclerosis, demyelination, myelin antigens, autoimmunity, HLA, DQB1*0602.Esclerose múltipla (EM) é doença crônica inflamatória e desmielinizante do sistema nervoso central (SNC) de natureza autoimune, que apresenta intenso infiltrado perivenular de células mononucleares, perda de oligodendrócitos e lesão axonal [1][2][3][4] . Estudos epidemiológicos mostram distribuição heterogênea da doença pelo mundo e incidência em 0,1% da população nos países de clima temperado 2 . Nos países de clima tropical como o Brasil, a doença era considerada rara, porém dados recentes 3 relatam incidên-cia elevada da EM em indivíduos brancos e também nos de etnia negra (afro-brasileiros). EM é considerada doença de etiologia multifatorial, em que a existência de predisposição genética aliada a fatores externos seria determinante no desencadeamento dos eventos imunológicos relacionados com o processo inflamatório e desmielinizante no SNC ...

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Multiple Sclerosis and Central Nervous System Demyelination

Cited by 41 publications

References 125 publications

The IL-7Rα Pathway Is Quantitatively and Functionally Altered in CD8 T Cells in Multiple Sclerosis

The IL-7Rα Pathway Is Quantitatively and Functionally Altered in CD8 T Cells in Multiple Sclerosis

Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma

Determinação de autoanticorpos para antígenos da mielina no soro de pacientes HLA - DQB1*0602 com esclerose múltipla

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