Lymphotoxin in neurologic inflammation, lymphoid neoorganogenesis, and determinant spreading

Hjelmström, Peter; Marković-Pleše, Silva; Juedes, Amy E.; Ruddle, NH

doi:10.1016/s0165-5728(98)91228-0

Cited by 2 publications

(4 citation statements)

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“…In studying the role of ADCC in EAE, we had to initially resolve the dilemma that a vital role for Ig-binding FcRs for EAE development is in apparent conflict with the EAE susceptibility of B cell-deficient mice (16)(17)(18)(19)(20). To resolve this paradox, we generated mice deficient in both B cells and FcR␥ and demonstrated that the FcR␥ deficiency decreases immunity independently of B cells or Igs and that the EAE resistance of FcR␥ Ϫ/Ϫ mice cannot be attributed to humoral immunity.…”

Section: Discussionmentioning

confidence: 99%

“…The advantage here is that Abs raised by the immunization with MOG peptide do not facilitate the disease process, because mice deficient in B cells develop severe EAE (16)(17)(18)(19)(20)(21). Our aim was to determine the effector mechanism invoked by systemically administered demyelinating anti-MOG Abs by using mice deficient in either the classical complement or the Fc␥R pathway.…”

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confidence: 99%

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Autoantibody-mediated demyelination depends on complement activation but not activatory Fc-receptors

Urich

Gutcher

Prinz

2006

Proc. Natl. Acad. Sci. U.S.A.

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The precise mechanisms leading to CNS inflammation and myelin destruction in both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) remain the subject of intense debate. In both MS and EAE, autoantibodies (autoAbs) are thought to be involved in tissue destruction through recruiting Fc receptor (FcR)-bearing cells or direct cytotoxic effects through the activation of the complement pathway. Whereas intrathecal immunoglobulin (Ig) production and Ig deposition in inflammatory lesions is a hallmark of MS, mice deficient in B cells and Igs develop severe EAE. Paradoxically, mice of the same genetic background but deficient in FcR␥ are EAE-resistant. We found that the functional expression of FcR␥ on systemic accessory cells, but not CNS-resident cells, appears to be vital for the development of CNS inflammation, independent of antigenpresenting cell function or Ab involvement. On the other hand, we found that the injection of antimyelin oligodendrocyte glycoproteinAbs drastically worsens disease severity, inflammation, and demyelination. Using FcR␥ ؊/؊ and C1q ؊/؊ mice, we could definitively establish that the demyelinating capacity of such autoAb in vivo relies entirely on complement activation and is FcR-independent.autoimmunity ͉ multiple sclerosis ͉ neuropathology ͉ B cells ͉ humoral immunity

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Autoantibody-mediated demyelination depends on complement activation but not activatory Fc-receptors

Urich

Gutcher

Prinz

2006

Proc. Natl. Acad. Sci. U.S.A.

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“…T cells specific for an encephalitogenic MOG peptide can induce clinical signs and CNS inflammation and demyelination in EAE (14)(15)(16). A monoclonal antibody to MOG induces demyelination in vitro (17) and exacerbates T cell-mediated disease in mice and rats (18,19).…”

mentioning

confidence: 99%

“…A monoclonal antibody to MOG induces demyelination in vitro (17) and exacerbates T cell-mediated disease in mice and rats (18,19). We have previously demonstrated that immunization of C57BL͞6 mice with either rat MOG protein or rat MOG35-55 peptide results in a B cell-independent disease (16); in contrast, immunization with human MOG protein generates a B cell-dependent disease (20,21), whereas immunization with human MOG 35-55 peptide leads to only minimal clinical signs of EAE (21). In vitro assays have demonstrated that the predominant T cell response in C57BL͞6 mice to the extracellular domain of both human and rat MOG proteins is directed to their 35-55 regions (21,22).…”

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confidence: 99%

Pathogenic myelin oligodendrocyte glycoprotein antibodies recognize glycosylated epitopes and perturb oligodendrocyte physiology

Marta

Oliver

Sweet

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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122

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Antibodies to myelin components are routinely detected in multiple sclerosis patients. However, their presence in some control subjects has made it difficult to determine their contribution to disease pathogenesis. Immunization of C57BL͞6 mice with either rat or human myelin oligodendrocyte glycoprotein (MOG) leads to experimental autoimmune encephalomyelitis (EAE) and comparable titers of anti-MOG antibodies as detected by ELISA. However, only immunization with human (but not rat) MOG results in a B cell-dependent EAE. In this study, we demonstrate that these pathogenic and nonpathogenic anti-MOG antibodies have a consistent array of differences in their recognition of antigenic determinants and biological effects. Specifically, substituting proline at position 42 with serine in human MOG (as in rat MOG) eliminates the B cell requirement for EAE. All MOG proteins analyzed induced high titers of anti-MOG (tested by ELISA), but only antisera from mice immunized with unmodified human MOG were encephalitogenic in primed B cell-deficient mice. Nonpathogenic IgGs bound recombinant mouse MOG and deglycosylated MOG in myelin (tested by Western blot), but only pathogenic IgGs bound glycosylated MOG. Only purified IgG to human MOG bound to live rodent oligodendrocytes in culture and, after cross-linking, induced repartitioning of MOG into lipid rafts, followed by dramatic changes in cell morphology. The data provide a strong link between in vivo and in vitro observations regarding demyelinating disease, further indicate a biochemical mechanism for anti-MOGinduced demyelination, and suggest in vitro tools for determining autoimmune antibody pathogenicity in multiple sclerosis patients. multiple sclerosis ͉ experimental autoimmune encephalomyelitis ͉ lipid rafts ͉ B cell-deficient mice ͉ encephalitogenicity M ultiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) in which both T cells and antibodies against myelin antigens are routinely detected (1, 2). B cell responses in MS pathogenesis are implicated by the presence of Ig deposits and myelin debris in demyelinating lesions (3-8), and the observation that plasma exchange dramatically reduces clinical disease in a subset of patients (9). Of particular interest to the present study, antibodies to myelin oligodendrocyte glycoprotein (MOG) are detected in the sera and plaques of MS patients (10), and thus are possible predictors of disease progression (11). However, because some control subjects can also harbor anti-myelin antibodies (1, 2, 12), their contribution to MS pathogenesis has been controversial and difficult to identify in individual patients. Further complicating the issue, MS may be several diseases of differing etiologies (5), whereby anti-myelin antibodies may be pathogenic in some forms of MS but merely a reflection of tissue damage in others. Thus, an understanding of whether anti-myelin antibodies are in fact pathogenic, and if so, by what mechanisms they operate, could provide important information for novel diagnosti...

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Lymphotoxin in neurologic inflammation, lymphoid neoorganogenesis, and determinant spreading

Cited by 2 publications

References 0 publications

Autoantibody-mediated demyelination depends on complement activation but not activatory Fc-receptors

Autoantibody-mediated demyelination depends on complement activation but not activatory Fc-receptors

Pathogenic myelin oligodendrocyte glycoprotein antibodies recognize glycosylated epitopes and perturb oligodendrocyte physiology

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