Novel monoclonal antibodies against proteolipid protein peptide 139–151 demonstrate demyelination and myelin uptake by macrophages in MS and marmoset EAE lesions

Laman, Jon D.; Visser, L. H.; Maassen, C.B.M.; Groot, C. J. A. De; Jong, Laurina A. de; Hart, Bert A. ’t; Meurs, Marjan van; Schellekens, M.M.

doi:10.1016/s0165-5728(01)00356-3

Cited by 15 publications

(9 citation statements)

References 33 publications

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“…Primary antibodies were polyclonal rabbit antibodies against transcription growth factor (TGF)-β (Santa Cruz) and NF-L (Abcam), and monoclonal mouse antibodies against NSE (MIG M3; Abcam), microtubule-associated protein-2 (MAP-2; HSM 5; Pierce Biotechnology), NF-H (SMI-32; Sternberger Monoclonals), PLP (J1/06 [36]), HLA-DP/DQ/DR (CR3/43; DAKO), CD40 (5D12; dr. M. de Boer), interleukin 1 receptor antagonist (IL-1ra; A71B6D11; Bioscource), tumor necrosis factor (TNF)-α (61E71; U Cytech), IL-12p40/p70 (C8.6; BD), and CCR7 (2H4; BD).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

et al. 2008

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Drainage of central nervous system (CNS) antigens to the brain-draining cervical lymph nodes (CLN) is likely crucial in the initiation and control of autoimmune responses during multiple sclerosis (MS). We demonstrate neuronal antigens within CLN of MS patients. In monkeys and mice with experimental autoimmune encephalomyelitis (EAE) and in mouse models with non-inflammatory CNS damage, the type and extent of CNS damage was associated with the frequencies of CNS antigens within the cervical lymph nodes. In addition, CNS antigens drained to the spinal-cord-draining lumbar lymph nodes. In human MS CLN, neuronal antigens were present in pro-inflammatory antigen-presenting cells (APC), whereas the majority of myelin-containing cells were anti-inflammatory. This may reflect a different origin of the cells or different drainage mechanisms. Indeed, neuronal antigen-containing cells in J Mol Med (2009) human CLN did not express the lymph node homing receptor CCR7, whereas myelin antigen-containing cells in situ and in vitro did. Nevertheless, CLN from EAE-affected CCR7-deficient mice contained equal amounts of myelin and neuronal antigens as wild-type mice. We conclude that the type and frequencies of CNS antigens within the CLN are determined by the type and extent of CNS damage. Furthermore, the presence of myelin and neuronal antigens in functionally distinct APC populations within MS CLN suggests that differential immune responses can be evoked.

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Section: Immunohistochemistrymentioning

confidence: 99%

Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

et al. 2008

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“…Antimyelin component antibodies generated under pathological conditions might have either adverse or beneficial effects (van der Veen et al, 1986(van der Veen et al, , 1989Endoh et al, 1986;Sadler et al, 1991;Potter and Stephens, 1994;Genain et al, 1995;Laman et al, 2001;Morris-Downes et al, 2002;Mitsunaga et al, 2002;Schwab, 2004). Moreover, potential pathogenetic roles for antimyelin antibodies, including anti-PLP antibodies, have been suggested in MS (Sun et al, 1991;Warren et al, 1994;Sellebjerg et al, 1995Sellebjerg et al, , 2000Archelos et al, 2000;Carvalho et al, 2003;Berger et al, 2003;Qin et al, 2003;Kanter et al, 2005;Zhang et al, 2005a).…”

Section: Implications For Msmentioning

confidence: 99%

Monoclonal antibodies to distinct regions of human myelin proteolipid protein simultaneously recognize central nervous system myelin and neurons of many vertebrate species

Greenfield¹,

Reddy²,

Lees³

et al. 2006

J of Neuroscience Research

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Myelin proteolipid protein (PLP), the major protein of mammalian CNS myelin, is a member of the proteolipid gene family (pgf). It is an evolutionarily conserved polytopic integral membrane protein and a potential autoantigen in multiple sclerosis (MS). To analyze antibody recognition of PLP epitopes in situ, monoclonal antibodies (mAbs) specific for different regions of human PLP (50–69, 100–123, 139–151, 178–191, 200–219, 264–276) were generated and used to immunostain CNS tissues of representative vertebrates. mAbs to each region recognized whole human PLP on Western blots; the anti‐100–123 mAb did not recognize DM‐20, the PLP isoform that lacks residues 116–150. All of the mAbs stained fixed, permeabilized oligodendrocytes and mammalian and avian CNS tissue myelin. Most of the mAbs also stained amphibian, teleost, and elasmobranch CNS myelin despite greater diversity of their pgf myelin protein sequences. Myelin staining was observed when there was at least 40% identity of the mAb epitope and known pgf myelin proteins of the same or related species. The pgf myelin proteins of teleosts and elasmobranchs lack 116–150; the anti‐100–123 mAb did not stain their myelin. In addition to myelin, the anti‐178–191 mAb stained many neurons in all species; other mAbs stained distinct neuron subpopulations in different species. Neuronal staining was observed when there was at least approximately 30% identity of the PLP mAb epitope and known pgf neuronal proteins of the same or related species. Thus, anti‐human PLP epitope mAbs simultaneously recognize CNS myelin and neurons even without extensive sequence identity. Widespread anti‐PLP mAb recognition of neurons suggests a novel potential pathophysiologic mechanism in MS patients, i.e., that anti‐PLP antibodies associated with demyelination might simultaneously recognize pgf epitopes in neurons, thereby affecting their functions. © 2006 Wiley‐Liss, Inc.

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“…Such multideterminant specificity of the T cell response could contribute to the fact that there is no monocausative relation between a single T cell specificity and disease severity. After immunization of SJL mice with PLP:139-151, IgG2a and IgG2b antibodies directed against this antigen have been found (Laman et al, 2001). by secreting autoantibodies against myelin (Lyons et al, 1999) or axonal components (Mathey et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

The magnitude of the antigen‐specific T cell response is separated from the severity of spinal cord histopathology in remitting‐relapsing experimental autoimmune encephalomyelitis

Batoulis

Uhl

Addicks

et al. 2012

Glia

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Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system. The remitting-relapsing experimental autoimmune encephalomyelitis (EAE) in the SJL mouse strain is a common animal model for MS and similar to the human disease it is considered to be T helper cell mediated. Besides interferon-γ secreting T(H)1 cells in particular the T(H)17 subset is believed to be highly pathogenic. Spreading of the T(H)1 and T(H)17 response to newly emerging determinants has been used to explain clinical disease relapse, but if the magnitude of the T(H)1/T(H)17 response is linked to clinical relapse severity has remained unresolved. Here, we assessed clinical EAE severity, the extent of spinal cord histopathology and the magnitude of the antigen-specific T helper cell and autoantibody response in proteolipid protein peptide 139-151 (PLP:139-151)-immunized SJL mice in clinical remission and relapse. We demonstrate that spinal cord histopathology comprised inflammation, demyelination as well as axonal loss and correlated well with clinical disease severity. Although the degree of spinal cord histopathology and clinical severity was separated from the PLP:139-151-specific T(H)1/T(H)17 cell and antibody response, it was linked to the number of infiltrating macrophages and activated microglia. In particular, there was a correlation between their secretion product interleukin-1β and the degree of axonal loss. Although CD4(+) T cells seem to be mainly involved in disease initiation, we suggest that it is the downstream activation of the innate immune response that defines the magnitude of the disease outcome.

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Novel monoclonal antibodies against proteolipid protein peptide 139–151 demonstrate demyelination and myelin uptake by macrophages in MS and marmoset EAE lesions

Cited by 15 publications

References 33 publications

Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

Monoclonal antibodies to distinct regions of human myelin proteolipid protein simultaneously recognize central nervous system myelin and neurons of many vertebrate species

The magnitude of the antigen‐specific T cell response is separated from the severity of spinal cord histopathology in remitting‐relapsing experimental autoimmune encephalomyelitis

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