T-cell responses to neurofilament light protein are part of the normal immune repertoire

Huizinga, Ruth; Hintzen, Rogier Q.; Assink, Karin; Meurs, Marjan van; Amor, Sandra

doi:10.1093/intimm/dxp011

Cited by 16 publications

(20 citation statements)

References 45 publications

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“…For example, CD4 + T cells were found in the substantia nigra in PD patients and there was an alteration of CD4 + and CD8 + T cells in AD [93, 94]. …”

Section: Role Of the Adaptive Immune System In Huntington's Diseasementioning

confidence: 99%

“…As a result, they assumed that neuroinflammation in HD is solely based on interaction of microglia, neurons, and macroglia. In contrast, some evidence for a role of T cells in HD has emerged from studies that measured elevated T-cell responses to specific antigens as well as shifts in CD4 + and CD8 + cell populations in the CNS [93]. However, functional studies and comprehensive immunological analysis on T cells in HD have not been largely performed to date.…”

Section: Role Of the Adaptive Immune System In Huntington's Diseasementioning

confidence: 99%

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The Role of the Immune System in Huntington’s Disease

Ellrichmann

Reick

Saft

et al. 2013

Clinical and Developmental Immunology

126

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Huntington's disease (HD) is characterized by a progressive course of disease until death 15–20 years after the first symptoms occur and is caused by a mutation with expanded CAG repeats in the huntingtin (htt) protein. Mutant htt (mhtt) in the striatum is assumed to be the main reason for neurodegeneration. Knowledge about pathophysiology has rapidly improved discussing influences of excitotoxicity, mitochondrial damage, free radicals, and inflammatory mechanisms. Both innate and adaptive immune systems may play an important role in HD. Activation of microglia with expression of proinflammatory cytokines, impaired migration of macrophages, and deposition of complement factors in the striatum indicate an activation of the innate immune system. As part of the adaptive immune system, dendritic cells (DCs) prime T-cell responses secreting inflammatory mediators. In HD, DCs may contain mhtt which brings the adaptive immune system into the focus of interest. These data underline an increasing interest in the peripheral immune system for pathomechanisms of HD. It is still unclear if neuroinflammation is a reactive process or if there is an active influence on disease progression. Further understanding the influence of inflammation in HD using mouse models may open various avenues for promising therapeutic approaches aiming at slowing disease progression or forestalling onset of disease.

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“…For example, CD4 + T cells were found in the substantia nigra in PD patients and there was an alteration of CD4 + and CD8 + T cells in AD [93, 94]. …”

Section: Role Of the Adaptive Immune System In Huntington's Diseasementioning

confidence: 99%

Section: Role Of the Adaptive Immune System In Huntington's Diseasementioning

confidence: 99%

The Role of the Immune System in Huntington’s Disease

Ellrichmann

Reick

Saft

et al. 2013

Clinical and Developmental Immunology

126

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“…In MS, antibodies and T cells are also directed to neuroaxonal antigens (Derfuss et al, 2009;Forooghian et al, 2007;Huizinga et al, 2009;Mathey et al, 2007;Silber et al, 2002), and axon-reactive B cells are present in the cerebrospinal fluid (CSF; Zhang et al, 2005). In mice, extensive axonal damage occurs after immunization with the axonal protein neurofilament light (NF-L; Huizinga et al, 2007Huizinga et al, , 2008.…”

Section: Introductionmentioning

confidence: 99%

Phagocytosis of neuronal debris by microglia is associated with neuronal damage in multiple sclerosis

Huizinga

Star

Kipp

et al. 2011

Glia

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Neuroaxonal degeneration is a pathological hallmark of multiple sclerosis (MS) contributing to irreversible neurological disability. Pathological mechanisms leading to axonal damage include autoimmunity to neuronal antigens. In actively demyelinating lesions, myelin is phagocytosed by microglia and blood-borne macrophages, whereas the fate of degenerating or damaged axons is unclear. Phagocytosis is essential for clearing neuronal debris to allow repair and regeneration. However, phagocytosis may lead to antigen presentation and autoimmunity, as has been described for neuroaxonal antigens. Despite this notion, it is unknown whether phagocytosis of neuronal antigens occurs in MS. Here, we show using novel, well-characterized antibodies to axonal antigens, that axonal damage is associated with HLA-DR expressing microglia/macrophages engulfing axonal bulbs, indicative of axonal damage. Neuronal proteins were frequently observed inside HLA-DR 1 cells in areas of axonal damage. In vitro, phagocytosis of neurofilament light (NF-L), present in white and gray matter, was observed in human microglia. The number of NF-L or myelin basic protein (MBP) positive cells was quantified using the mouse macrophage cell line J774.2. Intracellular colocalization of NF-L with the lysosomal membrane protein LAMP1 was observed using confocal microscopy confirming that NF-L is taken up and degraded by the cell. In vivo, NF-L and MBP was observed in cerebrospinal fluid cells from patients with MS, suggesting neuronal debris is drained by this route after axonal damage. In summary, neuroaxonal debris is engulfed, phagocytosed, and degraded by HLA-DR 1 cells. Although uptake is essential for clearing neuronal debris, phagocytic cells could also play a role in augmenting autoimmunity to neuronal antigens. V

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“…However, accumulating evidence shows that immune responses to neuronal and axonal proteins are also present in a wide range of neurodegenerative disorders including MS [4-6]. That these responses may contribute to axonal and neuronal damage, pathological hallmarks of MS, is supported by observations that immunization with neuronal antigens and transfer of antibodies directed to neuronal and axonal proteins induce neuronal damage in animals [7-10].…”

Section: Introductionmentioning

confidence: 99%

Characterization of immune response to neurofilament light in experimental autoimmune encephalomyelitis

Puentes

Star

Victor

et al. 2013

J Neuroinflammation

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BackgroundAutoimmunity to neuronal proteins occurs in several neurological syndromes, where cellular and humoral responses are directed to surface as well as intracellular antigens. Similar to myelin autoimmunity, pathogenic immune response to neuroaxonal components such as neurofilaments may contribute to neurodegeneration in multiple sclerosis.MethodsWe studied the immune response to the axonal protein neurofilament light (NF-L) in the experimental autoimmune encephalomyelitis animal model of multiple sclerosis. To examine the association between T cells and axonal damage, pathology studies were performed on NF-L immunized mice. The interaction of T cells and axons was analyzed by confocal microscopy of central nervous system tissues and T-cell and antibody responses to immunodominant epitopes identified in ABH (H2-Ag7) and SJL/J (H2-As) mice. These epitopes, algorithm-predicted peptides and encephalitogenic motifs within NF-L were screened for encephalitogenicity.ResultsConfocal microscopy revealed both CD4+ and CD8+ T cells alongside damaged axons in the lesions of NF-L immunized mice. CD4+ T cells dominated the areas of axonal injury in the dorsal column of spastic mice in which the expression of granzyme B and perforin was detected. Identified NF-L epitopes induced mild neurological signs similar to the observed with the NF-L protein, yet distinct from those characteristic of neurological disease induced with myelin oligodendrocyte glycoprotein.ConclusionsOur data suggest that CD4+ T cells are associated with spasticity, axonal damage and neurodegeneration in NF-L immunized mice. In addition, defined T-cell epitopes in the NF-L protein might be involved in the pathogenesis of the disease.

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T-cell responses to neurofilament light protein are part of the normal immune repertoire

Cited by 16 publications

References 45 publications

The Role of the Immune System in Huntington’s Disease

The Role of the Immune System in Huntington’s Disease

Phagocytosis of neuronal debris by microglia is associated with neuronal damage in multiple sclerosis

Characterization of immune response to neurofilament light in experimental autoimmune encephalomyelitis

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