Multiple sclerosis

Eikelenboom, Merijn; Petzold, Axel; Lazeron, R.H.C.; Silber, Eli; Sharief, Mohammed; Thompson, Edward H.; Barkhof, Frederik; Giovannoni, Gavin; Polman, Chris H.; Uitdehaag, B. M. J.

doi:10.1212/01.wnl.0000041496.58127.e3

Cited by 121 publications

(115 citation statements)

References 26 publications

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“…What mechanisms drive the anti-SPAG16 humoral immune response and how could Abs against SPAG16 potentially contribute to the pathology of MS? Ab reactivity toward other intracellular targets such as SPAG16 (e.g., neurofilament and tubulin) is not uncommon in MS (24,25). There are several hypotheses on the generation of an Ab response toward intracellular proteins (26).…”

Section: Discussionmentioning

confidence: 99%

Sperm-Associated Antigen 16 Is a Novel Target of the Humoral Autoimmune Response in Multiple Sclerosis

Bock

Somers

Fraussen

et al. 2014

The Journal of Immunology

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We have previously identified eight novel autoantibody targets in the cerebrospinal fluid of multiple sclerosis (MS) patients, including sperm-associated Ag 16 (SPAG16). In the current study, we further investigated the autoantibody response against SPAG16—a protein with unknown function in the CNS—and its expression in MS pathology. Using isoelectric focusing, we detected SPAG16-specific oligoclonal bands in the cerebrospinal fluid of 5 of 23 MS patients (22%). Analysis of the anti-SPAG16 Ab reactivity in the plasma of a total of 531 donors using ELISA demonstrated significantly elevated anti-SPAG16 Ab levels (p = 0.002) in 32 of 153 MS patients (21%) compared with all other control groups with 95% specificity for the disease. To investigate the pathologic relevance of anti-SPAG16 Abs in vivo, anti-SPAG16 Abs were injected in mice with experimental autoimmune encephalomyelitis, resulting in a significant disease exacerbation. Finally, we demonstrated a consistent upregulation of SPAG16 in MS brain and experimental autoimmune encephalomyelitis spinal cord lesions, more specifically in reactive astrocytes. We conclude that SPAG16 is a novel autoantibody target in a subgroup of MS patients and in combination with other diagnostic criteria, elevated levels of anti-SPAG16 Abs could be used as a biomarker for diagnosis. Furthermore, the pathologic relevance of anti-SPAG16 Abs was shown in vivo.

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Section: Discussionmentioning

confidence: 99%

Sperm-Associated Antigen 16 Is a Novel Target of the Humoral Autoimmune Response in Multiple Sclerosis

Bock

Somers

Fraussen

et al. 2014

The Journal of Immunology

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“…In MS, humoral responses to neuronal antigens are also observed. Axon-reactive B cells are present in MS CNS, and antibodies to NF-L are present in the CSF of patients with MS (Ehling et al, 2004;Eikelenboom et al, 2003;Silber et al, 2002). Antibodies to neuronal antigens isolated from patients with MS induce damage in animals (Derfuss et al, 2009;Mathey et al, 2007).…”

Section: Discussionmentioning

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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“…Studies that analysed both allowed a direct comparison of their value. 2,17 In favor of the combined analysis of several neurofilament subunits, including also the intermediate subunit, are also the described different stoichiometries for the different subunits in different phases of the disease, i.e. the ratio for NfL: NfM: NfH being estimated as 24:5:2 in RRMS and 30:0:1 in CIS.…”

Section: Key Hypothesesmentioning

confidence: 99%

Neurofilaments as biomarkers in multiple sclerosis

2012

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Neurodegeneration is the correlate of disease progression in multiple sclerosis (MS) and thus biological biomarkers that sensitively reflect this process are much needed. Neurofilament protein subunits are potential cerebrospinal fluid (CSF) biomarkers for disease progression in MS. We argue that the neurofilament light subunit can reflect acute axonal damage mediated by inflammatory mechanisms and can imply prognostic value for conversion from clinically isolated syndrome (CIS) to definite MS. The neurofilament heavy subunit may rather reflect chronic irreversible damage and has prognostic value for disease progression or disability. The neurofilament intermediate subunit has not yet been studied. Recent studies showing higher neurofilament light or heavy subunit levels to be altered upon treatment regimes indicate their potential clinical value in monitoring treatment or side effects. Future studies should be aimed at the optimisation, standardisation and interlaboratory implementation of the assays and address the predictive value of these biomarkers.

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Multiple sclerosis

Abstract: Intrathecal production of anti-NfL antibodies may serve as a marker of tissue damage, particularly axonal loss, in MS.

Cited by 121 publications

References 26 publications

Sperm-Associated Antigen 16 Is a Novel Target of the Humoral Autoimmune Response in Multiple Sclerosis

Sperm-Associated Antigen 16 Is a Novel Target of the Humoral Autoimmune Response in Multiple Sclerosis

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

Neurofilaments as biomarkers in multiple sclerosis

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