CD44 variant isoforms control experimental autoimmune encephalomyelitis by affecting the lifespan of the pathogenic T cells

Ghazi-Visser, Lizette; Laman, Jon D.; Nagel, Sabine; Meurs, Marjan van; Riel, Debby van; Tzankov, Alexandar; Frank, Stephan; Adams, Heiner; Wolk, Kerstin; Terracciano, Luigi; Melief, Marie-José; Sabat, Robert; Günthert, Ursula

doi:10.1096/fj.13-228809

Cited by 14 publications

(10 citation statements)

References 61 publications

(93 reference statements)

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“…Increased expression of CD44 probably lends to Tregs cells a more suppressive phenotype because of CD44's known correlation with higher suppressive activity (Firan et al, 2006;Bollyky et al, 2009). The increased CD44 expression could also account for the increased frequency of Treg cells in the CNS, since Cd44 À/À mice with EAE have a lower frequency of Treg cells in the CNS (Ghazi-Visser et al, 2013). Our data showing that the CNS Tregs from treated animals contained more CD44 might imply that melatonin caused a highly suppressive milieu in the CNS.…”

Section: Discussionmentioning

confidence: 65%

Melatonin controls experimental autoimmune encephalomyelitis by altering the T effector/regulatory balance

Álvarez-Sánchez

Cruz‐Chamorro

López-González

et al. 2015

Brain, Behavior, and Immunity

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Section: Discussionmentioning

confidence: 65%

Melatonin controls experimental autoimmune encephalomyelitis by altering the T effector/regulatory balance

Álvarez-Sánchez

Cruz‐Chamorro

López-González

et al. 2015

Brain, Behavior, and Immunity

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“…Moreover, passive immunization with the human anti-OPN-C recombinant antibody ameliorated the disease course (Figure 6). These data identified a role for the CD44-binding site displayed by OPN-C, which is intriguing because CD44 is involved in EAE by favoring the homing and survival of the autoimmune T cells, and by increasing IL - 17A and IFN-γ production and decreasing IL-10 production (34–42). Moreover, data in the literature show that OPN stimulates IL - 17A and IFN-γ production and inhibits IL-10 production in EAE and MS (15).…”

Section: Discussionmentioning

confidence: 97%

Role of Anti-Osteopontin Antibodies in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

et al. 2017

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Osteopontin (OPN) is highly expressed in demyelinating lesions in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). OPN is cleaved by thrombin into N- (OPN-N) and C-terminal (OPN-C) fragments with different ligands and functions. In EAE, administering recombinant OPN induces relapses, whereas treatment with anti-OPN antibodies ameliorates the disease. Anti-OPN autoantibodies (autoAbs) are spontaneously produced during EAE but have never been detected in MS. The aim of the study was to evaluate anti-OPN autoAbs in the serum of MS patients, correlate them with disease course, and recapitulate the human findings in EAE. We performed ELISA in the serum of 122 patients collected cross-sectionally, and 50 patients with relapsing–remitting (RR) disease collected at diagnosis and followed longitudinally for 10 years. In the cross-sectional patients, the autoAb levels were higher in the RR patients than in the primary- and secondary-progressive MS and healthy control groups, and they were highest in the initial stages of the disease. In the longitudinal group, the levels at diagnosis directly correlated with the number of relapses during the following 10 years. Moreover, in patients with active disease, who underwent disease-modifying treatments, autoAbs were higher than in untreated patients and were associated with low MS severity score. The autoAb displayed neutralizing activity and mainly recognized OPN-C rather than OPN-N. To confirm the clinical effect of these autoAbs in vivo, EAE was induced using myelin oligodendrocyte glycoprotein MOG35–55 in C57BL/6 mice pre-vaccinated with ovalbumin (OVA)-linked OPN or OVA alone. We then evaluated the titer of antibodies to OPN, the clinical scores and in vitro cytokine secretion by spleen lymphocytes. Vaccination significantly induced antibodies against OPN during EAE, decreased disease severity, and the protective effect was correlated with decreased T cell secretion of interleukin 17 and interferon-γ ex vivo. The best effect was obtained with OPN-C, which induced significantly faster and more complete remission than other OPN vaccines. In conclusion, these data suggest that production of anti-OPN autoAbs may favor remission in both MS and EAE. Novel strategies boosting their levels, such as vaccination or passive immunization, may be proposed as a future strategy in personalized MS therapy.

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“…METHODS Animals. The targeted mice for the CD44 variant exons v7, v6v7, and v10 8,49 were backcrossed for 10 generations onto the BALB/c background. BALB/c mice (Iffa Credo BJico, Orléans, France) were used to backcross the targeted mutation in Rag2 for 10 generations to yield BALB/c Rag2 À / À mice.…”

Section: Cd44v7 Cd44v Cd44smentioning

confidence: 99%

Absence of specific alternatively spliced exon of CD44 in macrophages prevents colitis

et al. 2018

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CD44 is a transmembrane molecule appearing in numerous isoforms generated by insertions of alternatively spliced variant exons (CD44v) and having various binding partners. CD44v7 on T cells was proposed to promote colitis by preventing T-cell apoptosis. Here we demonstrate that Cd44v7-deficient T cells - like Cd44 wild-type (Cd44) T cells - provoked disease in two different colitis models: the model induced by CD4CD45RB T-cell transfer into Rag2-deficient mice and a new model based on ovalbumin (OVA)-specific T-cell transfer into Rag-sufficient, OVA-challenged mice. In contrast, CD44v7 absence on macrophages in recipient mice prevented colitis. Prevention was associated with the downregulation of signal transducer and activator of transcription 3 (STAT3)-activating and Foxp3-counteracting interleukin-6 (IL-6), lower numbers of phospho-STAT3-containing lymphocytes, and higher Foxp3 T-cell counts in the colon. Consequently, the protected colons showed lower IL-12, IL-1β expression, and decreased interferon-γ levels. Importantly, stimulation of T cells by Cd44v7-deficient macrophages induced upregulation of Foxp3 in vitro, while cotransfer of Cd44 macrophages into Cd44v7-deficient mice reduced Foxp3 T-cell counts and caused colitis. Accordingly, the CD44v7 ligand osteopontin, whose levels were elevated in Crohn's disease, specifically induced IL-6 in human monocytes, a cytokine also increased in these patients. We suggest macrophage-specific targeting of the CD44v7 pathway as a novel therapeutic option for Crohn's disease.

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CD44 variant isoforms control experimental autoimmune encephalomyelitis by affecting the lifespan of the pathogenic T cells

Cited by 14 publications

References 61 publications

Melatonin controls experimental autoimmune encephalomyelitis by altering the T effector/regulatory balance

Melatonin controls experimental autoimmune encephalomyelitis by altering the T effector/regulatory balance

Role of Anti-Osteopontin Antibodies in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

Absence of specific alternatively spliced exon of CD44 in macrophages prevents colitis

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