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Exploring the connections between the innate and adaptive immune responses at play in multiple sclerosis

English title Exploring the connections between the innate and adaptive immune responses at play in multiple sclerosis
Applicant Du Pasquier Renaud
Number 138411
Funding scheme Project funding
Research institution Service de Neurologie Département des Neurosciences Cliniques CHUV
Institution of higher education University of Lausanne - LA
Main discipline Immunology, Immunopathology
Start/End 01.01.2012 - 31.12.2014
Approved amount 438'000.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Neurology, Psychiatry

Keywords (5)

multiple sclerosis; innate immunity; antigen-presenting cells; virus; vitamin D

Lay Summary (English)

Lead
Lay summary

Multiple sclerosis (MS) is the most common cause of neurological disability in young adults following trauma. It is thought that MS is triggered by environmental agents in genetically-susceptible persons, a combination which will lead to autoimmunity. However, contrary to other autoimmune diseases, and despite numerous researches, what causes MS remains enigmatic. These elements point to the high complexity of this disease. So far, a lot of research has been devoted to the role of the adaptive immune response in MS. This type of immune response is antigen-specific, which means that the elements of this immune response (T cells, antibody-secreting plasmocytes) have been educated to recognize an antigen perceived as not friendly and to destroy it. In MS, such as in other auto-immune diseases, it has been logically postulated that an immune response directed against an auto-antigen (or an antigen of the self) would be instrumental.  In MS, myelin, the insulating sheath surrounding the axons, is primarily destroyed. Therefore, it has been hypothesized that anti-myelin T cells or antibodies would play a crucial role. However, despite decades of research and even if some anti-myelin immune response is involved, there are no convincing data supporting a primarily role of anti-myelin response as a cause of MS. The same is true for other auto-antigens. Thus, in this project, we will examine if another arm of the immune response, called the innate immunity, is involved in the pathogenesis of MS. Recently, major advances in our understanding of the innate immune response have been realized, which offer new tools to study such a response. Contrasting with adaptive immunity, the players of innate immunity do not need to be “educated” to recognize an antigen. Indeed, components of the innate immune system sense danger very rapidly thank to pattern recognition receptors (PRR).

Here, we would like to determine whether the innate immune response is dysregulated in MS. We also intend to assess the impact of this innate arm on the cellular adaptive arm of the immunity in MS. Using several read-outs (cytokine secretion, profile of chemokines, etc), we propose to examine the influence of various danger signals on cells of the innate immune response that are known to interact with the adaptive immune response, i.e. monocytes, dendritic cells and B lymphocytes. We will look in particular at stimuli that are known to activate Toll-like receptors and inflammasomes, which are major components of the innate immune system. Among the various compounds that will be used to stimulate these antigen-presenting cells (APCs), we will examine the effect of Epstein-Barr virus (EBV). Indeed, this virus a well-recognized environmental factor of MS and we have shown in previous studies that the EBV-specific CD8+ T cell response is dysregulated in patients in the early stages of MS, suggesting that this virus may be instrumental in triggering MS. Here, we would like to determine whether this EBV-specific CD8+ T cell dysregulation may stems from the innate immune response. Finally, we will take advantage of the proposed studies to determine the effect of vitamin D APCs. The lack of vitamin D is another environmental factor thought to trigger MS, which argues for studying the immunomodulatory role of this vitamin.

We believe that the proposed studies will significantly improve our understanding of the immunopathogenesis of MS as they are comprehensive, including the study of the innate and the adaptive immunity.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Natalizumab treatment alters the expression of T-cell trafficking marker LFA-1 α-chain (CD11a) in MS patients.
Jilek Samantha, Mathias Amandine, Canales Mathieu, Lysandropoulos Andreas, Pantaleo Giuseppe, Schluep Myriam, Du Pasquier Renaud A (2013), Natalizumab treatment alters the expression of T-cell trafficking marker LFA-1 α-chain (CD11a) in MS patients., in Multiple sclerosis (Houndmills, Basingstoke, England), 837.
Fatal PML associated with efalizumab therapy: insights into integrin αLβ2 in JC virus control.
Schwab N, Ulzheimer J C, Fox R J, Schneider-Hohendorf T, Kieseier B C, Monoranu C M, Staugaitis S M, Welch W, Jilek S, Du Pasquier R A, Brück W, Toyka K V, Ransohoff R M, Wiendl H (2012), Fatal PML associated with efalizumab therapy: insights into integrin αLβ2 in JC virus control., in Neurology, 78(7), 458.
HLA-B7-restricted EBV-specific CD8+ T cells are dysregulated in multiple sclerosis.
Jilek Samantha, Schluep Myriam, Harari Alexandre, Canales Mathieu, Lysandropoulos Andreas, Zekeridou Anastasia, Pantaleo Giuseppe, Du Pasquier Renaud A (2012), HLA-B7-restricted EBV-specific CD8+ T cells are dysregulated in multiple sclerosis., in Journal of immunology (Baltimore, Md. : 1950), 188(9), 4671-80.
Immunological and clinical consequences of treating a patient with natalizumab
Schwab N, Höhn KG, Schneider-Hohendorf T, Metz I, Stenner MP, Jilek S, Du Pasquier RA, Gold R, Meuth SG, Ransohoff RM, Brück W, Wiendl H (2012), Immunological and clinical consequences of treating a patient with natalizumab, in Mult Scler, 335.
Impairment of JCV-specific T-cell response by corticotherapy: effect on PML-IRIS management?
Antoniol C, Jilek S, Schluep M, Mercier N, Canales M, Le Goff G, Campiche C, Pantaleo G, Du Pasquier RA (2012), Impairment of JCV-specific T-cell response by corticotherapy: effect on PML-IRIS management?, in Neurology, 2258.
Type I IFN-mediated regulation of IL-1 production in inflammatory disorders.
Ludigs Kristina, Parfenov Valeriy, Du Pasquier Renaud A, Guarda Greta (2012), Type I IFN-mediated regulation of IL-1 production in inflammatory disorders., in Cellular and molecular life sciences : CMLS, 69(20), 3395-418.

Collaboration

Group / person Country
Types of collaboration
Université de Bâle Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Université de Münster Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
ISNI Poster New IL-22 function and its relevance in MS 10.11.2014 Mainz, Germany Du Pasquier Renaud; Mathias Amandine;
ISNI Poster Innate immune responses in MS: a systematic monocyte and B cell-based study 10.11.2014 Mainz, Germany Mathias Amandine; Du Pasquier Renaud;
ARSEP Talk given at a conference New Insight of IL-22 function and its putative role in MS 23.05.2014 Paris, France Du Pasquier Renaud; Mathias Amandine;
ECTRIMS Poster Nadir of CD11a expression on T lymphocytes of multiple sclerosis patients after two years of natalizumab 02.10.2013 Copenhague, Denmark Du Pasquier Renaud; Mathias Amandine;
ECTRIMS Poster HLA B7 is associated with higher relapse rate in multiple sclerosis patients 02.10.2013 Copenhague, Denmark Mathias Amandine; Du Pasquier Renaud;


Communication with the public

Communication Title Media Place Year
Media relations: radio, television La sclérose en plaques RTS-1 Western Switzerland 2014
Talks/events/exhibitions TEDXCHUV Western Switzerland 2012

Associated projects

Number Title Start Funding scheme
124893 CD8+ T lymphocytes, cytokines, Epstein-Barr virus: towards an unifying mechanism in Multiple Sclerosis? 01.05.2009 SNSF Professorships
159997 What happens upstream and downstream from T cell activation in multiple sclerosis? 01.07.2015 Project funding

Abstract

TITLE: EXPLORING THE CONNECTIONS BETWEEN THE INNATE AND ADAPTIVE IMMUNE RESPONSES AT PLAY IN MULTIPLE SCLEROSISMultiple sclerosis (MS) is the most common cause of neurological disability in young adults following trauma. It is thought that MS is triggered by environmental agents in genetically-susceptible persons, a combination which will lead to autoimmunity. However, contrary to other autoimmune diseases, and despite numerous researches, what causes MS remains enigmatic. These elements point to the high complexity of this disease and suggest that looking only at the adaptive immunity may not be sufficient to understand the immunopathogenesis of MS. In this context, an alternative model proposes a pivotal role of a dysregulated innate immune system that may, in turn, impact on the adaptive immune response, leading to autoreactive B and T cells. However, if some studies have explored the role of the innate immune system in experimental autoimmune encephalomyelitis (an animal model of MS), very few have looked at what happens in human MS. Yet, recently, major advances in our understanding of the innate immune response have been realized, which offer new tools to study such a response. In this proposal, we would like to determine whether the innate immune response is dysregulated in MS. We also intend to assess the impact of this innate arm on the cellular adaptive arm of the immunity in MS. Using several read-outs (cytokine secretion, profile of chemokines, etc), we propose to examine the influence of various danger signals on cells of the innate immune response that are known to interact with the adaptive immune response, i.e. monocytes, dendritic cells and B lymphocytes. We will look in particular at stimuli that are known to activate Toll-like receptors and inflammasomes, which are major components of the innate immune system. Among the various compounds that will be used to stimulate these antigen-presenting cells (APCs), we will examine the effect of Epstein-Barr virus (EBV). Indeed, this virus a well-recognized environmental factor of MS and we have shown in previous studies that the EBV-specific CD8+ T cell response is dysregulated in patients in the early stages of MS, suggesting that this virus may be instrumental in triggering MS. Here, we would like to determine whether this EBV-specific CD8+ T cell dysregulation may come stems from the innate immune response. Finally, we will take advantage of the proposed studies to determine the effect of vitamin D APCs. The lack of vitamin D is another environmental factor thought to trigger MS, which argues for studying the immunomodulatory role of this vitamin. Specifically, we will: -AIM :explore the response of APCs to different pathogen/danger-associated molecular patterns in MS-AIM 2: assess the link between the innate and the adaptive immunity in MSIn this second AIM, we will in particular:2.A. Study the influence of differentially stimulated APCs on T cells in MS2.B. Examine whether vitamin D modulates stimulated APCs and how this modulation acts on T cells. We believe that the proposed studies will significantly improve our understanding of the immunopathogenesis of MS as they are comprehensive, including the study of the innate and the adaptive immunity
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