Master 2 immunologie : 2018 2019


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MASTER 2 IMMUNOLOGIE : 2018 - 2019
Send to Secrétariat Pédagogique du M2 d'Immunologie : ines.lassoued@parisdescartes.fr

Before the 4th of June 2018

Internship proposal for Master 2


(Proposition de stage de M2)
1. Team
Administrative affiliation (CNRS, INSERM…) and number of the unit) : INSERM UMRS 1138,
Name of the head of laboratory : P Ferré
Name of the team : eq 10 "Complement and Diseases"
Adress : Centre de Recherche des Cordeliers, 15 rue de l'école de Médecine, 75006 Paris
Name of the responsible of the team : Dr V Frémeaux-Bacchi
Responsible for surpervising the student : Dr M-A Dragon-Durey
Tel : 01 56 09 59 99 E-mail : marie-agnes.durey@aphp.fr

2. Course ( Parcours)

 Immunologie approfondie (Basic Immunology)
x Immunologie-Immunopathologie (Immunology - Immunopathology)
3. Project title and summary (Thème du stage, titre et description du sujet)

(1 page maximum in english) :
Study of glycosylation and post-translational modifications of anti-Complement Factor H Autoantibodies in atypical Hemolytic Uremic syndrome and C3 Glomerulopathies.
Atypical Hemolytic Uremic syndrome (aHUS) and C3 Glomerulopathies (C3G) are rare renal diseases with poor prognosis.

aHUS is a acute, life-threatening thrombotic microangiopathy inducing possible relapses and renal sequelae. In contrast, C3G are chronic diseases characterized by C3 deposits along the glomerular basement membrane, leading to a chronic renal insufficiency. Both diseases are related to a dysregulation of the complement system. Among the etiologies of this dysregulation, presence of anti-Factor H autoantibodies accounts for about 10-20% of cases. Factor H (FH) is the main plasma regulator of the alternative pathway C3 convertase and the study of the anti-FH autoantibodies have shown the neutralization capacities of these autoantibodies. However, why the same autoantibodies can induce acute (aHUS) or chronic (C3G) diseases, remains poorly understood. Moreover, even if the autoantibodies levels correlate well with the disease, during the patients'follow up, it remains difficult to predict the risk of disease recurrence based on the anti-FH levels. So the autoantibodies characterization is potentially of high interest for managing the patients and adapting the therapy (plasma exchanges for aHUS,immunosuppression +/- anti-C5 therapeutic MAB : eculizumab).

The post translational modifications, notably of the glycosylation, of the IgG are known to play a role in their functional activity and avidity. These modifications have been shown to play a role in the pathogenicity of some autoantibodies such as rheumatoid factor in the rheumatoid arthritis or the anti-MPO or anti-PR3 antibodies in systemic vasculitis. The aim of the project is to study the post-translational modifications of the anti-FH autoantibodies and compare the glycosylation profile according to the disease association (aHUS vs C3G) and the disease stage (Acute vs remission).

Methodology, technics used by the student:

  1. Constitution of a plasma collection dedicated to this work (from the HEGP collection): patients and samples' selection (5 to 10 patients /disease - at least 3 time-point's samples with one at the acute phase)

  2. Immunopurification of anti-FH IgG

  3. Characterization of the immunopurified antibodies

    1. by SPR (association/dissociation rates),

    2. IgG subtypes determination

  4. Study of the immunopurified IgG glycosylation in collaboration with the team : " Analyse et Modélisation pour la Biologie et l’Environnement, équipe "Structure-réactivité de biomolécules : complexes organométalliques et macromoléculaires", Pr Florence Gonnet et Dr R Daniel http://www.lambe.univ-evry.fr

  5. Profiles analysis according to the pathology and the disease activity.

  6. Optional study (according to the project progression) : study of the anti-FH glycosylation profile on their avidity (by SPR) and their neutralization capacity in vitro and in vivo (with a mouse model to be established)


4. Composition of the team
Number of scientists : 3



Senior scientists : 3 with HDR* : 3
Technician-Engineer : 1
Postdoc : 0
Total : 4 Total HDR : 3
Number of students

Master 2 : 3
1° Year of PhD : 0
2° Year of PhD: : 0
3° Year of PhD : : 1
4° Year of PhD : :      
Total PhD Students : : 1

5. Publications (5 most significant during the 4 last years).
A novel CFHR1-CFHR5 hybrid leads to a familial dominant C3 glomerulopathy. Togarsimalemath SK, Sethi SK, Duggal R, Le Quintrec M, Jha P, Daniel R, Gonnet F, Bansal S, Roumenina LT, Fremeaux-Bacchi V, Kher V, Dragon-Durey MA. Kidney Int. 2017 Oct;92(4):876-887. PMID:28729035

C5 nephritic factors drive the biological phenotype of C3 glomerulopathies. Marinozzi MC, Chauvet S, Le Quintrec M, Mignotet M, Petitprez F, Legendre C, Cailliez M, Deschenes G, Fischbach M, Karras A, Nobili F, Pietrement C, Dragon-Durey MA, Fakhouri F, Roumenina LT, Fremeaux-Bacchi V. Kidney Int. 2017 Nov;92(5):1232-1241.PMID:28712854

Anti-complement-factor H-associated glomerulopathies. Durey MA, Sinha A, Togarsimalemath SK, Bagga A. Nat Rev Nephrol. 2016 Sep;12(9):563-78. PMID:27452363

Anti-factor H autoantibodies in C3 glomerulopathies and in atypical hemolytic uremic syndrome: one target, two diseases. Blanc C, Togarsimalemath SK, Chauvet S, Le Quintrec M, Moulin B, Buchler M, Jokiranta TS, Roumenina LT, Fremeaux-Bacchi V, Dragon-Durey MA. J Immunol. 2015 Jun 1;194(11):5129-38. PMID:25917093

Therapy for patients with antibodies to complement factor H associated HUS. Bagga A, Sinha A, Dragon-Durey MA. Pediatr Nephrol. 2014 May;29(5):939-40. PMID:24448737
     

Membership of the Doctoral School (Appartenance à L’Ecole Doctorale)

 BioSPC x PPATH

 B2T  Other :      

* Habilitation to supervise research

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