Roo savill biography samples

Abstract

We sought to identify an altered peptide ligand (APL) based on the endogenously expressed synovial auto-epitope of human cartilage glycoprotein-39 (HC gp-39) for modulation of cognate, HLA-DR4-restricted T cells. For this purpose we employed a panel of well-characterized T cell hybridomas generated from HC gp-39-immunized HLA-DR4 transgenic mice. The hybridomas all respond to the HC gp-39(263–275) epitope when bound to HLA-DR4(B1*0401) but differ in their fine specificities. First, the major histocompatibility complex (MHC) and T-cell receptor (TCR) contact residues were identified by analysis of single site substituted analogue peptides for HLA-DR4 binding and cognate T cell recognition using both T hybridomas and polyclonal T cells from peptide-immunized HLA-DR4 transgenic mice. Analysis of single site substituted APL by cognate T cells led to identification of Phe265 as the dominant MHC anchor. The amino acids Ala268, Ser269, Glu271 and Thr272 constituted the major TCR contact residues, as substitution at these positions did not affect HLA-DR4(B1*0401) binding but abrogated T cell responses. A structural model for visualisation of TCR recognition was derived. Second, a set of non-classical APLs, modified at the MHC key anchor position but with unaltered TCR contacts, was developed. When these APLs were analysed, a partial TCR agonist was identified and found to modulate the HC gp-39(263–275)-specific, pro-inflammatory response in HLA-DR4 transgenic mice. We identified a non-classical APL by modification of the p1 MHC anchor in a synovial auto-epitope. This APL may qualify for rheumatoid arthritis immunotherapy.

Introduction

In rheumatoid arthritis (RA), articular cartilage is destroyed by chronic inflammation that is characterised by activated lymphocytes and major histocompatibility complex (MHC) class II expressing cells in synovial tissue. The latter suggests the ongoing of an antigen-driven response [1]. Although the nature of the antigens resp

List of publications

Publications since the beginning of the LabEx ParaFrap are ranked per year and per alphabetic order.  

In blue, publications shared with at least two ParaFrap partners.

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2012 ⎪ 2013 ⎪ 2014 ⎪ 2015 ⎪ 2016 ⎪ 2017 ⎪ 2018 ⎪ 2019 ⎪ 2020 ⎪ 2021 ⎪ 2022 ⎪ 2023 ⎪ 2024 

2024

Alencar, M.B., Girard, R.M.B.M., Crispim, M., Baptista, C.G., Biran, M., Bringaud, F., Silber, A.M., (2024). Elucidating the Transport Mechanisms and Metabolic Roles of Serine, Threonine, and Glycine in Trypanosoma cruzi. bioRxiv [preprint] 2024.06.29.601350. doi: 10.1101/2024.06.29.601350

Antunes, A.V., Shahinas, M., Swale, C., Farhat, D.C., Ramakrishnan, C., Bruley, C., Cannella, D., Robert, M.G., Corrao, C., Couté, Y., Hehl, A.B., Bougdour, A., Coppens, I., Hakimi, M.-A., (2024). In vitro production of cat-restricted Toxoplasma pre-sexual stages. Nature [50.5] 625, 366–376. doi: 10.1038/s41586-023-06821-y

Audibert, A., Mas-Orea, X., Rey, L., Belloy, M., Bassot, E., Marodon, G., Masson, F., Cenac, N., Dietrich, G., Bonnart, C., Blanchard, N., (2024). Toxoplasma gondii chronic infection decreases visceral nociception through peripheral opioid receptor signaling. bioRxiv [preprint] 2024.09.13.612908. doi: 10.1101/2024.09.13.612908

Baillou, A., Tomal, F., Chaumeil, T., Barc, C., Levern, Y., Sausset, A., Pezier, T., Schulthess, J., Peltier-Pain, P., Laurent, F., Lacroix-Lamandé, S., (2024). Characterization of intestinal mononuclear phagocyte subsets in young ruminants at homeostasis and during Cryptosporidium parvum infection. Front Immunol [7.3] 15. doi: 10.3389/fimmu.2024.1379798

Barrett, J.R., Silk, S.E., Mkindi, C.G., Kwiatkowska, K.M., Hou, M.M., Lias, A.M., Kalinga, W.F., Mtaka, I.M., McHugh, K., Bardelli, M., Davies, H., King, L.D.W., Edwards, N.J., Chauhan, V.S., Mukherjee

Abstract

Considerable evidence indicates that CD4 T cells are important in the pathogenesis of rheumatoid arthritis (RA), but the antigens recognized by these T cells in the joints of patients remain unclear. Previous studies have suggested that type II collagen (CII) and human cartilage gp39 (HCgp39) are among the most likely synovial antigens to be involved in T cell stimulation in RA. Furthermore, experiments have defined dominant peptide determinants of these antigens when presented by HLA-DR4, the most important RA-associated HLA type. We used fluorescent, soluble peptide–DR4 complexes (tetramers) to detect synovial CD4 T cells reactive with CII and HCgp39 in DR4 patients. The CII-DR4 complex bound in a specific manner to CII peptide-reactive T cell hybridomas, but did not stain a detectable fraction of synovial CD4 cells. A background percentage of positive cells (<0.2%) was not greater in DR4 (DRB1*0401) patients compared with those without this disease-associated allele. Similar results were obtained with the gp39-DR4 complex for nearly all RA patients. In a small subset of DR4 patients, however, the percentage of synovial CD4 cells binding this complex was above background and could not be attributed to nonspecific binding. These studies demonstrate the potential for peptide–MHC class II tetramers to be used to track antigen-specific T cells in human autoimmune diseases. Together, the results also suggest that the major oligoclonal CD4 T cell expansions present in RA joints are not specific for the dominant CII and HCgp39 determinants.

Rheumatoid arthritis (RA) is a disease of unknown etiology characterized by chronic inflammation in multiple joints (1). In a significant fraction of patients, this persistent synovitis leads to destruction of articular cartilage and surrounding structures and is a cause of significant morbidity. Considerable evidence suggests that CD4 T cells are important in the pathogenesis of this disease