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Identifier

000375662

Title

Expression of programmed death-1(PD-1) and PD-1 ligands in rheumatoid arthritis,in human and murine tissue, and their role in immunological tolerance

Alternative Title

Ο ρόλος της περιφερικής ανοσολογικής ανοχής στην παθογένεια της ρευματοειδούς αρθρίτιδας Μελέτη του συστήματος PD1/PDL

Author

Raptopoulou, Amalia P

Thesis advisor

Μπούμπας, Δημήτριος

Reviewer

Μαμαλάκη, Κλειώ
Τσατσάνης, Χρήστος
Σιδηρόπουλος, Πρόδρομος
Γουλιέλμος, Γιώργος

Abstract

The immune system has evolved to protect the body from foreign invading pathogens. To accomplish this critical role, T lymphocytes must discriminate between self and non-self. Among the mechanisms involved in safeguarding of self-tolerance, B7/CD28 membrane receptors are crucial for fine-tuning of T cell function. Programmed death-1 (PD-1) is an inhibitory lymphocyte receptor that has recently emerged as a key player in induction and maintenance of tolerance. Rheumatoid arthritis (RA) is a chronic inflammatory disease of joints and extra-articular tissues, which causes severe disability and premature mortality [1, 2]. Numerous data support a central role of T cells in RA with these cells thought to be triggered locally in an antigen-specific manner resulting in breakdown of tolerance, synovial inflammation, and autoantibody production [3-7]. In the collagen-induced arthritis (CIA animal model of RA, type II collagen (CII)– reactive CD4+ T cells are primary mediators of disease induction driving autoantibody production by B cells and localized chronic inflammatory response [8-12]. Although the role of co-stimulation is well documented in RA and has been further supported by the efficacy of CTLA4-Ig in severe RA, the role of this family of molecules has not been explored in a systematic, organized fashion. We sought to determine the role of PD-1/PD-1 ligands (PD-1L) in RA and test the hypothesis whether defective expression and/or function of this pathway may contribute to T cell hyperactivity within the inflamed joint. Genomic DNA was extracted from peripheral whole blood obtained from patients and healthy blood donors. Genotyping for the PD1.3A was performed by polymerase chain reaction (PCR). PD-1/PD-1L expression was examined on synovial tissue and synovial fluid (SF) mononuclear cells from RA patients by immunohistochemistry and flow cytometry. PD-1 function was assessed in T cells stimulated with anti-CD3 and PD-L1.Fc to crosslink PD-1. Collagen-induced arthritis (CIA) was induced in PD-1-/- C57Bl/6 mice and recombinant PD-L1.Fc was injected to activate PD-1 in vivo. A. Human studies To determine whether PD-1 SNPs are associated with susceptibility to RA in our cohort, we analyzed the genomic DNA of 86 RA patients and 227 age- and sex- matched healthy controls for the PD1.3 SNP. No substantial difference in frequencies of PD1.3 heterozygosity (G/A) between RA patients and healthy controls (15,1% versus 19,4%, p>0,05) was found. We have shown that RA synovium and SF were enriched in PD-1+ T cells (24 ± 5% vs. 2 ± 1% in osteoarthritis, p<0.01) and PD-1L+ monocytes/macrophages. And that PD-1 crosslinking inhibited T cell 7 proliferation and IFN-γ production in RA patients. Howewver, despite high expression within the joint, PB T cells incubated with RA SF and SF T cells from active RA exhibited reduced PD-1–mediated inhibition at suboptimal –but not optimal– PD-L1.Fc concentrations, indicating a probable diminishing effect of the inflammatory microenvironment of RA on pathway’s function. B. Animal studies PD-1-/- mice demonstrated increased incidence (73% vs. 36% in wild-type mice, p<0.05) and severity (mean maximum arthritis score 4.8 vs. 2.5, p=0.001) of CIA, associated with enhanced T cell proliferation and cytokine (IFN-γ, IL-17) production in response to type II collagen. Most interestingly, PD-L1.Fc treatment ameliorated CIA (mean maximum arthritis score 1.8 ± 0.6 vs. 2.5 ± 0.7) and reduced anticollagen II T cell responses (induction in proliferation [9cpm] 9594 ± 2147 vs. 4712 ± 2256). Taken together, our data suggest that τhe negative costimulatory PD-1/PD-1L pathway regulates peripheral T cell responses in both human and murine RA. The PD-1/PD-1L in rheumatoid synovium may represent an additional target for immunomodulatory therapy in RA.

Language

Greek

Subject

Collagen induced arthritis

Costimulation

Immune tolerance

Musculoskeletal system Rheumatoid arthritis

Programmed death-1 ligand 1/2 (PD-L1/2)

Programmed death-1(PD-1)

Synovial fluid

T-cells

Ανοσολογική ανοχή