Immunomodulation of RA Patients’ PBMC with a Multiepitope Peptide Derived from Citrullinated Autoantigens

Abstract

Citrullinated peptides are used for measuring anticitrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA). Accumulation of citrullinated proteins in the inflamed synovium suggests that they may be good targets for inducing peripheral tolerance. In view of the multiplicity of citrullinated autoantigens described as ACPA targets, we generated a multiepitope citrullinated peptide (Cit-ME) from the sequences of major citrullinated autoantigens: filaggrin, β-fibrinogen, vimentin, and collagen type II. We assessed the ability of Cit-ME or the citrullinated β60-74 fibrinogen peptide (β60-74-Fib-Cit) which bears immunodominant citrullinated epitopes (i) to modify cytokine gene expression and (ii) to modulate Treg and Th17 subsets in PBMC derived from newly diagnosed untreated RA patients. RA patient's PBMC incubated with Cit-ME or β60-74-Fib-Cit, showed upregulation of TGF-β expression (16% and 8%, resp.), and increased CD4+Foxp3+ Treg (22% and 19%, resp.). Both peptides were shown to downregulate the TNF-α and IL-1β expression; in addition, Cit-ME reduced CD3+IL17+ T cells. We showed that citrullinated peptides can modulate the expression of anti- and proinflammatory cytokines in PBMC from RA patients as well as the proportions of Treg and Th17 cells. These results indicate that citrullinated peptides could be active in vivo and therefore might be used as immunoregulatory agents in RA patients.

A fructosylated peptide derived from a collagen II T cell epitope for long-term treatment of arthritis (FIA-CIA) in mice

“…In a rat model of adjuvant-induced arthritis (AIA), s.c. injections of a multi-epitope peptide reduced disease severity 17 . This peptide also modulated T cell subsets in RA patients´ peripheral blood cells 44 . Also nanoparticles coated with peptides improved disease symptoms in HLA-DR4-IE-transgenic mice or depleted patient specific B cells 45 , 49 .…”

Significance of Type II Collagen Posttranslational Modifications: From Autoantigenesis to Improved Diagnosis and Treatment of Rheumatoid Arthritis

“…The therapeutic application of ME-Cit ameliorated disease symptoms in rats with adjuvant-induced arthritis and induced higher levels of regulatory T-cells, while the magnitude of Th17 responses was decreased [ 182 ]. Subsequently, the results were confirmed using peripheral blood mononuclear cells (PBMCs) from early diagnosed RA patients [ 183 ]. It was shown that citrullinated peptides can modulate the expression of pro- and anti-inflammatory cytokines from RA PBMCs, regulatory T-cells and Th17 populations, providing evidence that citrullinated multiepitope peptides might be used as immunomodulatory agents in antigen-specific therapeutic approaches.…”

Peptide-Based Vaccination Therapy for Rheumatic Diseases

“…Another study by Gertel et al reported that vaccination with multiepitope peptides derived from citrullinated autoantigens could induce immune tolerance and attenuate arthritis manifestations by promoting Treg cells and inhibiting Th17 cells in an animal model of RA [147]. A further study by Gertel et al found that a multiepitope peptide derived from citrullinated autoantigens could modulate both the expressions of key cytokines and the frequencies of T cells in peripheral blood mononuclear cells (PBMCs) from RA patients [148].…”