T Cell Immunity to Type II Collagen in the Biobreeding Rat: The Identification and Characterization of RT1u-Restricted T Cell Epitopes on α1(II)

Abstract

Susceptibility to experimental collagen-induced arthritis in rodents is dependent on MHC class II elements to bind peptides from the type II collagen (CII) molecule. Although a substantial body of data has been reported in mice defining these peptide Ags, little has been reported in rats. In this study, we investigate the locations and sequences of CII peptides, which are bound by RT1u molecules, expressed by diabetic-resistant, arthritis-susceptible Biobreeding rats, and, in turn, stimulate CII-specific T cells. By using overlapping and substituted peptide homologues of CII, we have identified and characterized an immunodominant and five subdominant epitopes on CII, which stimulate RT1u-restricted T cell proliferation. The immunodominant epitope, CII (186–192), contains a QGPRG core sequence, which was found in a subdominant epitope CII (906–916). Similar sequences containing single conservative substitutions were identified in three other epitopes. One, CII (263–272), contained a conservatively substituted R→K substitution, whereas CII (880–889) and CII (906–916) contained nonconservative substitutions, i.e., P→D and R→M, respectively. Homologue peptides containing these sequences stimulated T cell proliferative responses, although less intensely than peptides containing CII (186–192). Substituting QGR residues in the QGPRG core with alanine, isoleucine, or proline reduced proliferation, as did substituting flanking E and G residues at the N terminus and E at the C terminus. Collectively, these data indicate that RT1u-restricted immunodominant and several subdominant epitopes on CII often share a QGPRG-like motif, with conservative substitutions present at either P or R positions. This motif is similar to one recognized by collagen-induced arthritis-susceptible HLA-DR1- and HLA-DR4-transgenic mice.

LEW.1WR1 Rats Develop Autoimmune Diabetes Spontaneously and in Response to Environmental Perturbation

“…In this regard, they are similar to BBDR rats (25,42,43) and the parental LEW rat (26), which are comparably susceptible. Rheumatoid arthritis occasionally occurs in patients and families with type 1 diabetes (44), and genetic analyses in both the rat and human suggest that some susceptibility loci for both diseases are in linkage disequilibrium (45,46).…”

Multifunctional PLA/Gelatin Bionanocomposites for Tailored Drug Delivery Systems

“…Gelatin is a natural biopolymer obtained from the denaturation of collagen [21] that preserves key bioactive functions of collagen for biomedical applications, such as cell adhesion and proliferation [22]. Moreover, gelatin is widely used in the food and cosmetic industries, and particularly, fish gelatin is becoming increasingly used for biomedical applications due to a likely less intense immune reaction in the human body than mammalian gelatin [23] as well as an approach to revalorize the by-products from fish industrial processes [24]. Moreover, gelatin can be processed in several formats depending on the intended applications, such as electrospun matrices for wound healing [25], microspheres for being loaded with a growth factor for bone regeneration [26], nanoparticles as nanocarriers for anticancer therapeutic agents [27], protein, gene and vaccines delivery [28], DDS for regenerative medicine or three-dimensional scaffolds for drug screening [29].…”