Arthritis Susceptibility in Mice Expressing Human Type II Collagen in Cartilage

Abstract

Collagen type II (CII) induced arthritis (CIA) in mice is an experimental model for rheumatoid arthritis. Induction with non-self (e.g. human) CII induces severe arthritis whereas the mice are less susceptible to induction with self CII (i.e. mouse). To analyse whether an autoimmune response to human CII can develop and is pathogenic the authors have established transgenic mice expressing human CII in cartilage and backcrossed them into two different gene backgrounds susceptible to CIA (DBA/1 and C3H.Q). The transgenic human CII expression was restricted to cartilage and did not disturb cartilage morphology or lead to chondrodystrophy. In addition, development of stress-induced arthritis was not affected by the transgene. The cartilage specific expression of human CII reduced, but did not eliminate, the susceptibility to CIA irrespective of the species source (human, bovine, chick, rat) of CII used for immunization. A common denominator between these heterologous CII in comparison with mouse CII is the previously defined CII 256-270 epitope. An expression level dependent T-cell tolerance was seen in this epitope as well as to the entire CII. However, all human transgenic mouse lines could still mount significant autoreactive T-and B-cell responses. Approximately 10% of the transgenic mice developed arthritis after immunization with human CII. These findings show, therefore, that cartilage-located human CII induce tolerance but can nevertheless be a target for development of arthritis.

Predominant selection of T cells specific for the glycosylated collagen type II epitope (263–270) in humanized transgenic mice and in rheumatoid arthritis

“…Our finding that T cells specific for glycosylated CII appeared less tolerized by endogenous expression of huCII than T cells specific for the nonmodified epitope is predictable from an earlier finding in A q -expressing mice (15,37). Mice with transgenic expression of either rat or human CII displayed strong T cell tolerance to the immunodominant CII epitope and were also partially protected from CIA when immunized with rat and human CII, respectively (15,37). Moreover, mice transgenic for the A q -restricted immunodominant T cell epitope CII256-270, present on heterologous CII, displayed relatively stronger tolerance against the nonglycosylated variant (20).…”

“…Therefore, to get a better understanding of autoimmunity to cartilage-derived proteins, we need to consider both posttranslational modifications and the aspect of T cell tolerance in these models. To achieve this result, we used a humanized mouse model expressing HLA-DRB1*0401͞ DRA1*0101, human CD4, and human CII (huCII) on a background deficient of murine class II expression (14,15). In these mice, T cell responses to huCII peptides and the impact of posttranslational modification on the induction of CII-specific T cell tolerance was investigated.…”

Breaking T cell tolerance against self type II collagen in HLA–DR4–transgenic mice and development of autoimmune arthritis

“…This has also been shown for other model autoantigens (37,38) and may be due to differences in transgenic promoter expression or number of transgene copies inserted. In fact, by comparing different lines (founders) of the HuCII transgene in A q mice, an expression level-dependent T cell tolerance to the CII 259-273 epitope could be observed (18). A second objective of the study was to investigate the extent to which T cells recognize posttranslational modifications of CII in DR4 mice.…”

“…Mice. Transgenic mice coexpressing DR4 and human CD4 as well as human CII (HuCII) while lacking endogenous murine class II MHC have been described previously (12,(17)(18)(19). These humanized mice were backcrossed for 10 generations onto the C3H.Q and B10.Q backgrounds and subsequently intercrossed before being used in experiments.…”

A Transient Post-Translationally Modified Form of Cartilage Type II Collagen Is Ignored by Self-Reactive T Cells

“…The T cell tolerance in MMC single-transgenic mice indicates that the heterologous CII epitope is actually presented to T cells in vivo. Similar to MMC mice, we have also observed T cell tolerance to heterologous CII in human CII transgenic mice (34). One of the major differences between these studies is the clonality of the responding T cells; in the TCR ϫ MMC double-transgenic system the responding T cells are monoclonal, whereas there is a polyclonal T cell response to CII in MMC single-transgenic mice or human CII transgenic mice.…”