Susceptibility of T cell receptor-alpha chain knock-out mice to ultraviolet B light and fluorouracil: a novel model for drug-induced cutaneous lupus erythematosus

Abstract

The anticancer agent 5-fluorouracil (FU) frequently induces cutaneous lupus erythematosus (LE) lesions on sun exposed sites. Based on this observation, we have tried to establish a cutaneous LE model of C57BL/6 J (B6) mice, B6 T cell receptor (TCR)-alpha(-/-) mice and B6 TCR-delta(-/-) mice treated with FU and/or ultraviolet B light (UVBL) in order to clarify the role of T cells and the cytokine profile of cutaneous lupus lesions. Cutaneous LE-like skin lesions could be induced in TCR-alpha(-/-) mice with low FU (0.2 mg) plus UVBL, and in B6 mice treated with a high dose of FU (2.0 mg) plus UVBL. In contrast, low FU plus UVBL induced such skin lesions in TCR-delta(-/-) mice at a very low incidence. Specifically, the skin lesions of TCR-alpha(-/-) mice with low FU plus UVBL appeared more rapidly and were more severe than lesions in B6 mice. The former had the common characteristic features of human chronic cutaneous LE such as typical histology, positive IgG at the dermoepidermal junction, low antinuclear antibody and low mortality. Furthermore, a Th1 response was induced in the development of drug-induced cutaneous LE. FU and UVBL-induced cutaneous LE-like eruption is an excellent model for better understanding the pathomechanisms of skin lesion development in LE.

Fig. 1

Time-dependent incidence of alopecia and erythema.

Fig. 2

Macroscopic and microscopic changes in examined mice. (a) TCR-α^–/– mice treated with low dose FU plus UVBL. Erythema and alopecia with scaling were observed. (b) Histological findings in TCR-α^–/– mice treated with low dose FU plus UVBL. Hyperkeratosis, acanthosis, plugging, liquefaction-like degeneration and perivascular mononuclear cell infiltration were observed. (c) B6 mouse treated with high FU plus UVBL. Alopecia and slight erythema were observed. The degree of skin changes was slightly decreased compared to that of TCR-α^–/– mice in Fig. 2a. (d) Histological findings in a B6 mouse treated with high FU plus UVBL. Hyperkeratosis, acanthosis, plugging and mononuclear cell infiltration were observed, but these changes were much milder than those of TCR-α^–/– mice in Fig. 2a,b. (e) Control B6 mouse treated with PBS. (f) Histological findings in a control B6 mouse treated with PBS. Marked changes were not observed.

Fig. 3

Photographs of immunohistochemical staining. (a, b) CD4⁺ T cells in TCR-α^–/– mice treated with low dose FU plus UVBL (a; × 100, b; × 200). (c, d) CD8⁺T cells in TCR-α^–/–mice treated with low dose FU plus UVBL (c; × 100, d; × 200). (e) CD4⁺T cells in control TCR-α^–/– mice ( × 100).

Fig. 4

Fluorescence photograph of IgG deposition. IgG deposition is observed at the dermo–epidermal junction (arrowhead) and at the basement membrane zone of the hair follicle (double arrowheads). Autofluorescence of hair is seen, one of which is indicated by an asterisk (original magnification × 100).

Fig. 5

Expression of cytokine mRNA in the skin of TCR-α^–/– mice by the RT-PCR method. The ratio was meausred based on amount of β-actin by zone densitometry. Data are mean ±s.e.m. of at least three independent experiments. *P < 0⋅05 versus control.

Fig. 6

Body weight changes of examined mice. Vertical bar represents s.d. of mean. N = ≥5; P < 0·01.