Differential ultraviolet-B-induced immunomodulation in XPA, XPC, and CSB DNA repair-deficient mice

Ultraviolet B irradiation has serious consequences for cellular immunity an d can suppress the rejection of skin tumors and the resistance to infectiou s diseases. DNA damage plays a crucial role in these immunomodulatory effec ts of ultraviolet B, as impaired repair of ultraviolet-B-induced DNA damage has been shown to cause suppression of cellular immunity, Ultraviolet-B-in duced DNA damage is repaired by the nucleotide excision repair mechanism ve ry efficiently. Nucleotide excision repair comprises two subpathways: trans cription-coupled and global genome repair. In this study the immunologic co nsequences of specific nucleotide excision repair defects in three mouse mo dels, XPA, XPC, and CSB mutant mice, were investigated. XPA mice carry a to tal nucleotide excision repair defect, whereas XPC and CSB mice only lack g lobal genome and transcription-coupled nucleotide excision repair, respecti vely. Our data demonstrate that cellular immune parameters in XPA, XPC, and CSB mice are normal compared with their wild-type (control) littermates. T his may indicate that the reported altered cellular responses in xeroderma pigmentosum patients are not constitutive but could be due to external fact ors, such as ultraviolet B, Upon exposure to ultraviolet B, only XPA mice a re very sensitive to ultraviolet-B-induced inhibition of Th1-mediated conta ct hypersensitivity responses and interferon-gamma production in skin drain ing lymph nodes. Lipopolysaccharide-stimulated tumor necrosis factor alpha and interleukin-10 production are significantly augmented in both XPA and C SB mice after ultraviolet B exposure. Lymph node cell numbers were increase d very significantly in XPA, mildly increased in CSB, and not in XPC mice. In general XPC mice do not exhibit any indication of enhanced ultraviolet B susceptibility with regard to the immune parameters analyzed, These data s uggest that both global genome repair and transcription-coupled repair are needed to prevent immunomodulation by ultraviolet B, whereas transcription- coupled repair is the major DNA repair subpathway of nucleotide excision re pair that prevents the acute ultraviolet-B-induced effects such as erythema .