title: Differential ultraviolet-B-induced immunomodulation in XPA, XPC, and CSB DNA repair-deficient mice.
abstract: Ultraviolet B irradiation has serious consequences for cellular immunity and can suppress the rejection of skin tumors and the resistance to infectious diseases. DNA damage plays a crucial role in these immunomodulatory effects of ultraviolet B, as impaired repair of ultraviolet-B-induced DNA damage has been shown to cause suppression of cellular immunity. Ultraviolet-B-induced DNA damage is repaired by the nucleotide excision repair mechanism very efficiently. Nucleotide excision repair comprises two subpathways: transcription-coupled and global genome repair. In this study the immunologic consequences of specific nucleotide excision repair defects in three mouse models, XPA, XPC, and CSB mutant mice, were investigated. XPA mice carry a total nucleotide excision repair defect, whereas XPC and CSB mice only lack global genome and transcription-coupled nucleotide excision repair, respectively. Our data demonstrate that cellular immune parameters in XPA, XPC, and CSB mice are normal compared with their wild-type (control) littermates. This may indicate that the reported altered cellular responses in xeroderma pigmentosum patients are not constitutive but could be due to external factors, such as ultraviolet B. Upon exposure to ultraviolet B, only XPA mice are very sensitive to ultraviolet-B-induced inhibition of Th1-mediated contact hypersensitivity responses and interferon-gamma production in skin draining lymph nodes. Lipopolysaccharide-stimulated tumor necrosis factor alpha and interleukin-10 production are significantly augmented in both XPA and CSB mice after ultraviolet B exposure. Lymph node cell numbers were increased 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 suggest 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 repair that prevents the acute ultraviolet-B-induced effects such as erythema.
authors.affiliation: Department of Immunology, Erasmus University and University Hospital Rotterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Boonstra
authors.forename: A
authors.initials: A
authors.lastname: van Oudenaren
authors.forename: M
authors.initials: M
authors.lastname: Baert
authors.forename: H
authors.initials: H
authors.lastname: van Steeg
authors.forename: P J
authors.initials: PJ
authors.lastname: Leenen
authors.forename: G T
authors.initials: GT
authors.lastname: van der Horst
authors.forename: J H
authors.initials: JH
authors.lastname: Hoeijmakers
authors.forename: H F
authors.initials: HF
authors.lastname: Savelkoul
authors.forename: J
authors.initials: J
authors.lastname: Garssen
mesh_terms: D000276:Adjuvants, Immunologic / Q000528:radiation effects*; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D004265:DNA Helicases / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics / Q000276:immunology*; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000235:genetics*; D006965:Hyperplasia; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000075223:Poly-ADP-Ribose Binding Proteins; D016601:RNA-Binding Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D012867:Skin / Q000276:immunology / Q000528:radiation effects; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014466:Ultraviolet Rays; D029867:Xenopus Proteins; D051760:Xeroderma Pigmentosum Group A Protein
chemical_list: D000276:Adjuvants, Immunologic; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C119382:XPc1 protein, Xenopus; D029867:Xenopus Proteins; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; D016753:Interleukin-10; D007371:Interferon-gamma; D004265:DNA Helicases; C513075:Ercc6 protein, mouse; D045643:DNA Repair Enzymes