Immune dysfunction in nucleotide excision repair disorders: an underrecognized clinical phenotype with relevance for inborn errors of immunity

<jats:p>Nucleotide excision repair (NER) is a conserved genome maintenance pathway that removes bulky, helix-distorting DNA lesions, including ultraviolet-induced photoproducts and chemically induced adducts. By restoring DNA integrity, NER preserves transcriptional continuity and replicative fitness, thereby limiting mutagenesis, replication stress, and cell death. Inherited defects in NER genes cause rare disorders such as xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD), classically associated with photosensitivity, neurodevelopmental impairment, growth failure, and, in some subtypes, marked cancer predisposition. Traditionally, clinical attention has focused on dermatologic and neurologic manifestations, whereas immune dysfunction has been regarded as peripheral or secondary. Recent clinical and immunological studies indicate that immune abnormalities may represent an underrecognized component of selected NER disorders. Reported findings include impaired vaccine responses, hypogammaglobulinemia, IgG subclass deficiency, altered B cell differentiation, CD4 lymphopenia, restricted T cell receptor repertoires, and defective dendritic cell maturation. These abnormalities are not evenly distributed across the NER spectrum and appear more prominent in selected molecular subgroups. In particular, disorders affecting transcription-associated NER functions, including TFIIH-linked conditions, may combine impaired DNA repair with reduced transcriptional capacity, thereby increasing immune-cell vulnerability during activation. By contrast, many repair-dominant XP subtypes seem to retain largely preserved baseline immune function, although clinically relevant abnormalities may become apparent during infection, vaccination, or other immune challenges. In this Mini Review, we summarize clinical evidence for immune dysfunction in NER disorders, interpret it in the context of global genome and transcription-coupled NER, and discuss implications for immunological assessment and inborn errors of immunity-oriented classification.</jats:p>