Immunodeficiency associated with DNA repair defects

AR Gennery, AJ Cant, PA Jeggo - Clinical & Experimental …, 2000 - academic.oup.com
AR Gennery, AJ Cant, PA Jeggo
Clinical & Experimental Immunology, 2000academic.oup.com
Cellular DNA is subjected to an onslaught of damaging insults which threaten cellular
control and replication. It is therefore unsurprising that a plethora of damage response
mechanisms operate to maintain genomic stability. These include processes that recognize
and repair the damage, cell cycle checkpoints that prevent cell cycle progression in the
presence of damage, and mechanisms, such as apoptosis, that remove damaged cells. In
contrast, the development of effective immune responses is totally dependent on the …
Cellular DNA is subjected to an onslaught of damaging insults which threaten cellular control and replication. It is therefore unsurprising that a plethora of damage response mechanisms operate to maintain genomic stability. These include processes that recognize and repair the damage, cell cycle checkpoints that prevent cell cycle progression in the presence of damage, and mechanisms, such as apoptosis, that remove damaged cells. In contrast, the development of effective immune responses is totally dependent on the generation of some 1012 genetically diverse cells, each bearing a unique receptor capable of recognizing a unique antigen/MHC combination. Only in this way can the immune system recognize the vast array of antigens that may be encountered. Higher organisms create this huge number of genetically diverse cells by breaking, randomly re-sorting and then joining the DNA sequences coding for antigen receptors by adapting the DNA repair mechanisms normally utilized to maintain genome stability. Individuals with defective DNA repair mechanisms have pleiotropic phenotypes including a predisposition to cancer, neurodegeneration and developmental abnormalities. Increasingly, immunodeficiency is recognized as a feature of some of these syndromes. Further evidence for the overlap between DNA repair and immune development is the finding that some individuals with poorly understood immunodeficiencies exhibit cellular ionizing radiation sensitivity, probably as a consequence of defective repair of radiation-induced DNA damage. This review discusses the common molecular defects identified in DNA repair-defective syndromes associated with immunodeficiency, as well as detailing the clinical features seen in affected individuals.
Oxford University Press