Abstract
BACKGROUND: Dedicator of cytokinesis 8 (DOCK8) deficiency is a combined immunodeficiency caused by autosomal recessive loss-of-function mutations in DOCK8. This disorder is characterised by recurrent cutaneous infections, elevated serum IgE, and severe atopic disease including anaphylaxis to foods. However, the contribution of defects in CD4(+) T cells to disease pathogenesis in these patients has not been thoroughly investigated.
OBJECTIVE: To investigate the phenotype and function of DOCK8-deficient CD4(+) T cells to determine (1) intrinsic and extrinsic CD4(+) T cell defects (2) how defects account for the clinical features of DOCK8 deficiency.
METHODS: We performed indepth analysis of the CD4(+) T cell compartment of DOCK8-deficient patients. We enumerated subets of CD4(+) T helper cells and assessed cytokine production and transcription factor expression. Finally, we determined the levels of IgE specific for staple foods and house dust mite allergens in DOCK8-deficient patients and normal controls.
RESULTS: DOCK8-deficient memory CD4(+) T cells were biased towards a Th2 type, and this was at the expense of Th1 and Th17 cells. In vitro polarisation of DOCK8-deficient naive CD4(+) T cells revealed the Th2 bias and Th17 defect to be T-cell intrinsic. Examination of allergen specific IgE revealed plasma IgE from DOCK8-deficient patients is directed against staple food antigens, but not house dust mites.
CONCLUSION: Investigations into the DOCK8-deficient CD4(+) T cells provided an explanation for some of the clinical signs of this disorder - the Th2 bias is likely to contribute to atopic disease, while defects in Th1 and Th17 cells compromise anti-viral and anti-fungal immunity, respectively explaining the infectious susceptibility of DOCK8-deficient patients.
Original language | English |
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Pages (from-to) | 933-949 |
Number of pages | 17 |
Journal | The Journal of allergy and clinical immunology |
Volume | 139 |
Issue number | 3 |
Early online date | 20 Aug 2016 |
DOIs | |
Publication status | Published - Mar 2017 |