Heterozygote loss-of-function germline mutations in the aryl hydrocarbon receptor (AhR) interacting protein (AIP) gene can result in familial pituitary adenomas. We have a cohort of 200 subjects with various AIP mutations. AIP’s partner, AhR, is known to play an important role in the development of T cells which make IL-17-family cytokines. We hypothesized that our patients might have immune abnormalities due to deficiency of AIP. Our preliminary data using blood samples from AIP-mutation-positive subjects show that PMA-stimulated T lymphocytes display a markedly reduced IL22 and IL17 production and reduced expression of RORγt (the transcription factor which drives IL22/IL17 production) (Fig. 1A,B). IL17 and IL22 concentrations in plasma samples of AIPmut+ patients are also significantly lower compared to controls. Furthermore, our preliminary data demonstrate that the analysis of IL17/IL22 production in T cells of relatives of AIPmut+ patients can accurately predict who is a carrier of the mutation. In sporadic cases of pituitary adenomas with an AIP mutation, the analysis of IL17/IL22 could be crucial in determining whether it is a functional relevant germline mutation or single nucleotide polymorphisms(SNP). IL-17 appears to be important in resistance to fungal infections. We found that AIPmut+ patients have mild but significantly increased levels of C-reactive protein (CRP) and raised Candida albicans antibody levels suggesting impaired immunity and inflammation. In summary, our study on AIPmut+ patients demonstrates a role for this protein in the IL17/IL22 immune response in humans.
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