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Background Monogenic autoinflammatory diseases (AID) are caused by mutations in innate immune genes. The effects of these mutations on allergic inflammation are unknown. Objectives We investigated allergic, immunological and clinical phenotypes in FMF (familial Mediterranean fever), CAPS (cryopyrin-associated periodic syndrome), TRAPS (tumour necrosis factor receptor-associated periodic syndrome), HIDS (hyper-IgD syndrome), PAPA (pyogenic arthritis, pyoderma gangrenosum and acne), DADA2 (deficiency of adenosine deaminase 2), HA20 (haploinsufficiency of A20), CANDLE (chronic atypical neutrophilic dermatosis, lipodystrophy, elevated temperature) and SAVI (STING-associated vasculopathy of infancy). Methods In this cross-sectional study, clinical data were assessed in 425 patients with AID using questionnaires and chart reviews. Comparator data were obtained from public databases. Peripheral blood mononuclear cells obtained from 55 patients were stimulated and CD4+ cytokine production assessed. Results Clinical laboratory features of Type 2 immunity were elevated in CAPS but reduced in most AID, particularly DADA2. Physician-diagnosed allergic diseases were prevalent in multiple AID, including CAPS and DADA2. T helper 2 (Th2) cells were expanded in CAPS, TRAPS and HIDS; Th9 cells were expanded in HA20. Conclusions CAPS is characterised by an enhanced Type 2 signature, whereas FMF and CANDLE are associated with reduced Type 2 responses. DADA2 is associated with reduced Type 2 responses but a high rate of physician-diagnosed allergy. Therefore, NLRP3-driven autoinflammation may promote Type 2 immunity, whereas AID like DADA2 may manifest clinical phenotypes that masquerade as allergic disorders. Further investigations are needed to determine the contribution of autoinflammation to allergic clinical and immunological phenotypes, to improve the treatment of patients with AID.

Background Two thirds of the 1700 patients seen at our NIH clinic for autoinflammatory diseases do not have a genetic diagnosis. Whole exome sequencing permits analysis of most of the protein coding regions of the human genome. Methods With the use of whole exome sequencing and candidate gene screening, we identified five children from four unrelated families, who had unexplained autoinflammatory disease and shared mutations in one common gene. One family from Saudi Arabia was consanguineous with two affected daughters. The second family of mixed Czech and British background had one affected boy. The third and fourth families were of mixed European ancestry from the United States and each family had one affected daughter. We performed additional experiments in patients samples including flow cytometry, immunophenotyping, cytokine profiling, mitochondria related function and ribosomal assembly assays. Protein function was studied with morpholino knockdowns in zebrafish embryos. Results All patients carried missense recessive mutations in one common gene, the TRNT1 (tRNA Nucleotidyl Transferase, CCA-Adding, 1), on chromosome 3. The two affected Saudi Arabian sisters were homozygous for a p. H215R missense mutation, while the other three children were compound heterozygous for a missense mutation, p. I223T or p. R99W, and one shared mutation p. D163V. The p. H215R mutation was not found in any public database neither in 1061 Arab control DNA samples. From the three Caucasian mutations, the p. R99W was novel whereas the p. I223T and p. D163V were found at a very low allele frequency ( Preliminary data from cytokine analysis in two patients have shown elevated levels of the proinflammatory cytokines interleukin 6 and type 1interferon, suggesting possible therapeutic targets. Knockdown of the zebrafish TRNT1 homologue caused hydrocephaly, defects in tail development, anaemia and a reduction in the number of hair cells present in the lateral line, that has function resembling human inner ear. Conclusion The CCA-adding TRNT1 enzyme catalyses the addition of the CCA terminus to the 3 prime end of all tRNAs precursors, a step that is essential for tRNA aminoacylation and protein synthesis. The discovery that missense mutations in this essential and ubiquitiously expressed gene cause a newly defined periodic fever syndrome, will allow further understanding of mechanisms underlying inflammation.