Autoinflammation in patients with inherited IRAK4 deficiency: a paradox – AIDIRAK

Since the first description in 2003, humans with autosomal recessive complete deficiency of either IRAK-4 or MyD88, two proteins essential for mediating cellular responses via IL-1 receptors (including IL-1Rs, IL-18R, and IL-33R) and Toll-like receptors (except TLR3), have been reported to selectively suffer from severe pyogenic bacterial infections (typically, Streptococcus pneumoniae or Staphylococcus aureus), with a delayed and ineffective biological inflammatory response mounted during infectious episodes. Notably, despite an associated broad and profound immunological dysfunction, such patients have only very rarely been described to suffer from viral, fungal or other bacterial infections, allergy, autoimmunity, autoinflammation or cancer. Remarkably then, the groups of Boisson and Crow have very recently identified 12 patients from 10 kindreds with biallelic IRAK-4 private or rare variants who display autoinflammation and/or autoimmunity as their primary phenotype. Of note, where tested, several of these patients demonstrate features of a classical type I interferonopathy (vasculitic skin lesions, intracranial calcification), associated with chronic upregulation of type I interferon signalling in blood and cerebrospinal fluid. Interestingly, in all but one of these kindreds the affected individuals harbour a missense variant on one allele, in contrast to patients with ‘classical’ IRAK4 deficiency, where disease is almost always seen in the context of biallelic nonsense alleles. Thus, we hypothesize that disease in these ‘atypical’ patients (i.e. those demonstrating autoinflammation/autoimmunity) is explained by a distinct mutational combination. Specifically, we wish to explore the possibility that the observed missense variants confer a gain-of-function / neomorphic, and kinase-dependent, activity in the context of a loss-of-function mutation in trans. We will test this hypothesis, aiming to establish causality between genotype and phenotype, while defining the mechanism of this novel, and ‘paradoxical’, inborn error of immunity. Since our pre-submission, we have recruited two further patients, and the first tools have been developed to test our hypothesis (IRAK-4 deficient cell lines and in vitro IRAK-4 activity assay). In this way, our study will shed new light on the biochemical and immunological functions of human IRAK-4. Further, it will impact patient health, allowing physicians to intervene based on a rationale understanding of disease mechanism.