OBJECTIVE: To understand the mechanisms of eczema in DOCK8 deficiency.
METHODS: Skin biopsies were characterized for histology, immuno-fluorescence microscopy, and gene expression. Skin barrier function was measured by trans-epidermal water loss. Allergic skin inflammation was elicited in mice by epicutaneous (EC) sensitization with ovalbumin (OVA) or cutaneous application of S. aureus.
RESULTS: Skin lesions of DOCK8-deficient patients exhibited type-2 inflammation and the patients' skin was colonized by S. aureus, like in AD. Unlike in AD, DOCK8-deficient patients had a reduced FOXP3:CD4 ratio in their skin lesions, and their skin barrier function was intrinsically intact. Dock8-/- mice exhibited reduced numbers of cutaneous T regulatory cells (Tregs) and a normal skin barrier. Dock8-/- mice and mice with an inducible Dock8 deletion in Tregs exhibited increased allergic skin inflammation following EC sensitization with OVA. DOCK8 was shown to be important for Treg stability at sites of allergic inflammation and for the generation, survival, and suppressive activity of inducible Tregs (iTregs). Adoptive transfer of wild-type, but not DOCK8-deficient, OVA-specific iTregs suppressed allergic inflammation in OVA-sensitized skin of Dock8-/- mice. These mice developed severe allergic skin inflammation and elevated serum IgE levels following topical exposure to S. aureus. Both were attenuated following adoptive transfer of WT but not DOCK8 deficient Tregs CONCLUSION: Treg cell dysfunction increases susceptibility to allergic skin inflammation in DOCK8 deficiency and synergizes with cutaneous exposure to S. aureus to drive eczema in DOCK8 deficiency.
METHODS: We analyzed the clinical, immunologic, and genetic data of IEI patients from 22 countries in the Middle East and North Africa (MENA) region. The data was collected from national registries and diverse databases such as the Asian Pacific Society for Immunodeficiencies (APSID) registry, African Society for Immunodeficiencies (ASID) registry, Jeffrey Modell Foundation (JMF) registry, J Project centers, and International Consortium on Immune Deficiency (ICID) centers.
RESULTS: We identified 17,120 patients with IEI, among which females represented 39.4%. Parental consanguinity was present in 60.5% of cases and 27.3% of the patients were from families with a confirmed previous family history of IEI. The median age of patients at the onset of disease was 36 months and the median delay in diagnosis was 41 months. The rate of registered IEI patients ranges between 0.02 and 7.58 per 100,000 population, and the lowest rates were in countries with the highest rates of disability-adjusted life years (DALY) and death rates for children. Predominantly antibody deficiencies were the most frequent IEI entities diagnosed in 41.2% of the cohort. Among 5871 patients genetically evaluated, the diagnostic yield was 83% with the majority (65.2%) having autosomal recessive defects. The mortality rate was the highest in patients with non-syndromic combined immunodeficiency (51.7%, median age: 3.5 years) and particularly in patients with mutations in specific genes associated with this phenotype (RFXANK, RAG1, and IL2RG).
CONCLUSIONS: This comprehensive registry highlights the importance of a detailed investigation of IEI patients in the MENA region. The high yield of genetic diagnosis of IEI in this region has important implications for prevention, prognosis, treatment, and resource allocation.