Distinguishing Clinical and Immunological Features of Combined Immune Deficiency due to Serine/Threonine Kinase 4 deficiency

Abstract Background: Serine/threonine kinase 4 (STK4) deficiency is a combined immunodeficiency with overlapping features with the autosomal dominant (AD)– and recessive (AR) forms of the Hyper IgE syndrome (HIES), including recurrent infections, eczema, eosinophilia and elevated serum IgE levels. The precise distinguishing features of STK4 deficiency versus the different forms of HIES remain unclear. Objective: We examined the comparative clinical and immunological features of STK4 deficiency versus AD- and AR forms of HIES, including signal transducer and activator of transcription 3 (STAT3) and dedicator of cytokinesis 8 (DOCK8) respectively, with a focus on those attributes that distinguish STK4 deficiency from those disorders. Methods : Six STK4, 4 STAT3 and 14 DOCK8 deficient patients and 16 healthy controls enrolled in this study. Clinical and immunological features of the patients including detailed analysis of naïve and memory T and B cell subsets including T helper (TH), T follicular helper (T FH ) and T regulatory (Treg) cells were evaluated and compared with age matched control subjects. Results: Recurrent infections and eczema were the most frequent clinical findings in AR- and eczema in AD-HIES. All STK4 deficient patients had recurrent herpetic facial lesions. Serum IgM level was significantly low in DOCK8 deficient patients compared to STAT3 and STK4 deficiency. Both CD4 + T cell numbers and ratio were significantly lower in STK4 and DOCK8 deficient patients compared to control subjects. On the other hand, recent thymic emigrant (RTE) cell ratio was significantly lower, and T helper type 1 (T H 1) cell frequencies were significantly higher in STK4 deficiency. While regulatory T (T reg ) cell frequencies were significantly lower in DOCK8 deficiency, T helper type 17 (T H 17) cell frequencies were significantly lower in both STAT3 and DOCK8 deficient patients. Conclusion: While STK4 deficiency presents with overlapping clinical and immunological features with DOCK8 deficiency, including recurrent herpetic lesion and CD4 + T cell lymphopenia, it is distinguished by the absence of severe allergic diseases and by a number of immunological findings including decreased RTE and increased T H 1 cell frequencies. STK4 deficiency should be considered in patients with AR-HIES with a clinical phenotype of DOCK8 deficiency but with otherwise normal DOCK8 protein expression.