br Recently MST emerged as a critical regulator of

Recently, MST1 emerged as a critical regulator of leukocyte function and autoimmunity in humans. Five independent groups reported on autosomal recessive nonsense mutations in the gene STK4 (which encodes for MST1) in human patients with a novel primary immunodeficiency disease (PID), now called STK4 deficiency. One of the two first reports describes three patients from a consanguineous Iranian family [13]. Six patients were identified from three consanguineous unrelated Turkish families 16, 17 and four patients from two consanguineous families living in France 14, 15. These 13 patients from six consanguineous unrelated families were diagnosed with STK4 deficiency, resulting from six different loss-of-function mutations in STK413, 14, 15, 16, 17 (Figure 2, Table 2). Patients with STK4 deficiency usually presented in their first months of life with signs of immunodeficiency consisting in recurrent bacterial, viral, and/or fungal infections including pulmonary infections and bronchiectasis, mucocutaneous candidiasis, skin abscesses, and other superficial infections. Some patients also suffered from nonregressing cutaneous warts caused by multiple types of human papillomavirus infections. Two patients exhibited autoimmune haemolytic anaemia, and one patient developed immune thrombocytopenia, emphasising the concomitant risk of developing autoimmune disease. Six patients, who all had a history of recurrent severe infections, received haematopoietic stem cell transplantation, which was successful in two patients. The other four patients died from transplantation-related complications. One cardinal finding in all patients consisted of lymphopenia, mostly affecting naïve T cells. In addition, T cell function tests revealed impaired T cell responses [17]. T cell proliferation assays using various stimuli including phytohaemagglutinin, phorbol 12-myristate 13-acetate (PMA), anti-CD28, and anti-CD3 consistently showed reduced proliferation of T IKK Inhibitor VII in STK4-deficient patients compared to control patients 13, 14, 15, 16, 17. Reduced proliferative response was mostly explained by an increased rate of T cell apoptosis, which was in line with elevated surface expression of FAS on T cells [17]. In addition, isolated T cells incubated with anti-FAS led to an increased induction of apoptosis in STK4-deficient T cells as assessed by annexin V and propidium iodide staining [13]. Transwell assays using chemokine CC ligand (CCL)19/21 in the bottom well revealed reduced chemotaxis of peripheral blood T cells from STK4 patients, which was accompanied by reduced expression of chemokine CC receptor (CCR)7 and L-selectin in T cells [17]. Similar findings were reported in Transwell assays using chemokine CXC ligand (CXCL)11 [15]. Furthermore, different autoantibodies were detectable in STK4-deficient patients. Most prominently, two of the reported 13 patients developed autoimmune haemolytic anaemia, and one patient suffered from immune thrombocytopenia 16, 17. Some of the patients also had elevated autoantibodies against thyroglobulin, rheumatoid factor, granulocytes, or proteinase 3 (PR3) 13, 14, although these patients did not develop symptoms of autoimmune disease. In addition, most of the patients did not develop appropriate antibody titres following the regular vaccination schedule, although this was not entirely consistent. Interestingly, almost all patients showed hypergammaglobulinemia. Besides the reported changes in adaptive immunity, some of the studies also reported on intermittent neutropenia. However, only one study performed additional analysis on neutrophil function [17]. Abdollahpour et al. investigated staurosporine-induced apoptosis in patient polymorphonuclear leukocytes (PMNs) and found an increased rate of apoptosis in STK4-deficient PMNs compared to control PMNs. Furthermore, the same authors demonstrated a strong increase in valinomycin-induced loss of mitochondrial transmembrane potential and consecutive apoptosis in patient neutrophils, suggesting that MST1 has a critical role in neutrophil function and might therefore contribute to the recurrent appearance of infections in STK4 deficient patients.