Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by atopic manifestations and susceptibility to infections with extracellular pathogens, typically Staphylococcus aureus, which preferentially affect the skin and lung. Previous studies reported the defective differentiation of T helper 17 (Th17) cells in HIES patients caused by hypomorphic STAT3 mutations. However, the apparent contradiction between the systemic Th17 deficiency and the skin/lung-restricted susceptibility to staphylococcal infections remains puzzling. We present a possible molecular explanation for this enigmatic contradiction. HIES T cells showed impaired production of Th17 cytokines but normal production of classical proinflammatory cytokines including interleukin 1β. Normal human keratinocytes and bronchial epithelial cells were deeply dependent on the synergistic action of Th17 cytokines and classical proinflammatory cytokines for their production of antistaphylococcal factors, including neutrophil-recruiting chemokines and antimicrobial peptides. In contrast, other cell types were efficiently stimulated with the classical proinflammatory cytokines alone to produce such factors. Accordingly, keratinocytes and bronchial epithelial cells, unlike other cell types, failed to produce antistaphylococcal factors in response to HIES T cell–derived cytokines. These results appear to explain, at least in part, why HIES patients suffer from recurrent staphylococcal infections confined to the skin and lung in contrast to more systemic infections in neutrophil-deficient patients.

Autoimmune lymphoproliferative syndrome (ALPS) is classically defined as a disease with defective FAS-mediated apoptosis (type I-III). Germline NRAS mutation was recently identified in type IV ALPS. We report 2 cases with ALPS-like disease with somatic KRAS mutation. Both cases were characterized by prominent autoimmune cytopenia and lymphoadenopathy/splenomegaly. These patients did not satisfy the diagnostic criteria for ALPS or juvenile myelomonocytic leukemia and are probably defined as a new disease entity of RAS-associated ALPS-like disease (RALD).

Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by recurrent staphylococcal infections and atopic dermatitis associated with elevated serum IgE levels. Although defective differentiation of IL-17–producing CD4⁺ T cells (Th17) partly accounts for the susceptibility to staphylococcal skin abscesses and pneumonia, the pathogenesis of atopic manifestations in HIES still remains an enigma. In this study, we examined the differentiation and function of Th1, Th2, regulatory T cells (T_reg cells), and dendritic cells (DCs) in HIES patients carrying either STAT3 or TYK2 mutations. Although the in vitro differentiation of Th1 and Th2 cells and the number and function of T_reg cells in the peripheral blood were normal in HIES patients with STAT3 mutations, primary and monocyte-derived DCs showed defective responses to IL-10 and thus failed to become tolerogenic. When treated with IL-10, patient DCs showed impaired up-regulation of inhibitory molecules on their surface, including PD-L1 and ILT-4, compared with control DCs. Moreover, IL-10–treated DCs from patients displayed impaired ability to induce the differentiation of naive CD4⁺ T cells to FOXP3⁺ induced T_reg cells (iT_reg cells). These results suggest that the defective generation of IL-10–induced tolerogenic DCs and iT_reg cells may contribute to inflammatory changes in HIES.

Granulysin is a cytolytic granule protein of natural killer (NK) cells and cytotoxic T lymphocytes (CTL) with a broad range of antimicrobial and tumoricidal activities. Two molecular forms of granulysin, the 15‐kDa precursor and 9‐kDa mature form, are produced in these cells. In this study, we developed monoclonal antibodies against granulysin and found that the 15‐kDa granulysin is spontaneously secreted by peripheral blood NK and T cells via a non‐granule exocytotic pathway. When NK cells killed the target cells, the released granulysin levels in culture supernatants significantly increased through the granule exocytosis. The granulysin protein was found in the sera of healthy individuals at an average concentration of 3.7±3.2 ng/ml (age 0–99 years, n=244). The serum levels of granulysin were transiently highly elevated among patients with acute viral infections. In addition, the serum granulysin levels in patients with severe immunodeficiency treated bycell therapy fluctuated proportionately to the improvement of other immunological parameters. Our results suggest that granulysin is well associated with diverse activities of NK cells and CTL in physiological and pathological settings and could be a useful novel serum marker to evaluate the overall status of host cellular immunity.

Epstein–Barr virus (EBV)‐associated T/NK‐cell lymphoproliferative disease (LPD) has been linked to several different disorders. Its prognosis is generally poor and a treatment strategy has yet to be established. There are reports, however, that hematopoietic stem cell transplantation (HSCT) can cure this disease. To clarify the current situation regarding allogeneic hematopoietic stem cell transplantation (allo‐HSCT) for EBV‐associated T/NK‐LPD, a nationwide survey was performed in Japan. Data for 74 patients were collected. There were 42 cases of chronic active EBV infection (CAEBV), 10 cases of EBV‐associated hemophagocytic lymphohistiocytosis (EBV‐HLH), and 22 cases of EBV‐associated lymphoma/leukemia (EBV‐lymphoma/leukemia). Of those with CAEBV, 54% had the EBV‐infected T‐cell type and 59% with EBV‐lymphoma/leukemia had the EBV‐infected NK‐cell type. Most patients with EBV‐HLH and EBV‐lymphoma/leukemia received allo‐HSCT within 1 year after onset compared to only 14% of patients with CAEBV. The event‐free survival (EFS) rate following allo‐HSCT was 0.561 ± 0.086 for CAEBV, 0.614 ± 0.186 for EBV‐HLH, and 0.309 ± 0.107 for EBV‐lymphoma/leukemia. The EFS of allo‐HSCT with conventional conditioning was 0.488 ± 0.074 and with reduced‐intensity conditioning was 0.563 ± 0.124. Thus, in a substantial number of cases, EBV‐associated T/NK‐LPD can be cured by either allogeneic conventional stem cell transplantation or reduced‐intensity stem cell transplantation. © 2008 Wiley‐Liss, Inc. Am. J. Hematol., 2008.

The carboxyl terminus of p70 S6 kinase (p70^s6k) has a set of Ser and Thr residues (Ser⁴¹¹, Ser⁴¹⁸, Ser⁴²⁴, and Thr⁴²¹) phosphorylated in vivo by an unidentified kinase(s). These Ser/Thr sites are immediately followed by proline, a motif that is commonly seen in the substrates of cyclin-dependent kinases (Cdk) and mitogen-activated protein kinases. A previous study has shown that Cdc2 (Cdk1) indeed phosphorylates these p70^s6k Ser/Thr residues in vitro. Here, we demonstrate that Cdc2-cyclin B complex phosphorylates Ser⁴¹¹ in the KIRSPRR sequence, whereas other Cdk-cyclin complexes including those containing Cdk2, Cdk4, or Cdk6 do not. Additionally, Ser⁴¹¹ phosphorylationin vivo was increased at mitosis in parallel with Cdc2 activation, and it was suppressed by a dominant negative form of Cdc2. These data indicate that p70^s6k is a physiological substrate of Cdc2-cyclin B in mitosis. Since the activity of p70^s6k is low during mitosis, Cdc2-cyclin B may play a role in inactivating p70^s6k during mitosis, where protein synthesis is suppressed.