iPS cells from Chediak-Higashi syndrome patients recapitulate the giant granules in myeloid cells.

BACKGROUND: Chediak-Higashi syndrome (CHS) is a congenital disease characterized by immunodeficiency, hemophagocytic lymphohistiocytosis, oculocutaneous albinism, and neurological symptoms. The presence of giant granules in peripheral blood leukocytes is an important hallmark of CHS. Here we prepared induced pluripotent stem cells (iPSCs) from CHS patients (CHS-iPSCs) and differentiated them into hematopoietic cells to model the disease phenotypes. METHODS: Fibroblasts were obtained from two CHS patients and then reprogrammed into iPSCs. The iPSCs were differentiated into myeloid cells; the size of the cytosolic granules was quantified by May-Grunwald Giemsa staining and myeloperoxidase staining. RESULTS: Two clones of iPSCs were established from each patient. The differentiation efficiency to CD33+ CD45+ myeloid cells was not significantly different in CHS-iPSCs compared with control iPSCs, but significantly larger granules were observed. CONCLUSIONS: We succeeded in reproducing a characteristic cellular phenotype, giant granules in myeloid cells, using CHS-iPSCs, demonstrating that iPSCs can be used to model the pathogenesis of CHS patients.

Living-Donor Lung Transplantation After Bone Marrow Transplantation for Chediak-Higashi Syndrome.

An 8-year-old girl with Chediak-Higashi syndrome (CHS) had pulmonary complications after hematopoietic stem cell transplantation (HSCT) for hemophagocytic lymphohistiocytosis (HLH) and eventually underwent single living-donor lobar lung transplantation (LDLLT). Electron micrographic findings showed vagus nerve tissue in extracted lung having granular inclusions, which are pathognomonic for CHS. Because her mother was the donor for both hematopoietic stem cell and lung transplantations, she was weaned from immunosuppression and is doing well 3 years after lung transplantation. Furthermore, an induced pluripotent stem (iPS) cell line was established from her skin fibroblasts for investigation and potential future treatment for CHS.

Usefulness of lymphocyte stimulation test for the diagnosis of intestinal cow's milk allergy in infants.

BACKGROUND: Bottle-fed infants sometimes develop intestinal cow's milk allergy (ICMA). Because cow's milk-specific IgE antibody (CM-IgE) levels are normal, the lymphocyte stimulation test (LST) has been proposed as an alternative diagnostic test for ICMA. The present study evaluated the diagnostic value of LST in a large number of patients with ICMA in Japan. METHODS: Ninety-six infants who developed intestinal symptoms after ingestion of cow's milk formula and showed remission of symptoms after elimination of this food were enrolled as patients with probable ICMA. Seventy-two subjects with normal CM-IgE levels and a positive result in an oral food challenge test (OFCT) for cow's milk formula were diagnosed with ICMA. Another 10 infants with normal CM-IgE levels and a negative OFCT result were diagnosed with nonspecific intestinal symptoms (NIS). The status of cell-mediated immunity against cow's milk proteins was estimated by LST for κ-casein. RESULTS: In the 72 patients with ICMA (38 boys and 34 girls), the median age at onset was 9 days. Sixty-two of 72 (86.1%) patients with ICMA tested positive in the LST for κ-casein. In contrast, only 2 of the 10 NIS infants tested positive. The incidence of a positive LST result was significantly higher in the ICMA group than in the NIS group (p < 0.0001). The area under the receiver-operating characteristic curve for this test was as high as 0.856. CONCLUSIONS: This study strongly suggests that the LST for κ-casein is a useful diagnostic test for ICMA.

Novel Heterogenous CHS1 Mutations Identified in Five Japanese Patients with Chediak-Higashi Syndrome.

Chediak-Higashi syndrome (CHS) is a rare, autosomal recessive disorder characterized by oculocutaneous albinism, recurrent bacterial infections and progressive neurological dysfunction. We demonstrate novel heterogenous mutations of CHS1, the responsive gene of CHS, identified in five Japanese patients with CHS. Patients 1, 2, and 3 were siblings, and they had albinism of the skin and hair. They all had a heterogenous two-base deletion (c.5541-5542 del AA, p.Q1847fsX1850) in exon 18. Patient 4 had a heterogenous single-base insertion (c.3944-3945 ins C, p.T1315fsX1331) in exon 10. The patient exhibited severe early-onset phenotype and suffered from hemophagocytic lymphohistiocytosis. Patient 5 had two heterogenous nonsense mutations; c.7982C>G, p.S2661X in exon 30 and c.8281A>T, p.R2761X in exon 31. The patient suffered from infections in childhood and had visual disturbance and albinism of the skin and hair. The CHS1 mutations described here have not been reported previously.