R. Inoue

Reduced IFNγ production in response to IL‐12 stimulation and/or reduced IL‐12 production in atopic patients

Several studies have shown that interleukin (IL)‐4 and interferon‐gamma (IFNγ) are important for the regulation of IgE production and that IL‐12 induces IFNγ.

IFN-gamma production in response to IL-18 or IL-12 stimulation by peripheral blood mononuclear cells of atopic patients.

Background Several studies have shown that interleukin (IL)‐4 and interferon‐gamma (IFN‐γ) are important for the regulation of immunoglobulin E (IgE) production and that IL‐18 and IL‐12 induce IFN‐γ.

Reduced Expression of the Interferon‐Gamma Messenger RNA in IgG2 Deficiency

The specific defect that causes IgG2 deficiency, which is one of the primary immunodeficiencies, is unknown. Recently, it was shown that interferon‐γ (IFN‐γ) induces synthesis of human germline Cγ2 transcripts. In the authors’ previous study and the present one, peripheral blood lymphocytes (PBLs) of all five tested patients with IgG2 deficiency failed to produce enough IFN‐γ when stimulated with phytohaemagglutinin or concanavalin A although they produced a sufficient amount of interleukin‐2 (IL‐2). The low level of IgG2 production in pokeweed mitogen‐stimulated PBLs of four tested patients was improved by the addition of recombinant IFN‐γ. In this study, the amount of IFN‐γ messenger RNA showed various degrees of reduction in all five tested patients. Sequence analysis of the IFN‐γ coding regions and flanking regions revealed neither a point mutation nor a deletion for any of the patients. Thus the results suggest that the reduced expression of IFN‐γ messenger RNA may play an important role in the IgG2 deficiency of these patients.

Microsatellite instability in B-cell lymphoma originating from Bloom syndrome.

Bloom syndrome (BS) is a rare autosomal recessive genetic disorder characterized by lupus‐like erythematous telangiectasias of the face, sun sensitivity, stunted growth infertility and immunodeficiency. In addition, BS patients are highly predisposed to cancers. Although recently the causative gene of BS (BLM) was identified as a DNA helicase homologue, the function of BLM in DNA replication has not been elucidated. In this study, p53 mutation and microsatellite instability in B‐cell lymphomas originating from 2 sibling BS patients were investigated. In the originally developed tumor of both patients, no p53 mutation was detected. In one patient, however, after treatment by ionizing radiation the B‐cell lymphoma recurred, showing a 9‐bp deletion in exon 7. In lymphoma cells and an EB‐virus‐transformed cell line from BS lymphocytes of this patient, microsatellite instability was also detected from the reduced length of microsatellite DNA markers, although in the other patient microsatellite instability was not detected. Thus, 2 B‐cell lymphomas, despite having the same BLM mutation, showed different phenotypes in terms of p53 mutation and microsatellite instability.

Atopy and mutations of IL-12 receptor β2 chain gene

Atopy, which is characterized by enhanced IgE responses to environmental antigens, leads to clinical disorders such as asthma, eczema and rhinitis. These atopic disorders develop due to the interactions between genetic and environmental factors. The class switch to IgE and production of IgE in B lymphocytes are regulated by cytokines [1±6]. IL-12 is one of the most important cytokines which down-regulate IgE production. In this paper, the relationship between atopy and aberrant IL-12 signal transduction, particularly mutations in the IL-12 receptor (IL-12R) chain gene is focused upon.

The correlation between ovomucoid-derived peptides, human leucocyte antigen class II molecules and T cell receptor-complementarity determining region 3 compositions in patients with egg-white allergy.

Background Food allergies are more prevalent in children, due to the immature gastrointestinal epithelial membrane barrier allowing more proteins through the barrier and into circulation. Ovomucoid (OM) is one of the major allergens that is found in egg white.

MAGNETIC RESONANCE IMAGING FOR EARLY DETECTION OF BRONCHIAL FOREIGN BODIES

Sir: The diagnosis of radiolucent bronchial foreign body aspiration is sometimes difficult. Conventional radiography may show mediastinal shadow shifting, hyperinflation and pneumomediastinum. However, these alterations are also caused by mucous plugs, and bronchial foreign bodies are often difficult to locate with precision. Tl-weighted MRI has recently been introduced to detect fat-rich bronchial foreign bodies such as peanuts, the most common foreign body in children [1-3]. Its usefulness is documented by the following case. A 2-year-old girl was admitted to our hospital with a l-week history of fever and cough. The patient had been treated for a common cold at another hospital. On admission, a coarse crackling sound was detected on the left side of the chest, and a plain radiograph showed an infiltration shadow in the lower left pulmonary field. A diagnosis of pneumonia was made and antibiotic therapy instituted. Her fever abated but chest radiographs revealed hyperinflation of the left lung and mediastinal shadow shifting from left to right upon expiration. Chest MRI was performed 1 week after admission. The Tl-weighted image showed a high-intensity area in the left main bronchus (Fig. 1A). Using direct rigid bronchoscopy, a peanut was extracted measuring 6 ~ 8 mm in length. The location of the peanut was consistent with the MRI finding. To confirm the applicability of Tl-weighted MRI, peanut fragments were incubated in saline for various periods of time and examined by MRI (Fig. 1B). They were identified at all times including the native state before incubation. Removal of a foreign body with a bronchoscope is easiest shortly after aspiration when it is not yet swollen, and when bronchial inflammation and check valve mechanisms have not yet developed. Tl-weighted MRI can be readily performed with oral sedatives or suppositories. It reduces the possibility of misdiagnosis Fig. 1 A Lung of a 2-year-old girl who had a 1-week history of fever and cough. Tl-weighted MRI shows a high-intensity area in the left main bronchus caused by an aspirated peanut. B Peanut fragments incubated in saline at 37 ~ for 0 (a), 3.5 (b), and 7 (c) days and human lower extremity

Two Japanese siblings with Bloom syndrome gene mutation and B-cell lymphoma.

Bloom syndrome (BS) is a rare autosomal recessive genetic disorder characterized by lupus-like erythematous telangiectasia of the face, sun sensitivity, infertility and stunted growth. Upper respiratory tract and gastrointestinal infections are commonly associated with the decreased immunoglobulin levels found in BS patients. Chromosomal abnormalities are hallmarks of the disorder, and high frequencies of sister chromatid exchanges and quadriradial configurations in lymphocytes and fibroblasts are virtually diagnostic. Recently, the causative gene for BS (BLM) has been identified. We encountered and defined a family with a nonsense mutation in BLM. The brother and sister were homozygous for the mutation and both developed B-cell malignant lymphoma in their twenties. These findings indicate the importance of prenatal diagnosis and the detection of BS carriers based on molecular genetic analysis.

Cytolytic mechanisms involved in non‐MHC‐restricted cytotoxicity in Chediak‐Higashi syndrome

To determine the mechanisms responsible for the impaired lymphocyte‐mediated cytotoxicity in Chediak‐Higashi syndrome (CHS), we investigated the killing ability of peripheral blood lymphocytes (PBL) from three patients with CHS using several kinds of target cells that were sensitive to perforin, Fas ligand (FasL), and/or tumour necrosis factor‐alpha (TNF‐α). Freshly isolated CHS PBL did not kill K562 target cells, killing of which by normal PBL was perforin‐dependent, as demonstrated by complete inhibition by concanamycin A (CMA), an inhibitor of perforin‐based cytotoxicity. In contrast, the CHS PBL exhibited substantial cytotoxicity against Jurkat cells, which was only partially inhibited by CMA treatment but not by the addition of neutralizing anti‐FasL or anti‐TNF‐α antibodies. IL‐2‐activated CHS PBL exhibited substantial levels of cytotoxicity against K562 and Jurkat cells, the levels being 74% and 83% of the respective normal control values, respectively. CMA treatment showed that while the cytotoxicity of IL‐2‐activated CHS PBL against K562 was largely dependent on perforin, that against Jurkat was largely not. IL‐2‐activated CHS PBL expressed FasL mRNA, and killed Fas transfectants. These findings indicate that CHS PBL have an ability to kill some target cells via a perforin‐mediated pathway, especially when they are activated by IL‐2. It was also demonstrated that CHS PBL can exert cytotoxicity against certain target cells by utilizing FasL and an undefined effector molecule other than perforin, FasL, or TNF‐α.

Failure of IgG production due to a defect in the opening of the chromatin structure of Iγ1 region in a patient with IgG and IgA deficiency

Patients with common variable immunodeficiency (CVID) display reduced levels of two or all three of the major immunoglobulin isotypes, and the deficiency is characterized by failure of B cells to differentiate into plasma cells in many cases. A patient (14 years old, female) showed normal serum IgM levels and low serum IgG and IgA levels, including low levels of all IgG subclasses. Northern blot analysis suggested that the patients B cells may be defective at the immunoglobulin heavy chain isotype switch. The germ‐line Cγ1 transcript was amplified from cDNA of healthy controls by the addition of recombinant IL‐2 (rIL‐2) to pokeweed mitogen‐stimulated peripheral mononuclear cells or Staphylococcus aureus Cowan I (SAC)‐stimulated IgM‐producing lymphoblastoid cell lines (LCL) transformed by Epstein‐Barr virus, while it was not amplified from cDNA of the patient. In the Iγ1 region of LCL cultured with SAC plus rIL‐2, the inner cytosine in the 5′C‐C‐G‐G 3′sequence nearest the 3′site of the Iγ1 region, at least, was not completely unmethylated in the patient. Moreover, the DNase I hypersensitive site was not induced in the patients LCL by SAC plus rIL‐2. These results indicate that the defects of the immunoglobulin heavy chain isotype switch in the patients B cells are due to failure in the synthesis of germ‐line Cγ transcripts, and this may be caused by defects in opening of the chromatin structures of specific switch regions.