Early-Onset Inflammatory Bowel Disease Caused by Mutations in the X-Linked Gene IL2RG

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Subcutaneous abscess due to the basidiomycete Phellinus mori in a patient with chronic granulomatous disease.

Chronic granulomatous disease (CGD), a primary immunodeficiency caused by impaired phagocyte killing of intracellular pathogens, is characterized by recurrent, life-threatening, bacterial and fungal infections. As a result of improvements in microbiologic culture and identification techniques, a number of unique filamentous fungi have been reported as significant pathogens in patients with CGD. We report a case of subcutaneous basidiomycete Phellinus mori infection in a patient with CGD. To the best of our knowledge, this is the first reported case of human infection by this fungus. The causative fungus was identified on the basis of its morphological characteristics and nucleotide sequence on the internal transcribed spacer region of the ribosomal RNA gene. This is the fifth case report of filamentous basidiomycetes infecting a patient with CGD; all of these cases have been caused by Phellinus species. We highlight the importance of recognizing filamentous basidiomycetes Phellinus species as possible agents of non-Aspergillus fungal infections in patients with CGD.

Analysis of mutations in the IL2RG gene in 2 asian infants with X-linked severe combined immunodeficiency

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Expression of CD64 on polymorphonuclear neutrophils in patients with familial Mediterranean fever.

Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by recurrent episodes of fever and serosal or synovial inflammation. We examined the utility of CD64 (FcγRI) expression in polymorphonuclear neutrophils (PMNs) as clinical and biological parameters in patients with FMF. We studied 12 Japanese FMF patients (mean age; 22·8 ± 15·5 years, male/female: 2/10), along with rheumatoid arthritis patients (RA, n = 38 male/female: 6/32, mean age; 52·2 ± 15·3 years), systemic lupus erythematosus (SLE, n = 15 male/female: 0/15, mean age; 38·5 ± 15·9 years) and 12 healthy subjects (male/female: 3/9, mean age; 37·9 ± 17·2 years). CD64 expression on PMNs was determined using flow cytometry. The quantitative expression of CD64 in patients with FMF (2439·6 ± 2215·8 molecules per PMN) was significantly higher than in healthy subjects (547·8 ± 229·5, P = 0·003) or in patients with RA (606·5 ± 228·2, P < 0·0001) and SLE (681·3 ± 281·1, P = 0·004). The increased CD64 expression on PMNs isolated from untreated FMF patients was down-regulated by colchicine treatment. NACHT-LRR-PYD-containing protein 3 (NLRP3) activation using MurNAc-L-Ala-D-isoGln (MDP) resulted in increased CD64 expression on PMNs from healthy subjects. Our results suggest that quantitative measurement of CD64 expression on PMNs can be a valuable tool to discriminate between FMF and autoimmune diseases.

Femoral osteomyelitis due to Cladophialophora arxii in a patient with chronic granulomatous disease.

Fungal infections in patients with chronic granulomatous disease (CGD) are a poor prognostic factor. We describe the first case of CGD with femoral osteomyelitis due to Cladophialophora arxii, which is a member of the dematiaceous group. The causative fungus was identified on the basis of its morphological characteristics, growth temperature profile, and nucleotide sequence on the internal transcribed space region of the ribosomal gene. The patient was successfully treated with surgical debridement, subsequent administration of itraconazolem and interferon-gamma.

[Short-term outcome of extracardiac lateral tunnel using the atrial free wall and autologous pericardium].

BACKGROUND: Several modifications to the original Fontan procedure have been proposed in order to decrease postoperative morbidity. Lateral tunnel and extracardiac total cavo-pulmonary connection are 2 such modifications. PATIENTS: Between August 2005 and December 2005, the extracardiac lateral tunnel procedure was performed in 5 patients. The age at operation ranged from 19 to 59 months (median 24 months) and the weight ranged from 9.2 to 16.1 kg (median 11.4 kg). RESULTS: There was no mortality. The mean operation time was 466 +/-118 minutes. The mean cardiopulmonary bypass time was 198 +/- 61 minutes. The mean durations of intubation, intensive care unit stay, drainage tube use, and hospital stay were 1 +/- 1, 7 +/- 3, 12 +/- 5 and 30 +/- 2 days, respectively. Postoperative catheterization findings demonstrated that the mean superior venous caval pressure, inferior venous caval pressure, ventricular volume and ventricular ejection fraction were 10.0 +/- 1.4 mmHg, 11.0 +/- 2.4 mmHg, 140 +/- 47% of normal and 58.0 +/- 6.8% , respectively. CONCLUSIONS: The short-term results of the extracardiac lateral tunnel compared favorably with the results of different types of Fontan operation. In addition this procedure has the potential for growth and anticoagulation therapy is unnecessary.

Novel mutations in a Japanese patient with CD19 deficiency.

Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by recurrent bacterial infections, hypogammaglobulinemia and low to normal numbers of circulating B cells. Mutations in the ICOS, TACI and CD19 genes have recently been identified in <10% of CVID patients. We, herein, describe two novel CD19 gene disruptions in an 8-year-old Japanese boy, who had been clinically diagnosed as having CVID at the age of 5 years. Flow-cytometric analysis demonstrated absence of CD19 and reduced CD21 expression on CD20-postive peripheral blood B cells. Mutation analysis of CD19 revealed a mutation in the splice acceptor site of intron 5 (IVS5-1G>T) of the maternal allele, resulting in skipping of exon 6, and a truncated protein product. The paternal allele was disrupted by a gross deletion encompassing at least the ATP2A1, CD19 and NFATC2IP genes. The patient had a small number of IgD(-) CD27(+) memory B cells, in which somatic mutation were detected. His B cells showed substantial proliferation upon stimulation, but reduced IgG and IgA production in vitro. These findings extend the mutation spectrum of the CD19 deficiency to four, and confirm the homogeneity of the CD19 deficiency as a unique type of CVID.

Secretory IgA, salivary peroxidase, and catalase-mediated microbicidal activity during hydrogen peroxide catabolism in viridans streptococci: pathogen coaggregation.

Viridans streptococci can kill methicillin-resistant Staphylococcus aureus (MRSA) through the production of hydrogen peroxide (H2O2). However, several hundred viridans streptococci cells are necessary to kill 1 cfu of MRSA. We analyzed the potency of bactericidal and fungicidal effector molecules induced by catabolism of H2O2 in the oral cavity. Secretory IgA (SIgA) and an unidentified salivary component bound Streptococcus sanguinis, a viridans streprococcus, and MRSA into coaggregates. In these coaggregates, salivary peroxidase and the MRSA catalase produced singlet molecular oxygen (1O2) from H2O2 produced by viridans streptococci. SIgA converted 1O2 into ozone, which has potent bactericidal and fungicidal activity. We calculated that <10 cfu of Streptococcus sanguinis were necessary to kill 1 cfu of MRSA in the coaggregate. SIgA, Aspergillus niger catalase, and H2O2 in saliva killed Candida albicans, which is highly resistant to reagent H2O2. Together with indigenous bacteria and innate immunity, SIgA potentially constitutes a novel system that may sustain oral homeostasis.

[Mitral valve repair of valve insuffficiency with broad and complex lesions due to infective endocarditis; report of a case].

Surgical intervention is necessary for the treatment of infective endocarditis, although antibiotic therapy has been shown to be effective for treatment of this disorder. Mitral valve infective endocarditis frequently presents with broad and complex lesions, and thus a variety of valve repair is needed. A 40-year-old woman with mitral valve insufficiency due to infective endocarditis underwent mitral valve repair. During the operation, torn chordae, aneurysm with perforation of the anterior leaflet, and torn chordae of the posterior leaflet were found. The chordae of the anterior leaflet were reconstructed and the aneurysm was excised, and autopericardial patch repair was performed. Then, resection and suturing of the prolapsing lesion of posterior leaflet were performed. Mitral valve repair preserves the left ventricular apparatus and function. Therefore, mitral repair results in better prognosis than valve replacement. The repair of the mitral valve should be attempted for the treatment of valve insufficiency due to infective endocarditis.

Polarization of Th1/Th2 in human CD4 T cells separated by CD62L: analysis by transcription factors.

BACKGROUND: T-cell surface antigens that differentiate clearly between Th1 and Th2 have not been identified. Discrimination of Th1/Th2 subpopulations by CD62L expression has been reported. We investigated the expression of transcription factors that regulate Th1/Th2 cytokine synthesis in human CD4+ T-cell subpopulations separated by CD45RO and CD62L, and compared the ratio of CD62L+ to CD62L- cells between healthy individuals and patients with allergic diseases. METHODS: Human peripheral blood samples were obtained from healthy volunteers and patients. CD4+ T cells were isolated by negative selection. Three CD4+ T-cell subpopulations separated by CD45RO and CD62L were isolated using three-color fluorescence. Sorted cells were stimulated with anti-CD3 monoclonal antibody, and the cytokine levels were measured using a Cytometric Bead Array Kit. Transcription factor expression was examined by reverse transcriptase polymerase chain reaction (RT-PCR) and real-time RT-PCR. RESULTS: Interleukin (IL)-4 and IL-5 production levels by CD45RO+CD62L+CD4+ T cells were higher than those of CD45RO+CD62L-CD4+ T cells (P < 0.05), whereas interferon-gamma and tumor necrosis factor-alpha production were lower levels (P < 0.05). T-cell immunoglobulin mucin-3 and T-bet expression were detected in CD45RO-CD62L+ and CD45RO+CD62L- cells following stimulation, but not in CD45RO+CD62L+ cells. However, the ratio of CD62L+ to CD62L- cells was the same in both healthy individuals and patients (P = 0.54). There was no difference in Th1/Th2 cytokine synthesis by CD4+ T cells. CONCLUSION: Analyses of cytokine syntheses and transcription factor expression demonstrated that CD62-negative and -positive subpopulations of human CD45RO+CD4+ T cells represent characteristics of Th1 and Th2, respectively.

[Critical hypertrophic obstructive cardiomyopathy patient with improved hemodynamics following mitral valve replacement: report of a case].

A 75-year-old man with dyspnea was admitted to our hospital in critical condition. Catheterization showed normal coronary arteries and good left ventricular function. Transesophageal echocardiography showed left ventricular hypertrophy and severe mitral regurgitation. We decided to perform mitral valve replacement because the patient was in critical condition and it was necessary to complete the operation smoothly. During the operation, we could see the dilated mitral valve annulus and hypertrophic mitral valve, which was restricted. The patient's hemodynamics showed improvement after mitral valve replacement with a mechanical prosthesis, and he was discharged on postoperative day 21. In conclusion, mitral valve replacement is a beneficial method for the treatment of patients with critical hypertrophic obstructive cardiomyopathy.

[An anastomosis assist mirror; a new device for off-pump coronary artery bypass].

An anastomosis assist mirror for off-pump coronary artery bypass (OPCAB) is described. This new device is designed to make a view of the circumflex coronary artery which is often troublesome to access during OPCAB. It is composed of 3 parts: a small circular mirror, a paper clip and a flexible arm between the mirror and the clip. The paper clip is situated at an edge of a sternal retractor. The mirror is positioned beside the sheer surface of the lateral wall of the heart by regulating the flexible arm. It shows a flat, reflective view of the anastomotic site and makes an anastomosis easy. The device enables us to avoid excessive manipulation on the heart and hemodynamic instability, thereby reducing unnecessary volume overload, inotropic drugs or mechanical cardiac assistance.

[Clinical outcome of emergency off-pump coronary artery bypass grafting].

From January 2001 to January 2003, we performed 25 emergency off-pump coronary artery bypass grafting (CABG) procedures for patients with acute myocardial infarction (AMI) or unstable angina pectoris. During the same period, we also performed 2 emergency on-pump beating CABG procedures for patients with left main coronary trunk (LMT) shock syndrome. For the present study, we evaluated the operative results of the 25 cases of emergency or urgent off-pump CABG. The patients were divided into 3 groups, those with acute AMI with cardiogenic shock (group 1; n = 8), acute myocardial infarction without shock (group 2; n = 8), and unstable angina (group 3; n = 9). There were no differences between groups 1 and 2 with regard to age, number of diseased vessels, and preoperative use of an intraaortic balloon pump, however, patients in group 1 had a higher number of completely obstructed coronary arteries. Patients in groups 1 and 2 underwent off-pump CABG within 3.5 hours after a coronary angiography or coronary intervention procedure, while those in group 3 underwent off-pump CABG within 2 days of coronary angiography. The mean number of grafts per patient was 1.8, 2.1, and 2.3 in groups 1, 2, and 3, respectively. One group 1 patient with an LMT lesion was transferred to on-pump beating CABG because of hemodynamic instability. The 30-day mortality rate was 38% (3 of 8) in group 1, whereas it was 0% in groups 2 and 3. Intubation time, ICU stay, and postoperative stay were similar among the 3 groups. An early angiographic study was undertaken in all surviving patients and the results demonstrated patency in all of the examined grafts. Although our results are limited, emergency off-pump CABG was found to be safe and feasible for AMI without cardiogenic shock or unstable myocardial ischemia. However, the outcome of this procedure for patients with preoperative cardiogenic shock was not satisfactory, therefore, a combination therapy of appropriate mechanical circulatory support, prior revascularization by catheter intervention, and emergency surgical revascularization are considered to improve survival of those patients.

Involvement of CD27/CD70 interactions in antigen-specific cytotoxic T-lymphocyte (CTL) activity by perforin-mediated cytotoxicity.

CD27 molecules are shown to be essential in the regulation of the death, activation and differentiation of T and B cells. However, the influence of CD27 on cytotoxic T-cell function remains obscure. Autologous EBV transformed B-cell lines (LCL), which highly express CD27 ligand CD70, here stimulated T cells and induced the cytotoxic T-lymphocyte (CTL) activity via T-cell antigen receptors (TCR). The cytotoxicity against LCL was diminished when anti-CD70 blocking MoAb was added initially in the culture. Resting T cells killed more CD70-transfected P815 cells than wild type P815 cells in the presence of anti-CD3 MoAb as measured by a 4-h 51Cr release assay, and the cytotoxicity of both of the cell populations completely disappeared in the presence of concanamycin A (CMA). The expression of the perforin by the LCL-induced CTL in the presence of anti-CD70 blocking MoAb was diminished as compared with that without the blockage of CD27/CD70 interactions. The CTL induced by LCL did not kill Fas-transfected WR cells. CD27 signalling in the T cells did not affect Fas ligand (FasL) mRNA expression, LAK activity and IFN-gamma synthesis in humans. Our data demonstrate that CD27/CD70 interactions enhance the cytotoxicity of CTL in the induction phase through enhancement of killing activity induced via the perforin-dependent mechanism, but not via the Fas/FasL system.

IL-10 enhances B-cell IgE synthesis by promoting differentiation into plasma cells, a process that is inhibited by CD27/CD70 interaction.

Interleukin-10 (IL-10) is a major regulatory cytokine of inflammatory responses that is considered to play an important role in specific immunotherapy. However, whether IL-10 enhances or inhibits B-cell IgE production has remained a matter of contention. To clarify the effect of IL-10 on IgE synthesis in the presence of IL-4 and CD40 signalling, we examined B-cell proliferation, germline epsilon transcripts and plasma cell differentiation. In addition, the effect of CD27 signalling on IgE synthesis in the presence of IL-10, IL-4 and CD40 signalling was investigated. IL-10 facilitated the production of IgE in mononuclear cells and highly purified B-cells, enhanced B-cell proliferation and, most importantly, promoted the generation of plasma cells. However, IL-10 did not enhance expression of germline epsilon transcripts. The addition of CD27 signalling through the use of CD32-CD27 ligand (CD70) double transfectants significantly diminished the B-cell proliferation, IgE synthesis and plasma cell differentiation enhanced by IL-10. IL-10 enhances B-cell IgE production by promoting differentiation into plasma cells. CD27/CD70 interactions under IL-10 and sufficient CD40 cosignalling exert the opposite effect on IgE synthesis. The results of this study indicate that precautions are critical when planning immunotherapy using IL-10 in IgE-related allergic diseases.

A thiol proteinase inhibitor, E-64-d, corrects the abnormalities in concanavalin A cap formation and the lysosomal enzyme activity in leucocytes from patients with Chediak-Higashi syndrome by reversing the down-regulated protein kinase C activity.

We have reported previously that the abnormally down-regulated protein kinase C (PKC) causes cellular dysfunction observed in natural killer (NK) cells, polymorphonuclear leucocytes (PMNs) and fibroblasts from beige mouse, an animal model of Chediak-Higashi syndrome (CHS). Here we show that the abnormal down-regulation of PKC activity also occurs in Epstein-Barr (EB) virus-transformed cell lines from CHS patients. When CHS cell lines were stimulated with concanavalin A (Con A) for 20 min, the membrane-bound PKC activity declined markedly, whereas that in control cell lines increased. We found that E-64-d, which protects PKC from calpain-mediated proteolysis, reversed the declined PKC activity and corrected the increased Con A cap formation to almost normal levels in CHS cell lines. We confirmed that the dysregulation of PKC activity also occurred in peripheral blood mononuclear leucocytes (PBMC) from CHS patients and that E-64-d corrected both the declined PKC activity and increased Con A cap formation. E-64-d also corrected the reduced lysosomal elastase and cathepsin G activity in CHS cell lines. In contrast, chelerythrin, a specific inhibitor of PKC, and C2-ceramide, which promotes PKC breakdown induced by calpain, increased Con A cap formation and inhibited both elastase and cathepsin G activity in normal cell lines. Moreover, we found that ceramide production in CHS cell lines increased significantly after Con A stimulation, which coincides with our previous observation in fibroblasts from CHS mice. These results suggest an association between ceramide-induced PKC down-regulation and the cellular dysfunctions in CHS.

Mechanism of hypergammaglobulinemia by HIV infection: circulating memory B-cell reduction with plasmacytosis.

The mechanism of hypergammaglobulinemia in patients infected with HIV has remained unclear in spite of the identification of a reduction of CD4+ T cells. The amounts of CD27+ memory B cells were remarkably reduced in the peripheral blood and immunoglobulin (Ig) production was diminished in HIV-infected patients. Some of the freshly isolated patients' T cells expressed the CD70 (CD27 ligand) on the surface and the CD70 expression on both of the CD4+ and CD8+ T cells was greatly enhanced by various stimuli. It was also striking that plasmacytosis was observed in patients' bone marrow. Thus, our findings suggest that CD70 expressed spontaneously or by activation on T cells of HIV-infected patients stimulates memory B cells via CD27 and promotes their differentiation into plasma cells, resulting in the elevation of serum Ig levels and the elimination of circulating memory B cells in HIV-infected patients.