Autosomal dominant anhidrotic ectodermal dysplasia with immunodeficiency caused by a novel NFKBIA mutation, p.Ser36Tyr, presents with mild ectodermal dysplasia and non-infectious systemic inflammation.

PURPOSE: Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) is characterized by hypohidrosis, dental abnormalities, sparse hair, and immunodeficiency. Autosomal dominant (AD)-EDA-ID, caused by a heterozygous mutation within NFKBIA, is very rare and its clinical features remain largely unknown. This study describes a patient with AD-EDA-ID harboring a novel NFKBIA mutation who presented with mild EDA and non-infectious systemic inflammation. METHODS: The clinical presentation of an AD-EDA-ID patient was described and immunological, genetic, and biochemical analyses were performed, with a focus on nuclear factor kappa B (NF-κB) activation. RESULTS: The patient presented with symptoms of mild EDA-ID, namely sparse hair and hypohidrosis, although a skin biopsy confirmed the presence of sweat glands. There were no dental abnormalities. The patient also suffered from non-infectious inflammation, which responded to systemic corticosteroid therapy; however, the patient remained ill. Immunological analyses revealed reduced Toll-like receptor/IL-1 (TLR/IL-1) and tumor necrosis factor (TNF) receptor family responses to various stimuli. Genetic analysis identified a de novo heterozygous missense mutation, p.Ser36Tyr, in NFKBIA, resulting in defective NFKBIA degradation and impaired NF-κB activation. The patient was diagnosed with AD-EDA-ID and underwent hematopoietic stem cell transplantation. Engraftment was successful, with few signs of acute graft versus host disease. However, the patient suffered hemolytic anemia and thrombocytopenia, and died from a brain hemorrhage due to intractable thrombocytopenia. CONCLUSION: AD-EDA-ID patients can present with mild ectodermal dysplasia and non-infectious inflammation, rather than with recurrent infections. Also, hematopoietic stem cell transplantation for AD-EDA-ID is still a clinical challenge.

Depressed levels of interferon-gamma and HLA-DR+CD3+ T cells in infants with transient hyperferritinemia.

Familial hemophagocytic lymphohistiocytosis (FHL), which typically has its onset during infancy, is uniformly fatal if not treated. It therefore requires prompt therapeutic intervention. Although hyperferritinemia has been emphasized as a useful marker for FHL, some nonfatal cases in infants with spontaneous remission also manifest with hyperferritinemia. However, distinguishing them is difficult because initial clinical features of these infants are similar. The authors encountered 14 infants with hyperferritinemia (serum ferritin >674 ng/mL), which normalized within 3 weeks following a benign clinical course. The authors compared the levels of HLA-DR+CD3+ T-cell subsets and interferon-gamma (IFN-γ) in the peripheral blood between these infants and FHL cases: one of the authors' own patients and others from the literature. Serum IFN-γ was not detected in infants with hyperferritinemia. Moreover, levels of HLA-DR+CD3+ T cells were extremely depressed. In contrast, serum IFN-γ was elevated and HLA-DR+CD3+ T cells were not depressed in FHL. Measurement of activated T cells and serum IFN-γ might help differentiate FHL in febrile infants with transient hyperferritinemia.

Hereditary spherocytosis in 3 children coexisting with UDP-glucuronyl transferase 1A1 deficiency.

Simultaneous presence of hemolytic anemia and bilirubin UDP-glucuronosyltransferase deficiency is a possible cause of misdiagnosis. Seven-year-old and 17-year-old brothers and a 15-year-old sister consecutively suffered from aplastic crises. Although few spherocytes were present, the siblings and their mother had diagnoses of hereditary spherocytosis with flow cytometric analysis of eosin-5'-maleimide-labeled red blood cells in addition to osmotic fragility test. However, inappropriately high values of bilirubin compared with mild hemolysis persisted. Further analysis of UDP-glucuronyltransferase 1A1 revealed all 3 siblings were heterozygous for A(TA)7TAA-P229Q. We report here the importance of careful evaluation of mild hereditary spherocytosis masking UDP-glucuronyltransferase 1A1 deficiency.

Successful Conservative Treatment of Mycotic Pulmonary Artery Aneurysms Caused by MRSA Bacteremia.

Mycotic pulmonary artery aneurysms (MPAAs) are rare and life-threatening with currently no recommended treatment strategies. In this report, we describe a successfully treated case of ventricular septal defect in an 11-month-old girl who developed bacteremia, infective endocarditis, and MPAA caused by methicillin-resistant Staphylococcus aureus (MRSA). We first started vancomycin, gentamycin, and panipenem-betamipron for infective endocarditis but switched to teicoplanin and arbekacin on day 3 after initiating treatment because bacteremia persisted, and vancomycin minimum inhibitory concentration was relatively high at 2 mg/L. Although we added clindamycin on day 5 and fosfomycin on day 7, MRSA bacteremia persisted, and we finally added daptomycin at 10 mg/kg per day on day 8, whereupon the bacteremia subsided within a day. Although the bacteremia subsided, the patient developed septic pulmonary embolisms and septic arthritis on her left knee. We continued daptomycin but switched the concomitant drug to linezolid, trimethoprim-sulfamethoxazole, and rifampicin on day 11. After several repeats of puncture and lavage of her knee joint, she became afebrile on day 16. Computed tomography scans taken on day 32 revealed right pulmonary artery MPAAs. She was treated with long-term multidrug therapy, and MPAAs were absent on subsequent computed tomography scans on day 184. Multidrug therapy mainly based on daptomycin could be a possible salvage therapy for refractory MRSA bacteremia with high vancomycin minimum inhibitory concentration. Conservative treatment should be selectively considered as a treatment option for clinically stable MPAA instead of surgical and endovascular treatment.

[Changes in food allergen sensitization rates of Japanese allergic children during the last 15 years].

In order to evaluate the changes in food allergen sensitization rates of allergic children, serum samples from 85 patients about 15 years ago (past group) and those from 90 current patients (present group) were randomly selected, and the specific IgE for six food allergens (wheat, peanuts, sesame, mackerel, ovomucoid, and kiwi) were measured with the CAP-RAST system. Sensitivity rates (class 2 or higher) for wheat and peanuts were significantly higher in the present than in the past group. Although there was no statistical difference in sensitivity rates (class 2 or higher) for kiwi between the groups, sensitivity rates (class 1 or higher) of the present group were significantly higher than those of the past group, indicating that the number of cases mildly sensitized to kiwi has been increasing. This trend was especially marked among children aged 6 or younger, and there was no statistical difference in sensitivity rates among those aged 7 or older. For the management of food allergy, special attention should therefore be paid not only to an increase in the number of patients, but also to changes in the kinds of causative foods.

[Changes in Japanese cedar sensitization rates of Japanese allergic children during the last 15 years].

In order to evaluate the changes in Japanese Cedar (JC) sensitization rates of allergic children, serum samples from 88 patients about 15 years ago (past group) and those from 91 current patients (present group) were randomly selected, and their JC specific IgE were measured with the CAP-RAST system. Sensitivity rate (class 2 or more) for JC of the present group was 65.9%, which was significantly higher than that of the past group, which was 46.6%. However, there was no significant difference between these two groups for children aged 6 or younger. For children aged 7 or older, the sensitivity rate of the present group was significantly higher than that of the past group. Thus, protection against JC sensitization, especially during early childhood, should be given serious attention.

Low response to a monovalent inactivated unadjuvanted influenza A (H1N1) pdm09 vaccine in pediatricians of a general hospital in Japan.

Immunization of health care personnel (HCP) is critically important to reduce healthcare-associated influenza infections substantially. During 2009-2010, 74% of all HCP at Kitano Hospital, Osaka, Japan, including 94% of pediatricians, received the monovalent unadjuvanted influenza A (H1N1) pdm09 vaccine. We evaluated the vaccine's immunogenicity. Sixteen pediatricians received 15 µg hemagglutinin antigen subcutaneously. Antibody titer assays were conducted using hemagglutination-inhibition antibody assay on days 0 and 21, and at 5 mo after vaccination. Seroprotection rates, seroconversion rates, and geometric mean titer folds at 21 d were, respectively, 43.8%, 43.8%, and 5.4 in all subjects, 70.0%, 70.0%, and 8.0 in subjects aged 27-34 y, and 0.0%, 0.0%, and 8.0 in subjects aged ≥ 35 y. None of the latter group met the European Medicines Agency criteria. We hope to adopt intradermal routes and further the development of the influenza vaccine using new technology to improve immunogenicity in Japan.

Role of the NOD2 genotype in the clinical phenotype of Blau syndrome and early-onset sarcoidosis.

OBJECTIVE: Blau syndrome and its sporadic counterpart, early-onset sarcoidosis (EOS), share a phenotype featuring the symptom triad of skin rash, arthritis, and uveitis. This systemic inflammatory granulomatosis is associated with mutations in the NOD2 gene. The aim of this study was to describe the clinical manifestations of Blau syndrome/EOS in Japanese patients and to determine whether the NOD2 genotype and its associated basal NF-kappaB activity predict the Blau syndrome/EOS clinical phenotype. METHODS: Twenty Japanese patients with Blau syndrome/EOS and NOD2 mutations were recruited. Mutated NOD2 was categorized based on its basal NF-kappaB activity, which was defined as the ratio of NF-kappaB activity without a NOD2 ligand, muramyldipeptide, to NF-kappaB activity with muramyldipeptide. RESULTS: All 9 mutations, including E383G, a novel mutation that was identified in 20 patients with Blau syndrome/EOS, were detected in the centrally located NOD region and were associated with ligand-independent NF-kappaB activation. The median age of the patients at disease onset was 14 months, although in 2 patients in Blau syndrome families (with mutations R334W and E383G, respectively) the age at onset was 5 years or older. Most patients with Blau syndrome/EOS had the triad of skin, joint, and ocular symptoms, the onset of which was in this order. Clinical manifestations varied even among familial cases and patients with the same mutations. There was no clear relationship between the clinical phenotype and basal NF-kappaB activity due to mutated NOD2. However, when attention was focused on the 2 most frequent mutations, R334W and R334Q, R334W tended to cause more obvious visual impairment. CONCLUSION: NOD2 genotyping may help predict disease progression in patients with Blau syndrome/EOS.

Disease-associated CIAS1 mutations induce monocyte death, revealing low-level mosaicism in mutation-negative cryopyrin-associated periodic syndrome patients.

Cryopyrin-associated periodic syndrome (CAPS) is a spectrum of systemic autoinflammatory disorders in which the majority of patients have mutations in the cold-induced autoinflammatory syndrome (CIAS)1 gene. Despite having indistinguishable clinical features, some patients lack CIAS1 mutations by conventional nucleotide sequencing. We recently reported a CAPS patient with mosaicism of mutant CIAS1, and raised the possibility that CIAS1 mutations were overlooked in "mutation-negative" patients, due to a low frequency of mosaicism. To determine whether there were latent mutant cells in "mutation-negative" patients, we sought to identify mutation-associated biologic phenotypes of patients' monocytes. We found that lipopolysaccharide selectively induced necrosis-like cell death in monocytes bearing CIAS1 mutations. Monocyte death correlated with CIAS1 up-regulation, was dependent on cathepsin B, and was independent of caspase-1. Cell death was intrinsic to CIAS1-mutated monocytes, was not mediated by the inflammatory milieu, and was independent of disease severity or anti-IL-1 therapy. By collecting dying monocytes after lipopolysaccharide treatment, we succeeded in enriching CIAS1-mutant monocytes and identifying low-level CIAS1-mosaicism in 3 of 4 "mutation-negative" CAPS patients. Our findings reveal a novel effect of CIAS1 mutations in promoting necrosis-like cell death, and demonstrate that CIAS1 mosaicism plays an important role in mutation-negative CAPS patients.

Limited ability of antigen-specific Th1 responses to inhibit Th2 cell development in vivo.

Th1 and Th2 cells mutually antagonize each other's differentiation. Consequently, allergen-specific Th1 cells are believed to be able to suppress the development of Th2 cells and to prevent the development of atopic disorders. To determine whether a pre-existing Ag-specific Th1 response can affect the development of Th2 cells in vivo, we used an immunization model of Ag-pulsed murine dendritic cell (DC) transfer to induce distinct Th responses. When transferred into naive mice, Ag-pulsed CD8alpha(+) DCs induced a Th1 response and the production of IgG2a, whereas CD8alpha(-) DCs primed a Th2 response and the production of IgE. In the presence of a pre-existing Ag-specific Th2 environment due to Ag-pulsed CD8alpha(-) DC transfer, CD8alpha(+) DCs failed to prime Th1 cells. In contrast, CD8alpha(-) DCs could prime a Th2 response in the presence of a pre-existing Ag-specific Th1 environment. Moreover, exogenous IL-4 abolished the Th1-inducing potential of CD8alpha(+) DCs in vitro, but the addition of IFN-gamma did not effectively inhibit the potential of CD8alpha(-) DCs to prime IL-4-producing cells. Thus, Th1 and Th2 cells differ in their potential to inhibit the development of the other. This suggests that the early induction of allergen-specific Th1 cells before allergy sensitization will not prevent the development of atopic disorders.

Somatic mosaicism of CIAS1 in a patient with chronic infantile neurologic, cutaneous, articular syndrome.

Chronic infantile neurologic, cutaneous, articular syndrome (CINCA syndrome) is a severe inflammatory disease that was recently found to be associated with mutations in CIAS1. However, CIAS1 mutations have been detected in only half of CINCA syndrome patients, and it remains unclear which genes are responsible for the syndrome in the remaining patients. We describe here a patient with CINCA syndrome who exhibited CIAS1 somatic mosaicism. We genetically analyzed the CIAS1 gene in various blood cells and the buccal mucosa of the patient. The production of interleukin-1beta (IL-1beta) by peripheral blood mononuclear cells (PBMCs) was measured by enzyme-linked immunosorbent assay, and the ability of the mutant CIAS1 gene to enhance ASC-dependent NF-kappaB activation was assessed to confirm that the mutations of CIAS1 found were responsible for the patient's clinical manifestations of the CINCA syndrome. The patient had 1 heterologous single-nucleotide polymorphism, 587G>A (S196N), and 1 heterologous mutation, 1709A>G (Y570C), in exon 3 of CIAS1. The latter mutation was found to occur as somatic mosaicism. The patient's PBMCs produced a large amount of IL-1beta in the absence of stimulation, unlike those from controls or from his mother, who also bore the S196N polymorphism. In addition, the Y570C mutation (with or without the S196N polymorphism) increased the ability of CIAS1 to induce ASC-dependent NF-kappaB activation, unlike the wild-type gene or the gene bearing the S196N polymorphism alone. The findings in this patient indicate that somatic mosaicism is one reason CIAS1 mutations have not been detected in some patients with CINCA syndrome.

Differential requirement for the CD40-CD154 costimulatory pathway during Th cell priming by CD8 alpha+ and CD8 alpha- murine dendritic cell subsets.

Dendritic cells (DCs) regulate the development of distinct Th populations and thereby provoke appropriate immune responses to various kinds of Ags. In the present work, we investigated the role CD40-CD154 interactions play during the process of Th cell priming by CD8 alpha(+) and CD8 alpha(-) murine DC subsets, which have been reported to differently regulate the Th response. Adoptive transfer of Ag-pulsed CD8 alpha(+) DCs induced a Th1 response and the production of IgG2a Abs, whereas transfer of CD8 alpha(-) DCs induced Th2 cells and IgE Abs in vivo. Induction of distinct Th populations by each DC subset was also confirmed in vitro. Although interruption of CD80/CD86-CD28 interactions inhibited Th cell priming by both DC subsets, disruption of CD40-CD154 interactions only inhibited the induction of the Th1 response by CD8 alpha(+) DCs in vivo. CD40-CD154 interactions were not required for the proliferation of Ag-specific naive Th cells stimulated by either DC subset, but were indispensable in the production of IL-12 from CD8 alpha(+) DCs and their induction of Th1 cells in vitro. Taken together, in our immunization model of Ag-pulsed DC transfer, CD40-CD154 interactions play an important role in the development of CD8 alpha(+) DC-driven Th1 responses but not CD8 alpha(-) DC-driven Th2 responses to protein Ags.