Publications (4)18.12 Total impact
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Article: Partial recessive IFN-γR1 deficiency: genetic, immunological and clinical features of 14 patients from 11 kindreds.
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ABSTRACT: We report a series of 14 patients from 11 kindreds with recessive partial (RP)-interferon (IFN)-γR1 deficiency. The I87T mutation was found in nine homozygous patients from Chile, Portugal and Poland, and the V63G mutation was found in five homozygous patients from the Canary Islands. Founder effects accounted for the recurrence of both mutations. The most recent common ancestors of the patients with the I87T and V63G mutations probably lived 1600 (875-2950) and 500 (200-1275) years ago, respectively. The two alleles confer phenotypes that are similar but differ in terms of IFN-γR1 levels and residual response to IFN-γ. The patients suffered from bacillus Calmette-Guérin-osis (n= 6), environmental mycobacteriosis (n= 6) or tuberculosis (n= 1). One patient did not suffer from mycobacterial infections but had disseminated salmonellosis, which was also present in two other patients. Age at onset of the first environmental mycobacterial disease differed widely between patients, with a mean value of 11.25 ± 9.13 years. Thirteen patients survived until the age of 14.82 ± 11.2 years, and one patient died at the age of 7 years, 9 days after the diagnosis of long-term Mycobacterium avium infection and the initiation of antimycobacterial treatment. Up to 10 patients are currently free of infection with no prophylaxis. The clinical heterogeneity of the 14 patients was not clearly related to either IFNGR1 genotype or the resulting cellular phenotype. RP-IFN-γR1 deficiency is, thus, more common than initially thought and should be considered in both children and adults with mild or severe mycobacterial diseases.Human Molecular Genetics 02/2011; 20(8):1509-23. · 7.64 Impact Factor -
Article: Antimicrobial prophylaxis for primary immunodeficiencies.
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ABSTRACT: Antibiotic prophylaxis is one of the mainstays of therapy of primary immunodeficiencies. We aim to summarize what is known about antibiotic prophylaxis for select primary immunodeficiencies. In recent years, there has been a push towards more evidence-based practices for antimicrobial prophylaxis for many conditions such as antifungal prophylaxis for extremely premature neonates and antibiotic prophylaxis for neutropenia associated with chemotherapy. However, there are remarkably few data regarding antibiotic prophylaxis in primary immunodeficiencies and regimens vary greatly between practices. Currently, antibiotic prophylaxis is guided by the common microbial pathogens seen in specific immunodeficiencies, and experience with other chronic illnesses such as cystic fibrosis, HIV, and immunosuppression from transplantation. Controlled studies are necessary to address the preferred antimicrobial and immunomodulator regimens for most of the primary immunodeficiencies.Current Opinion in Allergy and Clinical Immunology 10/2009; 9(6):525-30. · 4.11 Impact Factor -
Article: Pathogenesis of hyper IgE syndrome.
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ABSTRACT: Hyper IgE syndrome (HIES) is a rare primary immunodeficiency characterized by the triad of elevated IgE and eosinophilia, eczema, and recurrent skin and pulmonary infections. The autosomal dominant (AD) form of HIES results from mutations in STAT3 and is characterized by disordered inflammation, connective tissue, and skeletal abnormalities. Tissue-specific STAT3 deficiency in animals, cytokine and transcriptional array data, and careful clinical phenotyping have explained some of the pathophysiology of the immunologic and non-immunologic abnormalities of AD-HIES. In depth study of the role of STAT3 mutations in specific aspects of HIES may lead to better understanding and new approaches to treatment of conditions intrinsic to HIES that are common in the general population, such as staphylococcal infections, scoliosis, osteoporosis, bronchiectasis, and arterial aneurysms. As the genotypes of STAT3 deficiency are further characterized, genotype-phenotype correlations may emerge that will be informative regarding specific molecular interactions. Autosomal recessive forms of hyper IgE (AR-HIES) have also been reported. A single case of homozygous deficiency of the signal protein Tyk2 has been reported as well as a recessive syndrome with some features overlapping AD-HIES, but for which the genetic etiology is unknown. Better understanding of the pathophysiology and mechanisms of dominant and recessive hyper IgE syndromes will shed light on somatic and immune biology and may improve quality of life and survival for HIES patients.Clinical Reviews in Allergy & Immunology 06/2009; 38(1):32-8. · 3.68 Impact Factor -
Article: Clinical manifestations, etiology, and pathogenesis of the hyper-IgE syndromes.
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ABSTRACT: Autosomal dominant Hyper-IgE syndrome (AD-HIES) is a rare primary immunodeficiency characterized by eczema, recurrent skin and lung infections, elevated serum IgE, and various connective tissue, skeletal, and vascular abnormalities. Mutations in signal transducer and activator of transcription 3 (STAT3) have recently been found to account for most cases; however, the pathogenesis of the varied features remains poorly defined. A distinct syndrome, known as autosomal recessive HIES (AR-HIES) manifests as severe eczema, recurrent bacterial and viral skin infections, and sinopulmonary infections. As opposed to STAT3 deficient HIES, AR-HIES lacks the connective tissue and skeletal manifestations but has an increase in neurologic abnormalities. In this review, we discuss the clinical presentations, genetic etiologies, and immunologic abnormalities of these two syndromes. In addition, we discuss animal models of STAT3 deficiency that provide insight into the pathogenesis of HIES. Further understanding of how STAT3 results in the diverse manifestations of HIES will allow us to develop more specific therapies for HIES as well as for many of the manifestations, such as scoliosis, recurrent staphylococcal infections, and eczema, which are common in the general population.Pediatric Research 02/2009; 65(5 Pt 2):32R-37R. · 2.70 Impact Factor
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2009
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National Institute of Allergy and Infectious Diseases
Bethesda, MD, USA -
National Institutes of Health
- Laboratory of Clinical Infectious Diseases
Bethesda, MD, USA
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