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Biomedical subjects

Gulbu Uzel

Publications and source records attributed to Gulbu Uzel.

9 recordsLinked to original sources
PubMed2005

Leptin replacement therapy modulates circulating lymphocyte subsets and cytokine responsiveness in severe lipodystrophy.

CONTEXT: We conducted this study to understand the role of leptin therapy in immunomodulation. OBJECTIVE: Our objective was to study lymphocyte subpopulations and in vitro peripheral blood mononuclear cell (PBMC) activation during a study evaluating the effects of leptin on metabolic functions in severe lipodystrophy (serum leptin levels < 4 ng/ml). DESIGN AND SETTING: We conducted an open-label study with patients serving as their own control at the Clinical Research Center of the National Institutes of Health. PATIENTS: Ten patients (age range, 15-63 yr; one male and nine females) with generalized forms of lipodystrophy were studied. INTERVENTION: Patients were treated with recombinant human leptin to achieve high normal concentrations for 4 to 8 months. RESULTS: Leptin levels increased from 1.8 +/- 0.4 to 16.5 +/- 3.9 ng/dl (P < 0.001), whereas metabolic control improved [glycosylated hemoglobin (HbA(1c)) fell from 9.3 +/- 0.4 to 7.1 +/- 1.4%, P < 0.001, and triglycerides decreased by 45 +/- 11% from a mean of 1490 +/- 710 mg/dl, P = 0.001]. Lymphocyte subsets were studied by flow cytometry at baseline and at 4 and 8 months of therapy. PBMC responsiveness was evaluated by cytokine release and proliferation after stimulation with phytohemagglutinin, phytohemagglutinin plus IL-12, lipopolysaccharide, and lipopolysaccharide plus interferon-gamma at baseline and 4 months. Various T lymphocyte subsets were significantly lower than age- and sex-matched controls at baseline; however, the CD4/CD8 ratio was normal. The relative percentages of B lymphocytes and monocytes were elevated, although the absolute levels were normal. Leptin therapy induced significant changes in T lymphocyte subsets, which normalized both the absolute number of T lymphocyte subsets and relative percentages of all lineages. Additionally, in vitro TNF-alpha secreted from PBMC of patients was significantly increased to normal after 4 months of leptin therapy compared with baseline. CONCLUSION: These data support existing evidence that leptin has a modest immunomodulatory effect in hypoleptinemic humans.

Adolescent↗
PubMed2005

The range of defects associated with nuclear factor kappaB essential modulator.

PURPOSE OF REVIEW: Impaired ability to signal and activate specific gene transcription through nuclear factor kappaB (NFkappaB) has been directly linked to immunodeficiency. Hypomorphic mutations in the gene encoding NFkappaB essential modulator (NEMO), located on the X chromosome, impair NFkappaB function and lead to ectodermal dysplasia with immunodeficiency (ED-ID) with increased susceptibility to pyogenic bacteria, viruses and nonpathogenic mycobacterial infections. This is due to impaired, but not abolished, response to a variety of stimuli including Toll-like receptor agonists. Alternatively, loss-of-function (amorphic) mutations in the same gene lead to incontinentia pigmenti. The purpose of this review is to explore the range of immunologic defects associated with mutations in NEMO, a key regulatory molecule in the NFkappaB pathway. RECENT FINDINGS: In addition to the discovery of X-linked recessive hypomorphic mutations in NEMO as the cause of anhidrotic ED-ID, autosomal-dominant hypermorphic mutations in inhibitor of NFkappaB (IkappaB) alpha have been described recently. In addition, a better understanding of genotype-phenotype correlation in ED-ID patients is evolving. SUMMARY: ED-ID is a combined, variable but profound immunodeficiency characterized by susceptibility to pyogenic bacteria and mycobacterial infection. Understanding the features of particular NEMO mutations will provide insight into the role of this gene and will help define the crucial role of the function and regulation of NFkappaB in the immune response.

Animals↗
PubMed2004

A novel mutation in IFN-gamma receptor 2 with dominant negative activity: biological consequences of homozygous and heterozygous states.

We identified two siblings homozygous for a single base pair deletion in the IFN-gammaR2 transmembrane domain (791delG) who presented with multifocal Mycobacterium abscessus osteomyelitis (patient 1) and disseminated CMV and Mycobacterium avium complex infection (patient 2), respectively. Although the patients showed no IFN-gammaR activity, their healthy heterozygous parents showed only partial IFN-gammaR activity. An HLA-identical bone marrow transplant from the mother led patient 1 to complete hemopoietic reconstitution, but only partial IFN-gammaR function. We cloned and expressed fluorescent fusion proteins of the wild-type IFN-gammaR2, an IFN-gammaR2 mutant previously described to produce a complete autosomal recessive deficiency (278del2), and of 791delG to determine whether the intermediate phenotype in the 791delG heterozygous state was caused by haploinsufficiency or a dominant negative effect. When cotransfected together with the wild-type vector into IFN-gammaR2-deficient fibroblasts, the fusion protein with 791delG inhibited IFN-gammaR function by 48.7 +/- 5%, whereas fusion proteins with 278del2 had no inhibitory effect. Confocal microscopy of 791delG fusion proteins showed aberrant diffuse intracellular accumulation without plasma membrane localization. The fusion protein created by 791delG did not complete Golgi processing, and was neither expressed on the plasma membrane, nor shed extracellularly. The mutant construct 791delG exerts dominant negative effects on IFN-gamma signaling without cell surface display, suggesting that it is acting on pathways other than those involved in cell surface recognition of ligand.

Cell Line↗
PubMed2003

Persistent Mycobacterium avium infection following nonmyeloablative allogeneic peripheral blood stem cell transplantation for interferon-gamma receptor-1 deficiency.

Interferon-gamma receptor-1 (IFNgammaR1) deficiency is a rare inherited immunodeficiency. We performed a nonmyeloablative allogeneic stem cell transplantation on a boy with complete IFNgammaR1 deficiency and refractory disseminated Myco- bacterium avium infection. Despite the patient's profound immune defect, early donor stem cell engraftment was low. Full donor engraftment was accomplished only following multiple donor lymphocyte infusions. Detection of IFNgammaR1 expression on peripheral blood monocytes and neutrophils corresponded with establishment of stable, complete donor hematopoietic chimerism. However, expression of, and signaling through IFNgammaR1 disappeared shortly thereafter. Disseminated Mycobacterium avium infection persisted and the patient died. Coculture of Myco- bacterium avium with normal myeloid cells resulted in an IFNgamma signaling defect similar to that observed in vivo. Active disseminated Mycobacterium avium infection may significantly compromise normal immune reconstitution following allogeneic stem cell transplantation. Patients with IFNgammaR1 deficiency should receive transplants before developing refractory mycobacterial infections.

Child, Preschool↗
PubMed2003

Cytokines in juvenile dermatomyositis pathophysiology: potential and challenge.

PURPOSE OF REVIEW: Cytokines are criticalmediators of the immune response. This review focuses on cytokine-specific information from children with juvenile dermatomyositis, and includes pertinent data from adults with polymyositis and dermatomyositis. RECENT FINDINGS: Much of the new data concern the role of possible antigens and the definition of genetic control of the immune response in juvenile dermatomyositis. Gene expression profile data of DQA1*0501 (present in 85% of patients) compared with age-matched control subjects show that the initial immune response is an interferon-alpha/beta-induced cascade with secondary stimulation of interferon-gamma. Specific epitopes of group A beta-hemolytic streptococcal M protein, with sequence homology for myosin, elicit both cell-mediated cytotoxicity and tumor necrosis factor-alpha production when incubated with mononuclear cells from children with active juvenile dermatomyositis. Tumor necrosis factor-alpha synthesis is increased in juvenile dermatomyositis patients with the tumor necrosis factor-alpha-308A allele, and is associated with increased thrombospondin-1 (an antiangiogenic agent) production and small vessel occlusion in untreated juvenile dermatomyositis. Studies in adults with polymyositis and dermatomyositis implicate interleukin-1alpha, transforming growth factor-beta, and endothelial cell perturbation early in the disease course. Cultured myoblasts were found to produce interleukin-15, which impacts local T-cell activation and proliferation. SUMMARY: The limited data suggest that a possible viral/microbial antigen may elicit an interferon-alpha/beta-induced response, and that antigenic epitopes may be shared. Increased synthesis of tumor necrosis factor-alpha, more common in juvenile dermatomyositis with the tumor necrosis factor-alpha-308A polymorphism, may augment this response and is associated with a wide range of pathologic consequences, as well as disease chronicity and calcifications. The muscle fibers themselves can regulate local inflammation by production of tumor necrosis factor-alpha, interleukin-15 and interleukin-1alpha, and transforming growth factor-beta.

Adolescent↗
PubMed2002

White blood cell defects: molecular discoveries and clinical management.

In this review, we present the most recent discoveries at the molecular level in white blood cell defects, and explain how their identification helped us to understand the underlying pathophysiology and directed our approach in clinical management. These lately discovered genes, relevant to immune disorders of mononuclear phagocytes and neutrophils, include defects in the interferon gamma (IFNg)/interleukin 12 (IL-12) pathway, such as IFNg receptor (IFNgR) defects, IL-12 defect, IL-12 receptor (IL-12R) defect, and signal transducer and activator of transcription 1 (STAT-1) defect. We have also included NF-kappaB essential modifier (NEMO) defects, which lead to X-linked ectodermal dysplasia, with or without lymphedema and osteopetrosis, and a wide range of involvement of the immune system, which can mimic the hyper-IgM phenotype. Neutrophil-specific granule deficiency and neutrophil elastase deficiency are discussed, the latter being the molecular defect in both cyclic neutropenia and in some sporadic cases of severe congenital neutropenia.

Hematologic Diseases↗