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Biomedical subjects

S M Holland

Publications and source records attributed to S M Holland.

At least 19 recordsLinked to original sources
PubMed2006

Human host genetic factors in nontuberculous mycobacterial infection: lessons from single gene disorders affecting innate and adaptive immunity and lessons from molecular defects in interferon-gamma-dependent signaling.

Mendelian defects in interferon-gamma (IFN-gamma) signaling most commonly lead to infection with nontuberculous mycobacteria. Mutations have been identified in the genes encoding IFN-gamma-receptor-1, IFN-gamma-receptor-2 and Stat-1. Partial and complete deficiencies in signaling are found, leading to parallel clinical, pathological, and cellular phenotypes. These rare defects have led to better molecular and mechanistic understanding of the role of IFN-gamma in the human immune system.

Animals↗
PubMed2006

The association between microsatellite polymorphisms in intron II of the human Toll-like receptor 2 gene and tuberculosis among Koreans.

The observation that Toll-like receptor (TLR)2-deficient mice are highly susceptible to mycobacteria suggests that mutations altering TLR2 expression may impair host response to Mycobacterium tuberculosis. We evaluated the association between guanine-thymine (GT) repeat polymorphism in intron II of the TLR2 gene and the presence of tuberculosis (TB) in Koreans. The numbers of GT repeats were determined by PCR and gene scans for 176 TB patients and 196 controls. The recombinant TLR2 promoter/exonI/exonII/intronII/luciferase constructs including three representative repeats: (GT)13, (GT)20, and (GT)24 were transfected into K562 cells, and luciferase activities were estimated and compared. The expression of TLR2 on CD14+ peripheral blood mononuclear cells (PBMC) from healthy volunteers were measured with flow cytometry. Genotypes with shorter GT repeats were more common among TB patients (49.4 vs 37.7%, P=0.02). This observation was confirmed among 82 other TB patients as a validation cohort. Shorter GT repeats were associated with weaker promoter activities and lower TLR2 expression on CD14+ PBMCs. In conclusion, the development of TB disease in Koreans was associated with shorter GT repeats in intron II of the TLR2 gene. This association is correlated with lower expression of TLR2 through weaker promoter activity for genes with shorter GT repeats.

Adolescent↗
PubMed2006

Penicillium piceum infection: diagnosis and successful treatment in chronic granulomatous disease.

Infections due to Penicillium species other than P.marneffei are rare. We identified a boy with X-linked chronic granulomatous disease (X-CGD) with a pulmonary nodule and adjacent rib osteomyelitis caused by Penicillium piceum. The only sign of infection was an elevated sedimentation rate. P. piceum was isolated by fine needle aspirate and from excised infected tissues. Surgical removal and one year of voriconazole treatment were very well tolerated and led to complete recovery. Microbiological, microscopic and molecular studies support the fungal diagnosis. P. piceum should be considered as a relevant pathogen in immunocompromised patients.

Antifungal Agents↗
PubMed2006

CD2 identifies a monocyte subpopulation with immunoglobulin E-dependent, high-level expression of Fc epsilon RI.

BACKGROUND: Fc epsilon RI expression by monocytes can affect monocyte function via multiple mechanisms, thereby potentially influencing the generation of allergic inflammation. Previous studies on the in vivo regulation of monocyte Fc epsilon RI expression by ambient IgE have yielded conflicting results. OBJECTIVE: We hypothesized that monocyte Fc epsilon RI expression is limited to a specific monocyte subset, and that within that subset Fc epsilon RI surface expression is correlated to serum IgE. METHODS: Study 1: Blood was obtained from non-allergic subjects (n=14) and subjects with allergic asthma (n=18), hypereosinophilic syndrome (n=2), hyper-IgE syndrome (n=6), and helminth infection (n=4). Study 2: Blood was obtained from allergic subjects in a clinical trial of omalizumab before and during study drug treatment. Monocyte surface Fc epsilon RI expression was measured using flow cytometry. RESULTS: Fc epsilon RI expression was significantly greater in the CD2(high) vs. CD2(low) monocyte subsets (31% vs. 1.9% median Fc epsilon RI+, respectively). In asthmatic and non-atopic healthy control subjects, CD2(low) monocytes expressed little or undetectable Fc epsilon RI. In study 1, Fc epsilon RI expression was highly correlated to serum IgE in the CD2(high), but not in the CD2(low) monocyte subpopulation (R values of 0.67 and 0.41, respectively). In study 2, omalizumab, but not placebo, caused a significant and sustained decline in Fc epsilon RI expression within the CD2(high) monocyte subset. CONCLUSIONS: CD2 defines a monocyte subset with high Fc epsilon RI expression, whose magnitude is highly correlated to serum IgE. As such, this new description of CD2(high) monocytes as Fc epsilon RI-bearing cells suggests that they may be potential targets of anti-IgE immunomodulatory therapies.

Adult↗
PubMed2006

Successful renal transplantation in patients with chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a genetic disease caused by structural mutations in the enzyme NADPH oxidase that results in severe immunodeficiency. End-stage renal disease occurs in this patient population, and is often attributed to the necessary use of nephrotoxic anti-infectives. In this report, we present the experiences of two centers in transplantation of three patients with CGD: one transplanted with CGD, one cured of his CGD with bone marrow transplantation who subsequently underwent kidney transplantation and one that received a kidney transplant prior to being cured of CGD via a sequential peripheral blood stem cell transplant (SCT). All three recipients have enjoyed excellent outcomes. Their courses demonstrate the absolute requirements for a multidisciplinary and compulsive approach before, during and after transplantation. These case reports also highlight the unexpectedly benign effects of immunosuppressive therapy in this patient population.

Adult↗
PubMed2005

Acute severe asthma presenting in late pregnancy.

Asthma is the commonest pre-existing medical condition to complicate pregnancy. Acute severe asthma in pregnancy is rare, but poses difficult problems. In particular, the decision about when and where to deliver the fetus is complex, since maternal response to asthma treatment is unpredictable. We report the successful management of a parturient presenting with acute severe asthma at 37 weeks' gestation. The controversies involved and the importance of adopting a multi-disciplinary team approach to optimise maternal and neonatal outcomes are discussed.

Acute Disease↗
PubMed2005

Invasive aspergillosis in primary immunodeficiencies.

Primary immunodeficiencies are rare and usually first manifest during childhood. Invasive aspergillosis is the leading cause of mortality in chronic granulomatous disease (CGD), reflecting the key role of the phagocyte NADPH oxidase in host defense against opportunistic fungi. Despite interferon-gamma prophylaxis, invasive filamentous fungal infections are a persistent problem in CGD. Key principles of management of fungal infections involve early recognition and aggressive treatment and appropriate surgical debridement of localized disease. Because CGD is a disorder of phagocyte stem cells in which the gene defects are well defined, it is a model disease to evaluate immune reconstitution through stem cell transplantation and gene therapy. Patients with the hyper-IgE syndrome with recurrent infections (Job syndrome) are prone to colonization of lung cavities (pneumatoceles) by Aspergillus species leading to local invasion and rarely disseminated infection. Other primary phagocytic disorders, T-cell disorders, and mitochondrial disorders are uncommonly associated with invasive aspergillosis. Taken together, these rare primary immunodeficiencies highlight the complex coordination of both innate and acquired pathways mediating host defense against Aspergillus infection.

Animals↗
PubMed2003

Infections with Haemophilus species in chronic granulomatous disease: insights into the interaction of bacterial catalase and H2O2 production.

Chronic granulomatous disease (CGD) is a rare inherited disorder in which phagocytes are incapable of generating bactericidal-reactive oxygen derivatives. Typically these patients are susceptible to life-threatening infections with catalase-producing organisms. Haemophilus species, particularly H. paraphrophilus, are not associated with CGD infections, because these organisms rarely if ever produce catalase. Haemophilus species are part of the indigenous oral microbial flora and, other than H. influenzae, are rarely recognized as pathogens. They are fastidious and require additional growth factors and capnophilic culture conditions for optimal growth and identification. Here we describe three cases of infection with non-H. influenzae (NHI) Haemophilus species in CGD patients. These organisms were catalase-negative and therefore not expected to be virulent in CGD patients, but they were also H(2)O(2) production-negative, thereby negating the putative loss of virulence of being catalase-negative. These are the first reports of NHI Haemophilus species in CGD and reinforce the critical need for careful microbiologic evaluation of infections in CGD patients.

Adult↗
PubMed2003

Recurrent 'sterile' verrucous cyst abscesses and epidermodysplasia verruciformis-like eruption associated with idiopathic CD4 lymphopenia.

Rupture of follicular (epidermoid) cysts is believed to be the consequence of bacterial infection. We report a 24-year-old man with idiopathic CD4 lymphopenia and chronic Mycobacterium avium intracellulare infection who developed multiple, recurring painful abscesses over the distal extremities that increased in number and severity when systemic steroid and interferon-gamma treatment was instituted for interstitial lung disease. Cultures were consistently negative for microorganisms, but pathological examination revealed ruptured epidermoid cyst walls with human papillomavirus (HPV) viropathic changes (keratinocytes with perinuclear halos and abundant basophilic keratohyaline granules). Cutaneous examination showed numerous, widespread flat-topped papules and achromic macules over the extremities, head and neck. Nested polymerase chain reaction analysis for HPV DNA revealed that the abscess-related cyst walls harboured epidermodysplasia verruciformis (EV)-associated HPV types 20, 24, alb-7 (AY013872) and 80. His cutaneous lesions harboured HPV types 3, 8 and 80. Similar to past reports, our patient developed an EV-like eruption in the setting of immunodeficiency. In this instance, EV-associated HPV infection of the follicular infundibular epithelium or pre-existing cysts in the setting of immunodeficiency may have led to cystic growth, rupture and subsequent painful inflammation.

Abscess↗
PubMed2003

Inducible nitric oxide synthase regulates production of isoprostanes in vivo during chlamydial genital infection in mice.

Urinary nitrite and F(2)-isoprostanes, an index of oxidant stress, were elevated during chlamydial genital infection of mice. Enhancement of urinary nitrite and F(2)-isoprostanes was observed in phagocyte oxidase-deficient mice. Inhibition of inducible nitric oxide synthase reduced isoprostane excretion. We conclude that nitrogen radicals induce F(2)-isoprostane production and excretion during murine chlamydial genital infection.

Animals↗
PubMed2003

Isolated intracranial infection with Mycobacterium avium complex.

UNLABELLED: Mycobacterium avium-M. complex (MAC) has been linked to devastating respiratory and systemic illnesses in patients, especially in those who are immunosuppressed. The purpose of this study is to describe a case of isolated central nervous system (CNS) infection with MAC. This is a single case report of a patient with isolated intracranial mycobacterial infection. SETTING: the patient was treated and the immunohistochemical investigations were undertaken at the National Institutes of Health in Bethesda, Maryland, USA. INTERVENTION: the patient initially was treated with a cocktail of antimycobacterial medications. However, because his disease was refractory, he underwent a suboccipital craniotomy and evacuation of his cerebellar mass. The patient was determined to have a low production of interferon-gamma (INF-gamma) and tumor necrosis factor-alpha (TNF-alpha) when compared to normal values. Despite extensive radiographic imaging studies and biopsies, there was no evidence of another focus of MAC infection in this patient. We conclude that intracranial infectious lesions in patients such as ours should be treated with conventional systemic antibiotic regimens as the first-line of therapy. We suggest neurosurgical intervention in medically refractory cases of intracranial infections.

Adult↗
PubMed2002

561del4 defines a novel small deletion hotspot in the interferon-gamma receptor 1 chain.

Patients with a dominant small deletion (818del4, hotspot) in the interferon-gamma receptor 1 (IFNGR1) gene (6q23-q24) and increased susceptibility to mycobacterial infections have been recently reported. We describe a female patient homozygous for a 4-bp deletion in exon 5 of IFNGR1 (561del4) who developed postvaccinal disseminated Bacille Calmette-Guerin infection. She was born to unrelated Argentinean parents, each of whom was heterozygous for this mutation. 561del4 has been previously described as a maternally inherited mutation in a compound heterozygous German patient. By single nucleotide polymorphism analysis of the areas surrounding the deletion, we showed the independent inheritance of 561del4 in three heterozygous carriers. Polypurine runs and "direct repeats," previously shown to be associated with areas of recurrent small deletions, were found in the flanking region of 561del4. The independent inheritance of three identical mutational events defines 561del4 as a new hotspot in the IFNGR1 gene.

BCG Vaccine↗
PubMed2001

Human immunodeficiency virus-seronegative adults with extrapulmonary tuberculosis have abnormal innate immune responses.

Extrapulmonary tuberculosis is presumably a marker of underlying immunodeficiency, but cytokine response pathways in these patients have not been well studied. Cytokine responses of peripheral blood mononuclear cells from human immunodeficiency virus-seronegative adults with prior culture-confirmed extrapulmonary tuberculosis were compared with those of persons with latent Mycobacterium tuberculosis infection. Mitogen-stimulated interferon (IFN)-gamma production, interleukin (IL)-12 production, and IFN-gamma receptor- and IL-12 receptor-mediated cytokine production did not differ between case patients and control patients. However, median resting IL-8 production was significantly lower in case patients than control patients (8051 vs. 19,290 pg/mL; P=.009). In addition, the median tumor necrosis factor (TNF)-alpha response was lower in case patients than control patients after stimulation with lipopolysaccharide (833 vs. 1149 pg/mL; P=.06) and lipopolysaccharide plus IFN-gamma (3301 vs. 4411 pg/mL; P=.04). These abnormalities in resting IL-8 and lipopolysaccharide-induced TNF-alpha production were not associated with IFN-gamma or IL-12 abnormalities and were detected up to several years after cure of disease, suggesting an abnormality in innate immunity.

Case-Control Studies↗
PubMed2001

Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation.

Interferons (IFN) alpha/beta and gamma induce the formation of two transcriptional activators: gamma-activating factor (GAF) and interferon-stimulated gamma factor 3 (ISGF3). We report a natural heterozygous germline STAT1 mutation associated with susceptibility to mycobacterial but not viral disease. This mutation causes a loss of GAF and ISGF3 activation but is dominant for one cellular phenotype and recessive for the other. It impairs the nuclear accumulation of GAF but not of ISGF3 in heterozygous cells stimulated by IFNs. Thus, the antimycobacterial, but not the antiviral, effects of human IFNs are principally mediated by GAF.

Adult↗
PubMed2001

Genetic demonstration of p47phox-dependent superoxide anion production in murine vascular smooth muscle cells.

BACKGROUND: Previous investigations provide evidence that an enzyme related to the phagocyte NADPH oxidase produces superoxide in the blood vessel wall. These data, however, are confounded by observations that both NADPH and NADH serve as substrates for superoxide production in vascular cells. To clarify this issue, we compared the superoxide-generating capabilities of vascular smooth muscle cells (VSMCs) derived from wild-type (p47phox(+/+); phagocyte oxidase) mice with those from mice that lack p47phox (p47phox(-/-); "knockout"), an essential component of the phagocyte NADPH oxidase. METHODS AND RESULTS: VSMCs were derived from aortic explants harvested from p47phox(+/+) or p47phox(-/-) mice. VSMCs from p47phox(+/+) but not those from p47phox(-/-) mice produced superoxide after stimulation by phorbol myristate acetate. Consistent with this, p47phox was detected only in p47phox(+/+) VSMCs. p47phox-transduced p47phox(-/-) but not enhanced green fluorescent protein-transduced p47phox(-/-) VSMCs generated significant levels of superoxide after stimulation by angiotensin II or platelet-derived growth factor-BB (PDGF-BB). Enhanced expression of recombinant p47phox in p47phox-transduced p47phox(-/-) cells correlated with superoxide production in these cells. CONCLUSIONS: These data provide direct functional proof that an oxidase requiring the p47phox component mediates superoxide release from VSMCs in the blood vessel wall in response to angiotensin II or PDGF-BB.

Actins↗
PubMed2001

Disseminated nocardiosis in a patient with X-linked chronic granulomatous disease and human immunodeficiency virus infection.

We report the first case of HIV infection in a patient with underlying X-linked chronic granulomatous disease (CGD) who presented with hepatopulmonary nocardiosis. Despite the coexistence of CGD and HIV, the response to therapy was normal, and no unusual sequelae were noted. The patient's high virus burden was successfully repressed with antiretroviral therapy, suggesting that the nicotinamide adenine dinucleotide phosphate oxidase system is not essential for active viral replication or response to antiretroviral agents.

AIDS-Related Opportunistic Infections↗