Apart from the common alteration in elastic fibers, the other pathological features are not observed in the STAT3-deficient patient. ...interaction between STAT3 and elastin has never been reported. ......this is the first detailed report on a unique and previously uncharacterized vasculopathy associated with STAT3 deficiency.
Abstract Background Autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency (AD EDA-ID) is caused by heterozygous point mutations at or close to S32 and S36 or N-terminal ...truncations in IκBα that impair its phosphorylation and degradation, and thus activation of the canonical NF-κB pathway. The outcome of hematopoietic stem cell transplantation is poor in AD EDA-ID despite achievement of chimerism. Mice heterozygous for the S32I mutation in IκBα have impaired non-canonical NF-κB activity and defective lymphorganogenesis. Objective To establish genotype-phenotype correlation in AD EDA-ID. Methods A disease severity scoring system was devised. Stability of IκBα mutants was examined in transfected cells. Immunological, biochemical, and gene expression analyses were performed to evaluate canonical and non-canonical NF-κB signaling in skin-derived fibroblasts. Results Disease severity was greater in patients with IκBα point mutations than in patients with truncation mutations. IκBα point mutants were expressed at significantly higher levels in transfectants compared to truncation mutants. Canonical NF-κB-dependent IL-6 secretion and upregulation of the NF-κB2/p100 and RelB components of the non-canonical NF-κB pathway were diminished significantly more in patients with point mutations compared to those with truncations. Non-canonical NF-κB-driven generation of the transcriptionally active p100 cleavage product p52, and upregulation of CCL20 , ICAM1 and VCAM1 , important for lymphorganogenesis, were diminished significantly more in LPS+α-LTβR-stimulated fibroblasts from patients with point mutations compared to those with truncations. Conclusions IκBα point mutants accumulate at higher levels compared to truncation mutants and are associated with more severe disease and greater impairment of canonical and non-canonical NF-κB activity in AD EDA-ID.
Objective To better describe the natural history, mode of inheritance, and the epidemiological and clinical features of isolated congenital asplenia, a rare and poorly understood primary ...immunodeficiency. Study design A French national retrospective survey was conducted in hospital pediatric departments. A definitive diagnosis of ICA was based on the presence of Howell-Jolly bodies, a lack of detectable spleen, and no detectable cardiovascular malformation. Results The study included 20 patients (12 males and 8 females) from 10 kindreds neither related to each other nor consanguineous. The diagnosis of ICA was certain in 13 cases (65%) and probable in 7 cases (35%). Ten index cases led to diagnosis of 10 additional cases in relatives. Five cases were sporadic and 15 were familial, suggesting autosomal dominant inheritance. Median age was 12 months at first infection (range, 2-516 months), 11 months at diagnosis of asplenia (range, 0-510 months), and 9.9 years at last follow-up (range, 0.7-52 years). Fifteen patients sustained 18 episodes of invasive bacterial infection, caused mainly by Streptococcus pneumoniae (61%). Outcomes were poor, with 9 patients (45%) dying from fulminant infection. Conclusions ICA is more common than was previously thought, with an autosomal dominant inheritance in at least some kindreds. Relatives of cases of ICA should be evaluated for ICA, as should children and young adults with invasive infection.
Background Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by inborn errors of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex. From the first ...year of life onward, most affected patients display multiple, severe, and recurrent infections caused by bacteria and fungi. Mycobacterial infections have also been reported in some patients. Objective Our objective was to assess the effect of mycobacterial disease in patients with CGD. Methods We analyzed retrospectively the clinical features of mycobacterial disease in 71 patients with CGD. Tuberculosis and BCG disease were diagnosed on the basis of microbiological, pathological, and/or clinical criteria. Results Thirty-one (44%) patients had tuberculosis, and 53 (75%) presented with adverse effects of BCG vaccination; 13 (18%) had both tuberculosis and BCG infections. None of these patients displayed clinical disease caused by environmental mycobacteria, Mycobacterium leprae , or Mycobacterium ulcerans . Most patients (76%) also had other pyogenic and fungal infections, but 24% presented solely with mycobacterial disease. Most patients presented a single localized episode of mycobacterial disease (37%), but recurrence (18%), disseminated disease (27%), and even death (18%) were also observed. One common feature in these patients was an early age at presentation for BCG disease. Mycobacterial disease was the first clinical manifestation of CGD in 60% of these patients. Conclusion Mycobacterial disease is relatively common in patients with CGD living in countries in which tuberculosis is endemic, BCG vaccine is mandatory, or both. Adverse reactions to BCG and severe forms of tuberculosis should lead to a suspicion of CGD. BCG vaccine is contraindicated in patients with CGD.
Background Defects in the development or activation of T cells result in immunodeficiency associated with severe infections early in life. T-cell activation requires Ca2+ influx through Ca2+ -release ...activated Ca2+ (CRAC) channels encoded by the gene ORAI1. Objective Investigation of the genetic causes and the clinical phenotype of immunodeficiency in patients with impaired Ca2+ influx and CRAC channel function. Methods DNA sequence analysis for mutations in the genes ORAI1 , ORAI2 , ORAI3 , and stromal interaction molecule (STIM) 1 and 2, as well as mRNA and protein expression analysis of ORAI1 in immunodeficient patients. Immunohistochemical analysis of ORAI1 tissue distribution in healthy human donors. Results We identified mutations in ORAI1 in patients from 2 unrelated families. One patient is homozygous for a frameshift nonsense mutation in ORAI1 (ORAI1-A88SfsX25), and a second patient is compound heterozygous for 2 missense mutations in ORAI1 (ORAI1-A103E/L194P). All 3 mutations abolish ORAI1 expression and impair Ca2+ influx and CRAC channel function. The clinical syndrome associated with ORAI1 deficiency is characterized by immunodeficiency with a defect in the function but not in the development of lymphocytes, congenital myopathy, and anhydrotic ectodermal dysplasia with a defect in dental enamel calcification. In contrast with the limited clinical phenotype, we found ORAI1 protein expression in a wide variety of cell types and organs. Conclusion Ca2+ influx through ORAI1 is crucial for lymphocyte function in vivo . Despite almost ubiquitous ORAI1 expression, the channel has a nonredundant role in only a few cell types judging from the limited clinical phenotype in ORAI1-deficient patients.
To determine a role for the NADPH oxidase activity in monocyte and neutrophil cytokine responses toward bacterial and fungal pathogens, we analyzed 10 patients with CGD with previously described ...mutations in genes encoding for either the cytosolic NADPH oxidase proteins, that is, p47phox or p67phox, or the membrane-expressed cytochrome-b558 subunit gp91phox, all resulting in a failure to produce ROS (see Table E1 in this article's Online Repository at www.jacionline.org).1 The role of 2 known signaling pathways involved in bacterial and fungal host defense was determined in patients deficient in caspase recruitment domain-containing protein 9 (CARD9)- and IL-1 receptor-associated kinase 4 (IRAK4). ...we have demonstrated that monocytes and neutrophils from patients with CGD show an exacerbated proinflammatory response to intact fungal but not to bacterial pathogens.\n Control subjects originated from the same hospital as the patients.
Background The capacity of CD8+ T cells to control infections and mediate antitumor immunity requires the development and survival of effector and memory cells. IL-21 has emerged as a potent inducer ...of CD8+ T-cell effector function and memory development in mouse models of infectious disease. However, the role of IL-21 and associated signaling pathways in protective CD8+ T-cell immunity in human subjects is unknown. Objective We sought to determine which signaling pathways mediate the effects of IL-21 on human CD8+ T cells and whether defects in these pathways contribute to disease pathogenesis in patients with primary immunodeficiencies caused by mutations in components of the IL-21 signaling cascade. Methods Human primary immunodeficiencies resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Lymphocytes from patients with loss-of-function mutations in signal transducer and activator of transcription 1 (STAT1) , STAT3 , or IL-21 receptor (IL21R) were used to assess the respective roles of these genes in human CD8+ T-cell differentiation in vivo and in vitro. Results Mutations in STAT3 and IL21R , but not STAT1 , led to a decrease in multiple memory CD8+ T-cell subsets in vivo , indicating that STAT3 signaling, possibly downstream of IL-21R, regulates the memory cell pool. Furthermore, STAT3 was important for inducing the lytic machinery in IL-21–stimulated naive CD8+ T cells. However, this defect was overcome by T-cell receptor engagement. Conclusion The IL-21R/STAT3 pathway is required for many aspects of human CD8+ T-cell behavior but in some cases can be compensated by other signals. This helps explain the relatively mild susceptibility to viral disease observed in STAT3- and IL-21R–deficient subjects.
Background Recent identification of STAT3 mutations in autosomal dominant (AD) hyper-IgE syndrome (HIES) has improved the clinical, genetic, and molecular classification of the HIES. Objective We ...sought to characterize the cutaneous signs observed in molecularly diagnosed AD-HIES. Methods We conducted a retrospective study of 21 patients with AD-HIES and confirmed STAT3 mutations, treated at Necker-Enfants Malades Hospital, Paris, France. Results A papulopustular rash on the face and scalp before the age of 2 months was observed in 67% of patients. This “early rash” was distinguished from other neonatal pustular eruptions by crusted papules and pustules, rash intensity, and a continuum with chronic dermatitis. An eczematous dermatitis was almost always present before the age of 18 months (95% of patients) and was mainly confined to the face, scalp, chest, and buttocks. All patients presented with infected dermatitis ( Staphylococcus aureus ) and 59% had chronic candidiasis of the oral mucosa and nails. Cutaneous herpes virus infections were not unusually severe. Coarse facial skin at puberty, and sometimes at a younger age, with prominent follicular ostia resembling atrophoderma vermiculatum was not related to severe acne or facial abscesses. Limitations This was a retrospective study with a small number of patients. Conclusion When associated with serum IgE levels 10 times the age-appropriate level, a neonatal papulopustular rash progressing to a chronic impetiginized eczematous dermatitis that differs from classic atopic dermatitis is highly suggestive of AD-HIES. Early recognition is important for initiation of prophylactic antistaphylococcal and antifungal treatment.
...little is known about the mechanisms by which homozygous JAK3 R117C missense mutations impair JAK3 signaling in lymphocyte ontogeny to result in the persistence of dysfunctional NK cells, although ...a hypomorphic mutation could be possible. ...the present study describes a case of T-B+NK+ SCID caused by a homozygous JAK3 missense mutation, resulting in leaky SCID.
Background Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive disorder characterized by short-limbed skeletal dysplasia. Some patients also have defects in cell-mediated immunity and ...antibody production. Granulomatous inflammation has been described in patients with various forms of primary immunodeficiencies but has not been reported in patients with CHH. Objective We sought to describe granulomatous inflammation as a novel feature in patients with CHH, assess associated immunodeficiency, and evaluate treatment options. Methods In a retrospective observational study we collected clinical data on 21 patients with CHH to identify and further characterize patients with granulomatous inflammation. Results Four unrelated patients with CHH (with variable degrees of combined immunodeficiency) had epithelioid cell granulomatous inflammation in the skin and visceral organs. Anti–TNF-α mAb therapy in 3 of these patients led to significant regression of granulomas. However, 1 treated patient had fatal progressive multifocal leukoencephalopathy caused by the JC polyomavirus. In 2 patients immune reconstitution after allogeneic hematopoietic stem cell transplantation led to the complete disappearance of granulomas. Conclusion To the best of our knowledge, this is the first report of granulomatous inflammation in patients with CHH. Although TNF-α antagonists can effectively suppress granulomas, the risk of severe infectious complications limits their use in immunodeficient patients.
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