Background Primary immunodeficiencies are a rare group of inborn diseases characterized by a broad clinical and genetic heterogeneity. Substantial advances in the identification of the underlying ...molecular mechanisms can be achieved through the study of patients with increased susceptibility to specific infections and immune dysregulation. We evaluated 3 siblings from a consanguineous family presenting with EBV-associated B-cell lymphoproliferation at an early age (12, 7½, and 14 months, respectively) and profound naive T-cell lymphopenia. Objective On the basis of the hypothesis of a rare inborn immunodeficiency of autosomal recessive inheritance, we sought to characterize the underlying genetic defect. Methods We performed genome-wide homozygosity mapping, followed by whole-exome sequencing. Results We identified a homozygous inherited missense mutation in the gene encoding Coronin-1A (CORO1A) in the 3 siblings. This mutation, p. V134M, results in the substitution of an evolutionarily conserved amino acid within the β-propeller domain, which abrogates almost completely the protein expression in the patients' cells. In addition to a significant diminution of naive T-cell numbers, we found impaired development of a diverse T-cell repertoire, near-to-absent invariant natural killer T cells, and severely diminished mucosal-associated invariant T cell numbers. Conclusions Our findings define a new clinical entity of a primary immunodeficiency with increased susceptibility to EBV-induced lymphoproliferation in patients associated with hypomorphic Coronin-1A mutation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Signals emanating from the antigen T-cell receptor (TCR) are required for T-cell development and function. The T lymphocyte–specific protein tyrosine kinase (Lck) is a key component of the ...TCR signaling machinery. On the basis of its function, we considered LCK a candidate gene in patients with combined immunodeficiency. Objective We identify and describe a child with a T-cell immunodeficiency caused by a homozygous missense mutation of the LCK gene (c.1022T>C) resulting from uniparental disomy. Methods Genetic, molecular, and functional analyses were performed to characterize the Lck deficiency, and the associated clinical and immunologic phenotypes are reported. Results The mutant LCK protein (p.L341P) was weakly expressed with no kinase activity and failed to reconstitute TCR signaling in LCK-deficient T cells. The patient presented with recurrent respiratory tract infections together with predominant early-onset inflammatory and autoimmune manifestations. The patient displayed CD4+ T-cell lymphopenia and low levels of CD4 and CD8 expression on the T-cell surface. The residual T lymphocytes had an oligoclonal T-cell repertoire and exhibited a profound TCR signaling defect, with only weak tyrosine phosphorylation signals and no Ca2+ mobilization in response to TCR stimulation. Conclusion We report a new form of T-cell immunodeficiency caused by a LCK gene defect, highlighting the essential role of Lck in human T-cell development and responses. Our results also point out that defects in the TCR signaling cascade often result in abnormal T-cell differentiation and functions, leading to an important risk factor for inflammation and autoimmunity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
...neither patient displayed autoimmune cytopenia. Because no infectious cause of colitis could be demonstrated in patient 7, both manifestations might be explained by immune dysregulation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Eligibility to immunotherapy is based on the determination of IgE reactivity to a specific allergen by means of skin prick or in vitro testing. Biomarkers predicting the likelihood of ...clinical improvement during immunotherapy would significantly improve patient selection. Methods Proteins were differentially assessed by using 2-dimensional differential gel electrophoresis and label-free mass spectrometry in pretreatment sera obtained from clinical responders and nonresponders within a cohort of 82 patients with grass pollen allergy receiving sublingual immunotherapy or placebo. Functional studies of Fetuin-A (FetA) were conducted by using gene silencing in a mouse asthma model, human dendritic cell in vitro stimulation assays, and surface plasmon resonance. Results Analysis by using quantitative proteomics of pretreatment sera from patients with grass pollen allergy reveals that high levels of O-glycosylated sialylated FetA isoforms are found in patients exhibiting a strong decrease in rhinoconjunctivitis symptoms after sublingual immunotherapy. Although FetA is involved in numerous inflammatory conditions, its potential role in allergy is unknown. In vivo silencing of the FETUA gene in BALB/c mice results in a dramatic upregulation of airway hyperresponsiveness, lung resistance, and TH 2 responses after allergic sensitization to ovalbumin. Both sialylated and nonsialytated FetA bind to LPS, but only the former synergizes with LPS and grass pollen or mite allergens to enhance the Toll-like receptor 4–mediated proallergic properties of human dendritic cells. Conclusions As a reflection of the patient's inflammatory status, pretreatment levels of sialylated FetA in the blood are indicative of the likelihood of clinical responses during grass pollen immunotherapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Carbon nanotubes (CNTs) have promised a range of applications in biomedicine. Although influenced by the dispersants used, CNTs are recognized by the innate immune system, predominantly by ...the classical pathway of the complement system. Here, we confirm that complement activation by the CNT used continues up to C3 and C5, indicating that the entire complement system is activated including the formation of membrane-attack complexes. Using recombinant forms of the globular regions of human C1q (gC1q) as inhibitors of CNT-mediated classical pathway activation, we show that C1q, the first recognition subcomponent of the classical pathway, binds CNTs via the gC1q domain. Complement opsonisation of CNTs significantly enhances their uptake by U937 cells, with concomitant downregulation of pro-inflammatory cytokines and up-regulation of anti-inflammatory cytokines in both U937 cells and human monocytes. We propose that CNT-mediated complement activation may cause recruitment of cellular infiltration, followed by phagocytosis without inducing a pro-inflammatory immune response. From the Clinical Editor This study highlights the importance of the complement system in response to carbon nanontube administration, suggesting that the ensuing complement activation may cause recruitment of cellular infiltration, followed by phagocytosis without inducing a pro-inflammatory immune response.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The relationship of social determinants of health, Appalachian residence, and prostate cancer treatment delay among Tennessee adults is relatively unknown. We used multivariate logistic regression on ...2005–2015 Tennessee Cancer Registry data of adults aged ≥18 diagnosed with prostate cancer. The outcome of treatment delay was more than 90 days without surgical or nonsurgical intervention from date of diagnosis. Social determinants in the population-based registry were race (White, Black, Other) and marital status (single, married, divorced/separated, widow/widower). Tennessee residence was classified as Appalachian versus non-Appalachian (urban/rural). Covariates include age at diagnosis (18–54, 54–69, ≥70), health insurance type (none, public, private), derived staging of cancer (localized, regional, distant), and treatment type (non-surgical/surgical). We found that Black and divorced/separated patients had 32% (95% confidence interval CI: 1.22–1.42) and 15% (95% CI: 1.01–1.31) increased odds to delay prostate cancer treatment. Patients were at decreased odds of treatment delay when living in an Appalachian county, both urban (odds ratio OR = 0.89, 95% CI: 0.82–0.95) and rural (OR = 0.83, 95% CI: 0.78–0.89), diagnosed at ≥70 (OR = 0.59, 95% CI: 0.53–0.66), and received surgical intervention (OR = 0.72, 95% CI: 0.68–0.76). Our study was among the first to comprehensively examine prostate cancer treatment delay in Tennessee, and while we do not make clinical recommendations, there is a critical need to further explore the unique factors that may propagate disparities. Prostate cancer treatment delay in Black patients may be indicative of ongoing health and access disparities in Tennessee, which may further affect quality of life and survivorship among this racial group. Divorced/separated patients may need tailored interventions to improve social support.
The aim of this study was to determine the long-term efficacy and safety of tacrolimus (Tac) and cyclosporine immunosuppression in pediatric liver transplantation (LTx).
One hundred fifty-six ...patients who had taken part in a multicenter, randomized, open, parallel study of Tac and corticosteroids versus cyclosporine A microemulsion (CyA-ME), corticosteroids, and azathioprine. Patients were assessed at regular intervals up to 14 y after LTx. Analysis was conducted descriptively.
In a long-term follow-up, there was a similar incidence of acute rejection (Tac versus CyA-ME, 5 versus 8) and graft loss (5 versus 10). There were 11 deaths in the cohort, which were from infectious complications/malignancy in the Tac group (n = 2/5) and from chronic rejection/liver failure in the CyA-ME group (n = 3/6). A similar incidence of Epstein-Barr virus and posttransplant lymphoproliferative disease was observed (8 versus 8, 3 versus 3). However, there was a greater incidence of cosmetic adverse events in the CyA-ME cohort, with higher incidences of hypertrichosis (8 versus 27) and gum hyperplasia (20 versus 6). Growth improved equally in both groups. Overall, 81% of patients randomized to Tac remained on Tac therapy at study end, compared with 31% of patients randomized to CyA-ME. Common reasons for switching from CyA-ME included steroid-resistant/acute rejection (n = 12/8) and cosmetic changes (n = 8).
This study is the first prospective, observational follow-up study of pediatric patients randomized to Tac and CyA-ME to evaluate long-term outcomes. Our analysis was limited by the degree of switchover between the cohorts; however, there were fewer deaths from chronic rejection/liver failure and reduced adverse events with Tac. Long-term use of Tac and Tac combination therapy appears to be safe and effective immunosuppression for pediatric LTx recipients.
Objective Despite the increasing incidence of right ventricular (RV) failure in adult patients with congenital heart disease, current therapeutic options are still limited. By contrast to left-heart ...diseases, cell-based myocardial regeneration applied to the right ventricle is poorly studied, even though it may be a therapeutic solution. As human embryonic stem cell–derived cardiac progenitors seem to be good candidates owing to their proliferation capacity, our aim was to assess, in a large animal model of overloaded RV dysfunction, the feasibility and effects of such a cell therapy. Methods Human MesP1+ /SSEA-1+ cardiogenic mesodermal cells were administered using multiple intramyocardial injections 4 months after a surgical procedure mimicking the repaired tetralogy of Fallot, and their effects were observed 3 months later on hemodynamic, rhythmic, and histologic parameters. Results All pigs (sham n = 6, treated n = 6) survived without complication, and cell therapy was clinically well tolerated. Although functional, contractility, and energetics parameters evolved similarly in both groups, benefits regarding arrhythmic susceptibility were observed in the treated group, associated with a significant decrease of peri-myocyte fibrosis (5.71% ± 2.49% vs 12.12% ± 1.85%; P < .01) without interstitial fibrosis change (5.18% ± 0.81% vs 5.49% ± 1.01%). Such a decrease could be related to paracrine effects, as no human cells could be detected within the myocardium. Conclusions Cell therapy using intramyocardial injections of human MesP1+ /SSEA-1+ cardiogenic mesodermal cells seems to have benefits regarding overloaded RV tissue remodeling and arrhythmic susceptibility, but this mode of administration is not sufficient to obtain a significant improvement in RV function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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