Research

Hematopoietic Stem Cell Transplantation in Primary Immunodeficiencies Beyond Severe Combined Immunodeficiency.

J Pediatric Infect Dis Soc. 2018 Dec 26;7(suppl_2):S79-S82

Authors: Freeman AF

Abstract
Hematopoietic stem cell transplantation (HSCT) has been the standard of care for infants with severe combined immunodeficiency (SCID) for several decades due to the dismal prognosis early in life without immune reconstitution. In recent years, as HSCT conditioning regimens and supportive care have greatly improved, HSCT is gaining in acceptance for more non-SCID primary immunodeficiencies (PIDs) and outside the early childhood period. In addition, potential donor options for non-SCID PIDs are expanding with increasing success for haploidentical donor transplants. In this brief report of a presentation at the PIDS-St. Jude 2018 conference, PIDs for which transplants are increasingly performed outside of early childhood will be discussed.

PMID: 30590619 [PubMed – in process]

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Virus-Specific T Cells: Current and Future Use in Primary Immunodeficiency Disorders.

J Allergy Clin Immunol Pract. 2018 Dec 20;:

Authors: Harris KM, Davila BJ, Bollard CM, Keller MD

Abstract
Viral infections are common and can be potentially fatal in patients with primary immunodeficiency disorders (PIDDs). Because viral susceptibility stems from poor to absent T-cell function in most patients with moderate to severe forms of PIDD, adoptive immunotherapy with virus-specific T cells (VSTs) has been used to combat viral infections in the setting of hematopoietic stem cell transplantation in multiple clinical trials. Most trials to date have targeted cytomegalovirus, EBV, and adenovirus either alone or in combination, although newer trials have expanded the number of targeted pathogens. Use of banked VSTs produced from third-party donors has also been studied as a method of expanding access to this therapy. Here we review the clinical experience with VST therapy for patients with PIDDs as well as future potential targets and approaches for the use of VSTs to improve clinical outcomes for this specific patient population.

PMID: 30581131 [PubMed – as supplied by publisher]

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Tspan18 is a novel regulator of the Ca2+ channel Orai1 and von Willebrand factor release in endothelial cells.

Haematologica. 2018 Dec 20;:

Authors: Noy PJ, Gavin RL, Colombo D, Haining EJ, Reyat JS, Payne H, Thielmann I, Lokman AB, Neag G, Yang J, Lloyd T, Harrison N, Heath VL, Gardiner C, Whitworth KM, Robinson J, Koo CZ, Di Maio A, Harrison P, Lee SP, Michelangeli F, Kalia N, Rainger GE, Nieswandt B, Brill A, Watson SP, Tomlinson MG

Abstract
Ca2+ entry via Orai1 store-operated Ca2+ channels in the plasma membrane is critical to cell function, and Orai1 loss causes severe immunodeficiency and developmental defects. The tetraspanins are a superfamily of transmembrane proteins that interact with specific partner proteins and regulate their trafficking and clustering. The aim of this study was to functionally characterize tetraspanin Tspan18. We show that Tspan18 is expressed by endothelial cells at several-fold higher levels than most other cell types analyzed. Tspan18-knockdown primary human umbilical vein endothelial cells have 55-70% decreased Ca2+ mobilization upon stimulation with the inflammatory mediators thrombin or histamine, similar to Orai1-knockdown. Tspan18 interacts with Orai1, and Orai1 cell surface localization is reduced by 70% in Tspan18-knockdown endothelial cells. Tspan18 over-expression in lymphocyte model cell lines induces 20-fold activation of Ca2+-responsive NFAT signaling, in an Orai1-dependent manner. Tspan18-knockout mice are viable. They lose on average 6-fold more blood in a tail-bleed assay. This is due to Tspan18 deficiency in non-hematopoietic cells, as assessed using chimeric mice. Tspan18-knockout mice have 60% reduced thrombus size in a deep vein thrombosis model, and 50% reduced platelet deposition in the microcirculation following myocardial ischemia-reperfusion injury. Histamine- or thrombin-induced von Willebrand factor release from endothelial cells is reduced by 90% following Tspan18-knockdown, and histamine-induced increase of plasma von Willebrand factor is reduced by 45% in Tspan18-knockout mice. These findings identify Tspan18 as a novel regulator of endothelial cell Orai1/Ca2+ signaling and von Willebrand factor release in response to inflammatory stimuli.

PMID: 30573509 [PubMed – as supplied by publisher]

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Lymphocyte Apoptosis and FAS Expression in Patients with 22q11.2 Deletion Syndrome.

J Clin Immunol. 2018 Dec 19;:

Authors: Aresvik DM, Øverland T, Lima K, Pettersen RD, Abrahamsen TG

Abstract
PURPOSE: Immunodeficiency is one of the key features of 22q11.2 deletion syndrome (del), and it is seen in approximately 75% of the patients. The degree of immunodeficiency varies widely, from no circulating T cells to normal T cell counts. It has been hypothesized that the low number of T cells may at least in part be due to increased apoptosis of T cells. Increased spontaneous T cell apoptosis has been reported in one patient with 22q11.2del, but this has not been further investigated.
METHODS: A national cohort of patients with a proven heterozygous deletion of chromosome 22q11.2 diagnosed by FISH or MLPA and a group of age and sex matched controls were studied. Spontaneous and activation-induced apoptosis, in addition to FAS expression on lymphocytes, were measured using flow cytometry. Serum levels of FASL were analyzed using ELISA.
RESULTS: There was no increased spontaneous apoptosis in patients with 22q11.2del. Upon activation, anti-FAS-induced apoptosis was significantly increased in patients compared to those in controls, while there was no difference in activation induced cell death or activated cell autonomous death. We also found a significant increase in expression of FAS on freshly isolated lymphocytes from patients, while there was no difference in serum levels of FASL. Patients with congenital heart defects (CHD) had significantly higher serum levels of FASL compared to non-CHD patients.
CONCLUSION: We have shown increased FAS expression on lymphocytes from patients with 22q11.2del as well as increased levels of FASL in patients with CHD. Those changes may contribute to the pathophysiology of the 22q11.2del.

PMID: 30569262 [PubMed – as supplied by publisher]

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Emerging Aspergillus Species Almost Exclusively Associated With Primary Immunodeficiencies.

Open Forum Infect Dis. 2018 Sep;5(9):ofy213

Authors: Seyedmousavi S, Lionakis MS, Parta M, Peterson SW, Kwon-Chung KJ

Abstract
Invasive aspergillosis (IA) is the most serious mold infection encountered in patients with iatrogenic immunosuppression. IA is also a major cause of mortality and morbidity in individuals with primary immunodeficiency (PID). Although Aspergillus fumigatus is the most common etiologic agent of IA reported in PID patients, followed by A. nidulans, multiple poorly recognized Aspergillus species such as A. udagawae, A. quadrilineatus, A. pseudoviridinutans, A. tanneri, A. subramanianii, and A. fumisynnematus have been reported almost exclusively from patients with inborn defects in host antifungal defense pathways. Infection in PID patients exhibits patterns of disease progression distinct from those in iatrogenic immunosuppression. Specifically, the disease can be extrapulmonary and chronic with a tendency to disseminate in a contiguous manner across anatomical planes. It is also more refractory to standard antifungal therapy. This synopsis summarizes our understanding of emerging rare Aspergillus species that primarily affect patients with PIDs but not those with acquired immunodeficiencies.

PMID: 30568990 [PubMed]

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High-resolution computed tomography findings in humoral primary immunodeficiencies and correlation with pulmonary function tests.

World J Radiol. 2018 Nov 28;10(11):172-183

Authors: Cereser L, De Carli M, d’Angelo P, Zanelli E, Zuiani C, Girometti R

Abstract
AIM: To compare high-resolution computed tomography (HRCT) findings between humoral primary immunodeficiencies (hPIDs) subtypes; to correlate these findings to pulmonary function tests (PFTs).
METHODS: We retrospectively identified 52 consecutive adult patients with hPIDs who underwent 64-row HRCT and PFTs at the time of diagnosis. On a per-patient basis, an experienced radiologist recorded airway abnormalities (bronchiectasis, airway wall thickening, mucus plugging, tree-in-bud, and air-trapping) and parenchymal-interstitial abnormalities (consolidations, ground-glass opacities, linear and/or irregular opacities, nodules, and bullae/cysts) found on HRCT. The chi-square test was performed to compare the prevalence of each abnormality among patients with different subtypes of hPIDs. Overall logistic regression analysis was performed to assess whether HRCT findings predicted obstructive and/or restrictive PFTs results (absent-to-mild vs moderate-to-severe).
RESULTS: Thirty-eight of the 52 patients with hPIDs showed common variable immunodeficiency disorders (CVID), while the remaining 14 had CVID-like conditions (i.e., 11 had isolated IgG subclass deficiencies and 3 had selective IgA deficiencies). The prevalence of most HRCT abnormalities was not significantly different between CVID and CVID-like patients (P > 0.05), except for linear and/or irregular opacities (prevalence of 31.6% in the CVID group and 0 in the CVID-like group; P = 0.0427). Airway wall thickening was the most frequent HRCT abnormality found in both CVID and CVID-like patients (71% of cases in both groups). The presence of tree-in-bud abnormalities was an independent predictor of moderate-to-severe obstructive defects at PFTs (Odds Ratio, OR, of 18.75, P < 0.05), while the presence of linear and/or irregular opacities was an independent predictor of restrictive defects at PFTs (OR = 13.00; P < 0.05).
CONCLUSION: CVID and CVID-like patients showed similar HRCT findings. Tree-in-bud and linear and/or irregular opacities predicted higher risks of, respectively, obstructive and restrictive defects at PFTs.

PMID: 30568751 [PubMed]

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Newborn screening for severe combined immunodeficiency and T-cell lymphopenia.

Immunol Rev. 2019 Jan;287(1):241-252

Authors: Puck JM

Abstract
The development of a T cell receptor excision circle (TREC) assay utilizing dried blood spots (DBS) made possible universal newborn screening (NBS) for severe combined immunodeficiency (SCID) as a public health measure. Upon being flagged by an abnormal screening test in a SCID screening program, an infant can receive further diagnostic testing for SCID in the neonatal period, prior to onset of infectious complications, to permit immediate institution of protective measures and definitive, life-saving treatment to establish a functional immune system. SCID screening is now the accepted standard of care in state public health departments across the United States, and it is being adopted in many countries. It has proven effective, with infants having this otherwise inapparent but serious, rare disorder achieving survival and immune reconstitution. In addition to bringing to attention infants with the primary screening target diseases, typical SCID and leaky SCID (due to hypomorphic mutations in known SCID genes), the NBS assay for insufficient TRECs in DBS also reveals infants with non-SCID T lymphopenic conditions. Experience has accumulated regarding the range and limitations of diagnoses of newborns with low TRECs and low T cells. Previously unknown immune defects have been discovered, as well as conditions not formerly recognized to have low T cells in the neonatal period.

PMID: 30565242 [PubMed – in process]

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What did we learn from CTLA-4 insufficiency on the human immune system?

Immunol Rev. 2019 Jan;287(1):33-49

Authors: Mitsuiki N, Schwab C, Grimbacher B

Abstract
Cytotoxic-T-lymphocyte-antigen-4 (CTLA-4) is a negative immune regulator constitutively expressed on regulatory T (Treg) cells and upregulated on activated T cells. CTLA-4 inhibits T cell activation by various suppressive functions including competition with CD28, regulation of the inhibitory function of Treg cells, such as transendocytosis, and the control of adhesion and motility. Intrinsic CTLA-4 signaling has been controversially discussed, but so far no distinct signaling pathway has been identified. The CTLA-4-mediated Treg suppression plays an important role in the maintenance of peripheral tolerance and the prevention of autoimmune diseases. Human CTLA-4 insufficiency is caused by heterozygous germline mutations in CTLA4 and characterized by a complex immune dysregulation syndrome. Clinical studies on CTLA4 mutation carriers showed a reduced penetrance and variable expressivity, suggesting modifying factor(s). One hundred and forty-eight CTLA4 mutation carriers have been reported; patients showed hypogammaglobulinemia, recurrent infectious diseases, various autoimmune diseases, and lymphocytic infiltration into multiple organs. The CTLA-4 expression level in Treg cells was reduced, while the frequency of Treg cells was increased in CTLA-4-insufficient patients. The transendocytosis assay is a specific functional test for the assessment of newly identified CTLA4 gene variants. Immunoglobulin substitution, corticosteroids, immunosuppressive therapy, and targeted therapy such as with CTLA-4 fusion proteins and mechanistic target of rapamycin (mTOR) inhibitors were applied; patients with life-threatening, treatment-resistant symptoms underwent hematopoietic stem cell transplantation. The fact that in humans CTLA-4 insufficiency causes severe disease taught us that the amount of CTLA-4 molecules present in/on T cells matters for immune homeostasis. However, whether the pathology-causing activated T lymphocytes in CTLA-4-insufficient patients are antigen-specific is an unsolved question. CTLA-4, in addition, has a role in autoimmune diseases and cancer. Anti-CTLA-4 drugs are employed as checkpoint inhibitors to target various forms of cancer. Thus, clinical research on human CTLA-4 insufficiency might provide us a deeper understanding of the mechanism(s) of the CTLA-4 molecule and immune dysregulation disorders.

PMID: 30565239 [PubMed – in process]

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Early-onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms.

Immunol Rev. 2019 Jan;287(1):162-185

Authors: Pazmandi J, Kalinichenko A, Ardy RC, Boztug K

Abstract
Rare, monogenetic diseases present unique models to dissect gene functions and biological pathways, concomitantly enhancing our understanding of the etiology of complex (and often more common) traits. Although inflammatory bowel disease (IBD) is a generally prototypic complex disease, it can also manifest in an early-onset, monogenic fashion, often following Mendelian modes of inheritance. Recent advances in genomic technologies have spurred the identification of genetic defects underlying rare, very early-onset IBD (VEO-IBD) as a disease subgroup driven by strong genetic influence, pinpointing key players in the delicate homeostasis of the immune system in the gut and illustrating the intimate relationships between bowel inflammation, systemic immune dysregulation, and primary immunodeficiency with increased susceptibility to infections. As for other human diseases, it is likely that adult-onset diseases may represent complex diseases integrating the effects of host genetic susceptibility and environmental triggers. Comparison of adult-onset IBD and VEO-IBD thus provides beautiful models to investigate the relationship between monogenic and multifactorial/polygenic diseases. This review discusses the present and novel findings regarding monogenic IBD as well as key questions and future directions of IBD research.

PMID: 30565237 [PubMed – in process]

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