Blog

Long-term outcomes of fludarabine, melphalan and antithymocyte globulin as reduced-intensity conditioning regimen for allogeneic hematopoietic stem cell transplantation in children with primary immunodeficiency disorders: a prospective single center study.

Bone Marrow Transplant. 2015 Nov 23;

Authors: Hamidieh AA, Behfar M, Pourpak Z, Faghihi-Kashani S, Fazlollahi MR, Hosseini AS, Movahedi M, Mozafari M, Moin M, Ghavamzadeh A

Abstract
Reduced-intensity conditioning (RIC) has offered many primary immunodeficiency disorder (PID) patients who are ineligible for myeloablative regimens a chance of cure. However, the beneficial role of RIC was questioned following reports suggesting higher chance of rejection and lower symptom resolution rate in mixed chimerism settings. Forty-five children affected by PIDs with a median age of 21 months underwent allogeneic hematopoietic stem cell transplantation in our institute from 2007 to 2013. All patients received an identical RIC regimen. Forty-one patients had successful primary engraftment (91%). Of the successful engraftments, 80% (n=33) had stable full donor chimerism at last contact. Overall, eleven transplant-related mortalities were reported including five patients due to sepsis, three children due to grade IV acute GvHD, two due to chronic GvHD and one patient due to sepsis after primary graft failure. The median post-transplantation follow-up of deceased patients was 55 days. Five-year overall survival and disease-free survival was 75.6% and 68.89%, respectively. All surviving patients with successful engraftment became disease free, regardless of having full or mixed chimerism. Our study suggests that RIC regimen provides satisfactory rates of successful engraftment and full chimerism. Furthermore, patients with mixed chimerism were stable in long-term follow-up and this chimerism status offered the potential to resolve symptoms of immunodeficiency.Bone Marrow Transplantation advance online publication, 23 November 2015; doi:10.1038/bmt.2015.277.

PMID: 26595073 [PubMed – as supplied by publisher]

Powered by WPeMatico

Natural killer cell biology illuminated by primary immunodeficiency syndromes in humans.

Clin Immunol. 2015 Nov 16;

Authors: Voss M, Bryceson YT

Abstract
Natural killer (NK) cells are innate immune cytotoxic effector cells well known for their role in antiviral immunity and tumor immunosurveillance. In parts, this knowledge stems from rare inherited immunodeficiency disorders in humans that abrogate NK cell function leading to immune impairments, most notably associated with a high susceptibility to viral infections. Phenotypically, these disorders range from deficiencies selectively affecting NK cells to complex general immune defects that affect NK cells but also other immune cell subsets. Moreover, deficiencies may be associated with reduced NK cell numbers or rather impair specific NK cell effector functions. In recent years, genetic defects underlying the various NK cell deficiencies have been uncovered and have triggered investigative efforts to decipher the molecular mechanisms underlying these disorders. Here we review the associations between inherited human diseases and NK cell development as well as function, with a particular focus on defects in NK cell exocytosis and cytotoxicity. Furthermore we outline how reports of diverse genetic defects have shaped our understanding of NK cell biology.

PMID: 26592356 [PubMed – as supplied by publisher]

Powered by WPeMatico

Key findings to expedite the diagnosis of hyper-IgE syndromes in infants and young children.

Pediatr Allergy Immunol. 2015 Nov 23;

Authors: Hagl B, Heinz V, Schlesinger A, Spielberger BD, Sawalle-Belohradsky J, Senn-Rauh M, Magg T, Boos AC, Hönig M, Schwarz K, Dückers G, von Bernuth H, Christoph P, Karitnig-Weiss C, Belohradsky BH, Josef F, Niehues T, Wahn V, Albert MH, Wollenberg A, Jansson AF, Renner ED

Abstract
BACKGROUND: Hyper-IgE syndromes (HIES) are primary immunodeficiency disorders characterized by elevated serum-IgE, eczema and recurrent infections. Despite the availability of confirmatory molecular diagnosis of several distinct HIES entities the differentiation of HIES particularly from severe forms of atopic dermatitis remains a challenge. The two most common forms of HIES are caused by mutations in the genes STAT3 and DOCK8.
METHODS: Here we assess the clinical and immunological phenotype of DOCK8- and STAT3-HIES patients including the cell activation, proliferation, and cytokine release after stimulation.
RESULTS: Existing HIES scoring systems are helpful to identify HIES patients. However, those scores may fail in infants and young children due to the age-related lack of clinical symptoms. Furthermore, our long term observations showed a striking variation of laboratory results over time in the individual patient. Reduced memory B cell counts in concert with low specific antibody production are the most consistent findings likely contributing to the high susceptibility to bacterial and fungal infection. In DOCK8-HIES T cell lymphopenia and low IFNgamma secretion after stimulation were common, likely promoting viral infections. In contrast to STAT3-HIES, DOCK8-HIES patients showed more severe inflammation with regard to allergic manifestations, elevated activation markers (HLA-DR, CD69, CD86, CD154), and significantly increased inflammatory cytokines (IL1beta, IL4, IL6, IFNgamma).
CONCLUSION: To differentiate HIES from other diseases like atopic dermatitis early in life is essential for patients because treatment modalities differ. To expedite the diagnosis process we propose here a diagnostic workflow. This article is protected by copyright. All rights reserved.

PMID: 26592211 [PubMed – as supplied by publisher]

Powered by WPeMatico

Conserved IL-2Rγc Signaling Mediates Lymphopoiesis in Zebrafish.

J Immunol. 2015 Nov 20;

Authors: Sertori R, Liongue C, Basheer F, Lewis KL, Rasighaemi P, de Coninck D, Traver D, Ward AC

Abstract
The IL-2 receptor γ common (IL-2Rγc) chain is the shared subunit of the receptors for the IL-2 family of cytokines, which mediate signaling through JAK3 and various downstream pathways to regulate lymphopoiesis. Inactivating mutations in human IL-2Rγc result in SCID, a primary immunodeficiency characterized by greatly reduced numbers of lymphocytes. This study used bioinformatics, expression analysis, gene ablation, and specific pharmacologic inhibitors to investigate the function of two putative zebrafish IL-2Rγc paralogs, il-2rγc.a and il-2rγc.b, and downstream signaling components during early lymphopoiesis. Expression of il-2rγc.a commenced at 16 h post fertilization (hpf) and rose steadily from 4-6 d postfertilization (dpf) in the developing thymus, with il-2rγc.a expression also confirmed in adult T and B lymphocytes. Transcripts of il-2rγc.b were first observed from 8 hpf, but waned from 16 hpf before reaching maximal expression at 6 dpf, but this was not evident in the thymus. Knockdown of il-2rγc.a, but not il-2rγc.b, substantially reduced embryonic lymphopoiesis without affecting other aspects of hematopoiesis. Specific targeting of zebrafish Jak3 exerted a similar effect on lymphopoiesis, whereas ablation of zebrafish Stat5.1 and pharmacologic inhibition of PI3K and MEK also produced significant but smaller effects. Ablation of il-2rγc.a was further demonstrated to lead to an absence of mature T cells, but not B cells in juvenile fish. These results indicate that conserved IL-2Rγc signaling via JAK3 plays a key role during early zebrafish lymphopoiesis, which can be potentially targeted to generate a zebrafish model of human SCID.

PMID: 26590317 [PubMed – as supplied by publisher]

Powered by WPeMatico

Primary complement and antibody deficiencies in autoimmune rheumatologic diseases with juvenile onset: a prospective study at two centers.

Pediatr Rheumatol Online J. 2015;13(1):51

Authors: Spârchez M, Lupan I, Delean D, Bizo A, Damian L, Muntean L, Tămaș MM, Bolba C, Simionescu B, Slăvescu C, Felea I, Lazăr C, Spârchez Z, Rednic S

Abstract
BACKGROUND: Our aim was to investigate the prevalence and clinical relevance of inherited complement and antibody deficiency states in a large series of patients with various autoimmune rheumatologic diseases (ARD) with juvenile onset.
METHODS: A total number of 117 consecutive patients from 2 tertiary referral hospitals were included in the study. All patients underwent genetic screening for type I C2 deficiency and C4 allotyping. Serum levels of immunoglobulin classes measured systematically throughout their regular medical care were recorded retrospectively.
RESULTS: Our cohort of patients included 84 with juvenile idiopathic arthritis (JIA), 21 with systemic lupus erythematosus (SLE), 6 with systemic vasculitis, 2 with juvenile scleroderma, 2 with idiopathic uveitis, 1 with mixed connective tissue disease and 1 with SLE/scleroderma overlap syndrome. We have found 16 patients with evidence of primary immunodeficiency in our series (13.7 %), including 7 with C4 deficiency, 5 with selective IgA deficiency, 3 with C2 deficiency and 2 with unclassified hypogammaglobulinemia (one also presented C4D). Of the 84 patients with JIA, 4 (4.8 %) had a complement deficiency, which was less prevalent than in the SLE cohort (23.8 %), but all of them have exhibited an aggressive disease. Most of our patients with primary antibody deficiencies showed a more complicated and severe disease course and even the co-occurrence of two associated autoimmune diseases (SLE/scleroderma overlap syndrome and SLE/autoimmune hepatitis type 1 overlap).
CONCLUSIONS: Our findings among others demonstrate that complement and immunoglobulin immunodeficiencies need careful consideration in patients with ARD, as they are common and might contribute to a more severe clinical course of the disease.

PMID: 26590091 [PubMed – as supplied by publisher]

Powered by WPeMatico

Transcriptomic analysis of the host response to an iridovirus infection in Chinese giant salamander, Andrias davidianus.

Vet Res. 2015;46(1):136

Authors: Fan Y, Chang MX, Ma J, LaPatra SE, Hu YW, Huang L, Nie P, Zeng L

Abstract
The emergence of an infectious viral disease caused by the Chinese giant salamander iridovirus (GSIV) has led to substantial economic losses. However, no more molecular information is available for the understanding of the mechanisms associated with virus-host interaction. In this study, de novo sequencing was used to obtain abundant high-quality ESTs and investigate differentially-expressed genes in the spleen of Chinese giant salamanders that were either infected or mock infected with GSIV. Comparative expression analysis indicated that 293 genes were down-regulated and 220 genes were up-regulated. Further enrichment analysis showed that the most enriched pathway is “complement and coagulation cascades”, and significantly enriched diseases include “inherited thrombophilia”, “immune system diseases”, “primary immunodeficiency”, “complement regulatory protein defects”, and “disorders of nucleotide excision repair”. Additionally, 30 678 simple sequence repeats (SSRs) from all spleen samples, 26 355 single nucleotide polymorphisms (SNPs) from the spleens of uninfected animals and 36 070 SNPs from the spleens of infected animals were detected. The large amount of variation was specific for the Chinese giant salamanders that were infected with GSIV. The results reported herein provided significant and new EST information that could contribute greatly in investigations into the molecular functions of immune genes in the Chinese giant salamander.

PMID: 26589400 [PubMed – as supplied by publisher]

Powered by WPeMatico

Altered fraction of regulatory B and T cells is correlated with autoimmune phenomena and splenomegaly in patients with CVID.

Clin Immunol. 2015 Nov 13;

Authors: Kofod-Olsen E, Jørgensen SE, Nissen SK, Westh L, Møller BK, Østergaard L, Larsen CS, Mogensen TH

Abstract
Common variable immunodeficiency (CVID) is a heterogeneous primary immunodeficiency disease, leading to recurrent bacterial airway infections and often also autoimmune complications. To shed light on the regulatory lymphocytes from these patients, we analyzed the levels of regulatory B (pro-B10) cell and regulatory T (Treg) cell subpopulations in PBMCs from twenty-six patients diagnosed with CVID using multi-color flowcytometry. Pro-B10 cells were induced by 48h in vitro stimulation prior to analysis. Suppressor function was measured on a subset of patients with splenomegaly and autoimmune complications. The levels of regulatory B and T cells were correlated to clinical manifestations, including autoimmunity, splenomegaly and CVID EUROclass subgroups. We demonstrate a significant association between elevated levels of pro-B10 cells, decreased levels of Tregs and autoimmune phenomena in CVID patients. The finding of marked abnormalities in regulatory lymphocyte populations contribute to our understanding of the pathogenesis of CVID and potentially be valuable in the clinical management and treatment of patients.

PMID: 26586095 [PubMed – as supplied by publisher]

Powered by WPeMatico

A de novo whole gene deletion of XIAP detected by exome sequencing analysis in very early onset inflammatory bowel disease: a case report.

BMC Gastroenterol. 2015;15(1):160

Authors: Kelsen JR, Dawany N, Martinez A, Grochowski CM, Maurer K, Rappaport E, Piccoli DA, Baldassano RN, Mamula P, Sullivan KE, Devoto M

Abstract
BACKGROUND: Children with very early-onset inflammatory bowel disease (VEO-IBD), those diagnosed at less than 5 years of age, are a unique population. A subset of these patients present with a distinct phenotype and more severe disease than older children and adults. Host genetics is thought to play a more prominent role in this young population, and monogenic defects in genes related to primary immunodeficiencies are responsible for the disease in a small subset of patients with VEO-IBD.
CASE PRESENTATION: We report a child who presented at 3 weeks of life with very early-onset inflammatory bowel disease (VEO-IBD). He had a complicated disease course and remained unresponsive to medical and surgical therapy. The refractory nature of his disease, together with his young age of presentation, prompted utilization of whole exome sequencing (WES) to detect an underlying monogenic primary immunodeficiency and potentially target therapy to the identified defect. Copy number variation analysis (CNV) was performed using the eXome-Hidden Markov Model. Whole exome sequencing revealed 1,380 nonsense and missense variants in the patient. Plausible candidate variants were not detected following analysis of filtered variants, therefore, we performed CNV analysis of the WES data, which led us to identify a de novo whole gene deletion in XIAP.
CONCLUSION: This is the first reported whole gene deletion in XIAP, the causal gene responsible for XLP2 (X-linked lymphoproliferative Disease 2). XLP2 is a syndrome resulting in VEO-IBD and can increase susceptibility to hemophagocytic lymphohistocytosis (HLH). This identification allowed the patient to be referred for bone marrow transplantation, potentially curative for his disease and critical to prevent the catastrophic sequela of HLH. This illustrates the unique etiology of VEO-IBD, and the subsequent effects on therapeutic options. This cohort requires careful and thorough evaluation for monogenic defects and primary immunodeficiencies.

PMID: 26581487 [PubMed – as supplied by publisher]

Powered by WPeMatico

Peripheral blood monocyte and T cell subsets in children with specific polysaccharide antibody deficiency (SPAD).

Hum Immunol. 2015 Nov 11;

Authors: Otero C, Díaz D, Uriarte I, Bezrodnik L, Finiasz MR, Fink S

Abstract
Specific polysaccharide antibody deficiency (SPAD) is a well reported immunodeficiency characterized by a failure to produce antibodies against polyvalent polysaccharide antigens, expressed by encapsulated microorganisms. The clinical presentation of these patients involves recurrent bacterial infections, being the most frequent agent Streptococcus (S.) pneumoniae. In SPAD patients few reports refer to cells other than B cells. Since the immune response to S. pneumoniae and other encapsulated bacteria was historically considered restricted to B cells, the antibody deficiency seemed enough to justify the repetitive infections in SPAD patients. Our purpose is to determine if the B cell defects reported in SPAD patients are accompanied by defects in other leukocyte subpopulations necessary for the development of a proper adaptive immune response against S. pneumoniae. We here report that age related changes observed in healthy children involving increased percentages of classical monocytes (CD14++CD16- cells) and decreased intermediate monocytes (CD14++CD16+ cells), are absent in SPAD patients. Alterations can also be observed in T cells, supporting that the immune deficiency in SPAD patients is more complex than what has been described up to now.

PMID: 26577026 [PubMed – as supplied by publisher]

Powered by WPeMatico

The 11q Terminal Deletion Disorder Jacobsen Syndrome is a Syndromic Primary Immunodeficiency.

J Clin Immunol. 2015 Nov 14;

Authors: Dalm VA, Driessen GJ, Barendregt BH, van Hagen PM, van der Burg M

Abstract
BACKGROUND: Jacobsen syndrome (JS) is a rare contiguous gene syndrome caused by partial deletion of the long arm of chromosome 11. Clinical features include physical and mental growth retardation, facial dysmorphism, thrombocytopenia, impaired platelet function and pancytopenia. In case reports, recurrent infections and impaired immune cell function compatible with immunodeficiency were described. However, Jacobsen syndrome has not been recognized as an established syndromic primary immunodeficiency.
GOAL: To evaluate the presence of immunodeficiency in a series of 6 patients with JS.
METHODS: Medical history of 6 patients with JS was evaluated for recurrent infections. IgG, IgA, IgM and specific antibodies against S. pneumoniae were measured. Response to immunization with a polysaccharide vaccine (Pneumovax) was measured and B and T lymphocyte subset analyses were performed using flowcytometry.
RESULTS: Five out of 6 patients suffered from recurrent infections. These patients had low IgG levels and impaired response to S. pneumoniae polysaccharide vaccination. Moreover, we also found a significant decrease in the absolute number of memory B cells, suggesting a defective germinal center function. In a number of patients, low numbers of T lymphocytes and NK cells were found.
CONCLUSIONS: Most patients with JS suffer from combined immunodeficiency in the presence of recurrent infections. Therefore, we consider JS a syndromic primary immunodeficiency. Early detection of immunodeficiency may reduce the frequency and severity of infections. All JS patients should therefore undergo immunological evaluation. Future studies in a larger cohort of patients will more precisely define the pathophysiology of the immunodeficiency in JS.

PMID: 26566921 [PubMed – as supplied by publisher]

Powered by WPeMatico