Research

The role of toll-like receptors in B-cell development and immunopathogenesis of common variable immunodeficiency.

Expert Rev Clin Immunol. 2015 Dec 14;:1-13

Authors: Sharifi L, Mirshafiey A, Rezaei N, Azizi G, Magaji Hamid K, Amirzargar AA, Asgardoon MH, Aghamohammadi A

Abstract
Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immune deficiency and is characterized by hypogammaglobulinemia, defect in specific antibody response and increased susceptibility to recurrent infections, malignancy and autoimmunity. Patients with CVID often have defects in post-antigenic B-cell differentiation, with fewer memory B cells and impaired isotype switching. Toll-like receptors (TLRs) are expressed on various immune cells as key elements of innate and adaptive immunity. TLR signaling in B cells plays multiple roles in cell differentiation and activation, class-switch recombination and cytokine and antibody production. Moreover, recent studies have shown functional alteration of TLRs responses in CVID patients including poor cell proliferation, impaired upregulation of co-stimulatory molecules and failure in cytokine and immunoglobulin production. The purpose of the present review is to discuss the role of TLRs in B-cell development and function as well as their role in the immunopathogenesis of CVID.

PMID: 26654573 [PubMed – as supplied by publisher]

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Successful Granulocyte Colony Stimulating Factor Treatment of Relapsing Candida albicans Meningoencephalitis Caused by CARD9 Deficiency.

Pediatr Infect Dis J. 2015 Dec 9;

Authors: Celmeli F, Oztoprak N, Turkkahraman D, Seyman D, Mutlu E, Frede N, Köksoy S, Grimbacher B

Abstract
Caspase-associated recruitment domain-9 (CARD9) deficiency is an autosomal-recessive primary immunodeficiency with genetic defects in Th17 immunity marked by susceptibility to recurrent and invasive Candida infections. We present a case of relapsing C. albicans meningoencephalitis over one-year period despite appropriate antifungal therapy. We detected a homozygous p.Q295X mutation in CARD9 as well as a defective IL-17 and interferon gamma (IFN-γ) synthesis in Enzyme-Linked ImmunoSpot (ELISPOT) tests. We achieved complete clinical remission, and improvement of IL-17 secretion with subcutaneous granulocyte-colony stimulating factor (G-CSF) treatment.

PMID: 26658378 [PubMed – as supplied by publisher]

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Related Articles

Fertility, pregnancies and outcomes reported by females with common variable immune deficiency and hypogammaglobulinemia: results from an internet-based survey.

J Clin Immunol. 2015 Feb;35(2):125-34

Authors: Gundlapalli AV, Scalchunes C, Boyle M, Hill HR

Abstract
BACKGROUND: Issues of fertility and pregnancy place an extra burden on females with primary immunodeficiencies. Patients lack reliable information and providers lack guidelines to counsel patients on these anxiety-provoking matters.
OBJECTIVE: To collate concerns and experiences related to fertility and pregnancy from females with humoral immune deficiencies.
METHODS: We conducted an internet-based survey of female patients who self-identified as having a diagnosis of primary humoral immune deficiency.
RESULTS: Responses from 490 women with common variable immune deficiency and 100 with hypogammaglobulinemia were evaluated. The reported fertility measure (% of women who had had a birth) was statistically significantly lower as compared to the general US population (70 % vs. 85 %, p < 0.0001) whereas the rates of spontaneous pregnancy loss were comparable. This group reported a total of 966 pregnancies; 72 % resulted in a live birth. A majority of the pregnancies progressed with no incident and with continuation of their IgG replacement therapy; 23 % reported an increase in IgG dosing during pregnancy. Only 15 % of those reporting a first pregnancy indicated that they had been diagnosed with immune deficiency prior to their first pregnancy; these women expressed concern regarding the effect of immune deficiency on their fertility, pregnancy and decision to have children.
CONCLUSION: With inherent limitations of self-reported responses to surveys, females with humoral immune deficiencies reported relatively good rates of fertility and pregnancies ending in live births. Results of the survey will serve as peer support for patients and inform counseling guidelines for providers.

PMID: 25572592 [PubMed – indexed for MEDLINE]

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Clinical and laboratory correlates of lung disease and cancer in adults with idiopathic hypogammaglobulinemia.

Clin Exp Immunol. 2015 Dec 8;

Authors: Brent J, Guzman D, Bangs C, Grimbacher B, Fayolle C, Huissoon A, Bethune C, Thomas M, Patel S, Jolles S, Alachkar H, Kumaratne D, Baxendale H, Edgar JD, Helbert M, Hambleton S, Arkwright PD

Abstract
Idiopathic hypogammaglobulinemia, including CVID, has a heterogeneous clinical phenotype. This study used data from the national UKPID registry to examine factors associated with adverse outcomes, particularly lung damage and malignancy. 801 adults labeled with idiopathic hypogammaglobulinemia and CVID aged 18 to 96 years from ten UK cities were recruited using the UKPID registry database. Clinical and laboratory data (leukocyte numbers and serum immunoglobulin concentrations) were collated and analyzed using uni and multivariate statistics. Low serum IgG pre-immunoglobulin replacement therapy was the key factor associated with lower respiratory tract infections (LRTI) and history of LRTI was the main factor associated with bronchiectasis. History of overt LRTI was also associated with a significantly shorter delay in diagnosis and commencing immunoglobulin replacement therapy (5 (1-13 years) versus 9 (2-24) years). Patients with bronchiectasis started immunoglobulin replacement therapy significantly later than those without this complication (7 (2-22) years versus 5 (1-13) years). Patients with a history of LRTI had higher serum IgG concentrations on therapy and were twice as likely to be on prophylactic antibiotics. Ensuring prompt commencement of immunoglobulin therapy in patients with idiopathic hypogammaglobulinemia is likely to help prevent LRTI and subsequent bronchiectasis. Cancer was the only factor associated with mortality. Overt cancer, both hematological and non-hematological, was associated with significantly lower absolute CD8(+) T-cell but not NK-cell numbers, raising the question as to what extent immune senescence, particularly of CD8(+) T-cells, might contribute to the increased risk of cancers as individuals age. This article is protected by copyright. All rights reserved.

PMID: 26646609 [PubMed – as supplied by publisher]

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Gene expression profiling indicates an increased capacity for proline, serine, and ATP synthesis and mitochondrial mass by the liver of steers grazing high vs. low endophyte-infected tall fescue.

J Anim Sci. 2015 Dec;93(12):5659-5671

Authors: Liao SF, Boling JA, Matthews JC

Abstract
Grazing -infected forages results in a variety of reduced animal performance parameters, collectively known as “fescue toxicosis.” The initial, limited evaluations of hepatic mechanisms affected by fescue toxicosis have used transcriptomic expression profiling of experimental phenotypes developed by short-term feeding of concentrated ergot alkaloids or fescue seeds to rodents and steers. To assess the effects of fescue toxicosis in growing cattle using a commercially relevant phenotype, we induced fescue toxicosis in beef steers by summer-long grazing (89 to 105 d) of a single high toxic endophyte-infected tall fescue pasture (HE; 0.746 μg/g ergot alkaloids; 5.7 ha; = 10; BW = 267 ± 14.5 kg) vs. a low toxic endophyte tall fescue-mixed pasture (LE; 0.023 μg/g ergot alkaloids; 5.7 ha; = 9; BW = 266 ± 10.9 kg). High toxic endophyte tall fescue-mixed pasture steers had decreased BW (313 vs. 338 kg) and an increased potential for hepatic gluconeogenesis from AA-derived carbons. To gain a greater perspective into fescue toxicosis-induced hepatic metabolism and identify candidate regulatory mechanisms, the goal of the current research was to examine liver samples for changes in gene (mRNA) expression profiles using a Bovine Affymetrix microarray and selected reverse-transcription PCR and immunoblot analyses. The expression (false discovery rate < 10%; < 0.01) of 147 genes was increased (7 to 268%) and that of 227 was decreased (4 to 87%) in livers of HE vs. LE steers. The top (1) functional gene category was cell-mediated immune response (33 genes; ≤ 0.012), (2) canonical cell signaling pathway was primary immunodeficiency signaling (8 genes; ≤ 0.0003), and (3) canonical metabolic pathways were oxidative phosphorylation (5 genes; ≤ 0.016) and purine metabolism (8 genes; ≤ 0.029). High toxic endophyte tall fescue-mixed pasture steers had increased ( ≤ 0.022) expression of genes critical for increased (1) Pro () and Ser () synthesis, (2) shunting of AA carbons into pyruvate () and ATP synthesis (, , , COX4, , and ), and (3) mitochondrial mass (COX4). Targeted reverse-transcribed PCR or immunoblot assays corroborated ( ≤ 0.035) these latter microarray findings for , , , , and COX4. Moreover, network analysis identified glucocorticoid receptor-mediated signaling as the most probable mechanism to coordinate the above findings. These results greatly extend our knowledge of the consequences of summer-long grazing of endophyte-infected tall fescue to the hepatic metabolism of growing steers.

PMID: 26641175 [PubMed – as supplied by publisher]

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Preclinical and first clinical experience with the gastrin-releasing peptide receptor-antagonist [(68)Ga]SB3 and PET/CT.

Eur J Nucl Med Mol Imaging. 2015 Dec 2;

Authors: Maina T, Bergsma H, Kulkarni HR, Mueller D, Charalambidis D, Krenning EP, Nock BA, de Jong M, Baum RP

Abstract
PURPOSE: Gastrin-releasing peptide receptors (GRPR) represent attractive targets for tumor diagnosis and therapy because of their overexpression in major human cancers. Internalizing GRPR agonists were initially proposed for prolonged lesion retention, but a shift of paradigm to GRPR antagonists has recently been made. Surprisingly, radioantagonists, such as [(99m)Tc]DB1 ((99m)Tc-N4′-DPhe(6),Leu-NHEt(13)]BBN(6-13)), displayed better pharmacokinetics than radioagonists, in addition to their higher inherent biosafety. We introduce here [(68)Ga]SB3, a [(99m)Tc]DB1 mimic-carrying, instead of the (99m)Tc-binding tetraamine, the chelator DOTA for labeling with the PET radiometal (68)Ga.
METHODS: Competition binding assays of SB3 and [(nat)Ga]SB3 were conducted against [(125)I-Tyr(4)]BBN in PC-3 cell membranes. Blood samples collected 5 min postinjection (pi) of the [(67)Ga]SB3 surrogate in mice were analyzed using high-performance liquid chromatography (HPLC) for degradation products. Likewise, biodistribution was performed after injection of [(67)Ga]SB3 (37 kBq, 100 μL, 10 pmol peptide) in severe combined immunodeficiency (SCID) mice bearing PC-3 xenografts. Eventually, [(68)Ga]SB3 (283 ± 91 MBq, 23 ± 7 nmol) was injected into 17 patients with breast (8) and prostate (9) cancer. All patients had disseminated disease and had received previous therapies. PET/CT fusion images were acquired 60-115 min pi.
RESULTS: SB3 and [(nat)Ga]SB3 bound to the human GRPR with high affinity (IC50: 4.6 ± 0.5 nM and 1.5 ± 0.3 nM, respectively). [(67)Ga]SB3 displayed good in vivo stability (>85 % intact at 5 min pi). [(67)Ga]SB3 showed high, GRPR-specific and prolonged retention in PC-3 xenografts (33.1 ± 3.9%ID/g at 1 h pi – 27.0 ± 0.9%ID/g at 24 h pi), but much faster clearance from the GRPR-rich pancreas (≈160%ID/g at 1 h pi to <17%ID/g at 24 h pi) in mice. In patients, [(68)Ga]SB3 elicited no adverse effects and clearly visualized cancer lesions. Thus, 4 out of 8 (50 %) breast cancer and 5 out of 9 (55 %) prostate cancer patients showed pathological uptake on PET/CT with [(68)Ga]SB3.
CONCLUSION: [(67)Ga]SB3 showed excellent pharmacokinetics in PC-3 tumor-bearing mice, while [(68)Ga]SB3 PET/CT visualized lesions in about 50 % of patients with advanced and metastasized prostate and breast cancer. We expect imaging with [(68)Ga]SB3 to be superior in patients with primary breast or prostate cancer.

PMID: 26631238 [PubMed – as supplied by publisher]

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A Population-Based 16-Year Study on the Risk Factors of Surgical Site Infection in Patients after Bone Grafting: A Cross-Sectional Study in Taiwan.

Medicine (Baltimore). 2015 Nov;94(47):e2034

Authors: Lee FH, Shen PC, Jou IM, Li CY, Hsieh JL

Abstract
Bone grafting is a commonly used orthopedic surgical procedure that will provide bone formation in bone defects or regions of defective bone healing. A major complication following bone grafting is a postoperative recipient graft site infection that is associated with substantial mortality and increased use of medical resources. The purpose of the study was to identify the risk factors associated with infection after bone-grafting surgery.Data from 1,303,347 patients listed in the Taiwan National Health Insurance Research Database (NHIRD) and admitted to hospitals from 1997 through 2012 who underwent primary bone grafting (mean age: 46.57 years old; mean length of hospital stay: 8.04 days) were analyzed. The incidence of infection by age, hospital stay, gender, income, chronic disease (tuberculosis [TB]; diabetes mellitus [DM]; acquired immunodeficiency syndrome [AIDS]), fracture complications (nonunion; delayed union fracture), types of graft and hospital was evaluated.Three percent of the patients developed a postoperative recipient graft site infection. Multivariable analysis revealed that patients were more likely to develop a post bone-grafting surgery infection if they were older, had a longer hospital stay, were male, had a lower income, or had comorbid TB, DM, or AIDS. Patients were more likely to develop an infection if they had a nonunion, an alloplast graft, or treated in a local clinic.Our findings should provide a clinically relevant reference for surgeons who perform bone grafting. Patients should be informed of the potential risks.

PMID: 26632703 [PubMed – as supplied by publisher]

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Influence of follicle stage on artificial ovary outcome using fibrin as a matrix.

Hum Reprod. 2015 Nov 30;

Authors: Chiti MC, Dolmans MM, Orellana R, Soares M, Paulini F, Donnez J, Amorim CA

Abstract
STUDY QUESTION: Do primordial-primary versus secondary follicles embedded inside a fibrin matrix have different capabilities to survive and grow after isolation and transplantation?
SUMMARY ANSWER: Mouse primordial-primary follicles showed a lower recovery rate than secondary follicles, but both were able to grow.
WHAT IS KNOWN ALREADY: Fresh isolated mouse follicles and ovarian stromal cells embedded in a fibrin matrix are capable of surviving and developing after short-term autografting.
STUDY DESIGN, SIZE, DURATION: In vivo experimental model using 11 donor Naval Medical Research Institute (NMRI) mice and 11 recipient severe combined immunodeficiency (SCID) mice. Both ovaries from all NMRI mice were mechanically disrupted and primordial-primary and secondary follicles were isolated with ovarian stromal cells. They were then encapsulated in a fibrin matrix composed of 12.5 mg/ml of fibrinogen (F12.5) and 1 IU/ml of thrombin (T1) (F12.5/T1), and grafted to the inner part of the peritoneum of SCID mice for 2 and 7 days.
PARTICIPANTS/MATERIALS, SETTING, METHODS: This study was conducted at the Gynecology Research Unit, Université Catholique de Louvain. All materials were used to conduct histological (H-E staining) and immunohistochemical (Ki67, TUNEL) analyses.
MAIN RESULTS AND THE ROLE OF CHANCE: Although all grafted fibrin clots were recovered, the follicle recovery rate on day 2 was 16 and 40% for primordial-primary and secondary follicles respectively, while on day 7, it was 6 and 28%. The secondary group showed a significantly higher recovery rate than the primordial-primary group (23%, P-value <0.001). Follicles found in both groups were viable, as demonstrated by live/dead assays, and no difference was observed in the apoptosis rate between groups, as evidenced by TUNEL. Their growth to further stages was confirmed by Ki67 immunostaining.
LIMITATIONS, REASONS FOR CAUTION: As demonstrated by our results, secondary follicles appear to be more likely to survive and develop than primordial-primary follicles in a fibrin matrix after both periods of grafting. These findings may also be attributed to the specific features of the fibrin matrix, which could benefit larger follicles, but not smaller follicles.
WIDER IMPLICATIONS OF THE FINDINGS: This study is essential to understanding possible impairment caused by factors such as the isolation procedure or fibrin matrix composition to the survival and development of different follicle stages. It therefore provides the basis for further investigations with longer periods of grafting.
STUDY FUNDING/COMPETING INTERESTS: This study was supported by grants from the Fonds National de la Recherche Scientifique de Belgique (grant Télévie No. 7.4578.14 and 7.4627.13, grant 5/4/150/5 awarded to Marie-Madeleine Dolmans), Fonds Spéciaux de Recherche, Fondation St Luc, the Foundation Against Cancer, and the Region Wallone (Convention N°6519-OVART) and donations from Mr Pietro Ferrero, Baron Frère and Viscount Philippe de Spoelberch. None of the authors have any competing interests to declare.

PMID: 26628641 [PubMed – as supplied by publisher]

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Application of diagnostic and treatment criteria for common variable immunodeficiency disorder.

Expert Rev Clin Immunol. 2015 Dec 1;

Authors: Ameratunga R, Storey P, Barker R, Jordan A, Koopmans W, Woon ST

Abstract
Common variable immunodeficiency disorder (CVID) is the most frequent symptomatic primary immune deficiency disorder in adults. It probably comprises a spectrum of polygenic disorders with hypogammaglobulinemia being the overarching feature. While the majority of patients with CVID can be identified with relative ease, a significant proportion can present with minimal symptoms in spite of profound laboratory abnormalities. Here we discuss three patients who were presented to the Auckland Hospital Immunoglobulin treatment committee to determine if they qualified for immunoglobulin replacement. Two were asymptomatic with profound laboratory abnormalities while the third patient was severely ill with extensive bronchiectasis. The third patient had less severe laboratory abnormalities compared with the two asymptomatic patients. We have applied four sets of published diagnostic and treatment criteria to these patients to compare their clinical utility. We have chosen these patients from the broad phenotypic spectrum of CVID, as this often illustrates differences in diagnostic and treatment criteria.

PMID: 26623716 [PubMed – as supplied by publisher]

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Severe infectious diseases of childhood as monogenic inborn errors of immunity.

Proc Natl Acad Sci U S A. 2015 Nov 30;

Authors: Casanova JL

Abstract
This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications.

PMID: 26621750 [PubMed – as supplied by publisher]

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