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Fungal colonization – an additional risk factor for diseased dogs and cats?

Ann Parasitol. 2014;58(3):139-146

Authors: Biegańska M, Dardzińska W, Dworecka-Kaszak B

Abstract
The aim of the presented mini-review is to review the literature data referring to opportunistic mycoses in pet dogs and cats suffering from other concurrent diseases, comparable to human medical disorders with high risk of secondary mycoses. This review also presents the preliminary results of a project aimed at understanding the fungal colonization and occurrence of secondary mycoses in pets suffering from metabolic disorders, neoplasms and viral infections. The incidence of opportunistic mycoses is higher in such individuals, mostly because of their impaired immunity. The main risk factors are primary and secondary types of immunodeficiency connected with anti-cancer treatment or neoplastic disease itself. Moreover, literature data and the results of our investigations show that Candida yeasts are prevalent among diabetic animals and indicate that these fungi are the main etiological agents of secondary infections of the oral cavity, GI and urogenital tracts. Other important conditions possibly favoring the development of mycoses are concurrent infections of cats with FeLV and FIV viruses. Thus, in all cases of the mentioned underlying diseases, animals should be carefully monitored by repeated mycological examination, together with inspection of other parameters. Also, the prophylaxis of opportunistic mycoses should be carefully considered alike other factors influencing the prognosis and the outcome of primary diseases.

PMID: 25281810 [PubMed – as supplied by publisher]

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Genome-wide Association Study Identifies Five Susceptibility Loci for Follicular Lymphoma outside the HLA Region.

Am J Hum Genet. 2014 Oct 2;95(4):462-471

Authors: Skibola CF, Berndt SI, Vijai J, Conde L, Wang Z, Yeager M, de Bakker PI, Birmann BM, Vajdic CM, Foo JN, Bracci PM, Vermeulen RC, Slager SL, de Sanjose S, Wang SS, Linet MS, Salles G, Lan Q, Severi G, Hjalgrim H, Lightfoot T, Melbye M, Gu J, Ghesquières H, Link BK, Morton LM, Holly EA, Smith A, Tinker LF, Teras LR, Kricker A, Becker N, Purdue MP, Spinelli JJ, Zhang Y, Giles GG, Vineis P, Monnereau A, Bertrand KA, Albanes D, Zeleniuch-Jacquotte A, Gabbas A, Chung CC, Burdett L, Hutchinson A, Lawrence C, Montalvan R, Liang L, Huang J, Ma B, Liu J, Adami HO, Glimelius B, Ye Y, Nowakowski GS, Dogan A, Thompson CA, Habermann TM, Novak AJ, Liebow M, Witzig TE, Weiner GJ, Schenk M, Hartge P, De Roos AJ, Cozen W, Zhi D, Akers NK, Riby J, Smith MT, Lacher M, Villano DJ, Maria A, Roman E, Kane E, Jackson RD, North KE, Diver WR, Turner J, Armstrong BK, Benavente Y, Boffetta P, Brennan P, Foretova L, Maynadie M, Staines A, McKay J, Brooks-Wilson AR, Zheng T, Holford TR, Chamosa S, Kaaks R, Kelly RS, Ohlsson B, Travis RC, Weiderpass E, Clavel J, Giovannucci E, Kraft P, Virtamo J, Mazza P, Cocco P, Ennas MG, Chiu BC, Fraumeni JF, Nieters A, Offit K, Wu X, Cerhan JR, Smedby KE, Chanock SJ, Rothman N

Abstract
Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10(-20)) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10(-11)) near ETS1; 3q28 (rs6444305, p = 1.10 × 10(-10)) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10(-10)) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10(-8)) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRβ1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 × 10(-67) to 2.67 × 10(-70)). Additional independent signals included rs17203612 in HLA class II (odds ratio [ORper-allele] = 1.44; p = 4.59 × 10(-16)) and rs3130437 in HLA class I (ORper-allele = 1.23; p = 8.23 × 10(-9)). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk.

PMID: 25279986 [PubMed – as supplied by publisher]

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[A first pilot study on the neonatal screening of primary immunodeficiencies in Spain: TRECS and KRECS identify severe T- and B-cell lymphopenia.]

An Pediatr (Barc). 2014 Sep 29;

Authors: Olbrich P, de Felipe B, Delgado-Pecellin C, Rodero R, Rojas P, Aguayo J, Marquez J, Casanovas J, Sánchez B, Lucena JM, Ybot-Gonzalez P, Borte S, Neth O

Abstract
INTRODUCTION: Early diagnosis of primary immunodeficiency such as severe combined immunodeficiency (SCID) and X-linked agammaglobulinemia (XLA) improves outcome of affected infants/children. The measurement of T-cell receptor excision circles (TRECS) and kappa-deleting recombination excision circles (KRECS) can identify neonates with severe T or B-cell lymphopenia.
OBJECTIVES: To determine TRECS and KRECS levels from prospectively collected dried blood spot samples (DBS) and to correctly identify severe T and B-cell lymphopenia.
MATERIAL AND METHODS: Determination of TRECS and KRECS by multiplex PCR from neonates born in two tertiary hospitals in Seville between February 2014 and May 2014. PCR cut-off levels: TRECS<15 copies/μl, KRECS<10copies/μl, ACTB (β-actin)>1000 copies/μl. Internal (XLA, ataxia telangiectasia) and external (SCID) controls were included.
RESULTS: A total of 1068 out of 1088 neonates (mean GA 39 weeks (38-40) and BW 3238g (2930-3520) were enrolled in the study. Mean (median, min/max) copies/μl, were as follows: TRECS 145 (132, 8/503), KRECS 82 (71, 7/381), and ACTB 2838 (2763, 284/7710). Twenty samples (1.87%) were insufficient. Resampling was needed in one neonate (0.09%), subsequently giving a normal result. When using lower cut-offs (TRECS<8 and KRECS<4 copies/μl), all the samples tested were normal and the internal and external controls were correctly identified.
CONCLUSION: This is the first prospective pilot study in Spain using TRECS/KRECS/ACTB-assay, describing the experience and applicability of this method to identify severe lymphopenias. The ideal cut-off remains to be established in our population. Quality of sampling, storage and preparation need to be further improved.

PMID: 25278007 [PubMed – as supplied by publisher]

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SNAIL1 combines competitive displacement of ASCL2 and epigenetic mechanisms to rapidly silence the EPHB3 tumor suppressor in colorectal cancer.

Mol Oncol. 2014 Sep 16;

Authors: Rönsch K, Jägle S, Rose K, Seidl M, Baumgartner F, Freihen V, Yousaf A, Metzger E, Lassmann S, Schüle R, Zeiser R, Michoel T, Hecht A

Abstract
EPHB3 is a critical cellular guidance factor in the intestinal epithelium and an important tumor suppressor in colorectal cancer (CRC) whose expression is frequently lost at the adenoma-carcinoma transition when tumor cells become invasive. The molecular mechanisms underlying EPHB3 silencing are incompletely understood. Here we show that EPHB3 expression is anti-correlated with inducers of epithelial-mesenchymal transition (EMT) in primary tumors and CRC cells. In vitro, SNAIL1 and SNAIL2, but not ZEB1, repress EPHB3 reporter constructs and compete with the stem cell factor ASCL2 for binding to an E-box motif. At the endogenous EPHB3 locus, SNAIL1 triggers the displacement of ASCL2, p300 and the Wnt pathway effector TCF7L2 and engages corepressor complexes containing HDACs and the histone demethylase LSD1 to collapse active chromatin structure, resulting in rapid downregulation of EPHB3. Beyond its impact on EPHB3, SNAIL1 deregulates markers of intestinal identity and stemness and in vitro forces CRC cells to undergo EMT with altered morphology, increased motility and invasiveness. In xenotransplants, SNAIL1 expression abrogated tumor cell palisading and led to focal loss of tumor encapsulation and the appearance of areas with tumor cells displaying a migratory phenotype. These changes were accompanied by loss of EPHB3 and CDH1 expression. Intriguingly, SNAIL1-induced phenotypic changes of CRC cells are significantly impaired by sustained EPHB3 expression both in vitro and in vivo. Altogether, our results identify EPHB3 as a novel target of SNAIL1 and suggest that disabling EPHB3 signaling is an important aspect to eliminate a roadblock at the onset of EMT processes.

PMID: 25277775 [PubMed – as supplied by publisher]

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Hypogammaglobulinemia in BLT Humanized Mice – An Animal Model of Primary Antibody Deficiency.

PLoS One. 2014;9(10):e108663

Authors: Martinez-Torres F, Nochi T, Wahl A, Garcia JV, Denton PW

Abstract
Primary antibody deficiencies present clinically as reduced or absent plasma antibodies without another identified disorder that could explain the low immunoglobulin levels. Bone marrow-liver-thymus (BLT) humanized mice also exhibit primary antibody deficiency or hypogammaglobulinemia. Comprehensive characterization of B cell development and differentiation in BLT mice revealed other key parallels with primary immunodeficiency patients. We found that B cell ontogeny was normal in the bone marrow of BLT mice but observed an absence of switched memory B cells in the periphery. PC-KLH immunizations led to the presence of switched memory B cells in immunized BLT mice although plasma cells producing PC- or KLH- specific IgG were not detected in tissues. Overall, we have identified the following parallels between the humoral immune systems of primary antibody deficiency patients and those in BLT mice that make this in vivo model a robust and translational experimental platform for gaining a greater understanding of this heterogeneous array of humoral immunodeficiency disorders in humans: (i) hypogammaglobulinemia; (ii) normal B cell ontogeny in bone marrow; and (iii) poor antigen-specific IgG response to immunization. Furthermore, the development of strategies to overcome these humoral immune aberrations in BLT mice may in turn provide insights into the pathogenesis of some primary antibody deficiency patients which could lead to novel clinical interventions for improved humoral immune function.

PMID: 25271886 [PubMed – as supplied by publisher]

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New C1q mutation in a Tunisian family.

Immunobiology. 2014 Mar;219(3):241-6

Authors: Jlajla H, Sellami MK, Sfar I, Laadhar L, Zerzeri Y, Abdelmoula MS, Gorgi Y, Dridi MF, Makni S

Abstract
Hereditary C1q deficiency (C1qD) is the most penetrant genetic factor predisposing to the development of lupus pathology with more than 93% of C1q deficient patients developing this autoimmune pathology throughout their life. It is a rare autosomal recessive deficiency, with only 67 cases reported so far including one Tunisian girl who died at the age of three from complications resulting from severe systemic lupus erythematosus. Although C1qD was confirmed in the serum of this patient using C1q ELISA and classical pathway specific functional assays, no DNA sample had been obtained from this patient. Here we report the analysis of sera and DNA of members of this patient’s closer family. Our analysis identified a homozygous mutation within the gene encoding the C-chain of C1q leading to a deficiency of C1q in an older sister of our original patient. This mutation, termed g.5580G4C, represents a single basepair substitution in exon 1 of the C1q C chain gene which changes the codon of Gly61 to Arg 61. Amongst the other 14 mutations leading to C1qD, g.5580G4C represents the first reported transversion leading to human C1qD.

PMID: 24331529 [PubMed – indexed for MEDLINE]

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Intrinsic defect in B-lymphoblastoid cell lines from patients with X-linked lymphoproliferative disease type 1. II. receptor-mediated Akt/PKB and ERK1/2 activation and transcription factors expression profile.

Exp Oncol. 2014 Sep;36(3):162-169

Authors: Shlapatska LM, Kovalevska LM, Gordiienko IM, Sidorenko SP

Abstract
Background: X-linked lymphoproliferative disease type 1 (XLP1) belongs to genetically determined primary immunodeficiency syndromes with mutations in SH2D1A/DSHP/SAP gene. The dramatic increase of the risk of B-cell lymphoma development in XLP1 patients is linked not only to SAP deficiency of NK, NKT and T cells, but probably to the impairment of B cell differentiation. Aim: To analyze the receptor-mediated Akt/PKB and ERK1/2 phosphorylation and expression of transcription factors that are involved in B cell maturation in EBV-transformed B-lymphoblastoid cell lines (B-LCLs) from XLP1 patients (XLP B-LCLs) in comparison with conventional B-LCLs. Methods: Studies were performed on EBV-transformed XLP B-LCLs IARC 739, SC-XLP and RP-XLP in comparison with SAP-negative B-LCL T5-1 and SAP-positive B-LCL MP-1. Western blot analysis was used for evaluation of Akt (Ser473) and ERK1/2 (Thr202/Tyr204) phosphorylation in response to ligation of CD150, CD40, and IgM cell surface receptors. The expression levels of transcription factors IRF4, IRF8, BCL6, BLIMP1, SPIB, PU.1 and MITF were assessed using quantitative RT-PCR. Results: It was shown that SAP deficiency in XLP B-LCL did not abrogate CD150-mediated Akt and ERK1/2 phosphorylation. At the same time, ligation of CD150 or IgM affects kinetics and amplitude of ERK1/2 activation. In XLP B-LCL the CD150 signaling with IgM coligation play the dominant role in both Akt and ERK1/2 phosphorylation. We found that significantly reduced IRF4, IRF8 and PU.1 expression levels are the key features of XLP B-LCLs. Conclusion: XLP B-LCLs and conventional B-LCLs have differences in kinetics and amplitude of Akt and ERK1/2 phosphorylation. Analysis of transcription factors profile revealed the distinguishing features of XLP B-LCLs with SAP deficiency that may impair B cell differentiation.Key Words: B-lymphoblastoid cell lines, X-linked lymphoproliferative disease type 1, CD150, CD40, BCR, Akt/PKB, ERK1/2, transcription factors.

PMID: 25265348 [PubMed – as supplied by publisher]

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Recent advances in chronic granulomatous disease.

J Infect. 2014 Sep 25;

Authors: Goldblatt D

Abstract
Chronic Granulomatous Disease (CGD) is a primary immunodeficiency caused by abnormities in the NADPH Oxidase that is involved in the respiratory burst responsible for initiating the killing of microbes ingested by phagocytic cells. The hallmark of CGD is recurrent infection but the inflammatory complications can prove difficult to treat. New insights into the mechanisms responsible for the inflammatory complications have led to new therapies. The treatment of CGD colitis with an anti-tumour necrosis alpha agent has been shown to be successful but associated with significant infectious complications. Haematopoietic stem cell transplants offer the possibility of cure for those with ether a matched or unrelated donor transplant, with results of the latter improving significantly over recent years. Gene Therapy offers the promise of cure without the need for a transplant but better vectors are required.

PMID: 25264161 [PubMed – as supplied by publisher]

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Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma.

Nat Genet. 2014 Sep 28;

Authors: Cerhan JR, Berndt SI, Vijai J, Ghesquières H, McKay J, Wang SS, Wang Z, Yeager M, Conde L, de Bakker PI, Nieters A, Cox D, Burdett L, Monnereau A, Flowers CR, De Roos AJ, Brooks-Wilson AR, Lan Q, Severi G, Melbye M, Gu J, Jackson RD, Kane E, Teras LR, Purdue MP, Vajdic CM, Spinelli JJ, Giles GG, Albanes D, Kelly RS, Zucca M, Bertrand KA, Zeleniuch-Jacquotte A, Lawrence C, Hutchinson A, Zhi D, Habermann TM, Link BK, Novak AJ, Dogan A, Asmann YW, Liebow M, Thompson CA, Ansell SM, Witzig TE, Weiner GJ, Veron AS, Zelenika D, Tilly H, Haioun C, Molina TJ, Hjalgrim H, Glimelius B, Adami HO, Bracci PM, Riby J, Smith MT, Holly EA, Cozen W, Hartge P, Morton LM, Severson RK, Tinker LF, North KE, Becker N, Benavente Y, Boffetta P, Brennan P, Foretova L, Maynadie M, Staines A, Lightfoot T, Crouch S, Smith A, Roman E, Diver WR, Offit K, Zelenetz A, Klein RJ, Villano DJ, Zheng T, Zhang Y, Holford TR, Kricker A, Turner J, Southey MC, Clavel J, Virtamo J, Weinstein S, Riboli E, Vineis P, Kaaks R, Trichopoulos D, Vermeulen RC, Boeing H, Tjonneland A, Angelucci E, Di Lollo S, Rais M, Birmann BM, Laden F, Giovannucci E, Kraft P, Huang J, Ma B, Ye Y, Chiu BC, Sampson J, Liang L, Park JH, Chung CC, Weisenburger DD, Chatterjee N, Fraumeni JF, Slager SL, Wu X, de Sanjose S, Smedby KE, Salles G, Skibola CF, Rothman N, Chanock SJ

Abstract
Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 × 10(-21)), rs2523607 at 6p21.33 (HLA-B; P = 2.40 × 10(-10)), rs79480871 at 2p23.3 (NCOA1; P = 4.23 × 10(-8)) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 × 10(-13) and 3.63 × 10(-11), respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.

PMID: 25261932 [PubMed – as supplied by publisher]

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Stem cell transplantation for primary immunodeficiency diseases: the North American experience.

Curr Opin Allergy Clin Immunol. 2014 Sep 24;

Authors: Pai SY, Cowan MJ

Abstract
PURPOSE OF REVIEW: This review describes recent studies on outcomes after allogeneic hematopoietic cell transplantation for primary immunodeficiency in North America, including severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome and chronic granulomatous disease.
RECENT FINDINGS: Using uniform diagnostic criteria, the Primary Immune Deficiency Treatment Consortium described the baseline characteristics of newly diagnosed infants with SCID in North America. Analysis of outcomes of hematopoietic cell transplantation for SCID in North America from 2000 to 2009 showed that young infants, and older infants without active infection, had excellent survival irrespective of type of donor or transplant approach with regard to conditioning. Although pretransplant conditioning with chemotherapy had a clear and strong negative impact on survival in infants with active infection at the time of transplant, among survivors, conditioning was associated with improved immune reconstitution. However, the potential late effects of conditioning in these infants remain to be characterized. Advances in transplant outcomes for Wiskott-Aldrich syndrome and chronic granulomatous disease support the strategy of early transplantation before the onset of severe complications; additional multicenter studies are needed to fully define optimal approaches.
SUMMARY: The formation of the Primary Immune Deficiency Treatment Consortium, a multiinstitutional North American consortium, has contributed to our understanding of outcomes after transplant for primary immunodeficiency.

PMID: 25259542 [PubMed – as supplied by publisher]

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