Research

[Futher strengthen the immunoglobulin G replacement therapy of primary immunodeficiency diseases].

Zhonghua Er Ke Za Zhi. 2017 Jan 02;55(1):1-3

Authors: Mao HW, Zhao XD

PMID: 28072951 [PubMed – in process]

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Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts.

Proc Natl Acad Sci U S A. 2017 Jan 09;:

Authors: Della Mina E, Borghesi A, Zhou H, Bougarn S, Boughorbel S, Israel L, Meloni I, Chrabieh M, Ling Y, Itan Y, Renieri A, Mazzucchelli I, Basso S, Pavone P, Falsaperla R, Ciccone R, Cerbo RM, Stronati M, Picard C, Zuffardi O, Abel L, Chaussabel D, Marr N, Li X, Casanova JL, Puel A

Abstract
Most members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) families transduce signals via a canonical pathway involving the MyD88 adapter and the interleukin-1 receptor-associated kinase (IRAK) complex. This complex contains four molecules, including at least two (IRAK-1 and IRAK-4) active kinases. In mice and humans, deficiencies of IRAK-4 or MyD88 abolish most TLR (except for TLR3 and some TLR4) and IL-1R signaling in both leukocytes and fibroblasts. TLR and IL-1R responses are weak but not abolished in mice lacking IRAK-1, whereas the role of IRAK-1 in humans remains unclear. We describe here a boy with X-linked MECP2 deficiency-related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1 Like many boys with MECP2 null mutations, this child died very early, at the age of 7 mo. Unlike most IRAK-4- or MyD88-deficient patients, he did not suffer from invasive bacterial diseases during his short life. The IRAK-1 protein was completely absent from the patient’s fibroblasts, which responded very poorly to all TLR2/6 (PAM2CSK4, LTA, FSL-1), TLR1/2 (PAM3CSK4), and TLR4 (LPS, MPLA) agonists tested but had almost unimpaired responses to IL-1β. By contrast, the patient’s peripheral blood mononuclear cells responded normally to all TLR1/2, TLR2/6, TLR4, TLR7, and TLR8 (R848) agonists tested, and to IL-1β. The death of this child precluded long-term evaluations of the clinical consequences of inherited IRAK-1 deficiency. However, these findings suggest that human IRAK-1 is essential downstream from TLRs but not IL-1Rs in fibroblasts, whereas it plays a redundant role downstream from both TLRs and IL-1Rs in leukocytes.

PMID: 28069966 [PubMed – as supplied by publisher]

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Current Knowledge and Priorities for Future Research in Late Effects after Hematopoietic Stem Cell Transplantation (HCT) for Severe Combined Immunodeficiency Patients: A Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric HCT.

Biol Blood Marrow Transplant. 2017 Jan 06;:

Authors: Heimall J, Puck J, Buckley R, Fleisher TA, Gennery AR, Neven B, Slatter M, Haddad E, Notarangelo LD, Baker KS, Dietz AC, Duncan C, Pulsipher MA, Cowan MJ

Abstract
Severe combined immunodeficiency (SCID) is 1 of the most common indications for pediatric hematopoietic cell transplantation (HCT) in patients with primary immunodeficiency. Historically, SCID was diagnosed in infants who presented with opportunistic infections within the first year of life. With newborn screening (NBS) for SCID in most of the United States, the majority of infants with SCID are now diagnosed and treated in the first 3.5 months of life; however, in the rest of the world, the lack of NBS means that most infants with SCID still present with infections. The average survival for SCID patients who have undergone transplantation currently is >70% at 3 years after transplantation, although this can vary significantly based on multiple factors, including age and infection status at the time of transplantation, type of donor source utilized, manipulation of graft before transplantation, graft-versus-host disease prophylaxis, type of conditioning (if any) utilized, and underlying genotype of SCID. In at least 1 study of SCID patients who received no conditioning, long-term survival was 77% at 8.7 years (range out to 26 years) after transplantation. Although a majority of patients with SCID will engraft T cells without any conditioning therapy, depending on genotype, donor source, HLA match, and presence of circulating maternal cells, a sizable percentage of these will fail to achieve full immune reconstitution. Without conditioning, T cell reconstitution typically occurs, although not always fully, whereas B cell engraftment does not, leaving some molecular types of SCID patients with intrinsically defective B cells, in most cases, dependent on regular infusions of immunoglobulin. Because of this, many centers have used conditioning with alkylating agents including busulfan or melphalan known to open marrow niches in attempts to achieve B cell reconstitution. Thus, it is imperative that we understand the potential late effects of these agents in this patient population. There are also nonimmunologic risks associated with HCT for SCID that appear to be dependent upon the genotype of the patient. In this report, we have evaluated the published data on late effects and attempted to summarize the known risks associated with conditioning and alternative donor sources. These data, while informative, are also a clear demonstration that there is still much to be learned from the SCID population in terms of their post-HCT outcomes. This paper will summarize current findings and recommend further research in areas considered high priority. Specific guidelines regarding a recommended approach to long-term follow-up, including laboratory and clinical monitoring, will be forthcoming in a subsequent paper.

PMID: 28068510 [PubMed – as supplied by publisher]

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Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies.

Nat Med. 2017 Jan 09;:

Authors: Herold N, Rudd SG, Ljungblad L, Sanjiv K, Myrberg IH, Paulin CB, Heshmati Y, Hagenkort A, Kutzner J, Page BD, Calderón-Montaño JM, Loseva O, Jemth AS, Bulli L, Axelsson H, Tesi B, Valerie NC, Höglund A, Bladh J, Wiita E, Sundin M, Uhlin M, Rassidakis G, Heyman M, Tamm KP, Warpman-Berglund U, Walfridsson J, Lehmann S, Grandér D, Lundbäck T, Kogner P, Henter JI, Helleday T, Schaller T

Abstract
The cytostatic deoxycytidine analog cytarabine (ara-C) is the most active agent available against acute myelogenous leukemia (AML). Together with anthracyclines, ara-C forms the backbone of AML treatment for children and adults. In AML, both the cytotoxicity of ara-C in vitro and the clinical response to ara-C therapy are correlated with the ability of AML blasts to accumulate the active metabolite ara-C triphosphate (ara-CTP), which causes DNA damage through perturbation of DNA synthesis. Differences in expression levels of known transporters or metabolic enzymes relevant to ara-C only partially account for patient-specific differential ara-CTP accumulation in AML blasts and response to ara-C treatment. Here we demonstrate that the deoxynucleoside triphosphate (dNTP) triphosphohydrolase SAM domain and HD domain 1 (SAMHD1) promotes the detoxification of intracellular ara-CTP pools. Recombinant SAMHD1 exhibited ara-CTPase activity in vitro, and cells in which SAMHD1 expression was transiently reduced by treatment with the simian immunodeficiency virus (SIV) protein Vpx were dramatically more sensitive to ara-C-induced cytotoxicity. CRISPR-Cas9-mediated disruption of the gene encoding SAMHD1 sensitized cells to ara-C, and this sensitivity could be abrogated by ectopic expression of wild-type (WT), but not dNTPase-deficient, SAMHD1. Mouse models of AML lacking SAMHD1 were hypersensitive to ara-C, and treatment ex vivo with Vpx sensitized primary patient-derived AML blasts to ara-C. Finally, we identified SAMHD1 as a risk factor in cohorts of both pediatric and adult patients with de novo AML who received ara-C treatment. Thus, SAMHD1 expression levels dictate patient sensitivity to ara-C, providing proof-of-concept that the targeting of SAMHD1 by Vpx could be an attractive therapeutic strategy for potentiating ara-C efficacy in hematological malignancies.

PMID: 28067901 [PubMed – as supplied by publisher]

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Construction and Validation of a Novel Disease-Specific Quality of Life Instrument for Patients with Primary Antibody Deficiency Disease (PADQOL -16).

J Allergy Clin Immunol. 2017 Jan 05;:

Authors: Ballow M, Conaway MR, Sriaroon P, Rachid RA, Seeborg FO, Duff CM, Bonilla FA, Younger ME, Shapiro R, Burns TM

Abstract
A disease-specific Health-related Quality of Life survey was developed for adult patients with antibody immune deficiency disorders as a tool (PADQOL-16) for assessing a patient’s QOL issues and their relation to clinical status.

PMID: 28065678 [PubMed – as supplied by publisher]

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Detection of phosphoglucomutase-3 (PGM3) deficiency by lectin-based flow cytometry.

J Allergy Clin Immunol. 2017 Jan 04;:

Authors: Carlson RJ, Bond MR, Hutchins S, Brown Y, Wolfe LA, Lam C, Nelson C, DiMaggio T, Jones N, Rosenzweig SD, Stone KD, Freeman AF, Holland SM, Hanover JA, Milner JD, Lyons JJ

Abstract
Lectin-based flow cytometry using L-PHA provides a method to screen for PGM3 deficiency.

PMID: 28063873 [PubMed – as supplied by publisher]

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Fatal fungal endocarditis in a patient with primary antibody deficiency.

J Clin Pathol. 2017 Jan 06;:

Authors: Wong GK, King LZ, Stephens M, Huissoon AP

PMID: 28062657 [PubMed – as supplied by publisher]

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Oral Manifestations of Job’s Syndrome in a Paediatric Dental Patient – A Case Report.

J Clin Diagn Res. 2016 Nov;10(11):ZD04-ZD05

Authors: James J, Thekkeveetil AK, Vadakkepurayil K

Abstract
Job’s syndrome or Hyperimmunoglobulin E Syndrome (HIES) is a rare primary immunodeficiency with marked increase in serum immunoglobulin E (IgE) levels and eczematous dermatitis. Individuals with HIES share characteristic facial features, with many oral manifestations like retained deciduous teeth, fissured tongue, missing permanent tooth buds, recurrent oral candidiasis, oral mucosal and gingival lesions. Two forms of disease have been identified based on the defective gene as autosomal dominant form and autosomal recessive form. The therapeutic strategies are usually directed towards prevention and management of recurrent infections which are refractory to the conventional strategies. About 200 cases of HIES have been reported so far, in the present case report authors present the oral manifestations of a paediatric dental patient affected with HIES.

PMID: 28050511 [PubMed]

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Update on the use of immunoglobulin in human disease: A review of evidence.

J Allergy Clin Immunol. 2016 Dec 24;:

Authors: Perez EE, Orange JS, Bonilla F, Chinen J, Chinn IK, Dorsey M, El-Gamal Y, Harville TO, Hossny E, Mazer B, Nelson R, Secord E, Jordan SC, Stiehm ER, Vo AA, Ballow M

Abstract
Human immunoglobulin preparations for intravenous or subcutaneous administration are the cornerstone of treatment in patients with primary immunodeficiency diseases affecting the humoral immune system. Intravenous preparations have a number of important uses in the treatment of other diseases in humans as well, some for which acceptable treatment alternatives do not exist. We provide an update of the evidence-based guideline on immunoglobulin therapy, last published in 2006. Given the potential risks and inherent scarcity of human immunoglobulin, careful consideration of its indications and administration is warranted.

PMID: 28041678 [PubMed – as supplied by publisher]

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