Research

Systems Approach to Uncover Signaling Networks in Primary Immunodeficiency Diseases.

J Allergy Clin Immunol. 2017 Apr 12;:

Authors: Choi J, Fernandez R, Maecker HT, Butte MJ

Abstract
CAPSULE SUMMARY: This broad, unbiased approach of studying signaling across all circulating immune cells in healthy subjects allowed identification of disrupted signaling networks in patients with primary immunodeficiencies.

PMID: 28412396 [PubMed – as supplied by publisher]

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Hematopoietic Stem Cell Transplant for a New Primary Immunodeficiency Disorder: a Voyage Where No Transplant Physician Has Gone before.

Biol Blood Marrow Transplant. 2017 Apr 11;:

Authors: Connelly JA

PMID: 28411176 [PubMed – as supplied by publisher]

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Acute kidney injury in symptomatic primary Epstein-Barr virus infectious mononucleosis: Systematic review.

J Clin Virol. 2017 Mar 21;91:12-17

Authors: Moretti M, Lava SAG, Zgraggen L, Simonetti GD, Kottanattu L, Bianchetti MG, Milani GP

Abstract
BACKGROUND AND OBJECTIVES: Textbooks and reviews do not mention the association of symptomatic primary Epstein-Barr virus infectious mononucleosis with acute kidney injury in subjects without immunodeficiency or autoimmunity.
STUDY DESIGN: Stimulated by our experience with two cases, we performed a review of the literature.
RESULTS: The literature documents 38 cases (26 male and 12 female individuals ranging in age from 0.3 to 51, median 18 years) of symptomatic primary Epstein-Barr virus infectious mononucleosis complicated by acute kidney injury: 27 acute interstitial nephritides, 1 jaundice-associated nephropathy, 7 myositides and 3 hemolytic uremic syndromes. Acute kidney injury requiring renal replacement therapy was observed in 18 (47%) cases. Acute kidney injury did not resolve in one patient with acute interstitial nephritis. Two patients died because of systemic complications. The remaining 35 cases fully recovered.
CONCLUSIONS: In individuals with acute symptomatic Epstein-Barr virus infectious mononucleosis, a relevant kidney injury is rare but the outcome potentially fatal. It results from interstitial nephritis, myositis-associated acute kidney injury, hemolytic uremic syndrome or jaundice-associated nephropathy.

PMID: 28410496 [PubMed – as supplied by publisher]

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Haematopoietic stem cell transplantation in primary immunodeficiency patients in the Black Sea Region of Turkey.

Turk J Haematol. 2017 Apr 13;:

Authors: Yıldıran A, Çeliksoy MH, Borte S, Güner ŞN, Elli M, Fışgın T, Özyürek E, Sancak R, Oğur G

Abstract
OBJECTIVE: Haematopoietic stem cell transplantation is a promising curative therapy for many combined primary immunodeficiencies and phagocytic disorders.
MATERIALS AND METHODS: We retrospectively reviewed paediatric cases that were diagnosed with primary immunodeficiencies and scheduled for haematopoietic stem cell transplantation.
RESULTS: We identified 22 patients (median age, 6 months; age range, 1 month to 10 years) with various diagnoses who received haematopoietic stem cell transplantation. The patient diagnoses included severe combined immunodeficiency (n=11), Chediak-Higashi syndrome (n=2), leukocyte adhesion deficiency (n=2), MHC class-II deficiency (n=2), chronic granulomatous syndrome (n=2), hemophagocytic lymphohistiocytosis (n=1), Wiskott-Aldrich syndrome (n=1), and Omenn syndrome (n=1). Of the 22 patients, 7 received HLA-matched related haematopoietic stem cell transplantation, 12 received haploidentical haematopoietic stem cell transplantation, and 2 received matched unrelated haematopoietic stem cell transplantation. The results showed that 5 patients had graft failure. Fourteen patients survived, yielding an overall survival rate of 67%.
CONCLUSIONS: Screening newborn infants for primary immunodeficiency diseases may result in timely administration of haematopoietic stem cell transplantation.

PMID: 28404538 [PubMed – as supplied by publisher]

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Immune dysregulation in immunodeficiency disorders: The role of T-cell receptor sequencing.

J Autoimmun. 2017 Apr 08;:

Authors: Wong GK, Heather JM, Barmettler S, Cobbold M

Abstract
Immune dysregulation is a prominent feature of primary immunodeficiency disorders, which commonly manifested as autoimmunity, cytopenias and inflammatory bowel disease. In partial T-cell immunodeficiency disorders, it has been proposed that the imbalance between effector and regulatory T-cells drives the breakdown of peripheral tolerance. While there is no robust test for immune dysregulation, the T-cell receptor repertoire is used as a surrogate marker, and has been shown to be perturbed in a number of immunodeficiency disorders featuring immune dysregulation including Omenn’s Syndrome, Wiskott-Aldrich Syndrome, and common variable immunodeficiency. This review discusses how recent advances in TCR next-generation sequencing and bioinformatics have led to the in-depth characterization of CDR3 sequences and an exponential growth in examinable parameters. Specifically, we highlight the use of junctional diversity as a means to differentiate intrinsic T-cell defects from secondary causes of repertoire perturbation in primary immunodeficiency disorders. However, key questions, such as the identity of antigenic targets for large, expanded T-cell clonotypes, remain unanswered despite the fact that such clones are likely to play a pathogenic role in driving immune dysregulation and autoimmunity. Finally, we discuss a number of emerging technologies such as in silico reconstruction, high-throughput pairwise αβ sequencing and single-cell RNAseq that offer the potential to define the antigenic epitope and function of a given T-cell, thereby enhancing our understanding in this field.

PMID: 28400082 [PubMed – as supplied by publisher]

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B-Cell and Classical Hodgkin Lymphomas Associated With Immunodeficiency: 2015 SH/EAHP Workshop Report-Part 2.

Am J Clin Pathol. 2017 Feb 01;147(2):153-170

Authors: de Jong D, Roemer MG, Chan JK, Goodlad J, Gratzinger D, Chadburn A, Jaffe ES, Said J, Natkunam Y

Abstract
Objectives: The 2015 Workshop of the Society for Hematopathology/European Association for Haematopathology submitted small and large B-cell lymphomas (BCLs), including classical Hodgkin lymphoma (CHL), in the context of immunodeficiency.
Methods: Clinicopathologic and molecular features were studied to explore unifying concepts in malignant B-cell proliferations across immunodeficiency settings.
Results: Cases submitted to the workshop spanned small BCLs presenting as nodal or extranodal marginal zone lymphoma and lymphoplasmacytic lymphoma, Epstein-Barr virus (EBV) positive in 75% of cases. Submitted large BCLs formed a spectrum from diffuse large B-cell lymphoma (DLBCL) to CHL across immunodeficiency settings. Additional studies demonstrated overexpression of PD-L1 and molecular 9p24 alterations in the large BCL spectrum and across different immunodeficiency settings.
Conclusions: Small BCLs occur in all immunodeficiency settings, and EBV positivity is essential for their recognition as immunodeficiency related. Large BCLs include a spectrum from DLBCL to CHL across all immunodeficiency settings; immunohistochemical and molecular features are suggestive of shared pathogenetic mechanisms involving PD-L1 immune checkpoints.

PMID: 28395108 [PubMed – in process]

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Primary/Congenital Immunodeficiency: 2015 SH/EAHP Workshop Report-Part 5.

Am J Clin Pathol. 2017 Feb 01;147(2):204-216

Authors: Gratzinger D, Jaffe ES, Chadburn A, Chan JK, de Jong D, Goodlad JR, Said J, Natkunam Y

Abstract
Objectives: The 2015 Workshop of the Society for Hematopathology/European Association for Haematopathology aimed to review primary immunodeficiency and related lymphoproliferations.
Methods: Primary immunodeficiencies were divided into immune dysregulation, DNA repair defects, low immunoglobulins, and combined immunodeficiencies.
Results: Autoimmune lymphoproliferative syndrome (ALPS) is a prototypical immune dysregulation-type immunodeficiency, with defects in T-cell signaling or apoptosis, expansion of T-cell subsets, and predisposition to hemophagocytic lymphohistiocytosis. DNA repair defects directly predispose to malignancy. Low immunoglobulin immunodeficiencies such as common variable immunodeficiency (CVID) have underlying T-cell repertoire abnormalities predisposing to autoimmunity and B-cell lymphoproliferations. The full spectrum of B-cell lymphoproliferative disorders occurs in primary immunodeficiency.
Conclusions: Lymphoproliferations in primary immunodeficiency mirror those in other immunodeficiency settings, with monomorphic B- and sometimes T lymphoproliferative disorders enriched in DNA repair defects. Distinctive T-cell subset expansions in ALPS, CVID, and related entities can mimic lymphoma, and recognition of double-negative T-cell or cytotoxic T-cell expansions is key to avoid overdiagnosis.

PMID: 28395106 [PubMed – in process]

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Outcome of Hematopoietic Cell Transplantation for DNA-Double Strand Breakage Repair Disorders.

J Allergy Clin Immunol. 2017 Apr 06;:

Authors: Slack J, Albert MH, Balashov D, Belohradsky BH, Bertaina A, Bleesing J, Booth C, Büchner J, Buckley RH, Ouachée-Chardin M, Deripapa E, Drabko K, Eapen M, Feuchtinger T, Finocchi A, Gaspar HB, Ghosh S, Gillio A, Gonzalez-Granado LI, Grunebaum E, Güngör T, Heilmann C, Helminen M, Higuchi K, Imai K, Kalwak K, Kanazawa N, Karasu G, Kucuk ZY, Laberko A, Lange A, Mahlaoui N, Meisel R, Moshous D, Muramatsu H, Parikh S, Pasic S, Schmid I, Schuetz C, Schulz A, Schultz KR, Shaw PJ, Slatter MA, Sykora KW, Tamura S, Taskinen M, Wawer A, Wolska-Kus Nierz B, Cowan MJ, Fischer A, Gennery AR, Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation, European Society for Immunodeficiencies, Stem Cell Transplant for Immunodeficiencies in Europe (SCETIDE), the Center for International Blood and Marrow Transplant Research,, Primary Immunodeficiency Treatment Consortium

Abstract
BACKGROUND: Rare DNA breakage-repair disorders predispose to infection and lympho-reticular malignancies. Hematopoietic cell transplantation (HCT) is curative but co-administered chemo- or radio-therapy is damaging due to systemic radio-sensitivity. We collected HCT outcome data for Nijmegen Breakage syndrome (NBS), DNA ligase IV deficiency (LIG4), Cernunnos-XLF deficiency and ataxia-telangiectasia.
METHODS: Data from 38 centres worldwide, including indication, donor, conditioning regimen, graft-versus-host disease (GvHD) and outcome were analyzed. Conditioning was classified as myeloablative (MAC) if it contained radiotherapy or alkylators and reduced intensity (RIC) if no alkylators and/or fludarabine ≤150 mg/m(2) and cyclophosphamide ≤ 40 mg/kg were used.
RESULTS: 55 new, 14 updated and 18 previously published patients were analyzed. Median age at HCT was 48 (range 1.5 – 552) months. 29 were transplanted for infection, 21 malignancy, 13 bone marrow failure, 13 pre-emptively, 5 had multiple indications, and 6 had no information. 22 received MAC, 59 RIC, 4 were infused;- information unavailable for 2. 73/77 patients with LIG4, Cernunnos-XLF deficiency or NBS received conditioning. Survival was 53/77 (69%), worse for MAC than RIC (p=0.006). Most deaths occurred early post-transplant suggesting poor tolerance of conditioning. Survival in ataxia-telangiectasia patients was 25%. 41/83 patients experienced aGvHD (49%): less in RIC compared to MAC, 26/56 (46%) vs 12/21 (57%) (p=0.45). Median follow-up was 35 (range 2-168) months. No secondary malignancies were reported during 15 years follow-up. Growth and developmental delay remained post-HCT; immune-mediated complications resolved.
CONCLUSION: RIC-HCT resolves DNA repair disorder-associated immunodeficiency. Long-term follow-up is required for secondary malignancy surveillance. Routine HCT for ataxia-telangiectasia is not recommended.

PMID: 28392333 [PubMed – as supplied by publisher]

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The case for a national service for primary immune deficiency disorders in New Zealand.

N Z Med J. 2016 Jun 10;129(1436):75-90

Authors: Ameratunga R, Steele R, Jordan A, Preece K, Barker R, Brewerton M, Lindsay K, Sinclair J, Storey P, Woon ST

Abstract
Primary immune deficiency disorders (PIDs) are rare conditions for which effective treatment is available. It is critical these patients are identified at an early stage to prevent unnecessary morbidity and mortality. Treatment of these disorders is expensive and expert evaluation and ongoing management by a clinical immunologist is essential. Until recently there has been a major shortage of clinical immunologists in New Zealand. While the numbers of trained immunologists have increased in recent years, most are located in Auckland. The majority of symptomatic PID patients require life-long immunoglobulin replacement. Currently there is a shortage of subcutaneous and intravenous immunoglobulin (SCIG/IVIG) in New Zealand. A recent audit by the New Zealand Blood Service (NZBS) showed that compliance with indications for SCIG/IVIG treatment was poor in District Health Boards (DHBs) without an immunology service. The NZBS audit has shown that approximately 20% of annual prescriptions for SCIG/IVIG, costing $6M, do not comply with UK or Australian guidelines. Inappropriate use may have contributed to the present shortage of SCIG/IVIG necessitating importation of the product. This is likely to have resulted in a major unnecessary financial burden to each DHB. Here we present the case for a national service responsible for the tertiary care of PID patients and oversight for immunoglobulin use for primary and non-haematological secondary immunodeficiencies. We propose that other PIDs, including hereditary angioedema, are integrated into a national PID service. Ancillary services, including the customised genetic testing service, and research are also an essential component of an integrated national PID service and are described in this review. As we show here, a hub-and-spoke model for a national service for PIDs would result in major cost savings, as well as improved patient care. It would also allow seamless transition from paediatric to adult services.

PMID: 27355232 [PubMed – indexed for MEDLINE]

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Refining strategies to translate genome editing to the clinic.

Nat Med. 2017 Apr 03;23(4):415-423

Authors: Cornu TI, Mussolino C, Cathomen T

Abstract
Recent progress in developing programmable nucleases, such as zinc-finger nucleases, transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeat (CRISPR)-Cas nucleases, have paved the way for gene editing to enter clinical practice. This translation is a result of combining high nuclease activity with high specificity and successfully applying this technology in various preclinical disease models, including infectious disease, primary immunodeficiencies, hemoglobinopathies, hemophilia and muscular dystrophy. Several clinical gene-editing trials, both ex vivo and in vivo, have been initiated in the past 2 years, including studies that aim to knockout genes as well as to add therapeutic transgenes. Here we discuss the advances made in the gene-editing field in recent years, and specify priorities that need to be addressed to expand therapeutic genome editing to further disease entities.

PMID: 28388605 [PubMed – in process]

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