Research

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]

Powered by WPeMatico

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]

Powered by WPeMatico

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]

Powered by WPeMatico

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]

Powered by WPeMatico

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]

Powered by WPeMatico

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]

Powered by WPeMatico

Bronchus Associated Lymphoid Tissue Lymphoma Presenting with Immunodeficiency and Multiple Pulmonary Nodules.

Case Rep Pulmonol. 2017;2017:4804378

Authors: Borekci S, Ozbalak M, Ersen E, Akı H, Cem Ar M, Umut S

Abstract
Bronchus Associated Lymphoid Tissue Lymphoma (BALTOMA) is a rare subgroup of pulmonary non-Hodgkin’s lymphomas (NHLs) comprising less than 1% of all cases. It constitutes 3.6% of all extranodal lymphomas and only 0.5-1% of primary pulmonary malignancies. They are usually low grade B-cell lymphomas and are considered to originate from the mucosa associated lymphoid tissue (MALT) of the bronchi. Here, we represent a rare case of BALTOMA presenting with immunodeficiency and multiple pulmonary nodules.

PMID: 28386504 [PubMed]

Powered by WPeMatico

Host virus and pneumococcus-specific immune responses in high-count monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia: implications for disease progression.

Haematologica. 2017 Apr 06;:

Authors: Criado I, Muñoz-Criado S, Rodríguez-Caballero A, Nieto WG, Romero A, Fernández-Navarro P, Alcoceba M, Contreras T, González M, Orfao A, Almeida J, Primary Health Care Group of Salamanca for the Study of MBL

Abstract
Patients diagnosed with chronic lymphocytic leukemia display a high incidence of infections due to an associated immunodeficiency that includes hypogammaglobulinemia. A higher risk of infections has also been recently reported for high-count monoclonal B-cell lymphocytosis, while no information is available in low-count monoclonal B-cell lymphocytosis. Here, we evaluated the status of the humoral immune system in patients with chronic lymphocytic leukemia (n=58), as well as in low- (n=71) and high-count (n=29) monoclonal B-cell lymphocytosis vs. healthy donors (n=91). Total free plasma immunoglobulin titers and specific levels of antibodies against cytomegalovirus, Epstein-Barr Virus, Influenza and S.pneumoniae were measured by nephelometry and ELISA-based techniques, respectively. Overall, our results show that both chronic lymphocytic leukemia and high-count monoclonal B-cell lymphocytosis patients, but not low-count monoclonal B-cell lymphocytosis subjects, present with relatively high levels of antibodies specific for the latent viruses investigated, associated with progressively lower levels of S.pneumoniae-specific immunoglobulins. These findings probably reflect asymptomatic chronic reactivation of humoral immune responses against host viruses associated with expanded virus-specific antibody levels and progressively decreased protection against other microorganisms, denoting a severe humoral immunodeficiency state not reflected by the overall plasma immunoglobulin levels. Alternatively, these results could reflect a potential role of ubiquitous viruses in the pathogenesis of the disease. Further analyses are necessary to establish the relevance of such asymptomatic humoral immune responses against host viruses in the expansion of the tumor B-cell clone and progression from monoclonal B-cell lymphocytosis to chronic lymphocytic leukemia.

PMID: 28385786 [PubMed – as supplied by publisher]

Powered by WPeMatico

In vitro T lymphocyte proliferation by carboxyfluorescein diacetate succinimidyl ester method is helpful in diagnosing and managing primary immunodeficiencies.

J Clin Lab Anal. 2017 Apr 06;:

Authors: Azarsiz E, Karaca N, Ergun B, Durmuscan M, Kutukculer N, Aksu G

Abstract
BACKGROUND: Functional studies besides routine laboratory tests for the definitive diagnosis of T lymphocyte disorders with isolated T or combined T/B-cell immunodeficiencies are important. We hereby summarized our experience with a carboxyfluorescein diacetate succinimidyl ester (CFSE)-based assay for the assessment of mitogenic T-cell proliferation responses in primary immunodeficiency (PID) patients who have not been diagnosed yet or genetically analyzed, but classified as probably having T-cell defects.
METHODS: Unclassified patients (n=46) and controls (n=25) were evaluated for T-cell disorders with CFSE-based assay.
RESULTS: CD3(+) blast cells after PHA-L stimulation were significantly lower in patients (31.1±28.8) than controls (67.9±8.79; P<.001). Nine patients with low and four patients with normal CD3 values had severely decreased blastic transformation. The proliferation response decreased mostly in combined immunodeficiency group. Sixteen of them had impaired proliferation responses. Appropriate molecular genetical analyses were planned after thorough evaluation of each patient.
CONCLUSIONS: In vitro lymphocyte cell proliferation analysis by CFSE method is a reliable and practical choice for the assessment of mitogenic T lymphocyte responses in yet unclassified PID patients for targeting further genetical analyses.

PMID: 28383134 [PubMed – as supplied by publisher]

Powered by WPeMatico

Treatment of Pediatric Acute Graft-versus-Host Disease-Lessons from Primary Immunodeficiency?

Front Immunol. 2017;8:328

Authors: Flinn AM, Gennery AR

Abstract
Allogeneic hematopoietic stem cell transplant (HSCT) is used to treat increasing numbers of malignant and non-malignant disorders. Despite significant advances in improved human leukocyte antigens-typing techniques, less toxic conditioning regimens and better supportive care, resulting in improved clinical outcomes, acute graft-versus-host disease (aGvHD) continues to be a major obstacle and, although it principally involves the skin, gastrointestinal tract, and liver, the thymus is also a primary target. An important aim following HSCT is to achieve complete and durable immunoreconstitution with a diverse T-cell receptor (TCR) repertoire to recognize a broad range of pathogens providing adequate long-term adaptive T-lymphocyte immunity, essential to reduce the risk of infection, disease relapse, and secondary malignancies. Reconstitution of adaptive T-lymphocyte immunity is a lengthy and complex process which requires a functioning and structurally intact thymus responsible for the production of new naïve T-lymphocytes with a broad TCR repertoire. Damage to the thymic microenvironment, secondary to aGvHD and the effect of corticosteroid treatment, disturbs normal signaling required for thymocyte development, resulting in impaired T-lymphopoiesis and reduced thymic export. Primary immunodeficiencies, in which failure of central or peripheral tolerance is a major feature, because of intrinsic defects in hematopoietic stem cells leading to abnormal T-lymphocyte development, or defects in thymic stroma, can give insights into critical processes important for recovery from aGvHD. Extracorporeal photopheresis is a potential alternative therapy for aGvHD, which acts in an immunomodulatory fashion, through the generation of regulatory T-lymphocytes (Tregs), alteration of cytokine patterns and modulation of dendritic cells. Promoting normal central and peripheral immune tolerance, with selective downregulation of immune stimulation, could reduce aGvHD, and enable a reduction in other immunosuppression, facilitating thymic recovery, restoration of normal T-lymphocyte ontogeny, and complete immunoreconstitution with improved clinical outcome as the ability to fight infections improves and risk of secondary malignancy or relapse diminishes.

PMID: 28377772 [PubMed – in process]

Powered by WPeMatico