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Clinical and Immunological Phenotype of Patients With Primary Immunodeficiency Due to Damaging Mutations in NFKB2.

April 4, 2019 By Manish Butte

Clinical and Immunological Phenotype of Patients With Primary Immunodeficiency Due to Damaging Mutations in NFKB2.

Front Immunol. 2019;10:297

Authors: Klemann C, Camacho-Ordonez N, Yang L, Eskandarian Z, Rojas-Restrepo JL, Frede N, Bulashevska A, Heeg M, Al-Ddafari MS, Premm J, Seidl M, Ammann S, Sherkat R, Radhakrishnan N, Warnatz K, Unger S, Kobbe R, Hüfner A, Leahy TR, Ip W, Burns SO, Fliegauf M, Grimbacher B

Abstract
Non-canonical NF-κB-pathway signaling is integral in immunoregulation. Heterozygous mutations in NFKB2 have recently been established as a molecular cause of common variable immunodeficiency (CVID) and DAVID-syndrome, a rare condition combining deficiency of anterior pituitary hormone with CVID. Here, we investigate 15 previously unreported patients with primary immunodeficiency (PID) from eleven unrelated families with heterozygous NFKB2-mutations including eight patients with the common p.Arg853* nonsense mutation and five patients harboring unique novel C-terminal truncating mutations. In addition, we describe the clinical phenotype of two patients with proximal truncating mutations. Cohort analysis extended to all 35 previously published NFKB2-cases revealed occurrence of early-onset PID in 46/50 patients (mean age of onset 5.9 years, median 4.0 years). ACTH-deficiency occurred in 44%. Three mutation carriers have deceased, four developed malignancies. Only two mutation carriers were clinically asymptomatic. In contrast to typical CVID, most patients suffered from early-onset and severe disease manifestations, including clinical signs of T cell dysfunction e.g., chronic-viral or opportunistic infections. In addition, 80% of patients suffered from (predominately T cell mediated) autoimmune (AI) phenomena (alopecia > various lymphocytic organ-infiltration > diarrhea > arthritis > AI-cytopenia). Unlike in other forms of CVID, auto-antibodies or lymphoproliferation were not common hallmarks of disease. Immunophenotyping showed largely normal or even increased quantities of naïve and memory CD4+ or CD8+ T-cells and normal T-cell proliferation. NK-cell number and function were also normal. In contrast, impaired B-cell differentiation and hypogammaglobinemia were consistent features of NFKB2-associated disease. In addition, an array of lymphocyte subpopulations, such as regulatory T cell, Th17-, cTFH-, NKT-, and MAIT-cell numbers were decreased. We conclude that heterozygous damaging mutations in NFKB2 represent a distinct PID entity exceeding the usual clinical spectrum of CVID. Impairment of the non-canonical NF-κB pathways affects function and differentiation of numerous lymphocyte-subpopulations and thus causes a heterogeneous, more severe form of PID phenotype with early-onset. Further characteristic features are multifaceted, primarily T cell-mediated autoimmunity, such as alopecia, lymphocytic organ infiltration, and in addition frequently ACTH-deficiency.

PMID: 30941118 [PubMed – in process]

Asthma: An Undermined State of Immunodeficiency.

April 3, 2019 By Manish Butte

Asthma: An Undermined State of Immunodeficiency.

Int Rev Immunol. 2019 Apr 02;:1-9

Authors: Christou EAA, Giardino G, Stefanaki E, Ladomenou F

Abstract
Asthma is a heterogeneous chronic respiratory disease characterized by an increased burden of infections. Respiratory tract infections associated with an increased risk for asthma especially when occurring in the first months of life, also represent the most common cause of asthma exacerbations. The association between asthma and the increased frequency of infections and microbiota dysbiosis might be explained by a common mechanism, such as an underlying immune system defect. Apart from the well-established association between primary immunodeficiencies and asthma, several alterations in the immune response following infection have also been observed in asthmatic patients. An impairment in lung epithelial barrier integrity exists and is associated with both an increased susceptibility to infections and the development of asthma. Asthmatic patients are also found to have a deficient interferon (IFN) response upon infection. Additionally, defects in Toll-like receptor (TLR) signaling are observed in asthma and are correlated with both recurrent infections and asthma development. In this review, we summarize the common pathophysiological background of asthma and infections, highlighting the importance of an underlying immune system defect that predispose individuals to recurrent infections and asthma.

PMID: 30939053 [PubMed – as supplied by publisher]

Calculation of a Primary Immunodeficiency “Risk Vital Sign” via Population-Wide Analysis of Claims Data to Aid in Clinical Decision Support.

April 3, 2019 By Manish Butte

Calculation of a Primary Immunodeficiency “Risk Vital Sign” via Population-Wide Analysis of Claims Data to Aid in Clinical Decision Support.

Front Pediatr. 2019;7:70

Authors: Rider NL, Miao D, Dodds M, Modell V, Modell F, Quinn J, Schwarzwald H, Orange JS

Abstract
Background: Early diagnosis of primary immunodeficiency disease leads to reductions in illness and decreased healthcare costs. Analysis of electronic health record data may allow for identification of persons at risk of host-defense impairments from within the general population. Our hypothesis was that coded infection history would inform individual risk of disease and ultimately lead to diagnosis. Methods: In this study we assessed individual risk for primary immunodeficiency by analyzing diagnostic codes and pharmacy records from members (n = 185,892) of a large pediatric health network. Relevant infection-associated diagnostic codes were weighted and enumerated for individual members allowing for risk score calculations (“Risk Vital Sign”). At-risk individuals underwent further assessment by chart review and re-analysis of diagnostic codes 12 months later. Results: Of the original cohort, 2188 (1.2%) individuals were identified as medium-high-risk for having a primary immunodeficiency. This group included 41 subjects who were ultimately diagnosed with primary immunodeficiency. An additional 57 medium-high risk patients had coded diagnoses worthy of referral. Conclusions: Population-wide informatics approaches can facilitate disease detection and improve outcomes. Early identification of the 98 patients with confirmed or suspected primary immunodeficiency described here could represent an annual cost savings of up to $7.7 million US Dollars.

PMID: 30937298 [PubMed]

X-linked agammaglobulinemia (XLA):Phenotype, diagnosis, and therapeutic challenges around the world.

April 3, 2019 By Manish Butte

X-linked agammaglobulinemia (XLA):Phenotype, diagnosis, and therapeutic challenges around the world.

World Allergy Organ J. 2019;12(3):100018

Authors: El-Sayed ZA, Abramova I, Aldave JC, Al-Herz W, Bezrodnik L, Boukari R, Bousfiha AA, Cancrini C, Condino-Neto A, Dbaibo G, Derfalvi B, Dogu F, Edgar JDM, Eley B, El-Owaidy RH, Espinosa-Padilla SE, Galal N, Haerynck F, Hanna-Wakim R, Hossny E, Ikinciogullari A, Kamal E, Kanegane H, Kechout N, Lau YL, Morio T, Moschese V, Neves JF, Ouederni M, Paganelli R, Paris K, Pignata C, Plebani A, Qamar FN, Qureshi S, Radhakrishnan N, Rezaei N, Rosario N, Routes J, Sanchez B, Sediva A, Seppanen MR, Serrano EG, Shcherbina A, Singh S, Siniah S, Spadaro G, Tang M, Vinet AM, Volokha A, Sullivan KE

Abstract
Background: X-linked agammaglobulinemia is an inherited immunodeficiency recognized since 1952. In spite of seven decades of experience, there is still a limited understanding of regional differences in presentation and complications. This study was designed by the Primary Immunodeficiencies Committee of the World Allergy Organization to better understand regional needs, challenges and unique patient features.
Methods: A survey instrument was designed by the Primary Immunodeficiencies Committee of the World Allergy Organization to collect both structured and semi-structured data on X-linked agammaglobulinemia. The survey was sent to 54 centers around the world chosen on the basis of World Allergy Organization participation and/or registration in the European Society for Immunodeficiencies. There were 40 centers that responded, comprising 32 countries.
Results: This study reports on 783 patients from 40 centers around the world. Problems with diagnosis are highlighted by the reported delays in diagnosis>24 months in 34% of patients and the lack of genetic studies in 39% of centers Two infections exhibited regional variation. Vaccine-associated paralytic poliomyelitis was seen only in countries with live polio vaccination and two centers reported mycobacteria. High rates of morbidity were reported. Acute and chronic lung diseases accounted for 41% of the deaths. Unusual complications such as inflammatory bowel disease and large granular lymphocyte disease, among others were specifically enumerated, and while individually uncommon, they were collectively seen in 20.3% of patients. These data suggest that a broad range of both inflammatory, infectious, and autoimmune conditions can occur in patients. The breadth of complications and lack of data on management subsequently appeared as a significant challenge reported by centers. Survival above 20 years of age was lowest in Africa (22%) and reached above 70% in Australia, Europe and the Americas. Centers were asked to report their challenges and responses (n = 116) emphasized the difficulties in access to immunoglobulin products (16%) and reflected the ongoing need for education of both patients and referring physicians.
Conclusions: This is the largest study of patients with X-linked agammaglobulinemia and emphasizes the continued morbidity and mortality of XLA despite progress in diagnosis and treatment. It presents a world view of the successes and challenges for patients and physicians alike. A pivotal finding is the need for education of physicians regarding typical symptoms suggesting a possible diagnosis of X-linked agammaglobulinemia and sharing of best practices for the less common complications.

PMID: 30937141 [PubMed]

Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC.

April 3, 2019 By Manish Butte

Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC.

Front Immunol. 2019;10:479

Authors: Oda H, Beck DB, Kuehn HS, Sampaio Moura N, Hoffmann P, Ibarra M, Stoddard J, Tsai WL, Gutierrez-Cruz G, Gadina M, Rosenzweig SD, Kastner DL, Notarangelo LD, Aksentijevich I

Abstract
Background: HOIP is the catalytic subunit of the linear ubiquitination chain assembly complex (LUBAC) that is essential for NF-κB signaling and thus proper innate and adaptive immunity. To date only one patient with HOIP deficiency has been reported with clinical characteristics that include autoinflammation, immunodeficiency, amylopectinosis, and systemic lymphangiectasia. Case: We sought to identify a genetic cause of a disease for an 8 year-old girl who presented with early-onset immune deficiency and autoinflammation. Methods: Targeted next generation sequencing of 352 immune-related genes was performed. Functional studies included transcriptome analysis, cytokine profiling, and protein analysis in patients’ primary cells. Results: We identified biallelic variants in close proximity to splice sites (c.1197G>C and c.1737+3A>G) in the RNF31 gene. RNA extracted from patient cells showed alternatively spliced transcripts not present in control cells. Protein expression of HOIP and LUBAC was reduced in primary cells as shown by western blotting. Patient-derived fibroblasts demonstrated attenuated IL-6 production, while PBMCs showed higher TNF production after stimulation with proinflammatory cytokines. RNA sequencing of whole blood RNA and PBMCs demonstrated a marked transcriptome wide change including differential expression of type I interferon regulated genes. Conclusion: We report the second case of HOIP deficiency with novel compound heterozygous mutations in RNF31 and distinct clinical and molecular features. Our results expand on the clinical spectrum of HOIP deficiency and molecular signatures associated with LUBAC deficiency.

PMID: 30936877 [PubMed – in process]

Viral complementation of immunodeficiency confers protection against enteric pathogens via interferon-λ.

April 3, 2019 By Manish Butte

Viral complementation of immunodeficiency confers protection against enteric pathogens via interferon-λ.

Nat Microbiol. 2019 Apr 01;:

Authors: Ingle H, Lee S, Ai T, Orvedahl A, Rodgers R, Zhao G, Sullender M, Peterson ST, Locke M, Liu TC, Yokoyama CC, Sharp B, Schultz-Cherry S, Miner JJ, Baldridge MT

Abstract
Commensal microbes profoundly impact host immunity to enteric viral infections1. We have shown that the bacterial microbiota and host antiviral cytokine interferon-λ (IFN-λ) determine the persistence of murine norovirus in the gut2,3. However, the effects of the virome in modulating enteric infections remain unexplored. Here, we report that murine astrovirus can complement primary immunodeficiency to protect against murine norovirus and rotavirus infections. Protection against infection was horizontally transferable between immunocompromised mouse strains by co-housing and fecal transplantation. Furthermore, protection against enteric pathogens corresponded with the presence of a specific strain of murine astrovirus in the gut, and this complementation of immunodeficiency required IFN-λ signalling in gut epithelial cells. Our study demonstrates that elements of the virome can protect against enteric pathogens in an immunodeficient host.

PMID: 30936486 [PubMed – as supplied by publisher]

Fatal Enteroviral Encephalitis in a Patient with Common Variable Immunodeficiency Harbouring a Novel Mutation in NFKB2.

March 31, 2019 By Manish Butte

Fatal Enteroviral Encephalitis in a Patient with Common Variable Immunodeficiency Harbouring a Novel Mutation in NFKB2.

J Clin Immunol. 2019 Mar 29;:

Authors: Slade CA, McLean C, Scerri T, Giang TB, Megaloudis S, Strathmore A, Tempany JC, Nicholls K, D’Arcy C, Bahlo M, Hodgkin PD, Douglass JA, Bryant VL

Abstract
Common variable immunodeficiency is the most prevalent of the primary immunodeficiency diseases, yet its pathogenesis is largely poorly understood. Of the cases that are monogenic, many arise due to pathogenic variants in NFKB1 and NFKB2. Here, we report enteroviral encephalomyelitis as the cause of a fatal neurodegenerative condition in a patient with a novel heterozygous mutation in NFKB2 (c.2543insG, p.P850Sfs36*) that disrupts non-canonical NF-κB signaling. Investigations of primary and secondary lymphoid tissue demonstrated a complete absence of B cells and germinal centers. Despite multiple negative viral PCR testing of cerebrospinal fluid during her disease progression, post-mortem analysis of cerebral tissue revealed a chronic lymphocytic meningoencephalitis, in the presence of Cocksackie A16 virus, as the cause of death. The clinical features, and progression of disease reported here, demonstrate divergent clinical and immunological phenotypes of individuals within a single family. This is the first reported case of fatal enteroviral encephalomyelitis in a patient with NF-κB2 deficiency and mandates a low threshold for early brain biopsy and the administration of increased immunoglobulin replacement in any patient with a defect in this pathway and deterioration of neurological status.

PMID: 30927119 [PubMed – as supplied by publisher]

The clinical features and prognosis of 100 AIDS-related lymphoma cases.

March 31, 2019 By Manish Butte

The clinical features and prognosis of 100 AIDS-related lymphoma cases.

Sci Rep. 2019 Mar 29;9(1):5381

Authors: Wu D, Chen C, Zhang M, Li Z, Wang S, Shi J, Zhang Y, Yao D, Hu S

Abstract
To improve outcomes and risk assessment, we systematically analyzed the clinical features of patients with acquired immunodeficiency syndrome (AIDS)-related lymphoma (ARL) and identified survival-associated factors. Data were collected from 100 patients diagnosed with ARL at the Henan Provincial Infectious Disease Hospital in China. The progression-free survival (PFS) duration and 2-year overall survival (OS) rate were determined. A multivariate analysis was used to evaluate the associations between survival and the following variables: sex, age, histological subtype, Ann Arbor stage, lactate dehydrogenase (LDH) level, primary site, baseline CD4+ count, use of chemotherapy, and age-adjusted international prognostic index IPI (aaIPI). The timing of combined antiretroviral therapy (cART) relative to chemotherapy was also assessed. The PFS duration and 2-year OS rate were significantly higher in the chemotherapy vs. the non-chemotherapy group (P < 0.001), but did not differ significantly between patients who received chemotherapy before vs. simultaneously as cART (P > 0.05). Age, aaIPI, chemotherapy, LDH level, and the Burkitt/Burkitt-like lymphoma subtype were significant prognostic factors for 2-year OS; the other factors were not associated with prognosis. Our results show that cART plus chemotherapy significantly improves the survival of patients with ARL and identifies several prognostic factors.

PMID: 30926889 [PubMed – in process]

Regulatory T cell features in Chronic Granulomatous Disease.

March 30, 2019 By Manish Butte

Regulatory T cell features in Chronic Granulomatous Disease.

Clin Exp Immunol. 2019 Mar 29;:

Authors: van de Geer A, Cuadrado E, Slot MC, van Bruggen R, Amsen D, Kuijpers TW

Abstract
Chronic Granulomatous Disease (CGD) is a primary immunodeficiency caused by mutations in any of the genes encoding the phagocyte NADPH oxidase system, responsible for the production of reactive oxygen species (ROS). CGD is marked by invasive bacterial and fungal infections and by auto-inflammation/autoimmunity of which the exact pathophysiology remains elusive. Contributing factors include decreased neutrophil apoptosis, impaired apoptotic neutrophil clearance, increased pro-inflammatory protein expression and reduced ROS-mediated inflammasome dampening. We have explored a fundamentally different potential mechanism: it has been reported that macrophage-mediated induction of regulatory T cells (Tregs) depends on ROS production. We have investigated whether numerical or functional deficiencies exist in Tregs of CGD patients. Since the prevalence of auto-inflammation/autoimmunity differs between CGD subtypes, we have also investigated Tregs from gp91phox -, p47phox – and p40phox -deficient CGD patients separately. Results show that Treg numbers and -suppressive capacities are not different in CGD patients compared to healthy controls, with the exception that in gp91phox -deficiency effector Treg (eTreg) numbers are decreased. Expression of Treg markers CD25, ICOS, Helios, CTLA4 and GITR did not provide any clue for differences in Treg functionality or activation state. No correlation was seen between (e)Treg numbers and patients’ clinical phenotype. To conclude, the only difference between Tregs from CGD patients and healthy controls is a decrease in circulating eTregs in gp91phox -deficiency. This group is in terms of auto-inflammation/autoimmunity the most affected. However, upon culture patient-derived Tregs showed a normal phenotype and normal functional suppressor activity. No other findings pointed towards a role for Tregs in CGD-related auto-inflammation/autoimmunity. This article is protected by copyright. All rights reserved.

PMID: 30924925 [PubMed – as supplied by publisher]

Comparison of Zinc Finger Nucleases Versus CRISPR-Specific Nucleases for Genome Editing of the Wiskott-Aldrich Syndrome Locus.

March 29, 2019 By Manish Butte

Comparison of Zinc Finger Nucleases Versus CRISPR-Specific Nucleases for Genome Editing of the Wiskott-Aldrich Syndrome Locus.

Hum Gene Ther. 2018 03;29(3):366-380

Authors: Gutierrez-Guerrero A, Sanchez-Hernandez S, Galvani G, Pinedo-Gomez J, Martin-Guerra R, Sanchez-Gilabert A, Aguilar-González A, Cobo M, Gregory P, Holmes M, Benabdellah K, Martin F

Abstract
Primary immunodeficiencies, including Wiskott-Aldrich syndrome (WAS), are a main target for genome-editing strategies using specific nucleases (SNs) because a small number of corrected hematopoietic stem cells could cure patients. In this work, we have designed various WAS gene-specific CRISPR/Cas9 systems and compared their efficiency and specificity with homodimeric and heterodimeric WAS-specific zinc finger nucleases (ZFNs), using K-562 cells as a cellular model and plasmid nucleofection or integration-deficient lentiviral vectors (IDLVs) for delivery. The various CRISPR/Cas9 and ZFN SNs showed similar efficiency when using plasmid nucleofection for delivery. However, dual IDLVs expressing ZFNs were more efficient than dual IDLVs expressing Cas9 and guide RNA or all-in-one IDLVs, expressing Cas9 and guide RNA in the same vector. The specificity of heterodimeric ZFNs and CRISPR/Cas9, measured by increments in γ-H2AX focus formation in WAS-edited cells, was similar for both, and both outperformed homodimeric ZFNs independently of the delivery system used. Interestingly, we show that delivery of SNs, using IDLVs, is more efficient and less genotoxic than plasmid nucleofection. We also show the similar behavior of heterodimeric ZFNs and CRISPR/Cas9 for homology-directed gene knock-in strategies, with 88 and 83% of the donors inserted in the WAS locus, respectively, whereas when using homodimeric ZFNs only 45% of the insertions were on target. In summary, our data indicate that CRISPR/Cas9 and heterodimeric ZFNs are both good alternatives to further develop SN-based gene therapy strategies for WAS. However, IDLV delivery of WAS-specific heterodimeric ZFNs was the best option of all systems compared in this study.

PMID: 28922955 [PubMed – indexed for MEDLINE]