Research

Novel Combined Immune Deficiency and Radiation Sensitivity Blended Phenotype in an Adult with Biallelic Variations in ZAP70 and RNF168.

Front Immunol. 2017;8:576

Authors: Chinn IK, Sanders RP, Stray-Pedersen A, Coban-Akdemir ZH, Kim VH, Dadi H, Roifman CM, Quigg T, Lupski JR, Orange JS, Hanson IC

Abstract
With the advent of high-throughput genomic sequencing techniques, novel genetic etiologies are being uncovered for previously unexplained Mendelian phenotypes, and the underlying genetic architecture of disease is being unraveled. Although most of these “mendelizing” disease traits represent phenotypes caused by single-gene defects, a percentage of patients have blended phenotypes caused by pathogenic variants in multiple genes. We describe an adult patient with susceptibility to bacterial, herpesviral, and fungal infections. Immunologic defects included CD8(+) T cell lymphopenia, decreased T cell proliferative responses to mitogens, hypogammaglobulinemia, and radiation sensitivity. Whole-exome sequencing revealed compound heterozygous variants in ZAP70. Biallelic mutations in ZAP70 are known to produce a spectrum of immune deficiency that includes the T cell abnormalities observed in this patient. Analyses for variants in genes associated with radiation sensitivity identified the presence of a homozygous RNF168 variant of unknown significance. RNF168 deficiency causes radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties syndrome and may account for the radiation sensitivity. Thus, the patient was found to have a novel blended phenotype associated with multilocus genomic variation: i.e., separate and distinct genetic defects. These findings further illustrate the clinical utility of applying genomic testing in patients with primary immunodeficiency diseases.

PMID: 28603521 [PubMed – in process]

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CMCD: Chronic Mucocutaneous Candidiasis Disease.

Nihon Rinsho Meneki Gakkai Kaishi. 2017;40(2):109-117

Authors: Okada S

Abstract
  Chronic mucocutaneous candidiasis (CMC) is an infectious phenotype which is characterized by recurrent or persistent infections affecting the nails, skin, and oral and genital mucosae caused by Candida species. Th17 cells produce interleukin-17 (IL-17) and play an important role in host mucosal immunity to Candida. Recent studies revealed that an impairment of IL-17 immunity underlies development of CMC. CMC disease (CMCD) is a primary immunodeficiency disease which is defined as CMC in patients in the absence of other prominent clinical signs. However, this definition is not strict. Thus, CMCD is currently used to refer to patients presenting with CMC as the main clinical phenotype. As well as CMCD, CMC is a major infectious phenotype in syndromic CMC. However, patients with syndromic CMC also present other clinical and infectious manifestations in addition to CMC. The genetic defects which affect development and/or proliferation of Th17 cells have been identified in patients with syndromic CMC. In contrast, germline mutations in the genes which directly involved in IL-17 signaling have been identified in patients with CMCD. Here, we review current knowledge of IL-17-signaling defects and the genetic etiologies of CMCD and syndromic CMC.

PMID: 28603201 [PubMed – in process]

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Hematopoietic stem cell transplantation in patients with Gain of Function STAT1 Mutation.

J Allergy Clin Immunol. 2017 Jun 07;:

Authors: Leiding JW, Okada S, Hagin D, Abinun M, Shcherbina A, Balashov DN, Kim VHD, Ovadia A, Guthery SL, Pulsipher M, Lilic D, Devlin LA, Christie S, Depner M, Fuchs S, van Royen-Kerkhof A, Lindemans C, Petrovic A, Sullivan KE, Bunin N, Kilic SS, Arpaci F, Calle-Martin O, Martinez-Martinez L, Aldave JC, Kobayashi M, Ohkawa T, Imai K, Iguchi A, Roifman CM, Gennery AR, Slatter M, Ochs HD, Morio T, Torgerson TR, Inborn Errors Working Party of EBMT and the PIDTC

Abstract
BACKGROUND: Gain of function mutations in signal transducer and activator of transcription 1 (GOF-STAT1) cause a susceptibility to a range of infections, autoimmunity, immune dysregulation, and combined immunodeficiency. Disease manifestations can be mild or severe and life threatening. Hematopoietic stem cell transplantation (HSCT) has been utilized in some patients with more severe symptoms to treat and cure the disorder. The outcome of HSCT for this disorder is, however, not well established.
OBJECTIVE: To aggregate the worldwide experience of HSCT in GOF-STAT1 patients and to assess outcomes including donor engraftment, overall survival, graft versus host disease, and transplant related complications.
METHODS: Data were collected from an international cohort of 15 GOF-STAT1 patients that had undergone HSCT using a variety of conditioning regimens and donor sources. Retrospective data collection allowed the outcome of transplantation to be assessed. In vitro functional testing was performed to confirm that each of the identified STAT1 variants was, in-fact, a gain of function mutation.
RESULTS: Primary donor engraftment in this cohort of 15 GOF-STAT1 patients was 74% and overall survival was only 40%. Secondary graft failure was common (50%) and post-transplant event free survival was poor (10% by 100 days). A subset of patients developed hemophagocytic lymphohistiocytosis (HLH) prior to their transplant, contributing to their poor outcomes.
CONCLUSION: Our data indicate that HSCT for patients with GOF-STAT1 mutations is curative but has significant risk of secondary graft failure and death.

PMID: 28601685 [PubMed – as supplied by publisher]

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Flow cytometric measurement of STAT1 and STAT3 phosphorylation in CD4(+) and CD8(+) T cells – Clinical applications in PID diagnostics.

J Allergy Clin Immunol. 2017 Jun 07;:

Authors: Bitar M, Boldt A, Binder S, Borte M, Kentouche K, Borte S, Sack U

Abstract
Flow cytometry-based pSTAT1 and pSTAT3 profiling is an effective diagnostic tool to identify PID patients with aberrations in the STAT1 or STAT3 gene.

PMID: 28601682 [PubMed – as supplied by publisher]

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A novel pathogenic frameshift variant of CD3E gene in two T-B+ NK+ SCID patients from Turkey.

Immunogenetics. 2017 Jun 09;:

Authors: Firtina S, Ng YY, Ng OH, Nepesov S, Yesilbas O, Kilercik M, Burtecene N, Cinar S, Camcioglu Y, Ozbek U, Sayitoglu M

Abstract
Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency, which is characterized by the dysfunction and/or absence of T lymphocytes. Early diagnosis of SCID is crucial for overall survival, and if it remains untreated, SCID is often fatal. Next-generation sequencing (NGS) has become a rapid, high-throughput technology, and has already been proven to be beneficial in medical diagnostics. In this study, a targeted NGS panel was developed to identify the genetic variations of SCID by using SmartChip-TE technology, and a novel pathogenic frameshift variant was found in the CD3E gene. Sanger sequencing has confirmed the segregation of the variant among patients. We found a novel deletion in the CD3E gene (NM000733.3:p.L58Hfs*9) in two T-B+ NK+ patients. The variant was not found in the databases of dbSNP, ExAC, and 1000G. One sibling in family I was homozygous and the rest of the family members were heterozygous for this variant. T cell receptor excision circle (TREC) and kappa-deleting recombination excision circle (KREC) analyses were performed for T and B cell maturation. TRECs were not detected in both patients and the KREC copy numbers were similar to the other family members. In addition, heterozygous family members showed decreased TREC levels when compared with the wild-type sibling, indicating that carrying this variant in one allele does not cause immunodeficiency, but does effect T cell proliferation. Here, we report a novel pathogenic frameshift variant in CD3E gene by using targeted NGS panel.

PMID: 28597365 [PubMed – as supplied by publisher]

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Quality of Life, Treatment Beliefs, and Treatment Satisfaction in Children Treated for Primary Immunodeficiency with SCIg.

J Clin Immunol. 2017 Jun 08;:

Authors: Sultan S, Rondeau É, Levasseur MC, Dicaire R, Decaluwe H, Haddad É

Abstract
Despite the development of subcutaneous treatment, children and adolescents with primary immunodeficiency (PID) are vulnerable to a lower quality of life (QoL) than non-clinical participants. Comparisons have been offered in rare reports with limited sample sizes. No description is available of treatment beliefs and treatment satisfaction with standard tools. The objective of this study was to describe a large sample of patients with pediatric PID on QoL, treatment beliefs and satisfaction, and identify perceived benefits and issues of treatment both in children and parents. A mail-back survey was conducted in 60 patients with PID treated with subcutaneous Ig and their parents from a clinic in Montreal (QC, Canada). We used the standardized tools to assess for QoL levels, beliefs of necessity and concerns with treatment, and dimensions of satisfaction. We collected and coded perceived benefits and issues through open-ended questions. We found lower QoL in children with PID than in healthy non-clinical participants (median d = 0.40) and similar QoL levels to children with cancer (median d = 0.12). Participants considered their treatment as less necessary and able to control the illness and less convenient than patients with other conditions. Children were more prone to consider the treatment as convenient (69 vs. 47% p = .028) but reported more discomfort (24 vs. 10% p = .043) than parents. Results suggest a lower-than-expected QoL in pediatric PID. Aspects of the illness and treatment are probably unclear to patients and their families, as necessity beliefs were lower than expected. Educational strategies should be developed and assessed to address this issue.

PMID: 28597145 [PubMed – as supplied by publisher]

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Multicolor Flow Cytometry for the Diagnosis of Primary Immunodeficiency Diseases.

J Clin Immunol. 2017 Jun 08;:

Authors: Takashima T, Okamura M, Yeh TW, Okano T, Yamashita M, Tanaka K, Hoshino A, Mitsuiki N, Takagi M, Ishii E, Imai K, Kanegane H, Morio T

Abstract
PURPOSE: Primary immunodeficiency diseases (PIDDs) are rare inherited diseases that impair the human immune system. We established a multicolor flow cytometric assay to comprehensively evaluate the immune status and immunological characteristics of patients with PIDDs.
METHODS: Fifty-nine normal controls and 75 patients with PIDDs, including X-linked severe combined immunodeficiency (X-SCID), X-linked agammaglobulinemia (XLA), X-linked hyper IgM syndrome (X-HIGM), ataxia telangiectasia (AT), Wiskott-Aldrich syndrome (WAS), hyper IgE syndrome (HIES), and chronic mucocutaneous candidiasis disease (CMCD), were enrolled in this study. Immunophenotyes were evaluated by multicolor flow cytometry using seven different panels that allowed the detection of major leukocyte populations in peripheral blood.
RESULTS: Multicolor flow cytometry revealed distinct leukocyte populations and immunological features of patients with X-SCID, XLA, X-HIGM, AT, WAS, HIES, and CMCD.
CONCLUSIONS: Immunophenotyping by multicolor flow cytometry is useful to evaluate immune status and contributes to the diagnosis and management of patients with PIDDs.

PMID: 28597144 [PubMed – as supplied by publisher]

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[Primary immunodeficiency diseases with eosinophilia].

Zhonghua Er Ke Za Zhi. 2017 Jun 02;55(6):478-480

Authors: Ding JQ, Hou J, Wang XM

PMID: 28592021 [PubMed – in process]

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The Use of Salmonella Typhim Vaccine to Diagnose Antibody Deficiency.

J Clin Immunol. 2017 Jun 07;:

Authors: Bausch-Jurken MT, Verbsky JW, Gonzaga KA, Elms NP, Hintermeyer MK, Gauld SB, Routes JM

Abstract
PURPOSE: The specific antibody response to the unconjugated 23-valent pneumococcal polysaccharide vaccine is one of the most common tests used to assess for possible humoral immunodeficiency. The results can be difficult to interpret because most people have been immunized with one or more of the pneumococcal vaccines and there is controversy regarding what constitutes a normal response. To circumvent this problem, we developed an ELISA to measure IgG-specific antibodies to the Salmonella Vi Typhim (S. Typhim) vaccine, a pure polysaccharide vaccine, which is a neoantigen for the vast majority of people in the USA.
METHODS: We compared the pre- and post-vaccination serum titers to the Vi Typhim vaccine in healthy controls (n = 22), patients previously diagnosed with a primary immunodeficiency (n = 30), and patients referred for possible humoral immune deficiency (n = 29). We also determined if the S. Typhim vaccine could be used to assess specific antibody responses in people on antibody replacement therapy.
RESULTS: Following immunization with the S. Typhim vaccine, we found that a 2-fold increase in titers is 100% sensitive and specific in detecting known humoral immune deficiencies as determined by ROC curve analysis. This cut-off value was successfully applied to possible immune deficiency patients (n = 29), resulting in the diagnosis of seven subjects with humoral immunodeficiency. The use of immunoglobulin replacement therapy did not affect the median response ratios compared to subjects not receiving gammaglobulin.
CONCLUSION: This study suggests that measurement of the specific antibody response to the S. Typhim vaccine may have advantages over pneumococcal vaccination in the evaluation of the humoral immune response.

PMID: 28589420 [PubMed – as supplied by publisher]

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