Research

Primary immunodeficiences–options for the future.

Pediatr Allergy Immunol. 2014 Feb;25(1):27-9

Authors: Badolato R

PMID: 24588485 [PubMed – indexed for MEDLINE]

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Mitochondrial DNA copy number and future risk of B-cell lymphoma in a nested case-control study in the prospective EPIC cohort.

Blood. 2014 Jul 24;124(4):530-5

Authors: Hosnijeh FS, Lan Q, Rothman N, San Liu C, Cheng WL, Nieters A, Guldberg P, Tjønneland A, Campa D, Martino A, Boeing H, Trichopoulou A, Lagiou P, Trichopoulos D, Krogh V, Tumino R, Panico S, Masala G, Weiderpass E, Huerta Castaño JM, Ardanaz E, Sala N, Dorronsoro M, Quirós JR, Sánchez MJ, Melin B, Johansson AS, Malm J, Borgquist S, Peeters PH, Bueno-de-Mesquita HB, Wareham N, Khaw KT, Travis RC, Brennan P, Siddiq A, Riboli E, Vineis P, Vermeulen R

Abstract
It has been suggested that mitochondrial dysfunction and DNA damage are involved in lymphomagenesis. Increased copy number of mitochondrial DNA (mtDNA) as a compensatory mechanism of mitochondrial dysfunction previously has been associated with B-cell lymphomas, in particular chronic lymphocytic leukemia (CLL). However, current evidence is limited and based on a relatively small number of cases. Using a nested case-control study, we extended these findings with a focus on subtype-specific analyses. Relative mtDNA copy number was measured in the buffy coat of prospectively collected blood of 469 lymphoma cases and 469 matched controls. The association between mtDNA copy number and the risk of developing lymphoma and histologic subtypes was examined using logistic regression models. We found no overall association between mtDNA and risk of lymphoma. Subtype analyses revealed significant increased risks of CLL (n = 102) with increasing mtDNA copy number (odds ratio = 1.34, 1.44, and 1.80 for quartiles 2-4, respectively; P trend = .001). mtDNA copy number was not associated with follow-up time, suggesting that this observation is not strongly influenced by indolent disease status. This study substantially strengthens the evidence that mtDNA copy number is related to risk of CLL and supports the importance of mitochondrial dysfunction as a possible mechanistic pathway in CLL ontogenesis.

PMID: 24899624 [PubMed – indexed for MEDLINE]

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Targeted NGS: A Cost-Effective Approach to Molecular Diagnosis of PIDs.

Front Immunol. 2014;5:531

Authors: Stoddard JL, Niemela JE, Fleisher TA, Rosenzweig SD

Abstract
BACKGROUND: Primary immunodeficiencies (PIDs) are a diverse group of disorders caused by multiple genetic defects. Obtaining a molecular diagnosis for PID patients using a phenotype-based approach is often complex, expensive, and not always successful. Next-generation sequencing (NGS) methods offer an unbiased genotype-based approach, which can facilitate molecular diagnostics.
OBJECTIVE: To develop an efficient NGS method to identify variants in PID-related genes.
METHODS: We performed HaloPlex custom target enrichment and NGS using the Ion Torrent PGM to screen 173 genes in 11 healthy controls, 13 PID patients previously evaluated with either an identified mutation or SNP, and 120 patients with undiagnosed PIDs. Sensitivity and specificity were determined by comparing NGS and Sanger sequencing results for 33 patients. Run metrics and coverage analyses were done to identify systematic deficiencies.
RESULTS: A molecular diagnosis was identified for 18 of 120 patients who previously lacked a genetic diagnosis, including 9 who had atypical presentations and extensive previous genetic and functional studies. Our NGS method detected variants with 98.1% sensitivity and >99.9% specificity. Uniformity was variable (72-89%), and we were not able to reliably sequence 45 regions (45/2455 or 1.8% of total regions) due to low (<20) average read depth or <90% region coverage; thus, we optimized probe hybridization conditions to improve read-depth and coverage for future analyses, and established criteria to help identify true positives.
CONCLUSION: While NGS methods are not as sensitive as Sanger sequencing for individual genes, targeted NGS is a cost-effective, first-line genetic test for the evaluation of patients with PIDs. This approach decreases time to diagnosis, increases diagnostic rate, and provides insight into the genotype-phenotype correlation of PIDs in a cost-effective way.

PMID: 25404929 [PubMed]

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TLR-mediated inflammatory responses to Streptococcus pneumoniae are highly dependent on surface expression of bacterial lipoproteins.

J Immunol. 2014 Oct 1;193(7):3736-45

Authors: Tomlinson G, Chimalapati S, Pollard T, Lapp T, Cohen J, Camberlein E, Stafford S, Periselneris J, Aldridge C, Vollmer W, Picard C, Casanova JL, Noursadeghi M, Brown J

Abstract
Streptococcus pneumoniae infections induce inflammatory responses that contribute toward both disease pathogenesis and immunity, but the host-pathogen interactions that mediate these effects are poorly defined. We used the surface lipoprotein-deficient ∆lgt pneumococcal mutant strain to test the hypothesis that lipoproteins are key determinants of TLR-mediated immune responses to S. pneumoniae. We show using reporter assays that TLR2 signaling is dependent on pneumococcal lipoproteins, and that macrophage NF-κB activation and TNF-α release were reduced in response to the ∆lgt strain. Differences in TNF-α responses between Δlgt and wild-type bacteria were abrogated for macrophages from TLR2- but not TLR4-deficient mice. Transcriptional profiling of human macrophages revealed attenuated TLR2-associated responses to ∆lgt S. pneumoniae, comprising many NF-κB-regulated proinflammatory cytokine and chemokine genes. Importantly, non-TLR2-associated responses were preserved. Experiments using leukocytes from IL-1R-associated kinase-4-deficient patients and a mouse pneumonia model confirmed that proinflammatory responses were lipoprotein dependent. Our data suggest that leukocyte responses to bacterial lipoproteins are required for TLR2- and IL-1R-associated kinase-4-mediated inflammatory responses to S. pneumoniae.

PMID: 25172490 [PubMed – indexed for MEDLINE]

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Newborn screening for SCID: where are we now?

Expert Rev Clin Immunol. 2014 Nov 12;:1-9

Authors: Buelow BJ, Routes JM, Verbsky JW

Abstract
Newborn screening (NBS) for severe T-cell lymphopenia/severe combined immunodeficiency using the T-cell receptor excision circle assay continues to expand in the USA and worldwide. Here, we will review why severe combined immunodeficiency is an excellent case for NBS, the outcomes of the first 6 years of screening, and dilemmas surrounding screening and management of infants detected by NBS. We will also discuss the future of NBS for primary immunodeficiencies.

PMID: 25387596 [PubMed – as supplied by publisher]

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A novel immunodeficiency syndrome associated with partial trisomy 19p13.

J Med Genet. 2014 Apr;51(4):254-63

Authors: Seidel MG, Duerr C, Woutsas S, Schwerin-Nagel A, Sadeghi K, Neesen J, Uhrig S, Santos-Valente E, Pickl WF, Schwinger W, Urban C, Boztug K, Förster-Waldl E

Abstract
BACKGROUND: Subtelomeric deletions and duplications may cause syndromic disorders that include features of immunodeficiency. To date, no phenotype of immunological pathology has been linked to partial trisomy 19. We report here on two unrelated male patients showing clinical and laboratory signs of immunodeficiency exhibiting a duplication involving Chromosome 19p13.
METHODS: Both patients underwent a detailed clinical examination. Extended laboratory investigations for immune function, FISH and array comparative genome hybridization (CGH) analyses were performed.
RESULTS: The reported patients were born prematurely with intrauterine growth retardation and share clinical features including neurological impairment, facial dysmorphy and urogenital malformations. Array CGH analyses of both patients showed a largely overlapping terminal duplication affecting Chromosome 19p13. In both affected individuals, the clinical course was marked by recurrent severe infections. Signs of humoral immunodeficiency were detected, including selective antibody deficiency against polysaccharide antigens in patient 1 and reduced IgG1, IgG3 subclass levels and IgM deficiency in patient 2. Class-switched B memory cells were almost absent in both patients. Normal numbers of T cells, B cells and natural killer cells were observed in both boys. Lymphocytic proliferation showed no consistent functional pathology, however, function of granulocytes and monocytes as assessed by oxidative burst test was moderately reduced. Moreover, natural killer cytotoxicity was reduced in both patients. Immunoglobulin substitution resulted in a decreased number and severity of infections and improved thriving in both patients.
CONCLUSIONS: Partial trisomy 19p13 represents a syndromic disorder associating organ malformation and hitherto unrecognised immunodeficiency.

PMID: 24431329 [PubMed – indexed for MEDLINE]

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Current treatment options with immunoglobulin G for the individualisation of care in patients with primary immunodeficiency disease.

Clin Exp Immunol. 2014 Nov 10;

Authors: Jolles S, Orange JS, Gardulf A, Stein MR, Shapiro R, Borte M, Berger M

Abstract
Primary antibody deficiencies require lifelong replacement therapy with immunoglobulin G (IgG) to reduce the incidence and severity of infections. Both subcutaneous and intravenous routes of administering IgG can be effective and well tolerated. Treatment regimens can be individualised to provide optimal medical and quality of life outcomes in infants, children, adults and the elderly. Frequency, dose, route of administration, home or infusion-centre administration, and the use of self- or health-professional administered infusion can be tailored to suit individual patient needs and circumstances. Patient education is needed to understand the disease and the importance of continuous therapy. Both the subcutaneous and intravenous routes have advantages and disadvantages, which should be considered in selecting each patient’s treatment regimen. The subcutaneous route is attractive to many patients because of a reduced incidence of systemic adverse events, flexibility in scheduling and its comparative ease of administration, at home or in a clinic. Self-infusion regimens, however, require independence and self-reliance, good compliance on the part of the patient/parent, and confidence of the physician and the nurse. Intravenous administration in a clinic setting may be more appropriate in patients with reduced manual dexterity, reluctance to self-administer or a lack of self-reliance, and intravenous administration at home for those with good venous access who prefer less frequent treatments. Both therapy approaches have been demonstrated to provide protection from infections and improve health-related quality of life. Data supporting current options in IgG replacement are presented, and considerations in choosing between the two routes of therapy are discussed.

PMID: 25384609 [PubMed – as supplied by publisher]

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Incidence and clinical presentation of primary hemophagocytic lymphohistiocytosis in Sweden.

Pediatr Blood Cancer. 2014 Nov 8;

Authors: Meeths M, Horne A, Sabel M, Bryceson YT, Henter JI

Abstract
BACKGROUND: Primary hemophagocytic lymphohistiocytosis (HLH) represents a group of inherited hyperinflammatory immunodeficiencies, including familial HLH (FHL), Griscelli syndrome type 2 (GS2), and X-linked lymphoproliferative syndrome (XLP). We previously reported an annual incidence of suspected primary HLH in Sweden 1971-1986 of 0.12 per 100,000 children. Here, we determined if the incidence had increased with concomitant awareness.
PROCEDURE: Children <15 years old presenting with HLH 1987-2006 in Sweden were identified through the national mortality registry as well as by nation-wide inquiries to all pediatric centers. HLH was diagnosed according to the HLH-2004 diagnostic guidelines (in case of missing data of at least three of the eight diagnostic criteria, fulfillment of four was sufficient for inclusion). We defined primary HLH as patients presenting with HLH requiring transplantation or dying of disease.
RESULTS: Remarkably, the minimal annual incidence rate of primary HLH remained 0.12 per 100,000 children, equating to 1.8 per 100,000 live births. Notably, an increased overall survival was observed in 1997-2006, relative to the period 1987-1996. During the subsequent 5-year period, 2007-2011, the incidence of genetically and/or functionally verified primary HLH was 0.15 per 100,000 children per year, suggesting that new assays may aid the identification of patients with primary HLH.
CONCLUSION: The annual incidence of primary HLH in Sweden is 0.12-0.15 per 100,000 children per year. Pediatr Blood Cancer 2014;9999: 1-7. © 2014 Wiley Periodicals, Inc.

PMID: 25382070 [PubMed – as supplied by publisher]

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Common variable immunodeficiency disorder – An uncommon cause for bronchiectasis.

Lung India. 2014 Oct;31(4):394-6

Authors: Panigrahi MK

Abstract
Bronchiectasis continues to be a common respiratory problem of varied etiology. Common variable immunodeficiency disorder (CVID) is an uncommon cause for bronchiectasis. However, the prevalence of bronchiectasis remains very high in patients with CVID. This remains largely an underdiagnosed entity as primary immunodeficiency is not suspected in adults as a cause of bronchiectasis and hence, serum immunoglobulin (Ig) levels are not measured routinely. In addition to bronchiectasis, patients with CVID usually present with various extrapulmonary symptoms. I report here a case of young man who presented with bronchiectasis and multisystem complains who was diagnosed as CVID.

PMID: 25378851 [PubMed]

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Recurrent Skin and Lung Infections in Autosomal Dominant Hyper IgE Syndrome with Transactivation Domain STAT3 Mutation.

Case Reports Immunol. 2014;2014:136752

Authors: Cooper CJ, Said S, Hernandez GT

Abstract
Background. Hyper IgE is a rare systemic disease characterized by the clinical triad of high serum levels of IgE (>2000 IU/mL), eczema, and recurrent staphylococcal skin and lung infections. The presentation of hyper IgE syndrome is highly variable, which makes it easy to confuse the diagnosis with that of severe atopy or other rare immunodeficiency disorders. Case Report. A 23-year-old Hispanic presented with history of frequent respiratory and gastrointestinal infections as a child and multiple episodes of skin and lung infections (abscess) with Staphylococcus aureus throughout his adult life. He had multiple eczematous lesions and folliculitis over his entire body, oral/esophageal candidiasis, and retention of his primary teeth. The IgE was elevated (>5000 IU/mL). Genetic mutation analysis revealed a mutation affecting the transactivation domain of the STAT3 gene. Conclusion. The hallmark of hyper IgE syndrome is serum IgE of >2000 IU/mL. Hyper IgE syndrome is a genetic disorder that is either autosomal dominant or recessive. A definite diagnosis can be made with genetic mutation analysis, and in this case, it revealed a very rare finding of the transactivation domain STAT3 mutation. Hyper IgE syndrome is a challenge for clinicians in establishing a diagnosis in suspected cases.

PMID: 25379309 [PubMed]

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