Manish Butte

Food allergy in patients with primary immunodeficiency diseases: Prevalence within the US Immunodeficiency Network (USIDNET).

J Allergy Clin Immunol. 2014 Nov 25;

Authors: Tuano KS, Orange JS, Sullivan K, Cunningham-Rundles C, Bonilla FA, Davis CM

PMID: 25441296 [PubMed – as supplied by publisher]

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An update on the use of immunoglobulin for the treatment of immunodeficiency disorders.

Immunotherapy. 2014 Oct;6(10):1113-26

Authors: Albin S, Cunningham-Rundles C

Abstract
For patients with significant antibody deficiencies, immunoglobulin therapy is the mainstay of treatment as it significantly reduces both the frequency and severity of infections. The formulations and delivery methods of immunoglobulin have evolved over time, and continued improvements have allowed for increased access to this effective medication. This review is an update on the current status of immunoglobulin therapy in immunodeficiency disorders, and discusses the mechanisms, forms and dosing, and indications for immunoglobulin replacement.

PMID: 25428649 [PubMed – in process]

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Chronic Granulomatous Disease Presenting as Hemophagocytic Lymphohistiocytosis: A Case Report.

Pediatrics. 2014 Nov 24;

Authors: Valentine G, Thomas TA, Nguyen T, Lai YC

Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by recurrent infections and a dysregulated inflammatory response. Infection-triggered hemophagocytic lymphohistiocytosis (HLH), which manifests itself as pathologic hyperactive inflammation, has been observed in subjects with CGD. However, there have been no reports of HLH as the initial presentation with subsequent diagnosis of CGD. Furthermore, the primary therapeutic strategy for HLH focuses on immunosuppressive therapies, which limits immune-mediated tissue damage. With immunodeficiency, this therapeutic strategy may worsen the outcome. This article discusses an 8-week-old Hispanic male who presented with fever of unknown origin. The initial diagnostic evaluation demonstrated pathologic hyperactive inflammation, meeting the HLH-2004 diagnostic criteria without an identified infectious etiology. Immunosuppressive therapy was initiated, with subsequent disseminated candida septic shock and sepsis-induced multisystem organ failure. Additional evaluations ultimately established the diagnosis of CGD. We transitioned to an immune-enhancing strategy with granulocyte and immunoglobulin infusions, and intensified antifungal therapies. These interventions ultimately led to the clearance of the fungal infection and the resolution of the hyperactive inflammatory state. This case represents the first reported case of HLH as the presenting finding leading to the subsequent diagnosis of CGD. It serves as a reminder that both immunodeficiency and inflammatory disorders may share features of pathologic hyperactive inflammation and highlights the conundrum that clinicians face when treating HLH in the setting of an unresolved infection. In this case report, we demonstrate that immune-enhancing therapies may aid in the control and the clearance of the infection, thus paradoxically decreasing the pathologic hyperactive inflammatory response.

PMID: 25422023 [PubMed – as supplied by publisher]

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Early-onset Evans syndrome, immunodeficiency and premature immunosenescence associated with tripeptidyl-peptidase II deficiency.

Blood. 2014 Nov 20;

Authors: Stepensky P, Rensing-Ehl A, Gather R, Vilk SR, Fischer U, Nabhani S, Beier F, Brümmendorf TH, Fuchs S, Zenke S, Firat E, Pessach VM, Borkhardt A, Rakhmanov M, Keller B, Warnatz K, Eibel H, Niedermann G, Elpeleg O, Ehl S

Abstract
Autoimmune cytopenia is a frequent manifestation of primary immunodeficiencies. Two siblings presented with Evans syndrome, viral infections and progressive leukopenia. DNA available from one patient showed a homozygous frameshift mutation in tripeptidyl peptidase II (TPPII) abolishing protein expression. TPPII is a serine exopeptidase involved in extralysosomal peptide degradation. Its deficiency in mice activates cell death programs and premature senescence. Similar to cells from naïve, uninfected TPPII deficient mice, patient cells showed increased MHC I expression and most CD8+ T-cells had a senescent CCR7-CD127-CD28-CD57+ phenotype with poor proliferative responses and enhanced staurosporine-induced apoptosis. T-cells showed increased expression of the effector molecules perforin and IFN-γ with high expression of the transcription factor T-bet. Age-associated B-cells with a CD21- CD11c+ phenotype expressing T-bet were increased in humans and mice, combined with antinuclear antibodies. Moreover, markers of senescence were also present in human and murine TPP2 deficient fibroblasts. Telomere length was normal in patient fibroblasts and granulocytes and low normal in lymphocytes, compatible with activation of stress-induced rather than replicative senescence programs. TPPII deficiency is the first primary immunodeficiency linking premature immunosenescence to severe autoimmunity. Determination of senescent lymphocytes should be part of the diagnostic evaluation of children with refractory multilineage cytopenias.

PMID: 25414442 [PubMed – as supplied by publisher]

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O-017 Digenic Inheritance of Primary Immunodeficiency Gene Variants Identified by Whole Exome Sequence in Very Early Onset IBD Patients.

Inflamm Bowel Dis. 2014 Dec;20 Suppl 1:S9-S10

Authors: Judith K, Christopher M, Noor D, Helen PH, Eric R, Petar M, David P, Harland W, Mark D, Gregory S, David A, Robert B, Marcella D

Abstract
BACKGROUND:: Very early onset IBD (VEO-IBD) is frequently considered a different disease process than older onset IBD. The severe phenotype and young age suggest a more pronounced genetic susceptibility and dysregulated immune response. We hypothesized that rare or novel variants, including mutations in genes associated with primary immunodeficiencies (PI) involving pathways in both B and T cell development and activation, were enriched in patients with severe VEO-IBD. We adopted 2 models to evaluate this hypothesis, a recessive inheritance model and a digenic model.
METHODS:: IBD patients 5 years and younger, and parents were recruited. Exome capture was performed by Agilent SureSelect V4, and the Illumina HiSeq platform was utilized for sequencing. Following functional annotation, single base substitutions likely to alter protein function, such as missense and loss of function mutations, were kept for subsequent analysis. Primary focus of the analysis was on genes associated with PI and related pathways (> 400 genes). We then evaluated complete trios under 2 models; a recessive model defined by homozygosity or compound heterozygosity of pathogenic variants, and a digenic model, where 2 variants in different genes of the same or related pathways were inherited from different parents.
RESULTS:: Three hundred five samples were analyzed, including 69 trios. Patients’ age ranged from 4 weeks to 4 years. Candidate variants of the same or similar pathways were identified under the digenic model. Examples include heterozygous mutations detected in a 2 year old female with severe colonic VEO-IBD refractory to medical therapy, including a rare variant in RAG2 (V8I; Val-Ile) and novel variant in PI3K1 (Y294C; Tyr-Cys). Laboratory evaluation demonstrated low NK cells and Tregs. PI3K is important in Treg development as well as B cell development and maturation. RAG2, associated with SCID, is critical for V(D)J recombination to allow antibody and TCR diversity to be attained. Additionally, B cell activation defects were detected in a 20 month old with severe colonic and perianal VEO-IBD, with rare variants in CR2 P175L (Pro-Leu) and POLE 1225F (Ile-Phe). Human complement 2 receptor, CR2, among other immunological responsibilities, expressed on B cells and follicular DCs, mediates B cell activation and maturation. Mutations in the POLE gene can result in PI through defects in B cell proliferation. Finally, heterozygous mutations were detected in a 20 month old male with severe colonic VEO-IBD, with a novel variant in Zap70 (A168S; Ala-Ser), and a rare variant in LRBA (V2055M; Val-Met). Zap70, associated with SCID, plays an essential role in TCR signaling, and subsequent activation and migration of B cells. Mutations in LRBA can result in defective B cells, including B cell survival, plasmablast generation, and immunoglobulin secretion.
CONCLUSIONS:: While variants in single genes are responsible for some cases of VEO-IBD, multigenic inheritance may be responsible for the pathogenesis of the disease in a subset of the population. In addition, it is likely that some patients harbor mutations in both B and T cell pathways. Thus, the multigenic approach may provide insight to the development of disease in this population.

PMID: 25407208 [PubMed – as supplied by publisher]

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Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity.

Nat Commun. 2014;5:5360

Authors: Willmann KL, Klaver S, Doğu F, Santos-Valente E, Garncarz W, Bilic I, Mace E, Salzer E, Domínguez Conde C, Sic H, Májek P, Banerjee PP, Vladimer GI, Haskoloğlu S, Gökalp Bolkent M, Küpesiz A, Condino-Neto A, Colinge J, Superti-Furga G, Pickl WF, van Zelm MC, Eibel H, Orange JS, Ikincioğulları A, Boztuğ K

Abstract
Primary immunodeficiency disorders enable identification of genes with crucial roles in the human immune system. Here we study patients suffering from recurrent bacterial, viral and Cryptosporidium infections, and identify a biallelic mutation in the MAP3K14 gene encoding NIK (NF-κB-inducing kinase). Loss of kinase activity of mutant NIK, predicted by in silico analysis and confirmed by functional assays, leads to defective activation of both canonical and non-canonical NF-κB signalling. Patients with mutated NIK exhibit B-cell lymphopenia, decreased frequencies of class-switched memory B cells and hypogammaglobulinemia due to impaired B-cell survival, and impaired ICOSL expression. Although overall T-cell numbers are normal, both follicular helper and memory T cells are perturbed. Natural killer (NK) cells are decreased and exhibit defective activation, leading to impaired formation of NK-cell immunological synapses. Collectively, our data illustrate the non-redundant role for NIK in human immune responses, demonstrating that loss-of-function mutations in NIK can cause multiple aberrations of lymphoid immunity.

PMID: 25406581 [PubMed – as supplied by publisher]

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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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Related Articles

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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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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Related Articles

Historical perspectives in the diagnosis and treatment of primary immune deficiencies.

Clin Rev Allergy Immunol. 2014 Apr;46(2):101-3

Authors: Ballow M

Abstract
The field of Primary Immune Deficiency Disorders (PIDD) has advanced rapidly over the past several years with over 200 different gene mutations defined. With the recent institution of newborn screening for T cell deficiencies in many states and earlier recognition of the signs and symptoms of patients with immune deficiency, it is now apparent that PIDD is not as “rare” as was originally thought several decades ago. With the earlier recognition of patients with recurrent infections and various immune perturbations, advancements in the treatment of these immune deficiency disorders have led to enhanced survival and quality of life. In this issue, the diagnosis of PIDD through laboratory testing and skin manifestations is reviewed. The more recently described cellular immune deficiencies, selective immune deficiencies, and advances in the use of bone marrow transplantation in the correction of some of these immune deficiencies are discussed.

PMID: 23877724 [PubMed – indexed for MEDLINE]

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