Manish Butte

Latin-American Consensus on the Supportive Management of Patients with Severe Combined Immunodeficiency.

J Allergy Clin Immunol. 2019 Aug 13;:

Authors: Bustamante Ogando JC, Partida Gaytán A, Aldave Becerra JC, Álvarez Cardona A, Bezrodnik L, Borzutzky A, Blancas Galicia L, Cabanillas D, Condino-Neto A, De Colsa RA, Espinosa Padilla S, Fernandes Juliana F, García Campos JA, Gómez Tello H, González Serrano ME, Gutiérrez Hernández A, Hernández Bautista VM, Ivankovich Escoto G, King A, Lessa Mazzucchelli J, Llamas Guillén BA, Lugo Reyes SO, Moreno Espinosa S, Oleastro Matías, Otero Mendoza F, Poli Harlowe MC, Porras O, Ramirez Uribe N, Regairaz L, Rivas Larrauri F, Saracho Weber FJ, Sevciovic Grumach A, Staines Boone AT, Tavares Costa-Carvalho B, Yamazaki Nakashimada MA, Espinosa Rosales FJ

Abstract
SCID represent the most lethal form of PID with mortality rates >90% within the first year of life without treatment. HSCT and GT are the only curative treatments available, and the best-known prognostic factors for success are the age at diagnosis, age at HSCT, and the comorbidities that develop in-between. There are no evidence-based guidelines for standardized clinical care for SCID patients during the time between diagnosis and definitive treatment, and we aim to generate a consensus management strategy on the supportive care of SCID patients. First, we gathered available information about SCID diagnostic and therapeutic guidelines, then we developed a document including diagnostic and therapeutic interventions, and finally, we submitted the interventions for expert consensus through a modified Delphi technique. Interventions are grouped in 10 topic-domains, including 123 “agreed” and 38 “non-agreed” statements. This document intends to standardize supportive clinical care of patients with SCID from diagnosis to definitive treatment, reduce disease burden and ultimately improve prognosis, particularly in countries where newborn screening for SCID is not universally available and delayed diagnosis is the rule. Our work intends to help as a tool not only for immunologists, but primary care physicians and other specialists involved in SCID patient´s care.

PMID: 31419546 [PubMed – as supplied by publisher]

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Novel Heterozygous Mutation in NFKB2 Is Associated With Early Onset CVID and a Functional Defect in NK Cells Complicated by Disseminated CMV Infection and Severe Nephrotic Syndrome.

Front Pediatr. 2019;7:303

Authors: Aird A, Lagos M, Vargas-Hernández A, Posey JE, Coban-Akdemir Z, Jhangiani S, Mace EM, Reyes A, King A, Cavagnaro F, Forbes LR, Chinn IK, Lupski JR, Orange JS, Poli MC

Abstract
Nuclear factor kappa-B subunit 2 (NF-κB2/p100/p52), encoded by NFKB2 (MIM: 164012) belongs to the NF-κB family of transcription factors that play a critical role in inflammation, immunity, cell proliferation, differentiation and survival. Heterozygous C-terminal mutations in NFKB2 have been associated with early-onset common variable immunodeficiency (CVID), central adrenal insufficiency and ectodermal dysplasia. Only two previously reported cases have documented decreased natural killer (NK) cell cytotoxicity, and little is known about the role of NF-κB2 in NK cell maturation and function. Here we report a 13-year-old female that presented at 6 years of age with a history of early onset recurrent sinopulmonary infections, progressive hair loss, and hypogamaglobulinemia consistent with a clinical diagnosis of CVID. At 9 years of age she had cytomegalovirus (CMV) pneumonia that responded to ganciclovir treatment. Functional NK cell testing demonstrated decreased NK cell cytotoxicity despite normal NK cell numbers, consistent with a greater susceptibility to systemic CMV infection. Research exome sequencing (ES) was performed and revealed a novel de novo heterozygous nonsense mutation in NFKB2 (c.2611C>T, p.Gln871*) that was not carried by either of her parents. The variant was Sanger sequenced and confirmed to be de novo in the patient. At age 12, she presented with a reactivation of the systemic CMV infection that was associated with severe and progressive nephrotic syndrome with histologic evidence of pedicellar effacement and negative immunofluorescence. To our knowledge, this is the third NF-κB2 deficient patient in which an abnormal NK cell function has been observed, suggesting a role for non-canonical NF-κB2 signaling in NK cell cytotoxicity. NK cell function should be assessed in patients with mutations in the non-canonical NF-κB pathway to explore the risk for systemic viral infections that may lead to severe complications and impact patient survival. Similarly NF-κB2 should be considered in patients with combined immunodeficiency who have aberrant NK cell function. Further studies are needed to characterize the role of NF-κB2 in NK cell cytotoxic function.

PMID: 31417880 [PubMed]

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Editorial: The Relationship Between Cancer Predisposition and Primary Immunodeficiency.

Front Immunol. 2019;10:1781

Authors: Hauck F, Gennery AR, Seidel MG

PMID: 31417559 [PubMed – in process]

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The Phytopathogenic Fungus Pallidocercospora crystallina-Caused Localized Subcutaneous Phaeohyphomycosis in a Patient with a Homozygous Missense CARD9 Mutation.

J Clin Immunol. 2019 Aug 14;:

Authors: Guo Y, Zhu Z, Gao J, Zhang C, Zhang X, Dang E, Li W, Qiao H, Liao W, Wang G, Ma C, Fu M

Abstract
PURPOSE: In the past decade, an increasing number of otherwise healthy individuals suffered from invasive fungal infections due to inherited CARD9 mutations. Herein, we present a patient with a homozygous CARD9 mutation who was suffering from localized subcutaneous phaeohyphomycosis caused by the phytopathogenic fungus Pallidocercospora crystallina which has not been reported to cause infections in humans.
METHODS: The medical history of our patient was collected. P. crystallina was isolated from the biopsied tissue. To characterize this novel pathogen, the morphology was analyzed, whole-genome sequencing was performed, and the in vivo immune response was explored in mice. Whole-exome sequencing was carried out with samples from the patient’s family. Finally, the expression and function of mutated CARD9 were investigated.
RESULTS: A dark red plaque was on the patient’s left cheek for 16 years and was diagnosed as phaeohyphomycosis due to a P. crystallina infection. Whole-genome sequencing suggested that that this strain had a lower pathogenicity. The in vivo immune response in immunocompetent or immunocompromised mice indicated that P. crystallina could be eradicated within a few weeks. Whole-exome sequencing revealed ahomozygous missense mutation in CARD9 (c.1118G>C p.R373P). The mRNA and protein expression levels were similar among cells carrying homozygous (C/C), heterozygous (G/C), and wild-type (G/G) CARD9 alleles. Compared to PBMCs or neutrophils with heterozygous or wild-type CARD9 alleles, however, PBMCs or neutrophils with homozygous CARD9 alleles showed impaired anti-P. crystallina effects.
CONCLUSION: Localized subcutaneous phaeohyphomycosis caused by P. crystallina was reported in a patient with a homozygous CARD9 mutation. Physicians should be aware of the possibility of a CARD9 mutation in seemingly healthy patients with unexplainable phaeohyphomycosis.

PMID: 31414217 [PubMed – as supplied by publisher]

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RAS-associated Autoimmune Leukoproliferative disease (RALD) manifested with early-onset SLE-like syndrome: a case series of RALD in Chinese children.

Pediatr Rheumatol Online J. 2019 Aug 14;17(1):55

Authors: Wang W, Zhou Y, Zhong L, Wang L, Tang X, Ma M, Li J, Song H

Abstract
BACKGROUND: Primary immunodeficiency diseases (PIDs) patients may show systemic lupus erythematosus (SLE)-like autoimmunity disorders, such as cytopenias, as well as polyarthritis, which leads to concerns of misdiagnosis. We diagnosed three RALD cases between 2015 and 2018, who were suspected as SLE and summarized clinical characteristics.
METHODS: We collected and analyzed the clinical data of the 3 cases. DNA was extracted from the patients’ and their parents’ peripheral blood as well as oral mucosa cells, hair follicles, and nails. Genes were detected with the application of gene trapping high-throughput sequencing using PIDs panel and suspicious gene or mutation was further verified by Sanger sequencing.
RESULTS: 1.
CLINICAL FEATURES: On the one hand, the patients presented with severe thrombocytopenia, facial erythema, arthritis, positive autoantibodies and other manifestations, supporting the diagnosis of SLE. On the other hand, symptoms including early onset ages, recurrent infections, lymphadenopathy, hepatosplenomegaly, monocytosis and hypergammaglobulinemia, were common observed in PIDs. 2. Gene analysis: NRAS mutations (c.38G > A, p.G13D or c.37G > T, p.G13C) were found in the blood of the patients. Besides, the same set of mutations was detected in buccal mucosa of patient 1 and nails of patient 3 while the frequency was much lower. However, no mutation was found in other tissues or in their parents’ blood. Consequently, they were NRAS somatic mutated RALD.
CONCLUSIONS: For those early-onset SLE-like patients with predominant hematologic disorders, monocytosis, recurrent infectious history, accompanied with hepatosplenomegaly and lymphadenopathy, a genetic screening of PIDs might be required.

PMID: 31412876 [PubMed – in process]

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Application of Highly Immunocompromised Mice for the Establishment of Patient-Derived Xenograft (PDX) Models.

Cells. 2019 Aug 13;8(8):

Authors: Okada S, Vaeteewoottacharn K, Kariya R

Abstract
Patient-derived xenograft (PDX) models are created by engraftment of patient tumor tissues into immunocompetent mice. Since a PDX model retains the characteristics of the primary patient tumor including gene expression profiles and drug responses, it has become the most reliable in vivo human cancer model. The engraftment rate increases with the introduction of Non-obese diabetic Severe combined immunodeficiency (NOD/SCID)-based immunocompromised mice, especially the NK-deficient NOD strains NOD/SCID/interleukin-2 receptor gamma chain(IL2Rγ)null (NOG/NSG) and NOD/SCID/Jak3(Janus kinase 3)null (NOJ). Success rates differ with tumor origin: gastrointestinal tumors acquire a higher engraftment rate, while the rate is lower for breast cancers. Subcutaneous transplantation is the most popular method to establish PDX, but some tumors require specific environments, e.g., orthotropic or renal capsule transplantation. Human hormone treatment is necessary to establish hormone-dependent cancers such as prostate and breast cancers. PDX mice with human hematopoietic and immune systems (humanized PDX) are powerful tools for the analysis of tumor-immune system interaction and evaluation of immunotherapy response. A PDX biobank equipped with patients’ clinical data, gene-expression patterns, mutational statuses, tumor tissue architects, and drug responsiveness will be an authoritative resource for developing specific tumor biomarkers for chemotherapeutic predictions, creating individualized therapy, and establishing precise cancer medicine.

PMID: 31412684 [PubMed – in process]

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Peripheral immune cell markers in children with recurrent respiratory infections in the absence of primary immunodeficiency.

Exp Ther Med. 2019 Sep;18(3):1693-1700

Authors: Munteanu AN, Surcel M, Huică RI, Isvoranu G, Constantin C, Pîrvu IR, Chifiriuc C, Ulmeanu C, Ursaciuc C, Neagu M

Abstract
The immune system of a child has a degree of immaturity that is maintained until 6-7 years of age. Immaturity may be due to age-related functional disorders in the immune response. A healthy child can contract a series of infections which contribute to the maturation of the immune system during the pre-pubertal period. If repeated infections with prolonged or severe complications occur during childhood, the presence of an immunodeficiency should then be considered. Much more frequent than primary immunodeficiency are recurrent infections (frequently involving the upper respiratory tract), which are less severe and occur under the conditions of an immune system with no apparent major defects. A child can present with 4 to 8 episodes of respiratory infections within a year, during the first 5 years of its life. The average duration of infection is 8 days and up to 2 weeks; if the child presents with 3 episodes of acute infections over a period of 6 months, the respiratory infections are then considered recurrent. The aim of this study was to identify the immunological changes or deviations that cause this clinical syndrome in children. For this purpose, 30 children with recurrent respiratory infections and 10 healthy children were included. Immunoglobulin levels were examined and immunophenotyping was performed. We found that the serum immunoglobulin levels were in the normal range in 70% of the children. On the contrary, our data revealed changes in peripheral cell populations, the most important being the decrease in the T-cluster of differentiation (CD)8+ and total B cell percentages and the increase in the number of memory B cells. The data obtained herein indicated that the decrease in the number of total B cells was mainly due to the decrease in the number of naive IgD+ B cells. On the whole, the findings of this study indicate that recurrent respiratory infections may be associated with an altered cellular immune response. In such situations, the investigation of immunological parameters, such as T and B cell subtypes could complete the clinical diagnosis and guide the treatment strategy, thus increasing the quality of life of patients.

PMID: 31410127 [PubMed]

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Genetic overlap between autoimmune diseases and non-Hodgkin lymphoma subtypes.

Genet Epidemiol. 2019 Aug 13;:

Authors: Din L, Sheikh M, Kosaraju N, Smedby KE, Bernatsky S, Berndt SI, Skibola CF, Nieters A, Wang S, McKay JD, Cocco P, Maynadié M, Foretová L, Staines A, Mack TM, de Sanjosé S, Vyse TJ, Padyukov L, Monnereau A, Arslan AA, Moore A, Brooks-Wilson AR, Novak AJ, Glimelius B, Birmann BM, Link BK, Stewart C, Vajdic CM, Haioun C, Magnani C, Conti DV, Cox DG, Casabonne D, Albanes D, Kane E, Roman E, Muzi G, Salles G, Giles GG, Adami HO, Ghesquières H, De Vivo I, Clavel J, Cerhan JR, Spinelli JJ, Hofmann J, Vijai J, Curtin K, Costenbader KH, Onel K, Offit K, Teras LR, Morton L, Conde L, Miligi L, Melbye M, Ennas MG, Liebow M, Purdue MP, Glenn M, Southey MC, Din M, Rothman N, Camp NJ, Wong Doo N, Becker N, Pradhan N, Bracci PM, Boffetta P, Vineis P, Brennan P, Kraft P, Lan Q, Severson RK, Vermeulen RCH, Milne RL, Kaaks R, Travis RC, Weinstein SJ, Chanock SJ, Ansell SM, Slager SL, Zheng T, Zhang Y, Benavente Y, Taub Z, Madireddy L, Gourraud PA, Oksenberg JR, Cozen W, Hjalgrim H, Khankhanian P

Abstract
Epidemiologic studies show an increased risk of non-Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen-stimulation in one disease leads to another. Here we assess shared genetic risk in genome-wide-association-studies (GWAS). Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)”diseasome”, (d)meta-analysis. Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p = .0041). A meta-analysis (combing AD with NHL) implicated genes of apoptosis and telomere length. This GWAS-based analysis four NHL subtypes and three ADs revealed few weakly-associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.

PMID: 31407831 [PubMed – as supplied by publisher]

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Primary immunodeficiency disease: a cost-utility analysis comparing intravenous vs subcutaneous immunoglobulin replacement therapy in Australia.

Blood Transfus. 2019 Aug 05;:1-10

Authors: Windegger TM, Nghiem S, Nguyen KH, Fung YL, Scuffham PA

Abstract
BACKGROUND: Hospital-based intravenous immunoglobulin (IVIg) treatment has been the standard treatment mode for patients with primary immunodeficiency disease (PID). With the newer home-based subcutaneous immunoglobulin (SCIg) becoming approved for use in most countries, the question arises as to whether SCIg is a cost-effective treatment mode compared to IVIg in Australia.
MATERIALS AND METHODS: We developed a Markov cohort simulation model with six health states: PID without infection, PID with infection treated at home or hospital, bronchiectasis without infection, bronchiectasis with infection treated at home or hospital, bronchiectasis with chronic Pseudomonas aeruginosa infection, and death, from an Australian healthcare system perspective. A 10-year time horizon with weekly cycles was chosen, and the expected costs and quality-adjusted life-years (QALYs) of the two treatment options estimated.
RESULTS: The cumulative 10-year cost per patient was 297,547 Australian dollars (A$) with IVIg and A$ 251,713 for SCIg. IVIg resulted in 5.55 QALYs and SCIg 5.57 QALYs. Thus, SCIg appears to be a cost-saving option and possibly improves QALY from the Australian healthcare system perspective (i.e., the dominant treatment option). A probabilistic sensitivity analysis showed that the SCIg option is preferred in 93.2% of simulations given willingness to pay of A$ 50,000 per QALY gained.
DISCUSSION: The results suggest that home-based SCIg is a cost-effective treatment option for patients with PID in Queensland, Australia.

PMID: 31403930 [PubMed – as supplied by publisher]

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T and B-cell signaling in activated PI3K delta syndrome: From immunodeficiency to autoimmunity.

Immunol Rev. 2019 Sep;291(1):154-173

Authors: Preite S, Gomez-Rodriguez J, Cannons JL, Schwartzberg PL

Abstract
Phosphatidylinositol 3 kinases (PI3K) are a family of lipid kinases that are activated by a variety of cell-surface receptors, and regulate a wide range of downstream readouts affecting cellular metabolism, growth, survival, differentiation, adhesion, and migration. The importance of these lipid kinases in lymphocyte signaling has recently been highlighted by genetic analyses, including the recognition that both activating and inactivating mutations of the catalytic subunit of PI3Kδ, p110δ, lead to human primary immunodeficiencies. In this article, we discuss how studies on the human genetic disorder “Activated PI3K-delta syndrome” and mouse models of this disease (Pik3cdE1020K/+ mice) have provided fundamental insight into pathways regulated by PI3Kδ in T and B cells and their contribution to lymphocyte function and disease, including responses to commensal bacteria and the development of autoimmunity and tumors. We highlight critical roles of PI3Kδ in T follicular helper cells and the orchestration of the germinal center reaction, as well as in CD8+ T-cell function. We further  present data demonstrating the ability of the AKT-resistant FOXO1AAA mutant to rescue IgG1 class switching defects in Pik3cdE1020K/+ B cells, as well as data supporting a role for PI3Kδ in promoting multiple T-helper effector cell lineages.

PMID: 31402502 [PubMed – in process]

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