Manish Butte

Loss of human ICOSL results in combined immunodeficiency.

J Exp Med. 2018 Nov 29;:

Authors: Roussel L, Landekic M, Golizeh M, Gavino C, Zhong MC, Chen J, Faubert D, Blanchet-Cohen A, Dansereau L, Parent MA, Marin S, Luo J, Le C, Ford BR, Langelier M, King IL, Divangahi M, Foulkes WD, Veillette A, Vinh DC

Abstract
Primary immunodeficiencies represent naturally occurring experimental models to decipher human immunobiology. We report a patient with combined immunodeficiency, marked by recurrent respiratory tract and DNA-based viral infections, hypogammaglobulinemia, and panlymphopenia. He also developed moderate neutropenia but without prototypical pyogenic infections. Using whole-exome sequencing, we identified a homozygous mutation in the inducible T cell costimulator ligand gene (ICOSLG; c.657C>G; p.N219K). Whereas WT ICOSL is expressed at the cell surface, the ICOSLN219K mutation abrogates surface localization: mutant protein is retained in the endoplasmic reticulum/Golgi apparatus, which is predicted to result from deleterious conformational and biochemical changes. ICOSLN219K diminished B cell costimulation of T cells, providing a compelling basis for the observed defect in antibody and memory B cell generation. Interestingly, ICOSLN219K also impaired migration of lymphocytes and neutrophils across endothelial cells, which normally express ICOSL. These defects likely contributed to the altered adaptive immunity and neutropenia observed in the patient, respectively. Our study identifies human ICOSLG deficiency as a novel cause of a combined immunodeficiency.

PMID: 30498080 [PubMed – as supplied by publisher]

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Neutrophil and Granulocytic Myeloid-Derived Suppressor Cell-Mediated T Cell Suppression Significantly Contributes to Immune Dysregulation in Common Variable Immunodeficiency Disorders.

J Immunol. 2018 Nov 28;:

Authors: Vlkova M, Chovancova Z, Nechvatalova J, Connelly AN, Davis MD, Slanina P, Travnickova L, Litzman M, Grymova T, Soucek P, Freiberger T, Litzman J, Hel Z

Abstract
Common variable immunodeficiency disorders (CVID) represent a group of primary immunodeficiency diseases characterized by hypogammaglobulinemia and impaired specific Ab response, resulting in recurrent infections due to dysfunctional immune response. The specific mechanisms mediating immune deficiency in CVID remain to be determined. Previous studies indicated that immune dysregulation in CVID patients is associated with chronic microbial translocation, systemic immune activation, and altered homeostasis of lymphocytic and myeloid lineages. A detailed phenotypic, functional characterization of plasma markers and immune cell populations was performed in 46 CVID patients and 44 healthy donors. CVID patients displayed significantly elevated plasma levels of a marker of neutrophil activation neutrophil gelatinase-associated lipocalin. Neutrophils from CVID patients exhibited elevated surface levels of CD11b and PD-L1 and decreased levels of CD62L, CD16, and CD80, consistent with a phenotype of activated neutrophils with suppressive properties. Neutrophils from CVID patients actively suppressed T cell activation and release of IFN-γ via the production of reactive oxygen species. Furthermore, CVID was associated with an increased frequency of low-density neutrophils (LDNs)/granulocytic myeloid-derived suppressor cells. LDN/granulocytic myeloid-derived suppressor cell frequency in CVID patients correlated with reduced T cell responsiveness. Exogenous stimulation of whole blood with bacterial LPS emulated some but not all of the phenotypic changes observed on neutrophils from CVID patients and induced neutrophil population with LDN phenotype. The presented data demonstrate that neutrophils in the blood of CVID patients acquire an activated phenotype and exert potent T cell suppressive activity. Specific targeting of myeloid cell-derived suppressor activity represents a novel potential therapeutic strategy for CVID.

PMID: 30487174 [PubMed – as supplied by publisher]

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Identification of potential biomarkers for differential diagnosis between rheumatoid arthritis and osteoarthritis via integrative genome‑wide gene expression profiling analysis.

Mol Med Rep. 2018 Nov 20;:

Authors: Zhang R, Yang X, Wang J, Han L, Yang A, Zhang J, Zhang D, Li B, Li Z, Xiong Y

Abstract
The present study aimed to identify potential novel biomarkers in synovial tissue obtained from patients with Rheumatoid Arthritis (RA) and Osteoarthritis (OA) for differential diagnosis. The genome‑wide expression profiling datasets of synovial tissues from RA and OA cohorts, including GSE55235, GSE55457 and GSE55584 datasets, were retrieved and used to identify differentially expressed genes (DEGs; P<0.05; false discovery rate <0.05 and Fold Change >2) between RA and OA using R software. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of DEGs were performed to determine molecular and biochemical pathways associated with the identified DEGs, and a protein‑protein interaction (PPI) network of the DEGs was constructed using Cytoscape software. Significant modules in the PPI network and candidate driver genes were screened using the Molecular Complex Detection Algorithm. Potential biomarkers were evaluated by receiver operating characteristic and logistic regression analyses. Large numbers of DEGs were detected, including 273, 205 and 179 DEGs in the GSE55235, GSE55457 and GSE55584 datasets, respectively. Among them, 80 DEGs exhibited identical expression trends in all the three datasets, including 49 upregulated and 31 downregulated genes in patients with RA. DEGs in patients suffering from RA compared with patients suffering from OA were predominantly associated with the primary immunodeficiency pathway, including interleukin 7 receptor (IL7R) and signal transducer activator of transcription 1 (STAT1). The sensitivity of IL7R + STAT1 to differentiate RA from OA was 93.94% with a specificity of 80.77%. The results generated from analyses of the GSE36700 dataset were closely associated with results generated from analyses of GSE55235, GSE55457 and GSE55584 datasets, which further verified the reliability of the aforementioned results. The results of the present study suggested that increased expression of IL7R and STAT1 in synovial tissue as well as in the primary immunodeficiency may be associated with RA occurrence. These identified novel biomarkers may be used to predict disease occurrence and clinically differentiate RA from OA.

PMID: 30483789 [PubMed – as supplied by publisher]

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Reproductive factors, exogenous hormone use and risk of B-cell non-Hodgkin lymphoma in a cohort of women from the European Prospective Investigation into Cancer and Nutrition.

Am J Epidemiol. 2018 Nov 27;:

Authors: Costas L, Lujan-Barroso L, Benavente Y, Allen NE, Amiano P, Ardanaz E, Besson C, Boeing H, Bueno-de-Mesquita B, Cervenka I, Fortner RET, Fournier A, Gunter M, Harlid S, Huerta JM, Jerkeman M, Jirström K, Kaaks R, Karakatsani A, Khaw KT, Kotanidou A, Lund E, Masala G, Mattiello A, Melin B, Menéndez V, Murphy N, Nieters A, Overvad K, Riboli E, Sacerdote C, Sánchez MJ, Schmidt JA, Sieri S, Tjønneland A, Trichopoulou A, Tumino R, Vermeulen R, Weiderpass E, de Sanjosé S, Agudo A, Casabonne D

Abstract
The role of hormonal factors in lymphoid neoplasms etiology remains unclear. Previous studies have yielded conflicting results, been underpowered to assess many lymphoma subtypes, or lacked detailed information on relevant exposures. Within the European Prospective Investigation into Cancer and Nutrition cohort, we analyzed comprehensive data collected at baseline (1992-2000) on reproductive factors and exogenous hormone use among 343,458 women, including 1,427 incident B-cell non-Hodgkin lymphomas (NHL) and its major subtypes identified after a mean follow-up of 14 years (through 2015). We estimated hazard ratios and 95% confidence intervals using multivariable proportional hazards modeling. Overall, we observed no statistically significant associations between parity, age at first birth, breastfeeding, oral contraceptive use or ever use of postmenopausal hormone therapy and risk of B-cell NHL or its subtypes. Women who had a surgical menopause had a 51% higher risk of B-cell NHL (based on 67 cases) compared with natural menopause (hazard ratio=1.51, 95% confidence interval=1.17, 1.94). Given that this result may be due to chance, our results provide little support for the hypothesis that sex hormones play a role in lymphomagenesis.

PMID: 30481275 [PubMed – as supplied by publisher]

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Skin disorders are prominent features in primary immunodeficiency diseases: a systematic overview of current data.

Allergy. 2018 Nov 27;:

Authors: de Wit J, Brada RJK, van Veldhuizen J, Dalm VASH, Pasmans SGMA

Abstract
Primary immunodeficiency diseases (PIDs) are characterized by an increased risk of infections, autoimmunity, autoinflammation, malignancy and allergic disorders. Skin disorders are also common clinical features in PIDs and may be among the presenting manifestations. Recognition of specific PID-associated skin conditions in combination with other clinical features as described in the currently used warning signs could raise suspicion of an underlying PID. We aimed to provide a systematically obtained overview of skin disorders and their prevalence in PIDs. Secondary, the prevalence of Staphylococcus (S.) aureus-associated skin disorders and atopy were reviewed, as these are the most prominent skin features in PIDs. A systematic search was performed in Embase, Medline, Web of Science, Cochrane and Google Scholar (up to May 9th 2018). All original observational and experimental human studies that address the presence of skin disorders in PIDs were selected. We rated study quality using the Institute of Health Economics Quality Appraisal Checklist for Case Series Studies. Sixty-seven articles (5030 patients) were included. Study quality ranged from 18.2-88.5%. A broad spectrum of skin disorders was reported in 30 PIDs, mostly in single studies with a low number of included patients. An overview of associated PIDs per skin disorder was generated. Data on S. aureus-associated skin disorders and atopy in PIDs were limited. In conclusion, skin disorders are prominent features in PIDs. Through clustering of PIDs per skin disorder, we provide a support tool to use in clinical practice that should raise awareness of PIDs based on presenting skin manifestations. This article is protected by copyright. All rights reserved.

PMID: 30480813 [PubMed – as supplied by publisher]

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Corticosteroids for septic arthritis in children.

Cochrane Database Syst Rev. 2018 Nov 21;11:CD012125

Authors: Delgado-Noguera MF, Forero Delgadillo JM, Franco AA, Vazquez JC, Calvache JA

Abstract
BACKGROUND: Septic arthritis is an acute infection of the joints characterised by erosive disruption of the articular space. It is the most common non-degenerative articular disease in developing countries. The most vulnerable population for septic arthritis includes infants and preschoolers, especially boys. Septic arthritis disproportionately affects populations of low socioeconomic status. Systemic corticosteroids and antibiotic therapy may be beneficial for treatment of septic arthritis. Even if the joint infection is eradicated by antibiotic treatment, the inflammatory process may produce residual joint damage and sequelae.
OBJECTIVES: To determine the benefits and harms of corticosteroids as adjunctive therapy in children with a diagnosis of septic arthritis.
SEARCH METHODS: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library, Latin American Caribbean Health Sciences Literature (LILACS), the World Health Organization (WHO) trials portal (www.who.int/ictrp/en/), ClinicalTrials.gov (www.ClinicalTrials.gov), and Google Scholar. We searched all databases from their inception to 17 April 2018, with no restrictions on language of publication.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) with patients from two months to 18 years of age with a diagnosis of septic arthritis who were receiving corticosteroids in addition to antibiotic therapy or as an adjuvant to other therapies such as surgical drainage, intra-articular puncture, arthroscopic irrigation, or debridement.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility, data extraction, and evaluation of risk of bias. We considered as major outcomes the presence of pain, activities of daily living, normal physical joint function, days of antibiotic treatment, length of hospital stay, and numbers of total and serious adverse events. We used standard methodological procedures expected by Cochrane. We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created a ‘Summary of findings’ table.
MAIN RESULTS: We included two RCTs involving a total of 149 children between three months and 18 years of age who were receiving antibiotics for septic arthritis. The most commonly affected joints were hips and knees. These studies were performed in Costa Rica and Israel. In both studies, dexamethasone administered intravenously (ranging from 0.15 to 0.2 mg/kg/dose every six to eight hours) during four days was the corticosteroid, and the comparator was placebo. Trials excluded patients with any degree of immunodeficiency or immunosuppression. The longest follow-up was one year. Trials did not report activities of daily living nor length of hospital stay. Both studies used adequate processes for randomisation, allocation concealment, and blinding, and review authors judged them to have low risk of selection and performance bias. Losses to follow-up were substantive in both studies, and we judged them to have high risk of attrition bias and of selective outcome reporting. We graded all outcomes as low quality due to concerns about study limitations and imprecision.The risk ratio (RR) for absence of pain at 12 months of follow-up was 1.33, favouring corticosteroids (95% confidence interval (CI) 1.03 to 1.72; P = 0.03; number needed to treat for an additional beneficial outcome (NNTB) = 13, 95% CI 6 to 139; absolute risk difference 24%, 95% CI 5% to 43%).The RR for normal function of the affected joint at 12 months of follow-up was 1.32, favouring corticosteroids (95% CI 1.12 to 1.57; P = 0.001; NNTB = 13, 95% CI 7 to 33; absolute risk difference 24%, 95% CI 11% to 37%).We found a reduction in the number of days of intravenous antibiotic treatment favouring corticosteroids (mean difference (MD) -2.77, 95% CI -4.16 to -1.39) based on two trials with 149 participants.Researchers did not report length of hospital stay. One trial (49 participants) reported that treatment with dexamethasone was associated with a shorter duration of IV antibiotic treatment, leading to a shorter hospital stay, and although duration of hospitalisation was a primary outcome of the study, study authors did not provide data on the duration of hospitalisation. We downgraded the quality by one level for concerns about study limitations (high risk of attrition bias and selective reporting), and by another level for imprecision.In one trial of 49 participants, researchers followed 29 children for 12 months, and parents reported that no children demonstrated adverse effects of the intervention.
AUTHORS’ CONCLUSIONS: Evidence for corticosteroids as adjunctive therapy in children with a diagnosis of septic arthritis is of low quality and is derived from the findings of two trials (N = 149). Corticosteroids may increase the proportion of patients without pain and the proportion of patients with normal function of the affected joint at 12 months, and may also reduce the number of days of antibiotic treatment. However, we cannot draw strong conclusions based upon these trial results. Additional randomised clinical trials in children with relevant outcomes are needed.

PMID: 30480764 [PubMed – as supplied by publisher]

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Hippo Pathway Kinase Mst1 Is Required for Long-Lived Humoral Immunity.

J Immunol. 2018 Nov 26;:

Authors: Yazdchi SB, Witalis M, Meli AP, Leung J, Li X, Panneton V, Chang J, Li J, Nutt SL, Johnson RL, Lim DS, Gu H, King IL, Suh WK

Abstract
The protein kinase Mst1 is a key component of the evolutionarily conserved Hippo pathway that regulates cell survival, proliferation, differentiation, and migration. In humans, Mst1 deficiency causes primary immunodeficiency. Patients with MST1-null mutations show progressive loss of naive T cells but, paradoxically, mildly elevated serum Ab titers. Nonetheless, the role of Mst1 in humoral immunity remains poorly understood. In this study, we found that early T cell-dependent IgG1 responses in young adult Mst1-deficient mice were largely intact with signs of impaired affinity maturation. However, the established Ag-specific IgG1 titers in Mst1-deficient mice decayed more readily because of a loss of Ag-specific but not the overall bone marrow plasma cells. Despite the impaired affinity and longevity of Ag-specific Abs, Mst1-deficient mice produced plasma cells displaying apparently normal maturation markers with intact migratory and secretory capacities. Intriguingly, in immunized Mst1-deficient mice, T follicular helper cells were hyperactive, expressing higher levels of IL-21, IL-4, and surface CD40L. Accordingly, germinal center B cells progressed more rapidly into the plasma cell lineage, presumably forgoing rigorous affinity maturation processes. Importantly, Mst1-deficient mice had elevated levels of CD138+Blimp1+ splenic plasma cell populations, yet the size of the bone marrow plasma cell population remained normal. Thus, overproduced low-affinity plasma cells from dysregulated germinal centers seem to underlie humoral immune defects in Mst1-deficiency. Our findings imply that vaccination of Mst1-deficient human patients, even at the early stage of life, may fail to establish long-lived high-affinity humoral immunity and that prophylactic Ab replacement therapy can be beneficial to the patients.

PMID: 30478091 [PubMed – as supplied by publisher]

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Primary intraspinal non-Hodgkin’s lymphoma: Case report and review of literature.

J Clin Neurosci. 2018 Nov 21;:

Authors: Beume LA, Wolf K, Urbach H, Klingler JH, Staszewski O, Marks R, Weiller C, Rauer S, Hosp JA

Abstract
We present the unique case of an 67-year-old female patient with primary intraspinal B-cell non-Hodgkin’s lymphoma without cerebral manifestation mimicking myelitis in clinical presentation and neuroradiological diagnostic. It illustrates the broad spectrum of differential diagnoses for paraplegia and the importance of rapid interdisciplinary diagnostic work-up since the neurologic status after treatment mainly depends on the delay of treatment. Review of existing literature suggests combined radio- and chemotherapy as well as high-dose intravenous methotrexate or rituximab. The rising incidence of spinal lymphomas especially in patients with acquired immunodeficiency underlines the importance of fast diagnosis and initiation of treatment of this rare entity.

PMID: 30472338 [PubMed – as supplied by publisher]

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Transplantation of Hematopoietic Stem Cells for Primary Immunodeficiencies in Brazil: Challenges in Treating Rare Diseases in Developing Countries.

J Clin Immunol. 2018 Nov 24;:

Authors: Fernandes JF, Nichele S, Daudt LE, Tavares RB, Seber A, Kerbauy FR, Koliski A, Loth G, Vieira AK, Darrigo-Junior LG, Rocha V, Gomes AA, Colturato V, Mantovani LF, Ribeiro AF, Ribeiro LL, Kuwahara C, Rodrigues ALM, Zecchin VG, Costa-Carvalho BT, Carneiro-Sampaio M, Condino-Neto A, Fasth A, Gennery A, Pasquini R, Hamerschlak N, Bonfim C

Abstract
The results of hematopoietic stem cell transplant (HSCT) for primary immunodeficiency diseases (PID) have been improving over time. Unfortunately, developing countries do not experience the same results. This first report of Brazilian experience of HSCT for PID describes the development and results in the field. We included data from transplants in 221 patients, performed at 11 centers which participated in the Brazilian collaborative group, from July 1990 to December 2015. The majority of transplants were concentrated in one center (n = 123). The median age at HSCT was 22 months, and the most common diseases were severe combined immunodeficiency (SCID) (n = 67) and Wiskott-Aldrich syndrome (WAS) (n = 67). Only 15 patients received unconditioned transplants. Cumulative incidence of GVHD grades II to IV was 23%, and GVHD grades III to IV was 10%. The 5-year overall survival was 71.6%. WAS patients had better survival compared to other diseases. Most deaths (n = 53) occurred in the first year after transplantation mainly due to infection (55%) and GVHD (13%). Although transplant for PID patients in Brazil has evolved since its beginning, we still face some challenges like delayed diagnosis and referral, severe infections before transplant, a limited number of transplant centers with expertise, and resources for more advanced techniques. Measures like newborn screening for SCID may hasten the diagnosis and ameliorate patients’ conditions at the moment of transplant.

PMID: 30470982 [PubMed – as supplied by publisher]

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