Research

Unbalanced Immune System: Immunodeficiencies and Autoimmunity.

Front Pediatr. 2016;4:107

Authors: Giardino G, Gallo V, Prencipe R, Gaudino G, Romano R, De Cataldis M, Lorello P, Palamaro L, Di Giacomo C, Capalbo D, Cirillo E, D’Assante R, Pignata C

Abstract
Increased risk of developing autoimmune manifestations has been identified in different primary immunodeficiencies (PIDs). In such conditions, autoimmunity and immune deficiency represent intertwined phenomena that reflect inadequate immune function. Autoimmunity in PIDs may be caused by different mechanisms, including defects of tolerance to self-antigens and persistent stimulation as a result of the inability to eradicate antigens. This general immune dysregulation leads to compensatory and exaggerated chronic inflammatory responses that lead to tissue damage and autoimmunity. Each PID may be characterized by distinct, peculiar autoimmune manifestations. Moreover, different pathogenetic mechanisms may underlie autoimmunity in PID. In this review, the main autoimmune manifestations observed in different PID, including humoral immunodeficiencies, combined immunodeficiencies, and syndromes with immunodeficiencies, are summarized. When possible, the pathogenetic mechanism underlying autoimmunity in a specific PID has been explained.

PMID: 27766253 [PubMed – in process]

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Symptomatic Primary Selective IgM Immunodeficiency – B Lymphoid Cell Defect in Adult Man with Secondary HLH Syndrome.

J Assoc Physicians India. 2016 Jul;64(7):91-93

Authors: Agarwal A, Sharma S, Airun M

Abstract
Selective immunoglobulin M deficiency(sIgMD) is a rare form of dysgammaglobulinaemia characterized by an isolated low level of serum immunoglobulin M (IgM). It was an incidence of less than 0.03% in the general population and 1% in hospitalized patients. sIgMD may occur as a primary or secondary condition. sIgMD is much more common than primary .Hemophagocytic lymphohistiocytosis (HLH) is also a rare but potentially fatal disease of normal but overactive histiocytes and lymphocytes and can be primary or secondary, characterized by the overwhelming activation of normal T lymphocytes and macrophages, invariably leading to clinical and hematologic alterations. We report an adult case of primary sIgMD with absent B lymphoid cells and secondary HLH syndrome who presented with recurrent infections, fever and pancytopenia.

PMID: 27759358 [PubMed – in process]

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Dendritic cell analysis in primary immunodeficiency.

Curr Opin Allergy Clin Immunol. 2016 Oct 13;

Authors: Bigley V, Barge D, Collin M

Abstract
PURPOSE OF REVIEW: Dendritic cells are specialized antigen-presenting cells which link innate and adaptive immunity, through recognition and presentation of antigen to T cells. Although the importance of dendritic cells has been demonstrated in many animal models, their contribution to human immunity remains relatively unexplored in vivo.Given their central role in infection, autoimmunity, and malignancy, dendritic cell deficiency or dysfunction would be expected to have clinical consequences.
RECENT FINDINGS: Human dendritic cell deficiency disorders, related to GATA binding protein 2 (GATA2) and interferon regulatory factor 8 (IRF8) mutations, have highlighted the importance of dendritic cells and monocytes in primary immunodeficiency diseases and begun to shed light on their nonredundant roles in host defense and immune regulation in vivo. The contribution of dendritic cell and monocyte dysfunction to the pathogenesis of primary immunodeficiency disease phenotypes is becoming increasingly apparent. However, dendritic cell analysis is not yet a routine part of primary immunodeficiency disease workup.
SUMMARY: Widespread uptake of dendritic cell/monocyte screening in clinical practice will facilitate the discovery of novel dendritic cell and monocyte disorders as well as advancing our understanding of human dendritic cell biology in health and disease.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0.

PMID: 27755182 [PubMed – as supplied by publisher]

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Chronic Norovirus Infection and Common Variable Immunodeficiency.

Clin Exp Immunol. 2016 Oct 18;:

Authors: Woodward J, Gkrania-Klotsas E, Kumararatne D

Abstract
Chronic infection with Norovirus is emerging as a significant risk for patients with immunodeficiency – either primary or secondary to therapeutic immunosuppression. Patients with primary immunodeficiency present a range of pathological responses to Norovirus infection. Asymptomatic infections occur and differentiating viral carriage or prolonged viral shedding after self-limiting infection from infection causing protracted diarrhoea can be challenging due to relatively mild pathological changes that may mimic other causes of diarrhoea in such patients (for instance pathogenic bacteria or parasites or graft-versus-host disease). However, a subset of patients with Common Variable Immunodeficiency (CVID) experience a severe Norovirus-associated enteropathy leading to intestinal villous atrophy and malabsorption. Symptomatic infection of up to 8 years has been demonstrated with clinical and histological recovery on viral clearance. Although oral immunoglobulins and Nitazoxanide have been used to treat Noroviral infections associated with immunosuppression, Ribavirin is the only agent to date that has been linked to viral clearance in the Noroviral enteropathy associated with CVID. This article is protected by copyright. All rights reserved.

PMID: 27753065 [PubMed – as supplied by publisher]

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Novel tools for primary immunodeficiency diagnosis: making a case for deep profiling.

Curr Opin Allergy Clin Immunol. 2016 Oct 5;

Authors: Hsieh EW, Hernandez JD

Abstract
PURPOSE OF REVIEW: This review gives an overview of the systems-immunology single-cell proteomic and transcriptomic approaches that can be applied to study primary immunodeficiency. It also introduces recent advances in multiparameter tissue imaging, which allows extensive immune phenotyping in disease-affected tissue.
RECENT FINDINGS: Mass cytometry is a variation of flow cytometry that uses rare earth metal isotopes instead of fluorophores as tags bound to antibodies, allowing simultaneous measurement of over 40 parameters per single-cell. Mass cytomety enables comprehensive single-cell immunophenotyping and functional assessments, capturing the complexity of the immune system, and the molecularly heterogeneous consequences of primary immunodeficiency defects. Protein epitopes and transcripts can be simultaneously detected allowing immunophenotype and gene expression evaluation in mixed cell populations. Multiplexed epitope imaging has the potential to provide extensive phenotypic characterization at the subcellular level, in the context of 3D tissue microenvironment.
SUMMARY: Mass cytometry and multiplexed epitope imaging can complement genetic methods in diagnosis and study of the pathogenesis of primary immunodeficiencies. The ability to understand the effect of a specific defect across multiple immune cell types and pathways, and in affected tissues, may provide new insight into tissue-specific disease pathogenesis and evaluate effects of therapeutic interventions.

PMID: 27749361 [PubMed – as supplied by publisher]

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Requirements for human natural killer cell development informed by primary immunodeficiency.

Curr Opin Allergy Clin Immunol. 2016 Oct 5;

Authors: Mace EM

Abstract
PURPOSE OF REVIEW: Human natural killer (NK) cell development is poorly understood; however, we gain important insight from cases of human primary immunodeficiency that affect the generation of mature human NK cell subsets. In this review, monogenic primary immunodeficiencies that highlight critical requirements for human NK cell development are discussed.
RECENT FINDINGS: Increased resolution in NK cell phenotyping has revealed NK cell deficiencies that affect the distribution of NK cell subsets found in peripheral blood. These, in addition to those that prevent the generation of mature NK cells, identify important requirements for the maturation and homeostasis of human NK cells. The serious and often life-threatening viral susceptibility that accompanies these highlights the nonredundant role that NK cells play in human health and disease.
SUMMARY: Human NK cell deficiency may occur in cases where NK cells are present in normal numbers but subsets are affected.

PMID: 27749362 [PubMed – as supplied by publisher]

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Severe Epstein-Barr virus infection in primary immunodeficiency and the normal host.

Br J Haematol. 2016 Oct 17;:

Authors: Worth AJ, Houldcroft CJ, Booth C

Abstract
Epstein-Barr virus (EBV) infection is ubiquitous in humans, but the majority of infections have an asymptomatic or self-limiting clinical course. Rarely, individuals may develop a pathological EBV infection with a variety of life threatening complications (including haemophagocytosis and malignancy) and others develop asymptomatic chronic EBV viraemia. Although an impaired ability to control EBV infection has long been recognised as a hallmark of severe T-cell immunodeficiency, the advent of next generation sequencing has identified a series of Primary Immunodeficiencies in which EBV-related pathology is the dominant feature. Chronic active EBV infection is defined as chronic EBV viraemia associated with systemic lymphoproliferative disease, in the absence of immunodeficiency. Descriptions of larger cohorts of patients with chronic active EBV in recent years have significantly advanced our understanding of this clinical syndrome. In this review we summarise the current understanding of the pathophysiology and natural history of these diseases and clinical syndromes, and discuss approaches to the investigation and treatment of severe or atypical EBV infection.

PMID: 27748521 [PubMed – as supplied by publisher]

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Targeted Sequencing and Immunological Analysis Reveal the Involvement of Primary Immunodeficiency Genes in Pediatric IBD: a Japanese Multicenter Study.

J Clin Immunol. 2016 Oct 17;

Authors: Suzuki T, Sasahara Y, Kikuchi A, Kakuta H, Kashiwabara T, Ishige T, Nakayama Y, Tanaka M, Hoshino A, Kanegane H, Abukawa D, Kure S

Abstract
PURPOSE: Pediatric inflammatory bowel disease (IBD) is a heterogeneous disorder caused by multiple factors. Although genetic and immunological analyses are required for a definitive diagnosis, no reports of a comprehensive genetic study of a Japanese population are available.
METHODS: In total, 35 Japanese patients <16 years of age suffering from IBD, including 27 patients aged <6 years with very early-onset IBD, were enrolled in this multicenter study. Exome and targeted gene panel sequencing was performed for all patients. Mutations in genes responsible for primary immunodeficiency diseases (PID) and clinical and immunological parameters were evaluated according to disease type.
RESULTS: We identified monogenic mutations in 5 of the 35 patients (14.3 %). We identified compound heterozygous and homozygous splice-site mutations in interleukin-10 receptor A (IL-10RA) in two patients, nonsense mutations in X-linked inhibitor of apoptosis protein (XIAP) in two patients, and a missense mutation in cytochrome b beta chain in one patient. Using assays for protein expression levels, IL-10 signaling, and cytokine production, we confirmed that the mutations resulted in loss of function. For each patient, genotype was significantly associated with clinical findings. We successfully treated a patient with a XIAP mutation by allogeneic cord blood hematopoietic stem cell transplantation, and his symptoms were ameliorated completely.
CONCLUSIONS: Targeted sequencing and immunological analysis are useful for screening monogenic disorders and selecting curative therapies in pediatric patients with IBD. The genes responsible for PID are frequently involved in pediatric IBD and play critical roles in normal immune homeostasis in the gastrointestinal tract.

PMID: 27747465 [PubMed – as supplied by publisher]

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The Role of Exercise in a Weight-loss Program on Clinical Control in Obese Adults with Asthma: a RCT.

Am J Respir Crit Care Med. 2016 Jul 19;

Authors: Freitas PD, Ferreira PG, Silva AG, Stelmach R, Carvalho-Pinto RM, Fernandes FL, Mancini MC, Sato MN, Martins MA, Carvalho CR

Abstract
RATIONALE: Clinical control is difficult to achieve in obese patients with asthma. Bariatric surgery has been recommended for weight-loss and to improve asthma control; however, the benefits of nonsurgical interventions have been poorly investigated.
OBJECTIVE: To examine the effect of exercise training in a weight-loss program on asthma control, quality of life, inflammatory biomarkers and lung function.
METHODS: Fifty-five obese patients with asthma were randomly assigned to either a weight-loss program + exercise (WL+E group, n=28) or a weight-loss program + sham (WL+S group, n=27) group, where the weight-loss program included nutrition (caloric restriction) and psychological therapies. The WL+E group incorporated aerobic and resistance muscle training, whereas the WL+S group incorporated breathing and stretching exercises.
MEASUREMENTS: The primary outcome was clinical improvement in asthma control over 3 months. Secondary outcomes included quality of life, lung function, body composition, aerobic capacity, muscle strength and inflammatory/anti-inflammatory biomarkers.
MAIN RESULTS: After 3 months, 51 patients were analyzed. Compared with the WL+S group, the WL+E group demonstrated improved clinical control scores (-0.7 [-1.3, -0.3] vs. -0.3 [-0.9, 0.4]; P=0.01) and greater weight-loss (-6.8%±3.5 vs. -3.1%±2.6; P<0.001) and aerobic capacities (3.0 [2.4, 4.0] vs. 0.9 [-0.3, 1.3] mL O2.kg.min-1; P<0.001). These improvements in the WL+E group were also accompanied by improvements in lung function, anti-inflammatory biomarkers and vitamin D levels, as well as reductions in airway and systemic inflammation.
CONCLUSIONS: Adding exercise to a short-term weight-loss program should be considered as a useful strategy to achieving clinical control of asthma in obese patients. Clinical trial registration available at www.clinicaltrials.gov, ID NCT02188940.

PMID: 27744739 [PubMed – as supplied by publisher]

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Vaccination practices in patients with inflammatory bowel disease among general internal medicine physicians in the USA.

Postgrad Med J. 2016 Oct 12;:

Authors: Gurvits GE, Lan G, Tan A, Weissman A

Abstract
BACKGROUND: Increasing prevalence of inflammatory bowel disease (IBD) poses significant challenges to medical community. Preventive medicine, including vaccination against opportunistic infections, is important in decreasing morbidity and mortality in patients with IBD. We conduct first study to evaluate general awareness and adherence to immunisation guidelines by primary care physicians in the USA.
METHODS: We administered an electronic questionnaire to the research panel of the American College of Physicians (ACP) assessing current vaccination practices, barriers to vaccination and provider responsibility for administering vaccinations and compared responses with the European Crohn’s and Colitis Organization consensus guidelines and expert opinion from the USA.
RESULTS: All of surveyed physicians (276) had experience with patients with IBD and spent majority of their time in direct patient care. 49% of physicians took immunisation history frequently or always, and 76% reported never or rarely checking immunisation antibody titres with only 2% doing so routinely. 65% of physicians believed that primary care providers (PCPs) were responsible for determining patient’s immunisation. Vaccine administration was felt to be the duty of primary care doctor 80% of the time. 2.5% of physicians correctly recommended vaccinations all the time. Physicians were more likely to recommend vaccination to immunocompetent than immunocompromised patients. Up to 23% of physicians would incorrectly recommend live vaccine to immunocompromised patients with IBD.
CONCLUSIONS: Current knowledge and degree of comfort among PCPs in the USA in preventing opportunistic infections in IBD population remain low. Management of patients with IBD requires structured approach to their healthcare maintenance in everyday practice, including enhanced educational policy aimed at primary care physicians.

PMID: 27733673 [PubMed – as supplied by publisher]

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