Research

Host genetic factors in susceptibility to mycobacterial disease.

Clin Med. 2014 Dec;14 Suppl 6:s17-21

Authors: Duncan CJ, Hambleton S

Abstract
Primary immunodeficiencies (PID) are a group of rare inherited disorders that manifest as heightened susceptibility to infection, autoimmunity and/or malignancy. By exploring their genetic and cellular aetiology, we can learn much about the basis of pathogen-specific immunity in humans. This is exemplified by mycobacterial susceptibility, which occurs across several types of PID, either as an isolated problem or as part of a broader pattern of susceptibility to infection. These experiments of nature have contributed to our understanding of the central role of T cells in activating infected macrophages to eliminate phagosomal mycobacteria through mutually activating, cytokine-dependent interactions. In recent years, the discovery of novel forms of PID has emphasised the important role of dendritic cells and monocytes in mycobacterial defence in humans. Here, we provide a brief overview of these new disorders alongside other genetic causes of susceptibility to mycobacterial disease.

PMID: 25468913 [PubMed – in process]

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Clinical characteristics, prognostic factors and outcomes of adult patients with hemophagocytic lymphohistiocytosis.

Am J Hematol. 2014 Dec 2;

Authors: Otrock ZK, Eby CS

Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome characterized by the activation of the mononuclear phagocytic system. The diagnosis of HLH in adults is challenging not only because the majority of the reported data are from pediatric patients, but also because HLH occurs in many disease entities. We report the clinical and laboratory findings and prognostic factors of adult HLH in a large cohort managed at Barnes-Jewish Hospital from 2003 to 2014. Seventy-three patients met the HLH-2004 diagnostic criteria. The median age was 51 years (range, 18-82); 41 (56.2%) were male. Patients manifested fever, cytopenias and elevated ferritin in >85% of cases. Likely causes of HLH were as follows: 30 (41.1%) infections, 21 (28.8%) malignancies, 5 (6.8%) attributed to autoimmune disorders, 1 (1.4%) primary immunodeficiency, 2 (2.7%) post solid organ transplantation, and 13 (17.8%) idiopathic. The median overall survival was 7.67 months. Patients with malignancy-associated HLH had a markedly worse survival compared to patients with non-malignancy-associated HLH (median overall survival 1.13 vs. 46.53 months, respectively; p < 0.0001). In a multivariable analysis malignancy (HR = 12.22; 95% CI: 2.53-59.02; p = 0.002) correlated with poor survival. Ferritin >50,000 mcg/L correlated with 30-day mortality. Survival after a diagnosis of HLH is dismal, especially among those with malignancy-associated HLH. The development of a registry for adults with HLH would improve our understanding of this syndrome, validate diagnostic criteria, and help develop effective treatment strategies. This article is protected by copyright. All rights reserved.

PMID: 25469675 [PubMed – as supplied by publisher]

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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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Attitudes toward allergy: what do the pediatricians think?

Ann Allergy Asthma Immunol. 2014 Nov;113(5):544-8

Authors: Convers KD, Slavin RG

Abstract
BACKGROUND: In 1971, we published a survey regarding pediatricians’ attitudes toward the field of allergy/immunology (A/I). Results indicated general attitudes and practices fell short of what most allergist-immunologists would hope. We revisited this in 1998 to determine how pediatricians’ attitudes toward A/I had changed nearly 3 decades later. Despite some advances, results from 1998 revealed that A/I remained a misunderstood specialty. With the increasing incidence of atopic disorders and improving awareness of primary immunodeficiency, it is more important today than ever before that pediatricians and general practitioners have a strong appreciation for the scope of disorders the subspecialty of A/I encompasses.
OBJECTIVE: To reevaluate attitudes and practices of pediatricians toward A/I 40 years after the initial study and 13 years after this topic was last addressed.
METHODS: A 25-question survey was mailed to 293 pediatricians in the St Louis area. Surveys were completed confidentially. Pearson correlation and χ(2) analyses were performed.
RESULTS: Of 293 pediatricians polled, 135 (46%) responded. Referrals to allergist-immunologists for urticaria have increased. Fewer pediatricians are referring asthma and atopic dermatitis patients to allergist-immunologists. Personal experience referring to an allergist-immunologist remains the greatest influence on current attitudes toward A/I. Prior exposure to A/I during medical education continues to have the least influence on pediatricians’ attitudes toward A/I.
CONCLUSION: Increased appropriate referrals and improved patient outcomes could result from efforts to enhance A/I education during medical school and residency, maintain effective communication with referring physicians, and break down referral barriers to improve physicians’ attitudes toward A/I.

PMID: 25442696 [PubMed – in process]

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PUMA is invovled in ischemia/reperfusion-induced apoptosis of mouse cerebral astrocytes.

Neuroscience. 2014 Nov 5;284C:824-832

Authors: Chen H, Tian M, Jin L, Jia H, Jin Y

Abstract
PUMA (p53-upregulated modulator of apoptosis), a BH3-only member of the Bcl-2 protein family, is required for p53-dependent and p53-independent forms of apoptosis. PUMA has been invovled in the onset and progress of several diseases, including cancer, acquired immunodeficiency syndrome, and ischemic brain disease. Although many studies have shown that ischemia and reperfusion (I/R) can induce the apoptosis of astrocytes, the role of PUMA in I/R-mediated apoptosis of cerebral astrocyte apoptosis remains unclear. To mimic in vivo I/R conditions, primary mouse cerebral astrocytes were incubated in a combinational cultural condition of oxygen, glucose, and serum deprivation (OSGD) for 1h followed by reperfusion (OSGD/R). Cell death determination assays and cell viability assays indicated that OSGD and OSGD/R induce the apoptosis of primary cerebral astrocytes. The expression of PUMA was significantly elevated in primary cerebral astrocytes during OSGD/R. Moreover, targeted down-regulation of PUMA by siRNA transfection significantly decreased the OSGD/R-induced apoptosis of primary cerebral astrocytes. We also found that OSGD and OSGD/R triggered the release of cytochrome c in astrocytes, indicating the dependence on a mitochondrial apoptotic pathway. Reactive oxygen species (ROS) was extremely generated during OSGD and OSGD/R, and the elimination of ROS by treated with N-acetyl-L-cysteine (NAC) remarkably inhibited the expression of PUMA and the apoptosis of primary cerebral astrocytes. The activation of Caspase 3 and Caspase 9 was extremely elevated in primary cerebral astrocytes during OSGD. In addition, we found that knockdown of PUMA led to the depressed expression of Bax, cleaved caspase-9 and caspase-3 during OSGD/R. These results indicate that PUMA is invovled in the apoptosis of cerebral astrocytes upon I/R injury.

PMID: 25451294 [PubMed – as supplied by publisher]

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Mendelian susceptibility to mycobacterial disease: Genetic, immunological, and clinical features of inborn errors of IFN-γ immunity.

Semin Immunol. 2014 Oct 26;26(6):454-470

Authors: Bustamante J, Boisson-Dupuis S, Abel L, Casanova JL

Abstract
Mendelian susceptibility to mycobacterial disease (MSMD) is a rare condition characterized by predisposition to clinical disease caused by weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria, in otherwise healthy individuals with no overt abnormalities in routine hematological and immunological tests. MSMD designation does not recapitulate all the clinical features, as patients are also prone to salmonellosis, candidiasis and tuberculosis, and more rarely to infections with other intramacrophagic bacteria, fungi, or parasites, and even, perhaps, a few viruses. Since 1996, nine MSMD-causing genes, including seven autosomal (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, and IRF8) and two X-linked (NEMO, and CYBB) genes have been discovered. The high level of allelic heterogeneity has already led to the definition of 18 different disorders. The nine gene products are physiologically related, as all are involved in IFN-γ-dependent immunity. These disorders impair the production of (IL12B, IL12RB1, IRF8, ISG15, NEMO) or the response to (IFNGR1, IFNGR2, STAT1, IRF8, CYBB) IFN-γ. These defects account for only about half the known MSMD cases. Patients with MSMD-causing genetic defects may display other infectious diseases, or even remain asymptomatic. Most of these inborn errors do not show complete clinical penetrance for the case-definition phenotype of MSMD. We review here the genetic, immunological, and clinical features of patients with inborn errors of IFN-γ-dependent immunity.

PMID: 25453225 [PubMed – as supplied by publisher]

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Identification of a novel non-coding mutation in C1qB in a Dutch child with C1q deficiency associated with recurrent infections.

Immunobiology. 2014 Oct 18;

Authors: van Schaarenburg RA, Daha NA, Schonkeren JJ, Nivine Levarht EW, van Gijlswijk-Janssen DJ, Kurreeman FA, Roos A, van Kooten C, Koelman CA, Ernst-Kruis MR, Toes RE, Huizinga TW, Lankester AC, Trouw LA

Abstract
INTRODUCTION: C1q deficiency is a rare genetic disorder that is strongly associated with development of systemic lupus erythematosus (SLE). Several mutations in the coding regions of the C1q genes have been described that result in stop-codons or other genetic abnormalities ultimately leading to C1q deficiency. Here we report on a Dutch boy suffering from recurrent infections with a complete C1q deficiency, without any SLE symptoms.
METHODS: The presence of C1q in serum was assessed using ELISA and hemolytic assay. By western blot we examined the different C1q chains in cell lysates. We identified the mutation using deep-sequencing. By qPCR we studied the mRNA expression of C1qA, C1qB and C1qC in the PBMCs of the patient.
RESULTS: Deep-sequencing revealed a homozygous mutation in the non-coding region of C1qB in the patient, whereas both parents were heterozygous. The mutation is located two nucleotides before the splice site of the second exon. In-silico analyses predict a complete abrogation of this natural splice site. Analyses of in vitro cultured cells from the patient revealed a lack of production of C1q and intracellular absence of C1qB in the presence of C1qA and C1qC peptides. Quantitative PCR analysis revealed total absence of C1qB mRNA, a reduced level of C1qA mRNA and normal levels of C1qC mRNA.
CONCLUSION: In this study we report a new mutation in the non-coding region of C1qB that is associated with C1q deficiency.

PMID: 25454803 [PubMed – as supplied by publisher]

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Medical immunology: Two-way bridge connecting bench and bedside.

Immunol Lett. 2014 Oct 16;162(2PB):127-133

Authors: Rijkers GT, Damoiseaux JG, Hooijkaas H

Abstract
Medical immunology in The Netherlands is a laboratory specialism dealing with immunological analyses as well as pre- and post-analytical consultation to clinicians (clinical immunologists and other specialists) involved in patients with immune mediated diseases. The scope of medical immunology includes immunodeficiencies, autoimmune diseases, allergy, transfusion and transplantation immunology, and lymphoproliferative disorders plus the monitoring of these patients. The training, professional criteria, quality control of procedures and laboratories is well organized. As examples of the bridge function of medical immunology between laboratory (bench) and patient (bedside) the contribution of medical immunologists to diagnosis and treatment of primary immunodeficiency diseases (in particular: humoral immunodeficiencies) as well as autoantibodies (anti-citrullinated proteins in rheumatoid arthritis) are given.

PMID: 25455599 [PubMed – as supplied by publisher]

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Hematopoietic Stem Cell Transplantation for Primary Immunodeficiencies.

Hematol Oncol Clin North Am. 2014 Dec;28(6):1157-1170

Authors: Kang E, Gennery A

Abstract
Allogeneic hematopoietic stem cell transplantation has been shown to be curative for well-described as well as newly discovered immunodeficiencies. However, it is difficulty to define a universal transplant regimen given the rarity of these disorders and the varied pathophysiology these disorders encompass. This article discusses those primary immunodeficiencies most commonly treated by hematopoietic stem cell transplant and describes the transplant issues specific to these disorders.

PMID: 25459185 [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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