Research

CADM1/TSLC1 Identifies HTLV-1-Infected Cells and Determines Their Susceptibility to CTL-Mediated Lysis.

June 2, 2017 By Manish Butte

CADM1/TSLC1 Identifies HTLV-1-Infected Cells and Determines Their Susceptibility to CTL-Mediated Lysis.

PLoS Pathog. 2016 Apr;12(4):e1005560

Authors: Manivannan K, Rowan AG, Tanaka Y, Taylor GP, Bangham CR

Abstract
Human T cell lymphotropic virus-1 (HTLV-1) primarily infects CD4+ T cells, causing inflammatory disorders or a T cell malignancy in 5% to 10% of carriers. The cytotoxic T lymphocyte (CTL) response is a key factor that controls the viral load and thus the risk of disease. The ability to detect the viral protein Tax in primary cells has made it possible to estimate the rate at which Tax-expressing infected cells are eliminated by CTLs in persistently infected people. However, most HTLV-1-infected cells are Tax-at a given time, and their immunophenotype is poorly defined. Here, we aimed to identify a cell-surface molecule expressed by both Tax+ and Tax-HTLV-1-infected cells and use it to analyse the CTL response in fresh peripheral blood mononuclear cells. Cell adhesion molecule 1 (CADM1/TSLC1) was the best single marker of HTLV-1 infection, identifying HTLV-1-infected cells with greater sensitivity and specificity than CD25, CCR4 or ICAM-1. CADM1+CD4+ T cells carried a median of 65% of proviral copies in peripheral blood. In a cohort of 23 individuals, we quantified the rate of CTL-mediated killing of Tax+ and Tax-CADM1+ cells. We show that CADM1 expression is associated with enhanced susceptibility of infected cells to CTL lysis: despite the immunodominance of Tax in the CTL response, Tax+CADM1- cells were inefficiently lysed by CTLs. Upregulation of the CADM1 ligand CRTAM on CD8+ T cells correlated with efficient lysis of infected cells. Tax-CADM1+ cells were lysed at a very low rate by autologous CTLs, however, were efficiently killed when loaded with exogenous peptide antigen. High expression of CADM1 on most HTLV-1-infected cells in the face of enhanced CTL counterselection implies that CADM1 confers a strong benefit on the virus.

PMID: 27105228 [PubMed – indexed for MEDLINE]

[Primary Immunodeficiency in Adults].

June 1, 2017 By Manish Butte

[Primary Immunodeficiency in Adults].

Dtsch Med Wochenschr. 2017 Jun;142(11):829-832

Authors: Salzer U, Warnatz K

PMID: 28564736 [PubMed – in process]

Life-Threatening Pneumopathy and U urealyticum in a STAT3-deficient Hyper-IgE Syndrome Patient.

June 1, 2017 By Manish Butte

Life-Threatening Pneumopathy and U urealyticum in a STAT3-deficient Hyper-IgE Syndrome Patient.

Pediatrics. 2017 May 17;:

Authors: Deverrière G, Lemée L, Grangé S, Boyer S, Picard C, Fischer A, Marguet C

Abstract
A deficiency in signal transducer and activator of transcription 3 (STAT3) is responsible for autosomal dominant hyperimmunoglobulin E syndrome, an immunodeficiency syndrome causing Staphylococcus aureus, Streptococcus pneumonia, Haemophilus influenzae, and, rarely, Pseudomonas aeruginosa and Aspergillus sp infections. Currently, intracellular pathogens are not targeted in the management of severe infections. The pathophysiologic mechanism of hyperimmunoglobulin E syndrome immunodeficiency has recently been linked to a disorder in the T helper 17 pathway and disruption of the interleukin -23/interleukin-17 axis. We report an unusual case of severe pleuropneumopathy by Ureaplasma urealyticum in a teenage girl with STAT3-deficient hyperimmunoglobulin E syndrome (STAT3 HIES). A previous case of severe lung infection by Mycoplasma pneumoniae has already been described in a STAT3-deficient patient, but U urealyticum has never been reported in patients with STAT3 HIES. After a review of the literature, it seems that the specific immunodeficiency pathway of STAT3 HIES exposes STAT3 HIES patients to Ureaplasma lung infections because the pathophysiology of STAT3 HIES and Ureaplasma is based on STAT3 and T helper 17 cells.

PMID: 28562253 [PubMed – as supplied by publisher]

Reversible and cachexia-associated feline skin fragility syndrome in three cats.

June 1, 2017 By Manish Butte

Reversible and cachexia-associated feline skin fragility syndrome in three cats.

Vet Dermatol. 2017 May 31;:

Authors: Furiani N, Porcellato I, Brachelente C

Abstract
BACKGROUND: Feline skin fragility syndrome (FSFS) is an acquired disorder characterized by altered collagen production resulting in an extremely thin and fragile skin. FSFS is associated with diseases characterized by excessive steroidal hormones that can inhibit collagen synthesis. It is also described concomitantly with severe inflammatory, infectious or neoplastic conditions where the pathogenesis remains largely unknown.
OBJECTIVES: To describe three cases of FSFS in cats that become cachectic secondary to different causes without glucocorticoid involvement. To describe the histopathological features of connective tissue for both fragile skin and the skin after healing.
RESULTS: All cats developed cachexia in less than two months (body condition score ranging from 1-1.5). Concomitant diseases were diagnosed in Case 1 (aspiration pneumonia due to mega-oesophagus) and Case 2 (feline immunodeficiency virus (FIV)). In Case 3, malnutrition was suspected as a primary cause. The main histological feature of fragile skin was an atrophic dermis with pale eosinophilic, thin and irregular collagen fibres with numerous red cores observed with Masson’s stain. Elastic fibres were normal. Postrecovery histopathological findings at 11 (Case 1) and six months (Case 3) after diagnosis, indicated normalization of the collagen and of the whole skin as compared with controls.
CONCLUSIONS AND CLINICAL IMPORTANCE: To the best of the authors’ knowledge, this is the first report describing a reversible, nonsteroid-induced FSFS, associated with rapidly developing cachexia in cats.

PMID: 28560784 [PubMed – as supplied by publisher]

Major CD4 T-Cell Depletion and Immune Senescence in a Patient with Chronic Granulomatous Disease.

May 30, 2017 By Manish Butte

Major CD4 T-Cell Depletion and Immune Senescence in a Patient with Chronic Granulomatous Disease.

Front Immunol. 2017;8:543

Authors: Albuquerque AS, Fernandes SM, Tendeiro R, Cheynier R, Lucas M, Silva SL, Victorino RMM, Sousa AE

Abstract
Chronic granulomatous disease (CGD) results from primary defects in phagocytic reactive oxygen species (ROS) production. T-cell evaluation is usually neglected during patients’ follow-up, although T-cell depletion has been reported in CGD through unknown mechanisms. We describe here a 36-year-old patient with X-linked CGD with severe CD4 T-cell depletion <200 CD4 T-cells/μl, providing insights into the mechanisms that underlie T-cell loss in the context of oxidative burst defects. In addition to the typical infections, the patient featured a progressive T-cell loss associated with persistent lymphocyte activation, expansion of interleukin (IL)-17-producing CD4 T-cells, and impaired thymic activity, leading to a reduced replenishment of the T-cell pool. A relative CD4 depletion was also found at the gut mucosal level, although no bias to IL-17-production was documented. This immunological pattern of exhaustion of immune resources favors prompt, potentially curative, therapeutic interventions in CGD patients, namely, stem-cell transplantation or gene therapy. Moreover, this clinical case raises new research questions on the interplay of ROS production and T-cell homeostasis and immune senescence.

PMID: 28553289 [PubMed – in process]

Novel RAG1 mutation and the occurrence of mycobacterial and Chromobacterium violaceum infections in a case of leaky SCID.

May 30, 2017 By Manish Butte

Novel RAG1 mutation and the occurrence of mycobacterial and Chromobacterium violaceum infections in a case of leaky SCID.

Microb Pathog. 2017 May 25;:

Authors: Khan TA, Ishfaq M, Iqbal A, Rahman H, Cabral-Marques O, Muhammad N

Abstract
Severe combined immunodeficiency (SCID) is a potentially fatal primary immunodeficiency (PID) that is caused by mutations in genes such as IL2RG, JAK3, IL7RA, RAG1, RAG2, and ADA. The products of these genes are involved in the development of several immune cells such as T, B and natural killer (NK) cells. Most of the SCID forms are autosomal recessive with the exception of IL2RG defects that cause an X-linked SCID. Among the different SCID types, there is a rare SCID form called leaky SCID, which is less severe when compared to the other classical SCID phenotypes. Leaky SCID can be caused by hypomorphic mutations in RAG1 and RAG2 that result in only partial loss of enzymatic function of the proteins respectively encoded by these genes. Here we report a novel missense mutation (c. 307C > T/p.H103Y) in the RAG1 gene in a patient with leaky SCID. In addition, we characterize the clinical and immunological features of this patient that developed along with other severe and recurrent infections such as mycobacterial diseases (BCGitis and pulmonary tuberculosis), the first occurrence of Chromobacterium violaceum in a patient with SCID. Understanding the increased susceptibility to mycobacteria presented by the patient, in which a functional investigation of IL-12/IFN-γ axis was performed, which demonstrated reduced production of IFN-γ in the supernatans of peripheral blood mononuclear cell cultures from the patient compared with those from healthy subjects. In conclusion, our data expands the molecular and clinical spectrum associated with the leaky SCID phenotype.

PMID: 28552805 [PubMed – as supplied by publisher]

Hematopoietic Stem Cell Transplantation For RelB Deficiency.

May 30, 2017 By Manish Butte

Hematopoietic Stem Cell Transplantation For RelB Deficiency.

J Allergy Clin Immunol. 2017 May 25;:

Authors: Ovadia A, Schejter YD, Grunebaum E, Kim VH, Reid B, Schechter T, Pope E, Roifman CM

Abstract
HSCT conditioning is tolerated well by patients with RelB deficiency and leads to immune reconstitution.

PMID: 28552761 [PubMed – as supplied by publisher]

Primary immune deficiencies with defects in neutrophil function.

May 30, 2017 By Manish Butte

Primary immune deficiencies with defects in neutrophil function.

Hematology Am Soc Hematol Educ Program. 2016 Dec 02;2016(1):43-50

Authors: Dinauer MC

Abstract
Immune deficiencies resulting from inherited defects in neutrophil function have revealed important features of the innate immune response. Although sharing an increased susceptibility to bacterial and fungal infections, these disorders each have distinctive features in their clinical manifestations and characteristic microbial pathogens. This review provides an update on several genetic disorders with impaired neutrophil function, their pathogenesis, and treatment strategies. These include chronic granulomatous disease, which results from inactivating mutations in the superoxide-generating nicotinamide dinucleotide phosphate oxidase. Superoxide-derived oxidants play an important role in the control of certain bacterial and fungal species, and also contribute to the regulation of inflammation. Also briefly summarized are updates on leukocyte adhesion deficiency, including the severe periodontal disease characteristic of this disorder, and a new immune deficiency associated with defects in caspase recruitment domain-containing protein 9, an adaptor protein that regulates signaling in neutrophils and other myeloid cells, leading to invasive fungal disease.

PMID: 27913461 [PubMed – indexed for MEDLINE]

Encephalitis associated with human herpesvirus-7 infection in an immunocompetent adult.

May 27, 2017 By Manish Butte

Encephalitis associated with human herpesvirus-7 infection in an immunocompetent adult.

Virol J. 2017 May 25;14(1):97

Authors: Parra M, Alcala A, Amoros C, Baeza A, Galiana A, Tarragó D, García-Quesada MÁ, Sánchez-Hellín V

Abstract
BACKGROUND: Primary Human herpesvirus-7 (HHV-7) infection usually occurs during childhood and causes several clinical manifestations: mainly exanthem subitum (roseola infantum), followed by a lifelong latent state with possible reactivation in case of immunodeficiency. Nevertheless, some considerably different approaches exist regarding the natural history of HHV-7 and the possible consequences of HHV-7 infection in immunocompetent adults. In particular, little is known about its pathogenic role in central nervous system (CNS) disease in nonimmunosuppressed adults. Specifically, in case of encephalitis, it is important to distinguish between infectious encephalitis and postinfectious encephalomyelitis for the management of patients CASE PRESENTATION: We describe here a case of encephalitis associated to human herpesvirus-7 with associated polymyeloradiculopathy in an immunocompetent patient which may contribute to the delineation of the approach to a patient profile with a similar clinical presentation and evolution to those presented in the literature.
CONCLUSIONS: This case may alert clinicians to consider this specific etiology in the differential diagnosis of encephalopathy in patients with suspected infectious encephalitis who do not respond to acyclovir or in patients who develop acute polymyeloradiculopathy, considering that HHV-7 may be a pathological factor and that a timely diagnosis is crucial for the early administration of specific treatment.

PMID: 28545483 [PubMed – in process]

Development of real-time RT-PCR assays for detection of three classes of HHV-6A gene transcripts.

May 26, 2017 By Manish Butte

Development of real-time RT-PCR assays for detection of three classes of HHV-6A gene transcripts.

J Med Virol. 2017 May 23;:

Authors: Ihira M, Urashima A, Miura H, Hattori F, Kawamura Y, Sugata K, Yoshikawa T

Abstract
Human herpesvirus 6 (HHV-6), a member of the betaherpesvirus family, has two distinct species: HHV-6A and HHV-6B. HHV-6B real-time reverse transcription polymerase chain reaction (RT-PCR) has been used to distinguish between active and latent viral infection. In this study, we developed a real-time RT-PCR assay to detect HHV-6A-specific transcripts and evaluated its reliability for analysis of clinical samples. To develop HHV-6A-specific real-time RT-PCR assays, three different classes of gene transcripts (immediate early: U90; early: U12; and late: U100) were selected as targets. Serial dilutions of plasmid DNAs containing target sequences and RNAs extracted from HHV-6A-infected cells were used to determine assay specificity and sensitivity. Peripheral blood mononuclear cells (PBMCs) collected from patients with either primary or reactivated HHV-6B infection, and one patient with X-linked severe combined immunodeficiency (X-SCID) with HHV-6A reactivation, were used to evaluate assay reliability. The HHV-6A-specific real-time RT-PCR assays amplified plasmids containing the target sequences at concentrations between 10 and 1 × 10(6) copies per reaction. The intra-assay coefficients of variation were less than 5%. The three classes of HHV-6A gene transcripts were not detected in any HHV-6B sample isolated from the patients. In the X-SCID patient, high copy numbers of HHV-6A U12 and U100 transcripts were detected in PBMC samples during viremia. Thus, we successfully established highly sensitive and reproducible real-time RT-PCR methods targeting three classes of HHV-6A gene transcripts. This method should be useful for discriminating active HHV-6A infection from either latent infection or chromosomally integrated HHV-6A (ciHHV-6A). This article is protected by copyright. All rights reserved.

PMID: 28543733 [PubMed – as supplied by publisher]