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Recurrent Respiratory Infections Revealing CD8α Deficiency.

November 14, 2015 By Manish Butte

Recurrent Respiratory Infections Revealing CD8α Deficiency.

J Clin Immunol. 2015 Nov 12;

Authors: Dumontet E, Osman J, Guillemont-Lambert N, Cros G, Moshous D, Picard C

Abstract
CD8A encodes the CD8α chain of the dimeric CD8 protein, a critical coreceptor of cytotoxic T cells. We report here the comprehensive immunological evaluation of a child with a CD8A missense mutation, providing evidence that CD8 deficiency increases susceptibility to recurrent respiratory infections without interfering with the TCR-mediated proliferation of T cells. These observations expand the known phenotypes associated with CD8 deficiency.

PMID: 26563160 [PubMed – as supplied by publisher]

[Rifampicin-resistant Mycobacterium bovis BCG strain isolated from an infant with NEMO mutation].

November 13, 2015 By Manish Butte

[Rifampicin-resistant Mycobacterium bovis BCG strain isolated from an infant with NEMO mutation].

Mikrobiyol Bul. 2015 Apr;49(2):272-7

Authors: Çavuşoğlu C, Edeer Karaca N, Azarsız E, Ulusoy E, Kütükçüler N

Abstract
It is well known that disseminated Mycobacterium bovis BCG infection is developed after BCG vaccination in infants with congenital cellular immune deficiencies such as mutations in genes along the interleukin (IL)-12/interferon (IFN)-γ pathway and mutations in nuclear factor-kB essential modulator (NEMO). In this report, a rifampicin-resistant M.bovis BCG strain isolated from an infant with NEMO defect was presented. An 8-month-old male infant with NEMO defect admitted to the pediatric outpatient clinic of our hospital with fever, generalized lymphadenopathy and hepatosplenomegaly. Microscopic examination of the smears prepared from lymph node and liver biopsy specimens revealed abundant amount (3+) of acid-fast bacilli (AFB). Rifampicin-susceptible Mycobacterium tuberculosis complex (MTC) was detected by real-time PCR (GeneXpert MTB/RIF; Cepheid, USA) in the samples. The growth of mycobacteria was determined on the 20th day of culture performed in MGIT960 system (Becton Dickinson, USA). The isolate was identified as M.bovis BCG by GenoType MTBC kit (Hain Lifescience, Germany) and defined as M.bovis BCG [SIT 482 (BOV_1)] by spoligotyping. In the primary anti-tuberculosis drug susceptibility test performed by MGIT960 system, the isolate was found susceptible to rifampicin (RIF), isoniazid (INH), streptomycin (STM) and ethambutol (EMB). Then anti-tuberculosis treatment was started to the patient. However, the patient at the age of 2 years, re-admitted to the hospital with the complaint of hepatosplenomegaly. Smear of spontaneously draining abscess material obtained from subcutaneous nodules revealed intensive AFB positivity (3+) once again. In the present instance RIF-resistant MTC was detected with GeneXpert system in the specimen. The growth of mycobacteria was determined on the 13th day of culture and isolate was identified as M.bovis BCG. The present isolate was found susceptible to INH, STM and EMB but resistant to RIF. A mutation in the rpoB gene (codon 531, S531L) associated with RIF resistance was detected by using the partial sequencing of the rpoB gene. Patient died due to disseminated bovis BCG infection and multiple organ failure. To our knowledge, there are only six RIF-resistant M.bovis BCG strains isolated from patients in the literature. However, this is the first RIF-resistant M.bovis BCG strain isolated from a NEMO-deficient patient.

PMID: 26167828 [PubMed – indexed for MEDLINE]

Two separate mechanisms of enforced viral replication balance innate and adaptive immune activation.

November 11, 2015 By Manish Butte

Two separate mechanisms of enforced viral replication balance innate and adaptive immune activation.

J Autoimmun. 2015 Nov 7;

Authors: Shaabani N, Khairnar V, Duhan V, Zhou F, Tur RF, Häussinger D, Recher M, Tumanov AV, Hardt C, Pinschewer D, Christen U, Lang PA, Honke N, Lang KS

Abstract
The induction of innate and adaptive immunity is essential for controlling viral infections. Limited or overwhelming innate immunity can negatively impair the adaptive immune response. Therefore, balancing innate immunity separately from activating the adaptive immune response would result in a better antiviral immune response. Recently, we demonstrated that Usp18-dependent replication of virus in secondary lymphatic organs contributes to activation of the innate and adaptive immune responses. Whether specific mechanisms can balance innate and adaptive immunity separately remains unknown. In this study, using lymphocytic choriomeningitis virus (LCMV) and replication-deficient single-cycle LCMV vectors, we found that viral replication of the initial inoculum is essential for activating virus-specific CD8(+) T cells. In contrast, extracellular distribution of virus along the splenic conduits is necessary for inducing systemic levels of type I interferon (IFN-I). Although enforced virus replication is driven primarily by Usp18, B cell-derived lymphotoxin beta contributes to the extracellular distribution of virus along the splenic conduits. Therefore, lymphotoxin beta regulates IFN-I induction independently of CD8(+) T-cell activity. We found that two separate mechanisms act together in the spleen to guarantee amplification of virus during infection, thereby balancing the activation of the innate and adaptive immune system.

PMID: 26553386 [PubMed – as supplied by publisher]

A New IL-2RG Gene Mutation in an X-linked SCID Identified through TREC/KREC Screening: a Case Report.

November 9, 2015 By Manish Butte

A New IL-2RG Gene Mutation in an X-linked SCID Identified through TREC/KREC Screening: a Case Report.

Iran J Allergy Asthma Immunol. 2015 Aug;14(4):457-461

Authors: Nourizadeh M, Borte S, Fazlollahi M, Hammarström L, Pourpak Z

Abstract
Severe combined immunodeficiency (SCID) represents a rare group of primary immunodeficiency disorders (PIDs), with known or unknown genetic alterations. Here, we report a new interleukin 2 receptor, gamma chain (IL-2RG) mutation in an Iranian SCID newborn.The patient was a 6-day old boy with a family history of PID. The child was screened using a molecular-based analysis for the assessment of T cell receptor excision circles (TRECs) and kappa-deleting recombination excision circles (KRECs). Moreover, a complete immunological evaluation and gene sequencing was performed.Results showed undetectable TREC but a high level of KREC copy numbers. Flowcytometric data indicated low numbers of T and NK cells, but elevated number of B cells. A novel substitution in IL2RG: c.675 C>A, leading to p.225 Ser>Arg was found. Based on the functional analysis, the mutation is predicted to be damaging. The patient was diagnosed as a T B+ NK X-linked SCID.

PMID: 26547715 [PubMed – as supplied by publisher]

[A survey of HTLV-1 carrier clinics in Japan].

November 7, 2015 By Manish Butte

[A survey of HTLV-1 carrier clinics in Japan].

Rinsho Ketsueki. 2015 Jun;56(6):666-72

Authors: Ishitsuka K, Yamano Y, Utsunomiya A, Uchimaru K

Abstract
Human T-lymphotropic virus type-I (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma and HTLV-1 associated myelopathy/tropical spastic paraparesis. Currently, mother-to-child transmission via breastfeeding and sexual intercourse are considered to be the two major routes for HTLV-1 infection. We surveyed four clinics in Japan (two HTLV-1 carrier clinics in non-endemic areas and one in an endemic area, and one hematology clinic in a highly endemic area) and reviewed the management of carriers. In HTLV-1 carrier clinics, more than half of visitors had learned of their infections based on an examination conducted either for blood donation or pregnancy. Although half of visitors had known of their infection more than 2 years prior to their visit, they became to visit the clinics probably due to recent awareness of HTLV-1 in public and of carrier clinics. They requested a detailed explanation, and check-ups for infection and its related diseases. In contrast, most visitors in highly endemic areas had apparently received good explanations from their primary care physicians. It is noteworthy that neither parent of more than half of the carriers who visited the two clinics in the non-endemic area had been born outside of Kyushu, a highly endemic area, indicating that carriers will disperse from known endemic areas. Configuring an appropriate and efficient system to support carriers is necessary, especially in non-endemic areas.

PMID: 26256877 [PubMed – indexed for MEDLINE]

Development of a duplex real-time RT-qPCR assay to monitor genome replication, gene expression and gene insert stability during in vivo replication of a prototype live attenuated canine distemper virus vector encoding SIV gag.

November 7, 2015 By Manish Butte

Development of a duplex real-time RT-qPCR assay to monitor genome replication, gene expression and gene insert stability during in vivo replication of a prototype live attenuated canine distemper virus vector encoding SIV gag.

J Virol Methods. 2015 Mar;213:26-37

Authors: Coleman JW, Wright KJ, Wallace OL, Sharma P, Arendt H, Martinez J, DeStefano J, Zamb TP, Zhang X, Parks CL

Abstract
Advancement of new vaccines based on live viral vectors requires sensitive assays to analyze in vivo replication, gene expression and genetic stability. In this study, attenuated canine distemper virus (CDV) was used as a vaccine delivery vector and duplex 2-step quantitative real-time RT-PCR (RT-qPCR) assays specific for genomic RNA (gRNA) or mRNA have been developed that concurrently quantify coding sequences for the CDV nucleocapsid protein (N) and a foreign vaccine antigen (SIV Gag). These amplicons, which had detection limits of about 10 copies per PCR reaction, were used to show that abdominal cavity lymphoid tissues were a primary site of CDV vector replication in infected ferrets, and importantly, CDV gRNA or mRNA was undetectable in brain tissue. In addition, the gRNA duplex assay was adapted for monitoring foreign gene insert genetic stability during in vivo replication by analyzing the ratio of CDV N and SIV gag genomic RNA copies over the course of vector infection. This measurement was found to be a sensitive probe for assessing the in vivo genetic stability of the foreign gene insert.

PMID: 25486083 [PubMed – indexed for MEDLINE]

Socioeconomic Impact of Immunoglobulin Replacement Therapy for Primary Immunodeficiency Patients on the Health Public System in Brazil: A Single Center Study.

November 5, 2015 By Manish Butte

Socioeconomic Impact of Immunoglobulin Replacement Therapy for Primary Immunodeficiency Patients on the Health Public System in Brazil: A Single Center Study.

Value Health. 2015 Nov;18(7):A878

Authors: Carmo EV, Correa M, Mazzucchelli JL, Tavares L, Damasceno E, Costa-Carvalho BT

PMID: 26534705 [PubMed – in process]

Increased serum IgM, immunodeficiency, and autoimmunity: A clinical series.

November 4, 2015 By Manish Butte

Increased serum IgM, immunodeficiency, and autoimmunity: A clinical series.

Int J Immunopathol Pharmacol. 2015 Dec;28(4):547-56

Authors: Picchianti Diamanti A, Rosado MM, Scarsella M, Ceccarelli S, Laganà B, D’Amelio R, Carsetti R

Abstract
BACKGROUND: Primary immunodeficiencies (PIDs) are generally characterized by recurrent infections; however they may be complicated by other clinical disorders such as allergy, autoimmunity, and lymphoproliferation. In particular, autoimmunity may be the first manifestation of the disease in patients with low serum immunoglobulins (Ig) levels. Here we describe a group of patients that share features of immunodeficiency and autoimmunity.
MATERIALS AND METHODS: All patients went through a complete T and B cell subset characterization and a B cell function analysis in the peripheral blood by flow-cytometry. B cell proliferation and plasma cell differentiation was measured, in vitro, after CpG stimulation for 7 days as previously described. Semi-quantitative PCR analysis for AID and UNG expression as well as serum levels of BAFF were carried out in order to better define the diagnosis.
RESULTS: Immunological and molecular analysis did not lead to the identification of known molecular defect typical of Hyper IgM syndrome. A comparative study of the peripheral blood B cell subsets between patients and healthy donors showed that in patients with autoimmune manifestations all circulating B cells expressed high amounts of surface IgM.
CONCLUSIONS: These results suggest that the increased IgM expression on circulating B cells, reflecting B cell activation, might identify a clinical condition characterized by hyper IgM serum levels of unknown molecular defects, associated with susceptibility to infections and autoimmunity.

PMID: 26526204 [PubMed – in process]

[Integration of Internal and Clinical Laboratory Medicine].

November 4, 2015 By Manish Butte

[Integration of Internal and Clinical Laboratory Medicine].

Rinsho Byori. 2015 Mar;63(3):392-6

Authors: Hirokawa M

Abstract
The mission of our department is to contribute to diagnostic improvement in medicine in order to promote better outcomes. We have clinical expertise in internal medicine including primary care medicine, hematology, allergy, rheumatology, and nephrology. We also have expertise in clinical laboratory medicine and hospital infection control. Specific areas of academic interest include immune-mediated hematological diseases, allergic diseases, autoimmune diseases, and chronic kidney disease. Immune recovery following hematopoietic stem cell transplantation and the immunopathophysiology of bone marrow failure syndrome have been our main topics of interest, and we have been applying our knowledge of T-cell receptor diversity to these areas in order to explore the mechanisms of immunodeficiency and autoimmunity in hematological disorders. We have found that the peripheral expansion of mature T cells in grafts plays an important role in immune reconstitution after stem cell transplantation in humans, and have also found altered T-cell repertoires in immune-mediated chronic acquired pure red cell aplasia. Thus, quantitative and qualitative analyses of immune receptors could be a promising method for assessing immunocompetence and exploring the pathophysiology of autoimmune diseases. Research and development of novel approaches in this field should be intensively conducted.

PMID: 26524863 [PubMed – in process]

Eliminating SCID row: new approaches to SCID.

November 4, 2015 By Manish Butte

Eliminating SCID row: new approaches to SCID.

Hematology Am Soc Hematol Educ Program. 2014 Dec 5;2014(1):475-80

Authors: Kohn DB

Abstract
Treatments for patients with SCID by hematopoietic stem cell transplantation (HSCT) have changed this otherwise lethal primary immune deficiency disorder into one with an increasingly good prognosis. SCID has been the paradigm disorder supporting many key advances in the field of HSCT, with first-in-human successes with matched sibling, haploidentical, and matched unrelated donor allogeneic transplantations. Nevertheless, the optimal approaches for HSCT are still being defined, including determining the optimal stem cell sources, the use and types of pretransplantation conditioning, and applications for SCID subtypes associated with radiosensitivity, for patients with active viral infections and for neonates. Alternatively, autologous transplantation after ex vivo gene correction (gene therapy) has been applied successfully to the treatment of adenosine deaminase-deficient SCID and X-linked SCID by vector-mediated gene addition. Gene therapy holds the prospect of avoiding risks of GVHD and would allow each patient to be their own donor. New approaches to gene therapy by gene correction in autologous HSCs using site-specific endonuclease-mediated homology-driven gene repair are under development. With newborn screening becoming more widely adopted to detect SCID patients before they develop complications, the prognosis for SCID is expected to improve further. This chapter reviews recent advances and ongoing controversies in allogeneic and autologous HSCT for SCID.

PMID: 25696897 [PubMed – indexed for MEDLINE]