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Spontaneous bacterial and fungal infections in genetically engineered mice: Is Escherichia coli an emerging pathogen in laboratory mouse?

August 19, 2015 By Manish Butte

Spontaneous bacterial and fungal infections in genetically engineered mice: Is Escherichia coli an emerging pathogen in laboratory mouse?

Berl Munch Tierarztl Wochenschr. 2015 Jul-Aug;128(7-8):278-84

Authors: Benga L, Benten WP, Engelhardt E, Gougoula C, Sager M

Abstract
The impact of particular microbes on genetically engineered mice depends on the genotype and the environment. Infections resulting in clinical disease have an obvious impact on animal welfare and experimentation. In this study, we investigated the bacterial and fungal aetiology of spontaneous clinical disease of infectious origin among the genetically engineered mice from our institution in relation to their genotype. A total of 63 mice belonging to 33 different mice strains, from severe immunodeficient to wild-type, were found to display infections as the primary cause leading to their euthanasia. The necropsies revealed abscesses localized subcutaneously as well as in the kidney, preputial glands, seminal vesicles, in the uterus, umbilicus or in the lung. In addition, pneumonia, endometritis and septicaemia cases were recorded. Escherichia coli was involved in 21 of 44 (47.72%) of the lesions of bacterial origin, whereas [Pasteurella] pneumotropica was isolated from 19 of 44 (43.18%) cases. The infections with the two agents mentioned above included three cases of mixed infection with both pathogens. Staphylococcus aureus was considered responsible for five of 44 (11.36%) cases whereas Enterobacter cloacae was found to cause lesions in two of 44 (4.54%) mice. Overall, 16 of the 44 (36.36%) cases of bacterial aetiology affected genetically engineered mice without any explicit immunodeficiency or wild-type strains. The remaining 19 cases of interstitial pneumonia were caused by Pneumocystis murina. In conclusion, the susceptibility of genetically modified mice to opportunistic infections has to be regarded with precaution, regardless of the type of genetic modification performed. Beside the classical opportunists, such as [Pasteurella] pneumotropica and Staphylococcus aureus, Escherichia coli should as well be closely monitored to evaluate whether it represents an emerging pathogen in the laboratory mouse.

PMID: 26281439 [PubMed – in process]

Genetic errors of the human caspase recruitment domain-B-cell lymphoma 10-mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (CBM) complex: Molecular, immunologic, and clinical heterogeneity.

August 19, 2015 By Manish Butte

Genetic errors of the human caspase recruitment domain-B-cell lymphoma 10-mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (CBM) complex: Molecular, immunologic, and clinical heterogeneity.

J Allergy Clin Immunol. 2015 Aug 12;

Authors: Pérez de Diego R, Sánchez-Ramón S, López-Collazo E, Martínez-Barricarte R, Cubillos-Zapata C, Ferreira Cerdán A, Casanova JL, Puel A

Abstract
Three members of the caspase recruitment domain (CARD) family of adaptors (CARD9, CARD10, and CARD11) are known to form heterotrimers with B-cell lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (MALT1). These 3 CARD-BCL10-MALT1 (CBM) complexes activate nuclear factor κB in both the innate and adaptive arms of immunity. Human inherited defects of the 3 components of the CBM complex, including the 2 adaptors CARD9 and CARD11 and the 2 core components BCL10 and MALT1, have recently been reported. Biallelic loss-of-function mutant alleles underlie several different immunologic and clinical phenotypes, which can be assigned to 2 distinct categories. Isolated invasive fungal infections of unclear cellular basis are associated with CARD9 deficiency, whereas a broad range of clinical manifestations, including those characteristic of T- and B-lymphocyte defects, are associated with CARD11, MALT1, and BCL10 deficiencies. Interestingly, human subjects with these mutations have some features in common with the corresponding knockout mice, but other features are different between human subjects and mice. Moreover, germline and somatic gain-of-function mutations of MALT1, BCL10, and CARD11 have also been found in patients with other lymphoproliferative disorders. This broad range of germline and somatic CBM lesions, including loss-of-function and gain-of-function mutations, highlights the contribution of each of the components of the CBM complex to human immunity.

PMID: 26277595 [PubMed – as supplied by publisher]

IRF4 Is a Critical Gene in Retinoic Acid-Mediated Plasma Cell Formation and Is Deregulated in Common Variable Immunodeficiency-Derived B Cells.

August 16, 2015 By Manish Butte

IRF4 Is a Critical Gene in Retinoic Acid-Mediated Plasma Cell Formation and Is Deregulated in Common Variable Immunodeficiency-Derived B Cells.

J Immunol. 2015 Aug 14;

Authors: Indrevær RL, Moskaug JØ, Paur I, Bøhn SK, Jørgensen SF, Blomhoff R, Aukrust P, Fevang B, Blomhoff HK

Abstract
In the present study, we aimed at identifying the mechanisms whereby the vitamin A metabolite all-trans retinoic acid (RA) promotes the formation of plasma cells upon stimulation of B cells via the innate immunity receptors TLR9 and RP105. Most often, differentiation of B cells involves the sequential events of class switch recombination and somatic hypermutations characteristic of germinal center reactions, followed by plasma cell formation. By studying the regulatory networks known to drive these reactions, we revealed that RA enhances the expression of the plasma cell-generating transcription factors IFN regulatory factor (IRF)4 and Blimp1, and paradoxically also activation-induced deaminase (AID) involved in somatic hypermutations/class switch recombination, in primary human B cells. IRF4 was identified as a particularly important protein involved in the RA-mediated production of IgG in TLR9/RP105-stimulated B cells. Based on kinetic studies, we present a model suggesting that the initial induction of IRF4 by RA favors AID expression. According to this model, the higher level of IRF4 that eventually arises results in sustained elevated levels of Blimp1. Regarded as a master regulator of plasma cell development, Blimp1 will in turn suppress AID expression and drive the formation of IgG-secreting plasma cells. Notably, we demonstrated IRF4 to be deregulated in B cells from common variable immunodeficiency patients, contributing to the observed aberrant expression of AID in these patients. Taken together, the present study both provides new insight into the mechanisms whereby RA induces differentiation of B cells and identifies IRF4 as a key to understand the defective functions of B cells in common variable immunodeficiency patients.

PMID: 26276871 [PubMed – as supplied by publisher]

SnapShot: Interactions between B Cells and T Cells.

August 16, 2015 By Manish Butte

SnapShot: Interactions between B Cells and T Cells.

Cell. 2015 Aug 13;162(4):926-926.e1

Authors: Tangye SG, Brink R, Goodnow CC, Phan TG

Abstract
Dynamic interactions between B and T cells underpin the development of adaptive humoral immune responses to infections and vaccines. Recent advances in the molecular and spatiotemporal control of these interactions during primary responses have contributed greatly to elucidating the molecular pathogenesis of numerous immunodeficiency and autoimmune diseases. The next challenge is to determine how and where memory B and T cells interact during secondary responses to facilitate the rapid and robust response that characterizes anamnestic immunity.

PMID: 26276638 [PubMed – in process]

Adverse reactions to Mycobacterium bovis bacille Calmette-Guérin vaccination against tuberculosis in Iranian children.

August 15, 2015 By Manish Butte

Adverse reactions to Mycobacterium bovis bacille Calmette-Guérin vaccination against tuberculosis in Iranian children.

Clin Exp Vaccine Res. 2015 Jul;4(2):195-9

Authors: Mahmoudi S, Khaheshi S, Pourakbari B, Aghamohammadi A, Keshavarz Valian S, Bahador A, Sabouni F, Ramezani A, Mamishi S

Abstract
PURPOSE: There are considerable variations in the number of adverse reaction reports related to vaccine from different countries. The aim of this study was to review the development of adverse reactions to bacille Calmette-Guérin (BCG) vaccination among hospitalized patients in an Iranian referral hospital.
MATERIALS AND METHODS: We identified hospitalized patients with BCG complications in Pediatric Infectious Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran during January 2007-April 2009. Data on demographics, clinical features, laboratory findings, personal history (including vaccination history), family history, and outcomes were retrieved from medical records.
RESULTS: There were 46 cases with BCG complication during the 2 years period. All of the children received vaccination at birth. Twenty-eight patients (61%) were male. The mean age of the patients was 13.5 ±11.3 months (range, 1 to 52 months; median, 10 months). The majority of children (57%) with BCG complication were less than 1 year old. Among hospitalized patients due to BCG complications, suppurative lymphadenitis was occurred in 28 children (61%) and lymphadenopathy was seen in 9 children (20%). Disseminated BCG was detected in 8 patients (17%) and only 1 child (2%) was presented with abscess. In 7% (n = 3) of children, the family history of BCG complications were positive.
CONCLUSION: The most common side effect of the BCG vaccine in our study was suppurative lymphadenitis. Disseminated BCG infection in complications leading to hospitalization in our study was 17%. With regard to the difficulty in implementing such a guideline in settings where BCG is given to all newborns, registration of Iranian primary immunodeficiency disorders (PID) patients would be helpful to increase the awareness of medical community of Iran to investigate underlying disease. In addition, BCG vaccination should postpone in each newborn with a family history of PID until the definite condition has been ruled out.

PMID: 26273579 [PubMed]

Different brands of intravenous immunoglobulin for primary immunodeficiencies: how to choose the best option for the patient?

August 15, 2015 By Manish Butte

Different brands of intravenous immunoglobulin for primary immunodeficiencies: how to choose the best option for the patient?

Expert Rev Clin Immunol. 2015 Aug 14;:1-15

Authors: Abolhassani H, Asgardoon MH, Rezaei N, Hammarstrom L, Aghamohammadi A

Abstract
Immunoglobulin (IG) replacement therapy has served as lifesaving treatment in primary immunodeficiency diseases (PID) for more than six decades. Approximately 70% of patients with PID require IG replacement to maintain their health during the course of disease. It is estimated that about one-third of IG products is used for replacement therapy in these patients. On the other hand, the introduction of newer IG preparations is continuing to improve and extend the quality of life in PID patients. Because of the options available including concentrations, formulations, osmolality, product stabilizers, sodium concentration, anti-infective activity, IgA content and pH, it is important to match the PID patient’s complications with potential side effects associated with the composition of a particular IG product. The purpose of this review is to present the clinical differences of intravenous IG among the various preparations regarding PID patients.

PMID: 26272002 [PubMed – as supplied by publisher]

Validity of Primary Immunodeficiency Disease Diagnoses in United States Medicaid Data.

August 15, 2015 By Manish Butte

Validity of Primary Immunodeficiency Disease Diagnoses in United States Medicaid Data.

J Clin Immunol. 2015 Aug 14;

Authors: Hernandez-Trujillo H, Orange JS, Roy JA, Wang Y, Newcomb CN, Liu Q, Hennessy S, Lo Re V

Abstract
PURPOSE: Primary immunodeficiency diseases (PID) are a rare group of disorders with a wide array of clinical presentations. The absence of validated methods to identify these diseases in electronic databases has limited understanding of their epidemiology and the impact of drug therapies on outcomes. We measured the positive predictive values (PPVs) of ICD-9 diagnoses for identifying PID within US Medicaid.
METHODS: We identified Medicaid patients from California, Florida, New York, Ohio, and Pennsylvania with PID ICD-9 diagnoses (common variable immunodeficiency [279.06], X-linked agammaglobulinemia [279.04], hyper-immunoglobulin M syndrome [279.05], Wiskott Aldrich Syndrome [279.12]) recorded at least twice from 1999 to 2007. Outpatient records were reviewed by a clinical immunologist to adjudicate diagnoses. PPVs with 95 % confidence intervals (CIs) for confirmed outcomes were determined for individual ICD-9 diagnoses and combinations of diagnoses and Current Procedural Terminology codes for a quantitative immunoglobulin test (82784) or immunoglobulin infusion (96365).
RESULTS: Among 83 patients with PID ICD-9 diagnoses, 16 were adjudicated as having the condition (PPV, 19.3 %; 95 % CI, 11.4-29.4 %). Individual ICD-9 diagnoses had low PPVs (range, 16.7-33.3 %). Requiring procedural codes for quantitative immunoglobulins or intravenous immunoglobulin did not increase PPVs of these diagnoses (range, 11.1-41.7 %). An X-linked agammaglobulinemia diagnosis plus intravenous immunoglobulin had the highest PPV among the algorithms evaluated (PPV, 41.7 %; 95 % CI, 15.1-72.3 %).
CONCLUSIONS: Algorithms comprising PID ICD-9 diagnoses and procedures for quantitative immunoglobulin tests and immunoglobulin infusion had low PPVs for adjudicated diagnoses in Medicaid. Alternative data sources should be evaluated to study the epidemiology of these diseases.

PMID: 26271389 [PubMed – as supplied by publisher]

Primary Diffuse Large B-cell Lymphoma Arising in the Tongue Accompanied by Ataxia-telangiectasia: A Case Report.

August 13, 2015 By Manish Butte

Primary Diffuse Large B-cell Lymphoma Arising in the Tongue Accompanied by Ataxia-telangiectasia: A Case Report.

J Clin Diagn Res. 2015 Jun;9(6):ZD25-7

Authors: Tomioka H, Kaneoya A, Mochizuki Y, Harada H

Abstract
Ataxia-telangiectasia (AT) is a rare autosomal recessive disorder that is characterized by progressive cerebellar ataxia, telangiectasia, immunodeficiency, and a predisposition to leukemia/lymphoma. Here we report a rare case of lymphoma of the tongue accompanied by AT. Tumour extirpation was performed and diffuse large B-cell lymphoma was diagnosed following pathologic examination. A whole-body survey showed no other enlarged lymph nodes or tumour. The female patient then received a modified dosage of COPAD (cyclophosphamide, vinblastine, pirarubicin, and prednisolone) plus rituximab to avoid severe complications. As of follow-up after 3 years and 5 months, she remains in complete remission. Patients showing AT need careful surveillance and long-term continuous follow-up.

PMID: 26266230 [PubMed]

Rare gastrointestinal lymphomas: The endoscopic investigation.

August 13, 2015 By Manish Butte

Rare gastrointestinal lymphomas: The endoscopic investigation.

World J Gastrointest Endosc. 2015 Aug 10;7(10):928-49

Authors: Vetro C, Bonanno G, Giulietti G, Romano A, Conticello C, Chiarenza A, Spina P, Coppolino F, Cunsolo R, Raimondo FD

Abstract
Gastrointestinal lymphomas represent up to 10% of gastrointestinal malignancies and about one third of non-Hodgkin lymphomas. The most prominent histologies are mucosa-associated lymphoid tissue lymphoma and diffuse large B-cell lymphoma. However, the gastrointestinal tract can be the site of rarer lymphoma subtypes as a primary or secondary localization. Due to their rarity and the multifaceted histology, an endoscopic classification has not been validated yet. This review aims to analyze the endoscopic presentation of rare gastrointestinal lymphomas from disease diagnosis to follow-up, according to the involved site and lymphoma subtype. Existing, new and emerging endoscopic technologies have been examined. In particular, we investigated the diagnostic, prognostic and follow-up endoscopic features of T-cell and natural killer lymphomas, lymphomatous polyposis and mantle cell lymphoma, follicular lymphoma, plasma cell related disease, gastrointestinal lymphomas in immunodeficiency and Hodgkin’s lymphoma of the gastrointestinal tract. Contrarily to more frequent gastrointestinal lymphomas, data about rare lymphomas are mostly extracted from case series and case reports. Due to the data paucity, a synergism between gastroenterologists and hematologists is required in order to better manage the disease. Indeed, clinical and prognostic features are different from nodal and extranodal or the bone marrow (in case of plasma cell disease) counterpart. Therefore, the approach should be based on the knowledge of the peculiar behavior and natural history of disease.

PMID: 26265987 [PubMed]

Zinc-binding metallothioneins are key modulators of IL-4 production by basophils.

August 12, 2015 By Manish Butte

Zinc-binding metallothioneins are key modulators of IL-4 production by basophils.

Mol Immunol. 2015 Aug;66(2):180-8

Authors: Ugajin T, Nishida K, Yamasaki S, Suzuki J, Mita M, Kubo M, Yokozeki H, Hirano T

Abstract
Zinc (Zn) is an essential nutrient, and Zn deficiency causes immunodeficiency and skin disorders. Basophils express FcɛRI on their surface and release multiple mediators after receptor cross-linking, including large amounts of IL-4. However, the mechanisms involved in the FcɛRI-mediated regulation of basophil IL-4 production are currently unclear. Here, we show that the Zn-binding metallothionein (MT) proteins are essential for the FcɛRI-induced basophil production of IL-4. Basophils from MT-I/II(-/-) mice produced significantly less FcɛRI-induced IL-4 than did wild-type basophils. The MTs were involved in maintaining intracellular Zn levels, thereby regulated the calcineurin activity and nuclear factor of activated T-cell (NFAT)-mediated IL-4 production. These results suggest that the MT-dependent control of Zn homeostasis is a novel mechanism for regulating basophil IL-4 production.

PMID: 25801306 [PubMed – indexed for MEDLINE]