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    374 results match your criteria Bruton Agammaglobulinemia

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    [Clinic of humoral primary immunodeficiencies in adults. Experience in a tertiary hospital].
    Rev Alerg Mex 2016 Oct-Dec;63(4):334-341
    Instituto Mexicano del Seguro Social, Centro Médico Nacional Siglo XXI, Hospital de Especialidades, Servicio de Alergia e Inmunología Clínica, Ciudad de México, México.
    Background: Primary immunodeficiencies (PID) are characterized by alteration of the components of the immune system. Humoral deficiencies represent 50%. The most common are selective IgA deficiency, Bruton agammaglobulinemia, and common variable immunodeficiency (CVID). Read More

    A Novel Aziridine-based Bruton's Tyrosine Kinase Inhibitor Induces Apoptosis Through Down-regulation of p65/RelA Phosphorylation on Serine 536 and ERK1/2 in Mantle Cell Lymphoma.
    Anticancer Res 2016 11;36(11):6133-6140
    Latvian Institute of Organic Synthesis, Riga, Latvia.
    Background: Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin's lymphoma characterized by hyperactive neoplastic B-cells and extended tumor cell survival. Bruton's tyrosine kinase (BTK), a crucial kinase in the B-cell antigen receptor signaling pathway, has emerged as a novel target of MCL therapy. A novel BTK-targeting inhibitor, JuSt-23F was prepared. Read More

    Ibrutinib inhibition of Bruton protein-tyrosine kinase (BTK) in the treatment of B cell neoplasms.
    Pharmacol Res 2016 Nov 15;113(Pt A):395-408. Epub 2016 Sep 15.
    Blue Ridge Institute for Medical Research, 3754 Brevard Road, Suite 116, Box 19, Horse Shoe, NC 28742-8814, United States. Electronic address:
    The Bruton non-receptor protein-tyrosine kinase (BTK), a deficiency of which leads to X-linked agammaglobulinemia, plays a central role in B cell antigen receptor signaling. Owing to the exclusivity of this enzyme in B cells, the acronym could represent B cell tyrosine kinase. BTK is activated by the Lyn and SYK protein kinases following activation of the B cell receptor. Read More

    Shulman disease (eosinophilic fasciitis) in X-linked agammaglobulinemia.
    Pol J Pathol 2016 Jun;67(2):183-8
    Prof. Anna Pituch-Noworolska MD, Department of Clinical Immunology, Polish-American Institute of Pediatrics, Medical College, Jagiellonian University, Wielicka 265, 30-663 Krakow, Poland, tel./fax +48 12 658 17 56, e-mail:
    X-linked agammaglobulinemia (XLA) diagnosed in the first year of life is an immunodeficiency with a life-long indication for substitution of immunoglobulins, due to lack of B lymphocytes in the periphery. The decrease of bacterial infection frequency and severity is an effect of immunoglobulin replacement. However, in the majority of patients bronchiectasis and chronic sinusitis with an overgrown mucous membrane develop despite regular substitution. Read More

    Clinical characteristics and genetic profiles of 174 patients with X-linked agammaglobulinemia: Report from Shanghai, China (2000-2015).
    Medicine (Baltimore) 2016 Aug;95(32):e4544
    aDepartment of Allergy and Immunology, Shanghai Children's Medical Center bDivision of Immunology, Institute of Pediatric Translational Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai cDepartment of Internal Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China dDivision of Allergy and Immunology, Department of Pediatrics, Virginia Commonwealth University, Richmond, VA.
    X-linked agammaglobulinemia (XLA) is a humoral primary immunodeficiency. XLA patients typically present with very low numbers of peripheral B cells and a profound deficiency of all immunoglobulin isotypes. Most XLA patients carry mutations in Bruton tyrosine kinase (BTK) gene. Read More

    Preclinical Evaluation of the Novel BTK Inhibitor Acalabrutinib in Canine Models of B-Cell Non-Hodgkin Lymphoma.
    PLoS One 2016 19;11(7):e0159607. Epub 2016 Jul 19.
    Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
    Acalabrutinib (ACP-196) is a second-generation inhibitor of Bruton agammaglobulinemia tyrosine kinase (BTK) with increased target selectivity and potency compared to ibrutinib. In this study, we evaluated acalabrutinib in spontaneously occurring canine lymphoma, a model of B-cell malignancy similar to human diffuse large B-cell lymphoma (DLBCL). First, we demonstrated that acalabrutinib potently inhibited BTK activity and downstream effectors in CLBL1, a canine B-cell lymphoma cell line, and primary canine lymphoma cells. Read More

    From immune substitution to immunomodulation.
    Semin Hematol 2016 Apr 7;53 Suppl 1:S7-9. Epub 2016 Apr 7.
    Department of Pediatric Pulmonology and Immunology, Charité University Hospital, Berlin, Germany. Electronic address:
    Intravenous immunoglobulins (IVIGs) are currently used in many fields of medicine for replacement and immunomodulation. This review focuses on the milestones in the history of human immunoglobulins since the initial observation by Ogden C. Bruton who described replacement therapy in a boy with agammaglobulinemia. Read More

    [Primary hypogammaglobulinemia complicated with liver cirrhosis and literature review].
    Zhonghua Er Ke Za Zhi 2016 May;54(5):379-82
    Department of Gastroenterology, Shanghai Children's Medical Center, Shanghai Jiao Tong University Medical College, Shanghai 200127, China.
    Objective: To explore the pathogenesis, treatment and prognosis of primary hypogammaglobulinemia complicated with liver cirrhosis in a child.

    Method: Pathogenesis, treatment and prognosis of X-linked agammaglobulinemia (XLA ) complicated with liver cirrhosis in a child were analyzed in Shanghai Children's Medical Center.Using"primary hypogammaglobulinemia"and"liver cirrhosis"as keywords, literatures were searched from Pubmed and Chinese data of Weipu and Wanfang data from January 1988 to January 2015. Read More

    [X-linked agammaglobulinemia in adults. Clinical evolution].
    Medicina (B Aires) 2016 ;76(2):65-70
    Unidad Inmunología e Histocompatibilidad, Hospital Dr. Carlos G. Durand, Buenos Aires, Argentina.
    X-linked agammaglobulinemia (XLA) is characterized by absent or severely reduced B cells, low or undetectable immunoglobulin levels and clinically by extracellular bacterial infections which mainly compromise the respiratory tract as well as recurrent diarrheas. The mainstay of treatment is gammaglobulin replacement therapy, which allows most patients to reach adulthood with high quality of life. We analyzed the clinical features of 14 patients over 18 years of age with XLA diagnosis that received treatment in our unit from the year 2003, the date the first patient was derived, until 2015. Read More

    [Shifting cellulitis in a patient with X-linked hypogammaglobulinemia].
    Ann Dermatol Venereol 2016 Jun-Jul;143(6-7):453-6. Epub 2016 Apr 11.
    Hôpital Pontchaillou, service de dermatologie, CHU de Rennes, 2, rue Henri-Le-Guilloux, 35000 Rennes, France; Université de Rennes 1, 2, avenue du Professeur-Léon-Bernard, 35043 Rennes cedex, France; Hôpital Pontchaillou, unité de pharmacoépidémiologie, CHU de Rennes, 2, rue Henri-Le-Guilloux, 35033 Rennes cedex 9, France.
    Background: In cases of immunodeficiency, a systemic infection may be revealed by atypical symptoms, particularly those involving the skin.

    Patients And Methods: The present case describes a 19-year-old male with X-linked hypogammaglobulinemia, or Bruton agammaglobulinemia, treated with intravenous immunoglobulin G antibodies. Over a 6-week period, the patient developed recurrent plaques in both legs, first on one and then on the other, without fever. Read More

    Bruton tyrosine kinase inhibition in chronic lymphocytic leukemia.
    Semin Oncol 2016 Apr 9;43(2):251-9. Epub 2016 Feb 9.
    The Ohio State University Comprehensive Cancer Center, Arthur G James Comprehensive Cancer Center, Columbus, OH.
    Chronic lymphocytic leukemia (CLL) is the most common adult leukemia and remains incurable outside of the setting of allogeneic stem cell transplant. While the standard therapy for both initial and relapsed CLL has traditionally included monoclonal antibody therapy in combination with chemotherapy, there are patients with high-risk disease features including unmutated IgVH, del(11q22) and del(17p13) that are associated with poor overall responses to these therapies with short time to relapse and shortened overall survival. Additionally, many of these therapies have a high rate of infectious toxicity in a population already at increased risk. Read More

    Clinical and mutational features of X-linked agammaglobulinemia in Mexico.
    Clin Immunol 2016 Apr 4;165:38-44. Epub 2016 Mar 4.
    Unidad de Investigación en Inmunodeficiencias, Instituto Nacional de Pediatría, SSA, México, DF, Mexico.
    X-linked agammaglobulinemia (XLA) is caused by BTK mutations, patients typically show <2% of peripheral B cells and reduced levels of all immunoglobulins; they suffer from recurrent infections of bacterial origin; however, viral infections, autoimmune-like diseases, and an increased risk of developing gastric cancer are also reported. In this work, we report the BTK mutations and clinical features of 12 patients diagnosed with XLA. Furthermore, a clinical revision is also presented for an additional cohort of previously reported patients with XLA. Read More

    Ibrutinib for treatment of chronic lymphocytic leukemia.
    Am J Health Syst Pharm 2016 Mar;73(6):367-75
    Division of Hematology, Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Solove Research Institute, Columbus, OH.
    Purpose: The pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of ibrutinib are described.

    Summary: Ibrutinib is a first-in-class oral inhibitor of Bruton tyrosine kinase (BTK) approved for treatment of relapsed chronic lymphocytic leukemia (CLL). Ibrutinib blocks downstream signaling of the B-cell receptor, disrupting stromal microenvironment interactions and B-cell cytokine signaling. Read More

    X-Linked Agammagobulinemia in a Large Series of North African Patients: Frequency, Clinical Features and Novel BTK Mutations.
    J Clin Immunol 2016 Apr 1;36(3):187-94. Epub 2016 Mar 1.
    Clinical Immunology Unit, Ibn Rochd Hospital, King Hassan II University-AinChok, Casablanca, Morocco.
    Purpose: X-linked agammagobulinemia (XLA) is a primary immunodeficiency caused by Bruton's tyrosine kinase (BTK) gene defect. XLA patients have absent or reduced number of peripheral B cells and a profound deficiency in all immunoglobulin isotypes. This multicenter study reports the clinical, immunological and molecular features of Bruton's disease in 40 North African male patients. Read More

    Cohort of Iranian Patients with Congenital Agammaglobulinemia: Mutation Analysis and Novel Gene Defects.
    Expert Rev Clin Immunol 2016 24;12(4):479-86. Epub 2016 Feb 24.
    a Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center , Tehran University of Medical Sciences , Tehran , Iran.
    Objectives: Impairment in early B-cell development can cause a predominantly antibody deficiency with severe depletion of peripheral B-cells. Mutations in the gene encoding for Bruton's-tyrosine-kinase (BTK) and the components of the pre-B-cell receptor complex or downstream signaling molecules have been related to this defect in patients with agammaglobulinemia.

    Methods: Iranian patients with congenital agammaglobulinemia were included and the correlation between disease-causing mutations and parameters such as clinical and immunologic phenotypes were evaluated in available patients. Read More

    Allogeneic stem cell transplantation for X-linked agammaglobulinemia using reduced intensity conditioning as a model of the reconstitution of humoral immunity.
    J Hematol Oncol 2016 Feb 13;9. Epub 2016 Feb 13.
    Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya City, Hyogo, 663-8501, Japan.
    Background: We herein report the first case of X-linked agammaglobulinemia (XLA) that underwent allogeneic stem cell transplantation using reduced intensity conditioning (RIC). We chronologically observed the reconstitution of humoral immunity in this case.

    Case Presentation: The patient was a 28-year-old Japanese male with XLA who previously had life-threatening infectious episodes and was referred for the possible indication of allogeneic stem cell transplantation. Read More

    Inhibition of the Bruton Tyrosine Kinase Pathway in B-Cell Lymphoproliferative Disorders.
    Cancer J 2016 Jan-Feb;22(1):34-9
    From the Bing Center for Waldenström's Macroglobulinemia and Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
    Activation of the Bruton tyrosine kinase (BTK) pathway plays an important role in the pathophysiology of a number of B-cell lymphoproliferative disorders (LPDs). A number of preclinical studies support inhibiting BTK as a mechanism to treat LPDs. Clinically, BTK inhibitors, specifically ibrutinib, have shown to be safe and effective on treating patients with indolent B-cell lymphomas and chronic lymphocytic leukemia (CLL). Read More

    Eosinophilic gastroenteritis in a patient with Bruton's tyrosine kinase deficiency.
    Pediatr Int 2016 May 3;58(5):417-419. Epub 2016 Feb 3.
    Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
    Eosinophilic gastrointestinal diseases (EGID) are relatively rare diseases characterized by eosinophilic infiltration of the gastrointestinal tract resulting in various gastrointestinal symptoms. EGID are often caused by allergic reactions or systemic eosinophilic disorders, but their comorbidity with Bruton's tyrosine kinase (BTK) deficiency has not been previously documented. Here, we report a case of eosinophilic gastroenteritis (EG) in a patient with BTK deficiency. Read More

    Btk inhibition treats TLR7/IFN driven murine lupus.
    Clin Immunol 2016 Mar 25;164:65-77. Epub 2016 Jan 25.
    TIP Immunology, EMD Serono Research and Development Institute, 45A Middlesex Turnpike, Billerica, MA 01821, USA.
    Bruton's tyrosine kinase (Btk) is expressed in a variety of immune cells and previous work has demonstrated that blocking Btk is a promising strategy for treating autoimmune diseases. Herein, we utilized a tool Btk inhibitor, M7583, to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon. In BXSB-Yaa lupus mice, Btk inhibition reduced autoantibodies, nephritis, and mortality. Read More

    Ibrutinib as a Bruton Kinase Inhibitor in the Management of Chronic Lymphocytic Leukemia: A New Agent With Great Promise.
    Clin Lymphoma Myeloma Leuk 2016 Feb 22;16(2):63-9. Epub 2015 Nov 22.
    Department of Hematology and Oncology, Oakland University, William Beaumont School of Medicine, William Beaumont Health System, Royal Oak, MI.
    The recent discovery of the role of the B-cell antigen receptor (BCR) signaling pathway in the propagation and maintenance of both normal B-cell function and in B-cell malignancies has highlighted the importance of many protein kinases involved in BCR signal propagation. Considerable research attention has focused on the Bruton tyrosine kinase (BTK) as a potential therapeutic target in B-cell malignancies. Treatment paradigms including ibrutinib, a potent inhibitor of the BTK recently approved by the US Food and Drug Administration, have significantly improved disease outcome among high-risk and relapsed/refractory cases of chronic lymphocytic leukemia. Read More

    Ibrutinib for mantle cell lymphoma.
    Future Oncol 2016 Feb 13;12(4):477-91. Epub 2016 Jan 13.
    Department of Haematology, Plymouth Hospitals NHS Trust, Plymouth, UK.
    Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin lymphoma. Ibrutinib is a first-in-class, oral inhibitor of Bruton's tyrosine kinase which acts by downstream inhibition of the B-cell receptor. Early clinical trials have demonstrated excellent tolerability and a modest side-effect profile in relapsed/refractory MCL. Read More

    Bruton Tyrosine Kinase-Dependent Immune Cell Cross-talk Drives Pancreas Cancer.
    Cancer Discov 2016 Mar 29;6(3):270-85. Epub 2015 Dec 29.
    Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, Oregon. Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.
    Unlabelled: Pancreas ductal adenocarcinoma (PDAC) has one of the worst 5-year survival rates of all solid tumors, and thus new treatment strategies are urgently needed. Here, we report that targeting Bruton tyrosine kinase (BTK), a key B-cell and macrophage kinase, restores T cell-dependent antitumor immune responses, thereby inhibiting PDAC growth and improving responsiveness to standard-of-care chemotherapy. We report that PDAC tumor growth depends on cross-talk between B cells and FcRγ(+) tumor-associated macrophages, resulting in T(H)2-type macrophage programming via BTK activation in a PI3Kγ-dependent manner. Read More

    Efficacy and safety of Gammaplex(®) 5% in children and adolescents with primary immunodeficiency diseases.
    Clin Exp Immunol 2016 May 15;184(2):228-36. Epub 2016 Feb 15.
    Rush University Medical Center, Chicago, IL, USA.
    This open-label multi-centre study evaluated Gammaplex(®) 5%, a human intravenous immunoglobulin (IVIG) 5% liquid, in 25 children and adolescent patients (aged 3-16 years) with primary immunodeficiency diseases (PIDs). Subjects received Gammaplex 5% (at doses of 300-800 mg/kg/infusion) for 12 months, with a 3-month follow-up. The primary efficacy end-point was the incidence of serious acute bacterial infections (SABIs) during the 12-month treatment period. Read More

    Oral administration of Bruton's tyrosine kinase inhibitors impairs GPVI-mediated platelet function.
    Am J Physiol Cell Physiol 2016 Mar 9;310(5):C373-80. Epub 2015 Dec 9.
    Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Cell, Developmental & Cancer Biology, School of Medicine, Oregon Health & Science University, Portland, Oregon; and Division of Hematology and Medical Oncology, School of Medicine, Oregon Health & Science University, Portland, Oregon.
    The Tec family kinase Bruton's tyrosine kinase (Btk) plays an important signaling role downstream of immunoreceptor tyrosine-based activation motifs in hematopoietic cells. Mutations in Btk are involved in impaired B-cell maturation in X-linked agammaglobulinemia, and Btk has been investigated for its role in platelet activation via activation of the effector protein phospholipase Cγ2 downstream of the platelet membrane glycoprotein VI (GPVI). Because of its role in hematopoietic cell signaling, Btk has become a target in the treatment of chronic lymphocytic leukemia and mantle cell lymphoma; the covalent Btk inhibitor ibrutinib was recently approved by the US Food and Drug Administration for treatment of these conditions. Read More

    Rev Inst Med Trop Sao Paulo 2015 Sep-Oct;57(5):455-7
    Departmento de Pediatria, Universidade Federal de São Paulo, São Paulo, SP, Brasil,
    We describe the case of an eight-year-old boy with X-linked agammaglobulinemia who developed mild varicella despite regular intravenous immunoglobulin (IVIG) therapy. He maintained protective antibody levels against varicella and the previous batches of IVIG that he received had adequate varicella-specific IgG levels. The case illustrates that IVIG may not prevent VZV infection. Read More

    A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies.
    Blood 2016 Jan 5;127(4):411-9. Epub 2015 Nov 5.
    Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Service d'Hématologie, Pierre-Bénite, Université Claude Bernard Lyon 1, Lyon, France;
    We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/refractory B-cell malignancies. There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Read More

    X-linked Agammaglobulinemia With Normal Immunoglobulin and Near-Normal Vaccine Seroconversion.
    Pediatrics 2015 Dec 2;136(6):e1621-4. Epub 2015 Nov 2.
    Department of Paediatrics, Tairawhiti District Health, Gisborne, New Zealand.
    We present a 22-month-old boy with X-linked agammaglobulinemia masked by normal immunoglobulin levels and vaccine seroconversion. Diagnosis was made after strong clinical suspicion of immune deficiency led to identification of markedly reduced B-cell numbers and confirmation with identification of a novel Bruton tyrosine kinase gene mutation. He was commenced on replacement immunoglobulin therapy with excellent clinical improvement. Read More

    CD19 controls Toll-like receptor 9 responses in human B cells.
    J Allergy Clin Immunol 2016 Mar 21;137(3):889-98.e6. Epub 2015 Oct 21.
    Department of Immunobiology, Yale University School of Medicine, New Haven, Conn. Electronic address:
    Background: CD19 is a B cell-specific molecule that serves as a major costimulatory molecule for amplifying B-cell receptor (BCR) responses. Biallelic CD19 gene mutations cause common variable immunodeficiency in human subjects. BCR- and Toll-like receptor (TLR) 9-induced B-cell responses are impaired in most patients with common variable immunodeficiency. Read More

    BTK mutations selectively regulate BTK expression and upregulate monocyte XBP1 mRNA in XLA patients.
    Immun Inflamm Dis 2015 Sep 4;3(3):171-81. Epub 2015 Jun 4.
    Center for Investigation in Pediatrics, University of Campinas (UNICAMP) Campinas, São Paulo, Brazil ; Department of Pediatrics, Faculty of Medical Sciences, University of Campinas (UNICAMP) Campinas, São Paulo, Brazil.
    Mutations in the Bruton agammaglobulinemia tyrosine kinase (BTK) gene are responsible for X-linked agammaglobulinemia (XLA). Unfolded or misfolded proteins can trigger stress pathways in the endoplasmic reticulum (ER), known as unfolded protein response (UPR). The aim was to clarify the involvement of UPR in XLA pathophysiology. Read More

    Next-Generation Sequencing for Diagnosis and Tailored Therapy: A Case Report of Astrovirus-Associated Progressive Encephalitis.
    J Pediatric Infect Dis Soc 2015 Sep 12;4(3):e53-7. Epub 2015 Jul 12.
    Institut Pasteur, Biology of Infection Unit, Institut National de la Santé et de la Recherche Médicale (INSERM) U1117, Pathogen Discovery Laboratory, Paris, France PathoQuest, Paris, France.
    A boy with X-linked agammaglobulinemia experienced progressive global motor decline, cerebellar syndrome, and epilepsy. All standard polymerase chain reactions for neurotropic viruses were negative on cerebrospinal fluid and brain biopsy. Next-generation sequencing allowed fast identification of a new astrovirus strain (HAstV-VA1/HMO-C-PA), which led to tailor the patient's treatment, with encouraging clinical monitoring over 1 year. Read More

    Prevalence of BTK mutations in male Algerian patterns with agammaglobulinemia and severe B cell lymphopenia.
    Clin Immunol 2015 Dec 24;161(2):286-90. Epub 2015 Sep 24.
    Immunology Department, Beni Messous Teaching Hospital, Algiers, Algeria; Laboratory of Immunology, Faculty of Medicine, University of Algiers 1, Algeria. Electronic address:
    X linked agammaglobulinemia (XLA) is the first described primary immunodeficiency and the most common form of agammaglobulinemia. It is characterized by susceptibility to recurrent infections, profound decrease of all immunoglobulin isotypes and very low level of B lymphocytes in peripheral blood. The disorder is caused by mutations in the Bruton's Tyrosine Kinase (BTK). Read More

    High-throughput sequencing reveals an altered T cell repertoire in X-linked agammaglobulinemia.
    Clin Immunol 2015 Dec 7;161(2):190-6. Epub 2015 Sep 7.
    Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Pediatrics, The Immunology Institute, Box 1089, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, United States.
    To examine the T cell receptor structure in the absence of B cells, the TCR β CDR3 was sequenced from DNA of 15 X-linked agammaglobulinemia (XLA) subjects and 18 male controls, using the Illumina HiSeq platform and the ImmunoSEQ analyzer. V gene usage and the V-J combinations, derived from both productive and non-productive sequences, were significantly different between XLA samples and controls. Although the CDR3 length was similar for XLA and control samples, the CDR3 region of the XLA T cell receptor contained significantly fewer deletions and insertions in V, D, and J gene segments, differences intrinsic to the V(D)J recombination process and not due to peripheral T cell selection. Read More

    Ibrutinib Inhibits Platelet Integrin αIIbβ3 Outside-In Signaling and Thrombus Stability But Not Adhesion to Collagen.
    Arterioscler Thromb Vasc Biol 2015 Nov 10;35(11):2326-35. Epub 2015 Sep 10.
    From the Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, United Kingdom.
    Objective: Ibrutinib is an irreversible Bruton tyrosine kinase inhibitor approved for treatment of Waldenstrom macroglobulinemia, chronic lymphocytic leukemia, and mantle cell lymphoma that increases the risk of bleeding among patients. Platelets from ibrutinib-treated patients exhibit deficiencies in collagen-evoked signaling in suspension; however, the significance of this observation and how it relates to bleeding risk is unclear, as platelets encounter immobile collagen in vivo. We sought to clarify the effects of ibrutinib on platelet function to better understand the mechanism underlying bleeding risk. Read More

    BTK Signaling in B Cell Differentiation and Autoimmunity.
    Curr Top Microbiol Immunol 2016 ;393:67-105
    Department of Pulmonary Medicine, Erasmus MC Rotterdam, Room Ee2251a, PO Box 2040, NL 3000, CA, Rotterdam, The Netherlands.
    Since the original identification of Bruton's tyrosine kinase (BTK) as the gene defective in the primary immunodeficiency X-linked agammaglobulinemia (XLA) in 1993, our knowledge on the physiological function of BTK has expanded impressively. In this review, we focus on the role of BTK during B cell differentiation in vivo, both in the regulation of expansion and in the developmental progression of pre-B cells in the bone marrow and as a crucial signal transducer of signals downstream of the IgM or IgG B cell antigen receptor (BCR) in mature B cells governing proliferation, survival, and differentiation. In particular, we highlight BTK function in B cells in the context of host defense and autoimmunity. Read More

    Partial reconstitution of humoral immunity and fewer infections in patients with chronic lymphocytic leukemia treated with ibrutinib.
    Blood 2015 Nov 3;126(19):2213-9. Epub 2015 Sep 3.
    Hematology Branch and.
    Chronic lymphocytic leukemia (CLL) is characterized by immune dysregulation, often including hypogammaglobulinemia, which contributes to a high rate of infections and morbidity. Ibrutinib, a covalent inhibitor of Bruton tyrosine kinase (BTK), inhibits B-cell receptor signaling and is an effective, US Food and Drug Administration (FDA)-approved treatment of CLL. Inactivating germline mutations in BTK cause a severe B-cell defect and agammaglobulinemia. Read More

    BTK gene targeting by homologous recombination using a helper-dependent adenovirus/adeno-associated virus hybrid vector.
    Gene Ther 2016 Feb 17;23(2):205-13. Epub 2015 Aug 17.
    Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
    X-linked agammaglobulinemia (XLA) is one of the most common humoral immunodeficiencies, which is caused by mutations in Bruton's tyrosine kinase (BTK) gene. To examine the possibility of using gene therapy for XLA, we constructed a helper-dependent adenovirus/adeno-associated virus BTK targeting vector (HD-Ad.AAV BTK vector) composed of a genomic sequence containing BTK exons 6-19 and a green fluorescence protein-hygromycin cassette driven by a cytomegalovirus promoter. Read More

    WHI-131 Promotes Osteoblast Differentiation and Prevents Osteoclast Formation and Resorption in Mice.
    J Bone Miner Res 2016 Feb 29;31(2):403-15. Epub 2015 Aug 29.
    Department of Anatomy, School of Medicine, Wonkwang University, Iksan, Korea.
    The small molecule WHI-131 is a potent therapeutic agent with anti-inflammatory, antiallergic, and antileukemic potential. However, the regulatory effects of WHI-131 on osteoblast and osteoclast activity are unclear. We examined the effects of WHI-131 on osteoblast and osteoclast differentiation with respect to bone remodeling. Read More

    Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib.
    Blood 2015 Sep 7;126(13):1565-74. Epub 2015 Aug 7.
    Departments of Leukemia and Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX;
    Mantle cell lymphoma (MCL) cells exhibit increased B-cell receptor and nuclear factor (NF)-κB activities. The bromodomain and extra-terminal (BET) protein bromodomain 4 is essential for the transcriptional activity of NF-κB. Here, we demonstrate that treatment with the BET protein bromodomain antagonist (BA) JQ1 attenuates MYC and cyclin-dependent kinase (CDK)4/6, inhibits the nuclear RelA levels and the expression of NF-κB target genes, including Bruton tyrosine kinase (BTK) in MCL cells. Read More

    Higher Cardiovascular Risk in Common Variable Immunodeficiency and X-Linked Agammaglobulinaemia Patients.
    Ann Nutr Metab 2015 14;66(4):237-41. Epub 2015 Jul 14.
    Federal University of Sao Paulo, Sao Paulo, Sao Paulo, Brazil.
    Introduction: Common variable immunodeficiency and X-linked agammaglobulinaemia are primary immunodeficiencies classified as antibody deficiencies, and they both result in hypogammaglobulinaemia.

    Objective: Evaluate the lipid profile and other cardiovascular risk biomarkers in CVID and XLA patients.

    Methods: In total, 24 patients and 12 healthy controls matched by age and gender were included in the study. Read More

    Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia.
    JAMA Oncol 2015 Apr;1(1):80-7
    Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus.
    Importance: The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is effective in patients with chronic lymphocytic leukemia (CLL). Reasons for discontinuing therapy with this drug and outcomes following discontinuation have not been evaluated outside of clinical trials with relatively short follow-up.

    Objective: To determine features associated with discontinuation of ibrutinib therapy and outcomes. Read More

    Ibrutinib for the treatment of Waldenström macroglobulinemia.
    Expert Rev Hematol 2015 Oct 2;8(5):569-79. Epub 2015 Jul 2.
    a Mayo Clinic, Rochester, MN, USA.
    Waldenström macroglobulinemia (WM) is a B-cell non-Hodgkin lymphoma (NHL) characterized by IgM monoclonal gammopathy and bone marrow infiltration by lymphoplasmacytic cells. Until recently, there was no drug specifically approved for WM by the US FDA, leading to wide variations in therapeutic strategies across the globe. Ibrutinib, an oral Bruton tyrosine kinase (BTK) inhibitor, is the first drug approved specifically for WM by the FDA after a clinical trial showed impressive response in previously treated WM. Read More

    Lung magnetic resonance imaging with diffusion weighted imaging provides regional structural as well as functional information without radiation exposure in primary antibody deficiencies.
    J Clin Immunol 2015 Jul 12;35(5):491-500. Epub 2015 Jun 12.
    Department of Molecular Medicine, Sapienza University of Rome, Viale dell'Università 37, Rome, Italy.
    Purpose: Primary antibody deficiency patients suffer from infectious and non-infectious pulmonary complications leading over time to chronic lung disease. The complexity of this pulmonary involvement poses significant challenge in differential diagnosis in patients with long life disease and increased radio sensitivity. We planned to verify the utility of chest Magnetic Resolution Imaging with Diffusion-Weighted Imaging as a radiation free technique. Read More

    Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results.
    Blood 2015 Aug 9;126(6):739-45. Epub 2015 Jun 9.
    Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, United Kingdom.
    Ibrutinib, an oral inhibitor of Bruton tyrosine kinase, is approved for patients with mantle cell lymphoma (MCL) who have received one prior therapy. We report the updated safety and efficacy results from the multicenter, open-label phase 2 registration trial of ibrutinib (median 26.7-month follow-up). Read More

    Hypermorphic mutation of phospholipase C, γ2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation.
    Blood 2015 Jul 13;126(1):61-8. Epub 2015 May 13.
    Department of Internal Medicine, Division of Hematology, and.
    Ibrutinib has significantly improved the outcome of patients with relapsed chronic lymphocytic leukemia (CLL). Recent reports attribute ibrutinib resistance to acquired mutations in Bruton agammaglobulinemia tyrosine kinase (BTK), the target of ibrutinib, as well as the immediate downstream effector phospholipase C, γ2 (PLCG2). Although the C481S mutation found in BTK has been shown to disable ibrutinib's capacity to irreversibly bind this primary target, the detailed mechanisms of mutations in PLCG2 have yet to be established. Read More

    Toll-like receptor signaling in primary immune deficiencies.
    Ann N Y Acad Sci 2015 Nov 30;1356:1-21. Epub 2015 Apr 30.
    Division of Clinical Immunology, Departments of Medicine and Pediatrics, Icahn School of Medicine at Mount Sinai, New York.
    Toll-like receptors (TLRs) recognize common microbial or host-derived macromolecules and have important roles in early activation of the immune system. Patients with primary immune deficiencies (PIDs) affecting TLR signaling can elucidate the importance of these proteins to the human immune system. Defects in interleukin-1 receptor-associated kinase-4 and myeloid differentiation factor 88 (MyD88) lead to susceptibility to infections with bacteria, while mutations in nuclear factor-κB essential modulator (NEMO) and other downstream mediators generally induce broader susceptibility to bacteria, viruses, and fungi. Read More

    Successful hematopoietic cell transplantation in a patient with X-linked agammaglobulinemia and acute myeloid leukemia.
    Pediatr Blood Cancer 2015 Sep 20;62(9):1674-6. Epub 2015 Apr 20.
    Pediatric Blood and Marrow Transplant, Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, Maryland.
    X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by marked reduction in all classes of serum immunoglobulins and the near absence of mature CD19(+) B-cells. Although malignancy has been observed in patients with XLA, we present the first reported case of acute myeloid leukemia (AML) in a patient with XLA. We also demonstrate the complete correction of the XLA phenotype following allogeneic hematopoietic cell transplantation for treatment of the patient's leukemia. Read More

    Mechanisms of ibrutinib resistance in chronic lymphocytic leukaemia and non-Hodgkin lymphoma.
    Br J Haematol 2015 Aug 9;170(4):445-56. Epub 2015 Apr 9.
    Division of Genomic and Molecular Pathology, Department of Pathology, University of Chicago, Chicago, IL, USA.
    Bruton tyrosine kinase (BTK), a mediator of B-cell receptor (BCR) signalling, has been implicated in the pathogenesis of chronic lymphocytic leukaemia (CLL) and other B-cell malignancies. Ibrutinib is an orally bioavailable and highly specific BTK inhibitor that was recently approved for treatment of patients with recurrent CLL and mantle cell lymphoma (MCL). In addition, ibrutinib has shown efficacy in subsets of patients with diffuse large B cell lymphoma (DLBCL) and Waldenstrom macroglobulinaemia (WM). Read More

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