Biomedical subjects

Raif Geha

Publications and source records attributed to Raif Geha.

9 recordsLinked to original sources

PubMed2006

A novel anti-WIP monoclonal antibody detects an isoform of WIP that lacks the WASP binding domain.

The majority of Wiskott-Aldrich syndrome protein (WASP) in T cells is in a complex with WASP interacting protein (WIP), a 503 a.a. long proline rich protein. Here we demonstrate that a novel anti-WIP mAb, 3D10, recognizes an epitope in the N-terminal domain of the WIP protein, within the sequence 13PTFALA18. mAb 3D10 competes with actin, but not with WASP or Nck, for WIP binding. Analysis of 3D10 immunoprecipitates failed to demonstrate dissociation of the WASP-WIP complex after TCR ligation that we previously reported using a polyclonal anti-WIP anti-serum raised against a C-terminal peptide (a.a. 459-503) that spanned the WASP binding site. 3D10 mAb allowed the detection of a novel isoform of WIP consisting of a truncated 403 a.a. long protein that includes the 377 a.a. encoded by the first 4 exons of WIP followed by a 26 a.a. sequence encoded by intron 4.

Actins↗

PubMed2006

Lessons learned from molecular defects in nuclear factor kappaB dependent signaling.

Nuclear factor (NF) kappaB is a ubiquitously expressed transcription factor that plays critical roles in normal development and inflammation. Characterization of naturally occurring defects in signaling pathways leading to activation of NFkappaB, complemented by mouse knockout models, has demonstrated the vital role of NFkappaB in normal host defense.

Animals↗

PubMed2004

Primary immunodeficiency diseases: an update.

Although relatively rare, primary immune deficiency diseases (PIDs) provide an excellent window into the functioning of the immune system. In the late 1960s, observations on these diseases, with their associated infections and genetics, bisected the immune system into humoral immunity and cell-mediated immunity. These diseases also represent a challenge in their diagnosis and treatment. Beginning in 1970, a unified nomenclature for the then-known primary immunodeficiency diseases was created by a committee convened by the World Health Organization. Since then, and later under the aegis of the International Union of Immunological Societies, an international committee of experts has met every 2 to 3 years to update the classification of PIDs. During the past 15 years, the molecular basis of more than 100 PIDs has been elucidated. This update results from the latest meeting of this committee in Sintra, Portugal, June 2003, which followed 2(1/2) days of scientific discussions.

Animals↗

PubMed2003

WAVE2 deficiency reveals distinct roles in embryogenesis and Rac-mediated actin-based motility.

The Wiskott-Aldrich syndrome related protein WAVE2 is implicated in the regulation of actin-cytoskeletal reorganization downstream of the small Rho GTPase, Rac. We inactivated the WAVE2 gene by gene-targeted mutation to examine its role in murine development and in actin assembly. WAVE2-deficient embryos survived until approximately embryonic day 12.5 and displayed growth retardation and certain morphological defects, including malformations of the ventricles in the developing brain. WAVE2-deficient embryonic stem cells displayed normal proliferation, whereas WAVE2-deficient embryonic fibroblasts exhibited severe growth defects, as well as defective cell motility in response to PDGF, lamellipodium formation and Rac-mediated actin polymerization. These results imply a non-redundant role for WAVE2 in murine embryogenesis and a critical role for WAVE2 in actin-based processes downstream of Rac that are essential for cell movement.

Actins↗

PubMed2003

Desloratadine inhibits allergen-induced airway inflammation and bronchial hyperresponsiveness and alters T-cell responses in murine models of asthma.

BACKGROUND: Histamine elicits many features of immediate hypersensitivity reactions. Recent evidence indicates that H1 receptors modulate immune responses to antigens. Desloratadine (DL), a new, long-acting, H1 receptor antagonist, has both a potent antihistaminic function and anti-inflammatory properties. OBJECTIVE: We sought to evaluate the effect of DL on allergic-airway responses in mice after inhalation of the naturally occurring aeroallergen Aspergillus fumigatus (Af ) and to examine the effects of DL on specific immune responses to a defined protein antigen with the use of an ovalbumin (OVA) model of asthma. METHODS: Mice were subjected either to repeated, intranasal application of Af extract or to intraperitoneal immunization with OVA, followed by inhalation challenge. DL or a control fluid was given daily throughout the sensitization process. Immunoglobulin E (IgE) levels, bronchoalveolar lavage-fluid cytokines and cytology, lung histology, and physiologic responses to methacholine were assessed in the allergen-treated mice. Anti-OVA IgE responses and OVA-driven T-cell cytokine production were examined. RESULTS: Treatment with DL did not impair IgE production but did inhibit bronchial inflammation and bronchial hyperresponsiveness in both Af- and OVA-treated mice. This inhibition required that DL be administered concurrently with allergen sensitization, indicating that the attenuation of bronchial hyperresponsiveness and inflammation was not caused by anticholinergic receptor effects. OVA-responsive T cells from DL-treated mice exhibited depressed production of IL-4, IL-5, and IL-13 and normal amounts of interferon-gamma. The amounts of IL-5 and IL-13 were also diminished in the bronchoalveolar lavage fluid. CONCLUSION: DL, given at the time of exposure to the allergen, inhibits T(H)2 responses, the induction of allergic pulmonary inflammation, and bronchial hyperresponsiveness. These results suggest that DL or similar agents given during times of antigen exposure might alter disease progression in patients with respiratory allergy.

Allergens↗

PubMed2003

The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients.

The X-linked hyper-IgM (XHIGM) syndrome is an uncommon primary immunodeficiency disease caused by mutations in the gene for CD40 ligand and characterized by normal or elevated serum IgM, reduced levels of IgG and IgA, and defective T-cell function. Because of its rarity, it has been difficult for any single investigator or institution to develop a comprehensive clinical picture of this disorder. Accordingly, a national registry was developed in the United States to provide demographic, genetic, immunologic, and clinical information on a relatively large number of patients with the XHIGM syndrome.A total of 79 patients from 60 unrelated families were registered between January 1997 and July 2002. The estimated minimal incidence was approximately 1/1,030,000 live births. All of the patients had significant IgG deficiency and most had IgA deficiency, but only one-half had elevated IgM levels. Most patients presented initially with a history of an increased susceptibility to infection including Pneumocystis carinii pneumonia. The average age of diagnosis was significantly earlier in patients born into a family with a previously affected individual. However, only one-third of the patients born into a family with a previously affected individual were diagnosed exclusively because of the presence of the positive family history before any clinical symptoms developed. Over half the patients developed symptoms of immunodeficiency and were diagnosed by 1 year of age, and over 90% by 4 years of age. The most prominent clinical infections were pneumonia (81% of patients), upper respiratory infections (49%) including sinusitis (43%) and recurrent otitis (43%), recurrent/protracted diarrhea (34%), central nervous system infections (14%), sepsis (13%), cellulitis (13%), hepatitis (9%), and osteomyelitis (1%). In addition to infections caused by encapsulated bacteria, opportunistic infections were relatively common and were caused by P. carinii, members of the herpes virus family (including cytomegalovirus), Cryptosporidium, Cryptococcus, Candida, Histoplasma, and Bartonella. Sclerosing cholangitis occurred in 5 patients and in 4 of these was associated with Cryptosporidium infection. Eight patients had died at the time of their entry into the Registry; 2 of pneumonia (1 P. carinii and 1 cytomegalovirus), 2 of encephalitis (1 ECHO virus and 1 cytomegalovirus), 2 of malignancy (both hepatocellular carcinoma), 1 of sclerosing cholangitis caused by Cryptosporidium, and 1 of hemolytic uremic syndrome.

Adolescent↗

PubMed2002

X-linked lymphoproliferative disease: genetic lesions and clinical consequences.

X-linked lymphoproliferative disorder (XLP) was first described almost 30 years ago; remarkably, the three major manifestations of XLP, fulminant infectious mononucleosis (FIM), lymphoma, and dysgammaglobulinemia, are all described in the report of the initial kindred. Subsequent establishment of an XLP registry has led to recognition of more unusual phenotypes in affected males; concurrently, much progress has been made in caring for boys with XLP, including treatment for the three major phenotypes, and curative bone marrow transplantation (BMT). The immunologic and genetic mechanisms resulting in XLP have also been intensively studied. Several years ago, the gene defective in XLP was identified as SAP (SLAM-associated protein), and recent data suggest that SAP plays a broad role in immune signaling. Here, we review the clinical manifestations and therapy of XLP, and briefly summarize recent research into the structure and function of SAP.

Genetic Linkage↗

PubMed2002

The binding site for TRAF2 and TRAF3 but not for TRAF6 is essential for CD40-mediated immunoglobulin class switching.

To define the role of TRAF proteins in CD40-dependent isotype switching in B cells, we introduced wild-type (WT) and mutant CD40 transgenes that lacked the binding motifs for TRAF6 (CD40deltaTRAF6), TRAF2 and TRAF3 (CD40deltaTRAF2/3), or both (CD40deltaTRAFs) into B cells of CD40(-/-) mice. The in vivo isotype switch defect in CD40(-/-) mice was fully corrected by WT and CD40deltaTRAF6, partially by CD40deltaTRAF2/3, and not at all by CD40deltaTRAFs transgenes. CD40-mediated isotype switching, proliferation, and activation of p38, JNK, and NFkappaB in B cells were normal in WT and CD40deltaTRAF6 mice, severely impaired in CD40deltaTRAF2/3, and absent in CD40deltaTRAFs mice. These results suggest that binding to TRAF2 and/or TRAF3 but not TRAF6 is essential for CD40 isotype switching and activation in B cells.

Amino Acid Motifs↗

PubMed2002

Upregulation of IL-13 concentration in vivo by the IL13 variant associated with bronchial asthma.

BACKGROUND: A substantial body of evidence exists to support the pivotal role of IL-13 in the pathogenesis of bronchial asthma. We recently found that a variant of the IL13 gene (Arg110Gln) is genetically associated with bronchial asthma, which is concordant with animal experiments using IL-13 in the development of asthma. OBJECTIVE: To address whether the Gln110 variant of IL13 influences IL-13 function, contributing to the pathogenesis of bronchial asthma, we studied the functional properties of the variant. METHODS: We generated 2 types of recombinant IL-13 proteins, the amino acids of which at 110 were arginine or glutamine, and analyzed the binding affinities with the IL-13 receptors, as well as the stability of the proteins. We further compared the relationship between the genotype and serum levels of IL-13. RESULTS: The variant showed a lower affinity with the IL-13 receptor alpha2 chain, a decoy receptor, causing less clearance. The variant also demonstrated an enhanced stability in both human and mouse plasma. We further identified that asthmatic patients homozygous for the Gln110 variant have higher serum levels of IL-13 than those without the variant. CONCLUSION: These results suggested that the variant might act as a functional genetic factor of bronchial asthma with a unique mechanism to upregulate local and systemic IL-13 concentration in vivo.

Amino Acid Substitution↗