Raif S Geha

Publications (124)1204.35 Total impact

• Article: A Phenotypic Approach for IUIS PID Classification and Diagnosis: Guidelines for Clinicians at the Bedside.

  Ahmed Aziz Bousfiha, Leïla Jeddane, Fatima Ailal, Waleed Al Herz, Mary Ellen Conley, Charlotte Cunningham-Rundles, Amos Etzioni, Alain Fischer, Jose Luis Franco, Raif S Geha, Lennart Hammarström, Shigeaki Nonoyama, Hans D Ochs, Chaim M Roifman, Reinhard Seger, Mimi L K Tang, Jennifer M Puck, Helen Chapel, Luigi D Notarangelo, Jean-Laurent Casanova
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  ABSTRACT: The number of genetically defined Primary Immunodeficiency Diseases (PID) has increased exponentially, especially in the past decade. The biennial classification published by the IUIS PID expert committee is therefore quickly expanding, providing valuable information regarding the disease-causing genotypes, the immunological anomalies, and the associated clinical features of PIDs. These are grouped in eight, somewhat overlapping, categories of immune dysfunction. However, based on this immunological classification, the diagnosis of a specific PID from the clinician's observation of an individual clinical and/or immunological phenotype remains difficult, especially for non-PID specialists. The purpose of this work is to suggest a phenotypic classification that forms the basis for diagnostic trees, leading the physician to particular groups of PIDs, starting from clinical features and combining routine immunological investigations along the way. We present 8 colored diagnostic figures that correspond to the 8 PID groups in the IUIS Classification, including all the PIDs cited in the 2011 update of the IUIS classification and most of those reported since.
  Journal of Clinical Immunology 05/2013; · 3.08 Impact Factor
• Article: Development of skin lesions in filaggrin-deficient mice is dependent on adaptive immunity.

  Sabine Leisten, Michiko K Oyoshi, Claire Galand, Jason L Hornick, Michael F Gurish, Raif S Geha
  The Journal of allergy and clinical immunology 04/2013; 131(4):1247-1250.e1. · 9.17 Impact Factor
• Article: Wiskott-Aldrich syndrome: a comprehensive review.

  Michel J Massaad, Narayanaswamy Ramesh, Raif S Geha
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  ABSTRACT: Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency characterized by microthrombocytopenia, eczema, recurrent infections, and an increased incidence of autoimmunity and malignancies. The disease is caused by mutations in the WAS gene expressed exclusively in hematopoietic cells. WAS protein (WASp) is a multidomain protein that exists in complex with several partners that play important roles in its function. WASp belongs to a family of proteins that relay signals from the surface of the cell to the actin cytoskeleton. Mutations in the WAS gene have various effects on the level of WASp, which, in turn, correlates with the severity of the disease. In addition to WAS, mutations in the WAS gene can result in the mild variant X-linked thrombocytopenia, or in X-linked neutropenia, characterized by neutropenia with myelodysplasia. The absence of functional WASp leads to a severe clinical phenotype that can result in death if not diagnosed and treated early in life. The treatment of choice with the best outcome is hematopoietic stem cell transplantation, preferably from a matched related donor.
  Annals of the New York Academy of Sciences 03/2013; · 3.15 Impact Factor
• Article: Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency.

  Melissa C Mizesko, Pinaki P Banerjee, Linda Monaco-Shawver, Emily M Mace, William E Bernal, Julie Sawalle-Belohradsky, Bernd H Belohradsky, Valerie Heinz, Alexandra F Freeman, Kathleen E Sullivan, Steven M Holland, Troy R Torgerson, Waleed Al-Herz, Janet Chou, Imelda C Hanson, Michael H Albert, Raif S Geha, Ellen D Renner, Jordan S Orange
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  ABSTRACT: BACKGROUND: Dedicator of cytokinesis 8 (DOCK8) mutations are responsible for a rare primary combined immunodeficiency syndrome associated with severe cutaneous viral infections, increased IgE levels, autoimmunity, and malignancy. Natural killer (NK) cells are essential for tumor surveillance and defense against virally infected cells. NK cell function relies on Wiskott-Aldrich syndrome protein for filamentous actin (F-actin) accumulation at the lytic NK cell immunologic synapse. DOCK8 activates cell division cycle 42, which, together with Wiskott-Aldrich syndrome protein, coordinates F-actin reorganization. Although abnormalities in T- and B-cell function have been described in DOCK8-deficient patients, the role of NK cells in this disease is unclear. OBJECTIVES: We sought to understand the role of DOCK8 in NK cell function to determine whether NK cell abnormalities explain the pathogenesis of the clinical syndrome of DOCK8 deficiency. METHODS: A cohort of DOCK8-deficient patients was assembled, and patients' NK cells, as well as NK cell lines with stably reduced DOCK8 expression, were studied. NK cell cytotoxicity, F-actin content, and lytic immunologic synapse formation were measured. RESULTS: DOCK8-deficient patients' NK cells and DOCK8 knockdown cell lines all had decreased NK cell cytotoxicity, which could not be restored after IL-2 stimulation. Importantly, DOCK8 deficiency impaired F-actin accumulation at the lytic immunologic synapse without affecting overall NK cell F-actin content. CONCLUSIONS: DOCK8 deficiency results in severely impaired NK cell function because of an inability to form a mature lytic immunologic synapse through targeted synaptic F-actin accumulation. This defect might underlie and explain important attributes of the DOCK8 deficiency clinical syndrome, including the unusual susceptibility to viral infection and malignancy.
  The Journal of allergy and clinical immunology 02/2013; · 9.17 Impact Factor
• Article: Epicutaneous sensitization results in IgE-dependent intestinal mast cell expansion and food-induced anaphylaxis.

  Lisa M Bartnikas, Michael F Gurish, Oliver T Burton, Sabine Leisten, Erin Janssen, Hans C Oettgen, Jacqueline Beaupré, Christopher N Lewis, K Frank Austen, Stephanie Schulte, Jason L Hornick, Raif S Geha, Michiko K Oyoshi
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  ABSTRACT: Sensitization to food antigen can occur through cutaneous exposure. We sought to test the hypothesis that epicutaneous sensitization with food antigen predisposes to IgE-mediated anaphylaxis on oral allergen challenge. BALB/c mice were epicutaneously sensitized by repeated application of ovalbumin (OVA) to tape-stripped skin over 7 weeks or orally immunized with OVA and cholera toxin (CT) weekly for 8 weeks and then orally challenged with OVA. Body temperature was monitored, and serum mouse mast cell protease 1 levels were determined after challenge. Tissue mast cell (MC) counts were examined by using chloroacetate esterase staining. Levels of serum OVA-specific IgE and IgG(1) antibodies and cytokines in supernatants of OVA-stimulated splenocytes were measured by means of ELISA. Serum IL-4 levels were measured by using an in vivo cytokine capture assay. Epicutaneously sensitized mice exhibited expansion of connective tissue MCs in the jejunum, increased serum IL-4 levels, and systemic anaphylaxis after oral challenge, as evidenced by decreased body temperature and increased serum mouse mast cell protease 1 levels. Intestinal MC expansion and anaphylaxis were IgE dependent because they did not occur in epicutaneously sensitized IgE(-/-) mice. Mice orally immunized with OVA plus CT did not have increased serum IL-4 levels, expanded intestinal MCs, or anaphylaxis after oral challenge, despite OVA-specific IgE levels and splenocyte cytokine production in response to OVA stimulation, which were comparable with those of epicutaneously sensitized mice. Epicutaneously sensitized mice, but not mice orally immunized with antigen plus CT, have expansion of intestinal MCs and IgE-mediated anaphylaxis after single oral antigen challenge. IgE is necessary but not sufficient for food anaphylaxis, and MC expansion in the gut can play an important role in the development of anaphylaxis.
  The Journal of allergy and clinical immunology 02/2013; 131(2):451-460.e6. · 9.17 Impact Factor
• Article: Intronic SH2D1A mutation with impaired SAP expression and agammaglobulinemia.

  Mike Recher, Ari J Fried, Michel J Massaad, Hye Young Kim, Michela Rizzini, Francesco Frugoni, Jolan E Walter, Divij Mathew, Hermann Eibel, Christoph Hess, Silvia Giliani, Dale T Umetsu, Luigi D Notarangelo, Raif S Geha
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  ABSTRACT: X-linked lymphoproliferative (XLP) disease is a primary immunodeficiency syndrome associated with the inability to control Epstein-Barr virus (EBV), lymphoma, and hypogammaglobulinemia. XLP is caused by mutations in the SH2D1A gene, which encodes the SLAM-associated protein (SAP), or in the BIRC4 gene, which encodes the X-linked inhibitor of apoptosis protein (XIAP). Here we report a patient with recurrent respiratory tract infections and early onset agammaglobulinemia who carried a unique disease-causing intronic loss-of-function mutation in SH2D1A. The intronic mutation affected SH2D1A gene transcription but not mRNA splicing, and led to markedly reduced level of SAP protein. Despite undetectable serum immunoglobulins, the patient's B cells replicated and differentiated into antibody producing cells normally in vitro.
  Clinical Immunology 12/2012; 146(2):84-89. · 4.05 Impact Factor
• Article: Use of whole exome and genome sequencing in the identification of genetic causes of primary immunodeficiencies.

  Janet Chou, Toshiro K Ohsumi, Raif S Geha
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  ABSTRACT: This review discusses the strengths and challenges of using whole genome sequencing (WGS)/whole exome sequencing (WES) for identifying novel genetic causes of primary immunodeficiencies. WGS permits comprehensive sequencing of introns and exons, whereas WES allows deeper sequencing of exonic regions at a lower cost. Due to the large number of genetic variants found in each genome, it is necessary to use filtering approaches to distinguish deleterious from benign variants. WES has been used successfully to identify novel genetic causes of primary immunodeficiency. Complex structural variations and non-Mendelian disorders remain challenges for WGS/WES. WGS/WES is a powerful screening tool with great potential to identify genetic causes of primary immunodeficiencies for research and clinical applications. To use WGS/WES effectively, it is necessary to understand how to filter the sequencing data and to realize its limitations as well as its strengths.
  Current Opinion in Allergy and Clinical Immunology 12/2012; 12(6):623-8. · 4.11 Impact Factor
• Article: Leukotriene b4-driven neutrophil recruitment to the skin is essential for allergic skin inflammation.

  Michiko K Oyoshi, Rui He, Yitang Li, Subhanjan Mondal, Juhan Yoon, Roshi Afshar, Mei Chen, David M Lee, Hongbo R Luo, Andrew D Luster, John S Cho, Lloyd S Miller, Allison Larson, George F Murphy, Raif S Geha
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  ABSTRACT: Scratching triggers skin flares in atopic dermatitis. We demonstrate that scratching of human skin and tape stripping of mouse skin cause neutrophil influx. In mice, this influx was largely dependent on the generation of leukotriene B4 (LTB4) by neutrophils and their expression of the LTB4 receptor BLT1. Allergic skin inflammation in response to epicutaneous (EC) application of ovalbumin to tape-stripped skin was severely impaired in Ltb4r1(-/-) mice and required expression of BLT1 on both T cells and non-T cells. Cotransfer of wild-type (WT) neutrophils, but not neutrophils deficient in BLT1 or the LTB4-synthesizing enzyme LTA4H, restored the ability of WT CD4(+) effector T cells to transfer allergic skin inflammation to Ltb4r1(-/-) recipients. Pharmacologic blockade of LTB4 synthesis inhibited allergic skin inflammation elicited by cutaneous antigen challenge in previously EC-sensitized mice. Our results demonstrate that a neutrophil-T cell axis reliant on LTB4-BLT1 interaction is required for allergic skin inflammation.
  Immunity 10/2012; 37(4):747-58. · 21.64 Impact Factor
• Article: EPEC and vaccinia virus do not require WIP family proteins for pathogen-induced actin assembly.

  John J Garber, Fuminao Takeshima, Inés M Antón, Michiko K Oyoshi, Anna Lyubimova, Archana Kapoor, Tomoyuki Shibata, Feng Chen, Frederick W Alt, Raif S Geha, John M Leong, Scott B Snapper
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  ABSTRACT: The human pathogens enteropathogenic Escherichia coli (EPEC) and vaccinia virus trigger actin assembly in host cells by activating the host adaptor Nck and the actin nucleation promoter N-WASP. EPEC translocates effector molecules into host cells via type III secretion, and the interaction between the translocated intimin receptor (Tir) and the bacterial membrane protein intimin stimulates Nck and N-WASP recruitment, leading to the formation of actin pedestals beneath adherent bacteria. Vaccinia virus also recruits Nck and N-WASP to generate actin tails that promote cell-to-cell spread of the virus. In addition to Nck and N-WASP, WASP-interacting protein (WIP) localizes to vaccinia tails, and inhibition of actin tail formation upon ectopic expression of WIP mutants led to the suggestion that WIP is required for this process. Similar studies of WIP mutants, however, did not affect the ability of EPEC to form actin pedestals, arguing against an essential role for WIP in EPEC-induced actin assembly. In this study, we demonstrate that Nck and N-WASP are normally recruited by vaccinia and EPEC in the absence of WIP, and neither WIP, nor the WIP family members CR16 and WIRE/WICH, are essential for pathogen induced actin assembly. In addition, although Nck binds EPEC Tir directly, N-WASP is required for its localization during pedestal formation. Overall, these data highlight similar pathogenic strategies shared by EPEC and vaccinia by demonstrating a requirement for both Nck and N-WASP, but not WIP or WIP-family members, in pathogen-induced actin assembly.
  Infection and immunity 09/2012; · 4.21 Impact Factor
• Article: A novel homozygous mutation in recombination activating gene 2 in 2 relatives with different clinical phenotypes: Omenn syndrome and hyper-IgM syndrome.

  Janet Chou, Rima Hanna-Wakim, Irit Tirosh, Jennifer Kane, David Fraulino, Yu Nee Lee, Soha Ghanem, Iman Mahfouz, André Mégarbané, Gérard Lefranc, Adlette Inati, Ghassan Dbaibo, Silvia Giliani, Luigi D Notarangelo, Raif S Geha, Michel J Massaad
  The Journal of allergy and clinical immunology 07/2012; · 9.17 Impact Factor
• Article: DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation.

  Haifa H Jabara, Douglas R McDonald, Erin Janssen, Michel J Massaad, Narayanaswamy Ramesh, Arturo Borzutzky, Ingrid Rauter, Halli Benson, Lynda Schneider, Sachin Baxi, [......], Maria Kanariou, Gerard Lefranc, Ismail Reisli, Katherine A Fitzgerald, Douglas Golenbock, John Manis, Sevgi Keles, Reuben Ceja, Talal A Chatila, Raif S Geha
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  ABSTRACT: The adaptors DOCK8 and MyD88 have been linked to serological memory. Here we report that DOCK8-deficient patients had impaired antibody responses and considerably fewer CD27(+) memory B cells. B cell proliferation and immunoglobulin production driven by Toll-like receptor 9 (TLR9) were considerably lower in DOCK8-deficient B cells, but those driven by the costimulatory molecule CD40 were not. In contrast, TLR9-driven expression of AICDA (which encodes the cytidine deaminase AID), the immunoglobulin receptor CD23 and the costimulatory molecule CD86 and activation of the transcription factor NF-κB, the kinase p38 and the GTPase Rac1 were intact. DOCK8 associated constitutively with MyD88 and the tyrosine kinase Pyk2 in normal B cells. After ligation of TLR9, DOCK8 became tyrosine-phosphorylated by Pyk2, bound the Src-family kinase Lyn and linked TLR9 to a Src-kinase Syk-transcription factor STAT3 cascade essential for TLR9-driven B cell proliferation and differentiation. Thus, DOCK8 functions as an adaptor in a TLR9-MyD88 signaling pathway in B cells.
  Nature Immunology 05/2012; 13(6):612-20. · 26.01 Impact Factor
• Source

  Available from: Raja'a Al-Attiyah

  Article: Clinical, immunologic and genetic profiles of DOCK8-deficient patients in Kuwait.

  Waleed Al-Herz, Raj Ragupathy, Michel J Massaad, Raja'a Al-Attiyah, Arti Nanda, Karin R Engelhardt, Bodo Grimbacher, Luigi Notarangelo, Talal Chatila, Raif S Geha
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  ABSTRACT: Deficiency of dedicator of cytokinesis 8 (DOCK8) is a newly described combined primary immunodeficiency disease. It was found to account for 15% of combined immune deficiency cases in the National Primary Immunodeficiency Disorders Registry in Kuwait, a country with high prevalence of consanguinity. We present the clinical, immunologic and molecular characteristics of 9 Kuwaiti patients with DOCK8 deficiency and discuss differences that distinguish DOCK8 deficiency from atopic dermatitis. Clinical immunologists in areas with high incidence of consanguinity should have a high index of suspicion of DOCK8 deficiency in children with recalcitrant eczema, recurrent non-cutaneous infections and lymphopenia.
  Clinical Immunology 03/2012; 143(3):266-72. · 4.05 Impact Factor
• Source

  Available from: pnas.org

  Article: Eosinophil-derived leukotriene C4 signals via type 2 cysteinyl leukotriene receptor to promote skin fibrosis in a mouse model of atopic dermatitis.

  Michiko K Oyoshi, Rui He, Yoshihide Kanaoka, Abdallah ElKhal, Seiji Kawamoto, Christopher N Lewis, K Frank Austen, Raif S Geha
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  ABSTRACT: Atopic dermatitis (AD) skin lesions exhibit epidermal and dermal thickening, eosinophil infiltration, and increased levels of the cysteinyl leukotriene (cys-LT) leukotriene C(4) (LTC(4)). Epicutaneous sensitization with ovalbumin of WT mice but not ΔdblGATA mice, the latter of which lack eosinophils, caused skin thickening, collagen deposition, and increased mRNA expression of the cys-LT generating enzyme LTC(4) synthase (LTC(4)S). Skin thickening and collagen deposition were significantly reduced in ovalbumin-sensitized skin of LTC(4)S-deficient and type 2 cys-LT receptor (CysLT(2)R)-deficient mice but not type 1 cys-LT receptor (CysLT(1)R)-deficient mice. Adoptive transfer of bone marrow-derived eosinophils from WT but not LTC(4)S-deficient mice restored skin thickening and collagen deposition in epicutaneous-sensitized skin of ΔdblGATA recipients. LTC(4) stimulation caused increased collagen synthesis by human skin fibroblasts, which was blocked by CysLT(2)R antagonism but not CysLT(1)R antagonism. Furthermore, LTC(4) stimulated skin fibroblasts to secrete factors that elicit keratinocyte proliferation. These findings establish a role for eosinophil-derived cys-LTs and the CysLT(2)R in the hyperkeratosis and fibrosis of allergic skin inflammation. Strategies that block eosinophil infiltration, cys-LT production, or the CysLT(2)R might be useful in the treatment of AD.
  Proceedings of the National Academy of Sciences 03/2012; 109(13):4992-7. · 9.68 Impact Factor
• Source

  Available from: Gerben Bouma

  Article: B cell-intrinsic deficiency of the Wiskott-Aldrich syndrome protein (WASp) causes severe abnormalities of the peripheral B-cell compartment in mice.

  Mike Recher, Siobhan O Burns, Miguel A de la Fuente, Stefano Volpi, Carin Dahlberg, Jolan E Walter, Kristin Moffitt, Divij Mathew, Nadine Honke, Philipp A Lang, [......], John Hartwig, John Manis, Cox Terhorst, Raif S Geha, Scott Snapper, Karl S Lang, Richard Malley, Lisa Westerberg, Adrian J Thrasher, Luigi D Notarangelo
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  ABSTRACT: Wiskott Aldrich syndrome (WAS) is caused by mutations in the WAS gene that encodes for a protein (WASp) involved in cytoskeleton organization in hematopoietic cells. Several distinctive abnormalities of T, B, and natural killer lymphocytes; dendritic cells; and phagocytes have been found in WASp-deficient patients and mice; however, the in vivo consequence of WASp deficiency within individual blood cell lineages has not been definitively evaluated. By conditional gene deletion we have generated mice with selective deficiency of WASp in the B-cell lineage (B/WcKO mice). We show that this is sufficient to cause a severe reduction of marginal zone B cells and inability to respond to type II T-independent Ags, thereby recapitulating phenotypic features of complete WASp deficiency. In addition, B/WcKO mice showed prominent signs of B-cell dysregulation, as indicated by an increase in serum IgM levels, expansion of germinal center B cells and plasma cells, and elevated autoantibody production. These findings are accompanied by hyperproliferation of WASp-deficient follicular and germinal center B cells in heterozygous B/WcKO mice in vivo and excessive differentiation of WASp-deficient B cells into class-switched plasmablasts in vitro, suggesting that WASp-dependent B cell-intrinsic mechanisms critically contribute to WAS-associated autoimmunity.
  Blood 02/2012; 119(12):2819-28. · 9.90 Impact Factor
• Source

  Available from: Silvia Giliani

  Article: A novel primary human immunodeficiency due to deficiency in the WASP-interacting protein WIP.

  Gaetana Lanzi, Daniele Moratto, Donatella Vairo, Stefania Masneri, Ottavia Delmonte, Tiziana Paganini, Silvia Parolini, Giovanna Tabellini, Cinzia Mazza, Gianfranco Savoldi, [......], Silvana Martino, Pierangelo Tovo, Itai M Pessach, Michel J Massaad, Narayanaswamy Ramesh, Fulvio Porta, Alessandro Plebani, Luigi D Notarangelo, Raif S Geha, Silvia Giliani
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  ABSTRACT: A female offspring of consanguineous parents, showed features of Wiskott-Aldrich syndrome (WAS), including recurrent infections, eczema, thrombocytopenia, defective T cell proliferation and chemotaxis, and impaired natural killer cell function. Cells from this patient had undetectable WAS protein (WASP), but normal WAS sequence and messenger RNA levels. WASP interacting protein (WIP), which stabilizes WASP, was also undetectable. A homozygous c.1301C>G stop codon mutation was found in the WIPF1 gene, which encodes WIP. Introduction of WIP into the patient's T cells restored WASP expression. These findings indicate that WIP deficiency should be suspected in patients with features of WAS in whom WAS sequence and mRNA levels are normal.
  Journal of Experimental Medicine 01/2012; 209(1):29-34. · 13.85 Impact Factor
• Article: Vaccinia Ig ameliorates eczema vaccinatum in a murine model of atopic dermatitis.

  Michiko K Oyoshi, Narayanaswamy Ramesh, Raif S Geha
  Journal of Investigative Dermatology 12/2011; 132(4):1299-301. · 6.31 Impact Factor
• Article: Immunization with modified vaccinia virus Ankara prevents eczema vaccinatum in a murine model of atopic dermatitis.

  Michiko K Oyoshi, James Y T Wang, Raif S Geha
  The Journal of allergy and clinical immunology 08/2011; 128(4):890-892.e3. · 9.17 Impact Factor
• Article: Toll-like receptor 9, transmembrane activator and calcium-modulating cyclophilin ligand interactor, and CD40 synergize in causing B-cell activation.

  Esra Ozcan, Ingrid Rauter, Lilit Garibyan, Stacey R Dillon, Raif S Geha
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  ABSTRACT: B cells receive activating signals from T cells through CD40, from microbial DNA through Toll-like receptor (TLR) 9, and from dendritic cells through transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI). TLR9 and CD40 ligation augment TACI-driven B-cell activation, but only the mechanism of synergy between CD40 and TACI has been explored. Synergy between CD40 and TLR9 in B-cell activation is controversial. We sought to examine the mechanisms by which TLR9 modulates CD40- and TACI-mediated activation of B cells and to determine whether all 3 receptors synergize to activate B cells. Naive murine B cells and human PBMCs were stimulated with combinations of anti-CD40, CpG, and a proliferation inducing ligand in the presence of IL-4. Proliferation was measured by means of tritiated thymidine incorporation. Immunoglobulin production was measured by means of ELISA. Class-switch recombination (CSR) was examined by measuring mRNA for germline transcripts, activation-induced cytidine deaminase (AICDA), and mature immunoglobulin transcripts. Plasma cell differentiation was examined by using syndecan-1/CD138 staining and mRNA expression of B lymphocyte-induced maturation protein 1 (Blimp-1). TLR9 synergized with CD40 and TACI in driving CSR and inducing IgG(1) and IgE secretion by naive murine B cells and synergized with TACI in driving B-cell proliferation and plasma cell differentiation. All 3 receptors synergized together in driving murine B-cell proliferation, CSR, plasma cell differentiation, and IgG(1) and IgE secretion. TLR9 synergized with CD40 and TACI in driving IgG secretion in IL-4-stimulated human B cells. Signals from TLR9, TACI, and CD40 are integrated to promote B-cell activation and differentiation.
  The Journal of allergy and clinical immunology 07/2011; 128(3):601-9.e1-4. · 9.17 Impact Factor
• Article: Epicutaneous challenge of orally immunized mice redirects antigen-specific gut-homing T cells to the skin.

  Michiko K Oyoshi, Abdallah Elkhal, Jordan E Scott, Marc-Andre Wurbel, Jason L Hornick, James J Campbell, Raif S Geha
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  ABSTRACT: Patients with atopic dermatitis (AD) often suffer from food allergy and develop flares upon skin contact with food allergens. However, it is unclear whether T cells sensitized to allergens in the gut promote this skin inflammation. To address this question, we orally immunized WT mice and mice lacking the skin-homing chemokine receptor Ccr4 (Ccr4-/- mice) with OVA and then challenged them epicutaneously with antigen. Allergic skin inflammation developed in the WT mice but not in the mutants and was characterized by epidermal thickening, dermal infiltration by eosinophils and CD4+ T cells, and upregulation of Th2 cytokines. T cells purified from mesenteric lymph nodes (MLNs) of orally immunized WT mice transferred allergic skin inflammation to naive recipients cutaneously challenged with antigen, but this effect was lost in T cells purified from Ccr4-/- mice. In addition, the ability of adoptively transferred OVA-activated T cells to home to the skin following cutaneous OVA challenge was ablated in mice that lacked lymph nodes. These results indicate that cutaneous exposure to food antigens can reprogram gut-homing effector T cells in LNs to express skin-homing receptors, eliciting skin lesions upon food allergen contact in orally sensitized AD patients.
  The Journal of clinical investigation 06/2011; 121(6):2210-20. · 15.39 Impact Factor
• Article: Functional analysis of transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) mutations associated with common variable immunodeficiency.

  Ari J Fried, Ingrid Rauter, Stacey R Dillon, Haifa H Jabara, Raif S Geha
  The Journal of allergy and clinical immunology 03/2011; 128(1):226-228.e1. · 9.17 Impact Factor