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  • AIRE expression controls the peripheral selection of autoreactive B cells. Science immunology Sng, J., Ayoglu, B., Chen, J. W., Schickel, J., Ferre, E. M., Glauzy, S., Romberg, N., Hoenig, M., Cunningham-Rundles, C., Utz, P. J., Lionakis, M. S., Meffre, E. 2019; 4 (34)

    Abstract

    Autoimmune regulator (AIRE) mutations result in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome characterized by defective central T cell tolerance and the production of many autoantibodies targeting tissue-specific antigens and cytokines. By studying CD3- and AIRE-deficient patients, we found that lack of either T cells or AIRE function resulted in the peripheral accumulation of autoreactive mature naive B cells. Proteomic arrays and Biacore affinity measurements revealed that unmutated antibodies expressed by these autoreactive naive B cells recognized soluble molecules and cytokines including insulin, IL-17A, and IL-17F, which are AIRE-dependent thymic peripheral tissue antigens targeted by autoimmune responses in APECED. AIRE-deficient patients also displayed decreased frequencies of regulatory T cells (Tregs) that lacked common TCRbeta clones found instead in their conventional T cell compartment, thereby suggesting holes in the Treg TCR repertoire of these patients. Hence, AIRE-mediated T cell/Treg selection normally prevents the expansion of autoreactive naive B cells recognizing peripheral self-antigens.

    View details for PubMedID 30979797

  • AIRE expression controls the peripheral selection of autoreactive B cells SCIENCE IMMUNOLOGY Sng, J., Ayoglu, B., Chen, J. W., Schickel, J., Ferre, E. N., Glauzy, S., Romberg, N., Hoenig, M., Cunningham-Rundles, C., Utz, P. J., Lionakis, M. S., Meffre, E. 2019; 4 (34)
  • Reprogramming human T cell function and specificity with non-viral genome targeting NATURE Roth, T. L., Puig-Saus, C., Yu, R., Shifrut, E., Carnevale, J., Li, P., Hiatt, J., Saco, J., Krystofinski, P., Li, H., Tobin, V., Nguyen, D. N., Lee, M. R., Putnam, A. L., Ferris, A. L., Chen, J. W., Schickel, J., Pellerin, L., Carmody, D., Alkorta-Aranburu, G., del Gaudio, D., Matsumoto, H., Morell, M., Mao, Y., Cho, M., Quadros, R. M., Gurumurthy, C. B., Smith, B., Haugwitz, M., Hughes, S. H., Weissman, J. S., Schumann, K., Esensten, J. H., May, A. P., Ashworth, A., Kupfer, G. M., Greeley, S. W., Bacchetta, R., Meffre, E., Roncarolo, M., Romberg, N., Herold, K. C., Ribas, A., Leonetti, M. D., Marson, A. 2018; 559 (7714): 405-+

    Abstract

    Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells.

    View details for PubMedID 29995861

  • Alternations in repertoire of T and B cell subsets in patients with partial recombination activating gene (RAG) deficiency with autoimmunity and history of viral infections Csomos, K., Ujhazi, B., Butte, M. J., Hernandez, J., Geha, R., Al-Herz, W., Notarangelo, L. D., Meffre, E., Walter, J. E. SPRINGER/PLENUM PUBLISHERS. 2018: 420–21
  • Naive B cells are prone to develop into polyreactive autoantibody secreting cells from adult RAG2-deficient patient with combined immunodeficiency Stowell, M. T., Walter, J. E., Pennix, T. C., Ujhazi, B., Mueller, G., Butte, M., Hoyte, E. G., Hernandez, J. D., Meffre, E. F., Csomos, K. MOSBY-ELSEVIER. 2018: AB22
  • Smith-Magenis Syndrome Patients Often Display Antibody Deficiency but Not Other Immune Pathologies JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE Perkins, T., Rosenberg, J. M., Le Coz, C., Alaimo, J. T., Trofa, M., Mullegama, S. V., Antaya, R. J., Jyonouchi, S., Elsea, S. H., Utz, P. J., Meffre, E., Romberg, N. 2017; 5 (5): 1344-+

    Abstract

    Smith-Magenis syndrome (SMS) is a complex neurobehavioral disorder associated with recurrent otitis. Most SMS cases result from heterozygous interstitial chromosome 17p11.2 deletions that encompass not only the intellectual disability gene retinoic acid-induced 1 but also other genes associated with immunodeficiency, autoimmunity, and/or malignancy.The goals of this study were to describe the immunological consequence of 17p11.2 deletions by determining the prevalence of immunological diseases in subjects with SMS and by assessing their immune systems via laboratory methods.We assessed clinical histories of 76 subjects with SMS with heterozygous 17p11.2 deletions and performed in-depth immunological testing on 25 representative cohort members. Laboratory testing included determination of serum antibody concentrations, vaccine titers, and lymphocyte subset frequencies. Detailed reactivity profiles of SMS serum antibodies were performed using custom-made antigen microarrays.Of 76 subjects with SMS, 74 reported recurrent infections including otitis (88%), pneumonia (47%), sinusitis (42%), and gastroenteritis (34%). Infections were associated with worsening SMS-related neurobehavioral symptoms. The prevalence of autoimmune and atopic diseases was not increased. Malignancy was not reported. Laboratory evaluation revealed most subjects with SMS to be deficient of isotype-switched memory B cells and many to lack protective antipneumococcal antibodies. SMS antibodies were not more reactive than control antibodies to self-antigens.Patients with SMS with heterozygous 17p.11.2 deletions display an increased susceptibility to sinopulmonary infections, but not to autoimmune, allergic, or malignant diseases. SMS sera display an antibody reactivity profile favoring neither recognition of pathogen-associated antigens nor self-antigens. Prophylactic strategies to prevent infections may also provide neurobehavioral benefits to selected patients with SMS.

    View details for PubMedID 28286158

    View details for PubMedCentralID PMC5591748

  • The Genotype and Phenotype (GAP) Registry: A National Resource for Studying Genetic Regulation of Immune Function in Normal Populations Gregersen, P., Keogh, M., Meffre, E., Nolan, G., Kimberly, R., Diamond, B. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2010: S136