Arthritis, Rheumatoid; Autoimmune Diseases; Diabetes Mellitus, Type 1; Immune System; Lupus Erythematosus, Systemic
Rheumatic Diseases Research Core
The long range goal of our research is to further elucidate the mechanisms that regulate B cell tolerance in healthy humans and that are altered in patients with autoimmune diseases. The working hypothesis is that B cells from rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and type 1 diabetes (T1D) patients suffer from intrinsic signaling defects that result in a central failure to remove autoreactive B cells. In addition, alterations in T cell/dendritic cell functions may affect the counterselection of autoreactive B cells in the periphery. We are currently studying patients with CD19, TACI, ICOS, Fas, and AID gene defects to identify the roles of these molecules in the establishment of B cell tolerance. The involvement of NKT and Treg cells on peripheral B cell tolerance is currently being assessed by analyzing XLP patients who display no NKT cells and IPEX patients with Foxp3-deficiency in which no functional Treg cells develop resulting in severe autoimmune manifestations. Finally, we aim to characterize gene expression profiles using Affimetrix gene chips in unstimulated and BCR-stimulated RA and T1D B cells and compare them to those from healthy donor B cells to potentially identify defective pathways through genes that would fail to be properly regulated.
Specialized Terms:Human B-cell tolerance; Primary immunodeficiencies; Autoimmune diseases
Extensive Research Description
Autoantibody production is a characteristic of most autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and type 1 diabetes (T1D). These autoantibodies appear in the serum many years before the onset of clinical disease suggesting an early break in B cell tolerance. We previously established in healthy donors that random V(D)J recombination produce large numbers of autoreactive antibodies. Most developing B cells that express polyreactive antibodies or B cell receptors (BCRs) are silenced in the bone marrow, and additional autoreactive B cells are removed in the periphery. We recently analyzed B cell tolerance in RA patients by testing the specificity of recombinant antibodies cloned from single B cells. RA patients exhibit defective central and peripheral B cell tolerance checkpoints that result in the accumulation of self-reactive mature naïve B cells, likely contributing to the pathogenesis of this disease. Yet the mechanisms that lead to the generation and survival of these autoreactive mature naïve B cells in RA patients are unknown.
Defects in BCR signaling have been reported in B cells from SLE patients who also suffer from defective central and peripheral B cell tolerance checkpoints, suggesting that BCR signaling may play an important role in counterselecting self-reactive B cells. By studying X-linked agammaglobulinemia (XLA) patients who carry mutations in the BTK gene that encodes an essential BCR signaling component, we demonstrated that Btk and therefore BCR signaling is essential in regulating thresholds for human central B cell tolerance. In addition, developing anti-nuclear B cells from IRAK-4- and MyD88-deficient patients failed to be counterselected and demonstrated an essential role for Toll-like receptors in the establishment of human B cell tolerance. Moreover, we recently reported that CD40ligand (CD40L)-and MHC class II-deficient patients who accumulated autoreactive B cells in their mature B cell compartment displayed decreased numbers of regulatory (Treg) and NK T cells in their blood suggesting that these cells may be involved in the establishment of peripheral B cell tolerance in humans.
The long range goal of our research is to further elucidate the mechanisms, molecules and cells that regulate B cell tolerance in healthy humans and that are altered in patients with autoimmune diseases. The working hypothesis is that B cells from RA, SLE and potentially T1D patients suffer from intrinsic signaling defects that result in a central failure to remove autoreactive B cells. In addition, alterations in T cell/dendritic cell functions may affect the counterselection of autoreactive B cells in the periphery. We are currently studying B cell tolerance in patients with CD19, TACI, ICOS, Fas, AID, uracil-DNA glycosylase (UNG) gene defects to identify new pathways and molecules required for the establishment of B cell tolerance. The role of NKT and Treg cells on peripheral B cell tolerance is currently being assessed by analyzing B cell tolerance checkpoints in two primary immunodeficiencies, XLP and IPEX. XLP patients suffer from defective SAP (SLAM associated protein) gene and display normal Treg cells but no NKT cells whereas IPEX patients suffer from Foxp3-deficiency in which no functional Treg cells develop resulting in severe autoimmune manifestations.
Finally, we aim to characterize gene expression profiles using Affimetrix gene chips in unstimulated and BCR-stimulated RA and T1D B cells and compare them to those from healthy donor B cells to potentially identify defective pathways through genes that would fail to be properly regulated.
Defective B cell tolerance in adenosine deaminase deficiency is corrected by gene therapy.
A. V. Sauer, H. Morbach, I. Brigida, Y.-S. Ng, A. Aiuti and E. Meffre. Defective B-cell tolerance due to adenosine deaminase deficiency is corrected by gene therapy. 2012. J. Clin. Invest. 122(6):2141-52.
The establishment of early B cell tolerance in humans: lessons from primary immunodeficiency diseases.
E. Meffre. The establishment of early B cell tolerance in humans: lessons from primary immunodeficiency diseases. 2011. Ann. N.Y. Acad. Sci. 1246: 1–10.
The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans.
L. Ménard, D. Saadoun, I. Isnardi, Y.-S. Ng, G. Meyers, C. Massad, C. Price, C. Abraham, R. Motaghedi, J. H. Buckner, P. K. Gregersen and E. Meffre. The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans. J Clin Invest. 2011 Sep;121(9):3635-44
Activation-induced cytidine deaminase (AID) is required for B-cell tolerance in humans.
G. Meyers, Y.-S. Ng, J. M. Bannock, A. Lavoie, J. E. Walter, L. D. Notarangelo, S. S. Kilic, G. Aksu, M. Debré, F. Rieux-Laucat, M. E. Conley, C. Cunningham-Rundles, A. Durandy and E. Meffre. Activation-induced cytidine deaminase (AID) is required for B-cell tolerance in humans. Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11554-9.
Inflammation-independent defective early B cell tolerance checkpoints in rheumatoid arthritis.
L. Ménard, J. Samuels, Y.-S. Ng and E. Meffre. Inflammation-independent defective early B cell tolerance checkpoints in rheumatoid arthritis. 2011. Arthritis Rheum. 63:1237-45.
Complement receptor 2/CD21- human naive B cells contain mostly autoreactive unresponsive clones.
I. Isnardi, Y.-S. Ng, L. Menard, G. Meyers, D. Saadoun, I. Srdanovic, J. Samuels, J. Berman, J. H. Buckner, C. Cunningham-Rundles and E. Meffre. Complement receptor 2/CD21- human naive B cells contain mostly autoreactive unresponsive clones. Blood. 2010 Jun 17;115(24):5026-36.
IRAK-4- and MyD88-dependent pathways are essential for the removal of developing autoreactive B cells in humans.
I. Isnardi, Y.-S. Ng, I. Srdanovic, R. Motaghedi, S. Rudchenko, H. von Bernuth, S.-Y. Zhang, A. Puel, E. Jouanguy, C. Picard, B.-Z. Garty, Y. Camcioglu, R. Doffinger, D. Kumararatne, G Davies, J. I. Gallin, S. Haraguchi, N. K. Day, J.-L. Casanova and E. Meffre. IRAK-4- and MyD88-dependent pathways are essential for the removal of developing autoreactive B cells in humans. 2008. Immunity 29:746-757.
B cell tolerance checkpoints in health and autoimmunity
E. Meffre and H. Wardemann. B cell tolerance checkpoints in health and autoimmunity. Curr. Opin. Immunol. 2008. 20:632-638.
Autoantibody selection and production in early human life.
E. Meffre and J. Salmon. Autoantibody selection and production in early human life. 2007. J. Clin. Invest. 117:598-601.
CD40L and MHC class II expression are essential for human peripheral B cell tolerance.
M. Hervé, I. Isnardi, Y.-S. Ng, J. B Bussel, H. Ochs, C. Cunningham-Rundles and E. Meffre. CD40L and MHC class II expression are essential for human peripheral B cell tolerance.J. Exp. Med. 2007. 204:1583-93.
Full List of PubMed Publications
- Sintes J, Gentile M, Zhang S, Garcia-Carmona Y, Magri G, Cassis L, Segura-Garzón D, Ciociola A, Grasset EK, Bascones S, Comerma L, Pybus M, Lligé D, Puga I, Gutzeit C, He B, DuBois W, Crespo M, Pascual J, Mensa A, Aróstegui JI, Juan M, Yagüe J, Serrano S, Lloreta J, Meffre E, Hahne M, Cunningham-Rundles C, Mock BA, Cerutti A: mTOR intersects antibody-inducing signals from TACI in marginal zone B cells. Nat Commun. 2017 Nov 13; 2017 Nov 13. PMID: 29133782
- Glauzy S, Sng J, Bannock JM, Gottenberg JE, Korganow AS, Cacoub P, Saadoun D, Meffre E: Defective Early B Cell Tolerance Checkpoints in Sjögren's Syndrome Patients. Arthritis Rheumatol. 2017 Nov; 2017 Oct 12. PMID: 28704602
- Glauzy S, Boccitto M, Bannock JM, Delmotte FR, Saadoun D, Cacoub P, Ice JA, Sivils KL, James JA, Wolin SL, Meffre E: Accumulation of Antigen-Driven Lymphoproliferations in Complement Receptor 2/CD21-/low B Cells From Patients With Sjögren's Syndrome. Arthritis Rheumatol. 2017 Oct 26; 2017 Oct 26. PMID: 29073352
- Borsotti C, Danzl NM, Nauman G, Hölzl MA, French C, Chavez E, Khosravi-Maharlooei M, Glauzy S, Delmotte FR, Meffre E, Savage DG, Campbell SR, Goland R, Greenberg E, Bi J, Satwani P, Yang S, Bathon J, Winchester R, Sykes M: HSC extrinsic sex-related and intrinsic autoimmune disease-related human B-cell variation is recapitulated in humanized mice. Blood Adv. 2017 Oct 24; 2017 Oct 13. PMID: 29296847
- Ma CA, Stinson JR, Zhang Y, Abbott JK, Weinreich MA, Hauk PJ, Reynolds PR, Lyons JJ, Nelson CG, Ruffo E, Dorjbal B, Glauzy S, Yamakawa N, Arjunaraja S, Voss K, Stoddard J, Niemela J, Zhang Y, Rosenzweig SD, McElwee JJ, DiMaggio T, Matthews HF, Jones N, Stone KD, Palma A, Oleastro M, Prieto E, Bernasconi AR, Dubra G, Danielian S, Zaiat J, Marti MA, Kim B, Cooper MA, Romberg N, Meffre E, Gelfand EW, Snow AL, Milner JD: Germline hypomorphic CARD11 mutations in severe atopic disease. Nat Genet. 2017 Aug; 2017 Jun 19. PMID: 28628108
- Sanjuan Nandin I, Fong C, Deantonio C, Torreno-Pina JA, Pecetta S, Maldonado P, Gasparrini F, Ordovas-Montanes J, Kazer SW, Kjaer S, Borley DW, Nair U, Coleman JA, Lingwood D, Shalek AK, Meffre E, Poignard P, Burton DR, Batista FD: Novel in vitro booster vaccination to rapidly generate antigen-specific human monoclonal antibodies. J Exp Med. 2017 Jul 24; 2017 Jul 24. PMID: 28739603
- Schickel JN, Glauzy S, Ng YS, Chamberlain N, Massad C, Isnardi I, Katz N, Uzel G, Holland SM, Picard C, Puel A, Casanova JL, Meffre E: Self-reactive VH4-34-expressing IgG B cells recognize commensal bacteria. J Exp Med. 2017 Jul 3; 2017 May 12. PMID: 28500047
- Yu H, Borsotti C, Schickel JN, Zhu S, Strowig T, Eynon EE, Frleta D, Gurer C, Murphy AJ, Yancopoulos GD, Meffre E, Manz MG, Flavell RA: A novel humanized mouse model with significant improvement of class-switched, antigen-specific antibody production. Blood. 2017 Feb 23; 2017 Jan 11. PMID: 28077418
- Rivas JR, Ireland SJ, Chkheidze R, Rounds WH, Lim J, Johnson J, Ramirez DM, Ligocki AJ, Chen D, Guzman AA, Woodhall M, Wilson PC, Meffre E, White C 3rd, Greenberg BM, Waters P, Cowell LG, Stowe AM, Monson NL: Peripheral VH4+ plasmablasts demonstrate autoreactive B cell expansion toward brain antigens in early multiple sclerosis patients. Acta Neuropathol. 2017 Jan; 2016 Oct 11. PMID: 27730299
- Perkins T, Rosenberg JM, Le Coz C, Alaimo JT, Trofa M, Mullegama SV, Antaya RJ, Jyonouchi S, Elsea SH, Utz PJ, Meffre E, Romberg N: Smith-Magenis Syndrome Patients Often Display Antibody Deficiency but Not Other Immune Pathologies. J Allergy Clin Immunol Pract. 2017 Sep - Oct; 2017 Mar 9. PMID: 28286158
- Schickel JN, Kuhny M, Baldo A, Bannock JM, Massad C, Wang H, Katz N, Oe T, Menard L, Soulas-Sprauel P, Strowig T, Flavell R, Meffre E: PTPN22 inhibition resets defective human central B cell tolerance. Sci Immunol. 2016 Jul 22; 2016 Jul 22. PMID: 28783674
- Garyu JW, Meffre E, Cotsapas C, Herold KC: Progress and challenges for treating Type 1 diabetes. J Autoimmun. 2016 Jul; 2016 May 17. PMID: 27210268
- Meffre E: Big impact of microRNAs on central B cell tolerance. Nat Immunol. 2016 Apr. PMID: 27002836
- Morbach H, Schickel JN, Cunningham-Rundles C, Conley ME, Reisli I, Franco JL, Meffre E: CD19 controls Toll-like receptor 9 responses in human B cells. J Allergy Clin Immunol. 2016 Mar; 2015 Oct 21. PMID: 26478008
- Meffre E, Louie A, Bannock J, Kim LJ, Ho J, Frear CC, Kardava L, Wang W, Buckner CM, Wang Y, Fankuchen OR, Gittens KR, Chun TW, Li Y, Fauci AS, Moir S: Maturational characteristics of HIV-specific antibodies in viremic individuals. JCI Insight. 2016; 2016 Mar 17. PMID: 27152362
- Schickel JN, Kuhny M, Baldo A, Bannock JM, Massad C, Wang H, Katz N, Oe T, Menard L, Soulas-Sprauel P, Strowig T, Flavell R, Meffre E: PTPN22 inhibition resets defective human central B cell tolerance. Sci Immunol. 2016; 2016 Jul 22. PMID: 27917411
- Cantaert T, Schickel JN, Bannock JM, Ng YS, Massad C, Oe T, Wu R, Lavoie A, Walter JE, Notarangelo LD, Al-Herz W, Kilic SS, Ochs HD, Nonoyama S, Durandy A, Meffre E: Activation-Induced Cytidine Deaminase Expression in Human B Cell Precursors Is Essential for Central B Cell Tolerance. Immunity. 2015 Nov 17; 2015 Nov 3. PMID: 26546282
- Young RM, Wu T, Schmitz R, Dawood M, Xiao W, Phelan JD, Xu W, Menard L, Meffre E, Chan WC, Jaffe ES, Gascoyne RD, Campo E, Rosenwald A, Ott G, Delabie J, Rimsza LM, Staudt LM: Survival of human lymphoma cells requires B-cell receptor engagement by self-antigens. Proc Natl Acad Sci U S A. 2015 Nov 3; 2015 Oct 19. PMID: 26483459
- Romberg N, Virdee M, Chamberlain N, Oe T, Schickel JN, Perkins T, Cantaert T, Rachid R, Rosengren S, Palazzo R, Geha R, Cunningham-Rundles C, Meffre E: TNF receptor superfamily member 13b (TNFRSF13B) hemizygosity reveals transmembrane activator and CAML interactor haploinsufficiency at later stages of B-cell development. J Allergy Clin Immunol. 2015 Nov; 2015 Jun 19. PMID: 26100089
- Berkowska MA, Schickel JN, Grosserichter-Wagener C, de Ridder D, Ng YS, van Dongen JJ, Meffre E, van Zelm MC: Circulating Human CD27-IgA+ Memory B Cells Recognize Bacteria with Polyreactive Igs. J Immunol. 2015 Aug 15; 2015 Jul 6. PMID: 26150533
- Teng G, Maman Y, Resch W, Kim M, Yamane A, Qian J, Kieffer-Kwon KR, Mandal M, Ji Y, Meffre E, Clark MR, Cowell LG, Casellas R, Schatz DG: RAG Represents a Widespread Threat to the Lymphocyte Genome. Cell. 2015 Aug 13; 2015 Jul 30. PMID: 26234156
- Di Niro R, Lee SJ, Vander Heiden JA, Elsner RA, Trivedi N, Bannock JM, Gupta NT, Kleinstein SH, Vigneault F, Gilbert TJ, Meffre E, McSorley SJ, Shlomchik MJ: Salmonella Infection Drives Promiscuous B Cell Activation Followed by Extrafollicular Affinity Maturation. Immunity. 2015 Jul 21; 2015 Jul 14. PMID: 26187411
- Zinöcker S, Schindler CE, Skinner J, Rogosch T, Waisberg M, Schickel JN, Meffre E, Kayentao K, Ongoïba A, Traoré B, Pierce SK: The V gene repertoires of classical and atypical memory B cells in malaria-susceptible West African children. J Immunol. 2015 Feb 1; 2015 Jan 2. PMID: 25556245
- Janssen E, Morbach H, Ullas S, Bannock JM, Massad C, Menard L, Barlan I, Lefranc G, Su H, Dasouki M, Al-Herz W, Keles S, Chatila T, Geha RS, Meffre E: Dedicator of cytokinesis 8-deficient patients have a breakdown in peripheral B-cell tolerance and defective regulatory T cells. J Allergy Clin Immunol. 2014 Dec; 2014 Sep 11. PMID: 25218284
- Romberg N, Al Moussawi K, Nelson-Williams C, Stiegler AL, Loring E, Choi M, Overton J, Meffre E, Khokha MK, Huttner AJ, West B, Podoltsev NA, Boggon TJ, Kazmierczak BI, Lifton RP: Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nat Genet. 2014 Oct; 2014 Sep 14. PMID: 25217960
- Kuehn HS, Ouyang W, Lo B, Deenick EK, Niemela JE, Avery DT, Schickel JN, Tran DQ, Stoddard J, Zhang Y, Frucht DM, Dumitriu B, Scheinberg P, Folio LR, Frein CA, Price S, Koh C, Heller T, Seroogy CM, Huttenlocher A, Rao VK, Su HC, Kleiner D, Notarangelo LD, Rampertaap Y, Olivier KN, McElwee J, Hughes J, Pittaluga S, Oliveira JB, Meffre E, Fleisher TA, Holland SM, Lenardo MJ, Tangye SG, Uzel G: Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science. 2014 Sep 26; 2014 Sep 11. PMID: 25213377
- Castiello MC, Bosticardo M, Pala F, Catucci M, Chamberlain N, van Zelm MC, Driessen GJ, Pac M, Bernatowska E, Scaramuzza S, Aiuti A, Sauer AV, Traggiai E, Meffre E, Villa A, van der Burg M: Wiskott-Aldrich Syndrome protein deficiency perturbs the homeostasis of B-cell compartment in humans. J Autoimmun. 2014 May; 2013 Dec 25. PMID: 24369837
- Menard L, Cantaert T, Chamberlain N, Tangye SG, Riminton S, Church JA, Klion A, Cunningham-Rundles C, Nichols KE, Meffre E: Signaling lymphocytic activation molecule (SLAM)/SLAM-associated protein pathway regulates human B-cell tolerance. J Allergy Clin Immunol. 2014 Apr; 2013 Dec 25. PMID: 24373350
- Kinnunen T, Chamberlain N, Morbach H, Cantaert T, Lynch M, Preston-Hurlburt P, Herold KC, Hafler DA, O'Connor KC, Meffre E: Specific peripheral B cell tolerance defects in patients with multiple sclerosis. J Clin Invest. 2013 Jun; 2013 May 15. PMID: 23676463
- Kinnunen T, Chamberlain N, Morbach H, Choi J, Kim S, Craft J, Mayer L, Cancrini C, Passerini L, Bacchetta R, Ochs HD, Torgerson TR, Meffre E: Accumulation of peripheral autoreactive B cells in the absence of functional human regulatory T cells. Blood. 2013 Feb 28; 2012 Dec 5. PMID: 23223361
- Meffre E: The establishment of early B cell tolerance in humans: lessons from primary immunodeficiency diseases. Ann N Y Acad Sci. 2011 Dec. PMID: 22236425
- Menard L, Saadoun D, Isnardi I, Ng YS, Meyers G, Massad C, Price C, Abraham C, Motaghedi R, Buckner JH, Gregersen PK, Meffre E: The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans. J Clin Invest. 2011 Sep; 2011 Aug 1. PMID: 21804190
- Meyers G, Ng YS, Bannock JM, Lavoie A, Walter JE, Notarangelo LD, Kilic SS, Aksu G, Debré M, Rieux-Laucat F, Conley ME, Cunningham-Rundles C, Durandy A, Meffre E: Activation-induced cytidine deaminase (AID) is required for B-cell tolerance in humans. Proc Natl Acad Sci U S A. 2011 Jul 12; 2011 Jun 23. PMID: 21700883
- Rutishauser RL, Martins GA, Kalachikov S, Chandele A, Parish IA, Meffre E, Jacob J, Calame K, Kaech SM: Transcriptional repressor Blimp-1 promotes CD8(+) T cell terminal differentiation and represses the acquisition of central memory T cell properties. Immunity. 2009 Aug 21; 2009 Aug 6. PMID: 19664941