B Cells, Immunoglobulin Genes, Lymphocytes, Mucosal Immunology
Multi-Disciplinary Training Area
Medical Degree, Padua University School of Medicine
American Society of Clinical Investigation
The Irma T. Hirschl Trust, New York, NY, USA
Irma T. Hirschl Career Scientist Award
Award for Excellence in Mentoring, Weill Medical College Postdoctoral Association, New York, NY, USA
Henry Kunkel Society, The Rockefeller University, New York, NY, USA
Travel Award, American Association of Immunologists, Rockville, MD, USA
Career Development Award, The S.L.E. Foundation, New York, NY, USA
Lorenza Ceschiatti Prize for Research in Oncology, Trento, Italy
“Young Scientists” Prize, Italian Association of Immunology and Immunopathology, Bari, Italy
Regulation of B cell differentiation and antibody production
We apply a diverse array of cellular, histological and molecular techniques to address basic questions related to the regulation of B cell activation and antibody production, including heavy chain class switching from IgM to IgG, IgA or IgE and somatic hypermutation. These processes are critical for the diversification of the antibody repertoire and in general are thought to be highly dependent on the activation of B cells by CD4+ T cells via CD40 ligand-CD40 interaction. We have recently identified an evolutionarily primitive pathway that stimulates class switching in a CD4+ T cell- and CD40-independent fashion. This pathway involves the activation of B cells by BAFF (B cell-Activation Factor of the TNF Family) and APRIL (A PRoliferation-Inducing Ligand), two innate B cell-stimulating factors structurally and functionally related to CD40 ligand. We found that dendritic cells, macrophages and epithelial cells release BAFF and APRIL upon sensing highly conserved microbial molecular patterns through Toll-like receptors (TLRs). This process ultimately triggers class switching and antibody production as a result of the engagement of three distinct receptors on B cells, known as TACI, BCMA and BAFF-R, by BAFF and APRIL. Antibodies produced through this T cell- and CD40-independent pathway may be important to control fast replicating pathogens, commensal bacteria and dietary antigens.
Currently, we are dissecting the mechanism by which BAFF and APRIL stimulate class switching in systemic and mucosal B cells. A better understanding of these mechanisms may lead to the identification of novel vaccine strategies to boost vaccine-induced antibody production. Recently, we found that BAFF and APRIL stimulate a non-canonical form of class switching from IgM to IgD in the upper respiratory mucosa. Ongoing efforts are aimed at characterizing the function of IgD and its pathogenetic role in autoinflammatory syndromes with periodic fever, including hyper-IgD syndrome. We are also studying the role of BAFF and APRIL in various B cell tumors. We found that HIV and HIV-associated opportunistic agents, including EBV, dysregulate BAFF and APRIL production. This process may enhance the expansion of malignant B cells emerging during HIV-1 and/or EBV infections. Consistent with this possibility, we determined that BAFF and APRIL stimulate malignant B cell growth through both paracrine and autocrine pathways. Finally, we are analyzing the mechanisms by which HIV-1 perturbs the antibody response. Our studies indicate that HIV-1 causes nonspecific IgG and IgA responses by hyperactivating extrafollicular B cells through BAFF. At the same time, HIV-1 impairs specific IgG and IgA responses by delivering viral class switch-suppressing factors to B cells via long-range conduits and vesicles from infected macrophages. The molecular mechanisms of this process are under investigation.
1. Cerutti A, Cols M, Puga I. Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes. Nature Rev Immunol. 2013, 13: 118-132.
2. Puga I, Cols M, Barra CM, He B, Cassis L, Gentile M, Comerma L, Chorny A, Shan M, Xu W, Magri G, Knowles DM, Tam W, Chiu A, Bussel JB, Serrano S, Lorente JA, Bellosillo B, Lloreta J, Juanpere N, Alameda F, Baro T, de Heredia CD, Toran N, Catala A, Torrebadell M, Fortuny C, Cusi V, Carreras C, Diaz GA, Blander JM, Farber CM, Silvestri G, Cunningham-Rundles C, Calvillo M, Dufour C, Notarangelo LD, Lougaris V, Plebani A, Casanova JL, Ganal SC, Diefenbach A, Arostegui JI, Juan M, Yague J, Mahlaoui N, Donadieu J, Chen K, Cerutti A. B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nature Immunol. 2012, 13: 170-180.
3. Chorny A, Cerutti A. A gut triumvirate rules homeostasis. Nature Med. 2011, 17: 1549-1550.
4. Chen K, Cerutti A. AIDing the pursuit of IgA diversity. Nature Immunol. 2011, 12:197-198.
5. Cerutti A, Chorny A, Chen K. Immunoglobulin responses at the mucosal interface. Annu. Rev. Immunol. 2011, 29:273-293.
6. Cerutti A, Chen K. Vaccination strategies to promote mucosal antibody responses. Immunity 2010, 33:479-491.
7. He B, Santamaria R, Xu W, Cols M, Chen K, Puga I, Shan MM, Xiong H, Bussel J B, Chiu A, Puel A, Reichenbach J, Laszlo M, Doffinger R, Vasconcelos J, Issekutz A, Krause J, Davies G, Li X, Grimbacher B, Plebani A, Meffre E, Picard C, Cunningham-Rundles C, Casanova J-L, Cerutti A. TACI triggers immunoglobulin class switching by activating B cells through the adaptor protein MyD88. Nature Immunol. 2010, 11:236-245.
8. Xu W, Santini PA, Sullivan JS, He B, Shan M, Ball SC, Dyer DW, Chadburn A, Knowles DM, Chiu A, Chen K, Cerutti A. HIV-1 evades virus-specific IgG2 and IgA class switching by targeting systemic and intestinal B cells via long-range intercellular conduits. Nature Immunol. 2009, 10:1008-1017.
9. Chen K, Xu W, Wilson M, He B, Miller BH, Bengten E, Edholm ES, Santini PA, Rath P, Chiu A, Cattalini M., Litzman J, Bussel J, Huang B, Riesbeck K, Cunningham-Rundles C, Plebani A, Cerutti A. Immunoglobulin D enhances immune surveillance by activating antimicrobial, inflammatory and B cell-stimulating programs in basophils. Nature Immunol. 2009, 10:889-898.
10. Cerutti A. The regulation of IgA class switching. Nature Rev. Immunol. 2008, 8:421-434.
11. Cerutti A and Rescigno M. The biology of intestinal IgA responses. Immunity 2008, 28:740-750.
12. He B, Xu W, Santini P, Polydorides A, Chiu A, Estrella J, Shan M, Chadburn A, Villanacci V, Plebani A, Knowles DM, Rescigno M, Cerutti A. Intestinal bacteria induce T cell-independent immunoglobulin A2 class switching by triggering epithelial-cell secretion of the cytokine APRIL. Immunity 2007, 26:812-826.
13. Xu W, Santini P, Chiu A, Shan S, Chadburn A, Knowles DM, He B, Cerutti A. Epithelial cells trigger frontline immunoglobulin class switching through a pathway regulated by the inhibitor SLPI. Nature Immunol. 2007, 8:294-303.
14. Qiao X, He B, Chiu A, Knowles MD, Chadburn A, Cerutti A. Human immunodeficiency virus Nef suppresses CD40-dependent immunoglobulin class switching in bystander B cells. Nature Immunol. 2006, 7:302-310.
15. Litinskiy BM, Nardelli B, Hilbert D, He B, Schaffer A, Casali P, Cerutti A. Dendritic cells induce CD40-independent immunoglobulin class switching by stimulating B cells through BLyS and APRIL. Nature Immunol. 2002, 3:822-829.
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