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The William Harvey Research Institute - Faculty of Medicine and Dentistry

Professor Michele Bombardieri

Michele

Clinical Senior Lecturer in Rheumatology

Centre: Experimental Medicine and Rheumatology

Email: m.bombardieri@qmul.ac.uk
Telephone: +44(0) 20 7882 5890

Profile

Michele Bombardieri is Professor of Immuno-Rheumatology (HCC) at the Centre for Experimental Medicine and RheumatologyProfessor Bombardieri graduated at Catholic University of Rome and completed his specialist Rheumatology training with Prof Valesini at University of Rome “La Sapienza”. Since 2003 he joined Prof Pitzalis’ group at Kings College London where he completed his PhD in Experimental Rheumatology in 2007 with support from a Clinical Research Fellowship from the Arthritis Research Campaign (now Arthritis Research UK). In 2007 he relocated to the William Harvey Research Institute at Queen Mary University of London as part of the Centre for Experimental Medicine and Rheumatology. He held an ARUK Clinician Scientist Fellowship until 2010 when he was awarded an NIHR “new blood” senior clinical lectureship.

Research

Group members
Post-doctoral fellows: Dr Elisa Astorri, Dr Emanuela Carlotti, Dr Elisa Corsiero, Dr Cristina Croia, Dr Nikola Lepse, Dr Davide Lucchesi, Dr William Murray-Brown, Dr Vidalba Rocher-Ros
PhD Students: Dr Sophia Grigoriadou, Dr Alessandra Nerviani, Ms Elena Pontarini
Visiting Research Fellows: Mr Edoardo Prediletto

Summary

Professor Bombardieri leads the Immuno-Rheumatology Research group at EMR (10 researchers) and the Sjogren’s Clinical Research Team (1 clinical trial coordinator, 1 specialist nurse, 2 clinical research fellows). His major research interests focus on the elucidation of the cellular and molecular mechanisms regulating autoreactive B cell activation, breach of self-tolerance and perpetuation of autoimmunity in Sjogren’s syndrome and rheumatoid arthritis. In addition, he has significant interest in translational research with the aim to identify new therapeutic targets and novel biomarkers in order to develop early phase clinical trials based on patients’ stratification and target validation in Sjogren’s syndrome and inflammatory arthritis. Furthermore, Dr Bombardieri is currently investigating the cellular and molecular mechanisms involved in the response/relapse/resistance to B cell depleting agents in rheumatic diseases.

Professor Bombardieri seats on the International Scientific Committee for the International Symposia in Sjogren’s syndrome and the Medical Council of the British Sjogren’s Syndrome Association (BSSA). He serves as a regular reviewer for UK and International Research Funding Bodies and several International Scientific Journals including top speciality Journals such as Arthritis and Rheumatology, Annals of the Rheumatic Diseases and the Journal of Immunology. He has authored over 60 peer-reviewed publications in International Journals in the field of autoimmunity, Sjogren’s syndrome and inflammatory arthritis and attracted £2.4million in research income since he joined QMUL.

Evolution of TLS in response to viral infection in the SGs and development of autoimmunity
(A) Viral infection of the SG mucosa induces activation of epithelial and stromal cells and resident macrophages, triggering the production of inflammatory chemokines and the expression of adhesion molecules on blood vessels, leading to the recruitment of innate immune cells from the peripheral compartment to the SGs. Inflammatory chemokines attract inflammatory monocytes and within the first week from infection, T cells leading to the secretion of inflammatory cytokines (e.g., IFN-γ, TNF-α, IL-1β) that in turn, activate resident NK cells and drive macrophage polarization and a Th1-mediated antiviral response.

(B) Despite potent antiviral immune responses, several viruses (e.g., CMV, EBV, and Coxsackie) can escape immune surveillance, leading to lack of viral clearance and persistent infection, preferentially within ductal epithelial cells. Chronic antigen stimulation promotes the lymphoneogenetic program through the interaction between inducer and organizer cells. This triggers the activation of the LTβ pathway and the production of lymphoid chemokines CXCL13, CCL19, and CCL21 by stromal cells and monocyte-derived cells with the accumulation of B and T cells in the gland.

(C) In the context of persistent chronic stimulation, the LTβ condition vessels to acquire a HEV phenotype with expression of PNAd, whereas CCL19 and CCL21 facilitate T lymphocyte influx and organize the T cell area of the ectopic follicle. Similarly, stromal cells via CXCL13 production promote the organization of the ectopic B cell follicle and favor the ingress of Tfh cells into the B cell area. Further differentiation of stromal cells into FDCs leads to the GC response, which is sustained by the production of B cell-activating cytokines, such as BAFF and IL-21, leading to in situ activation and proliferation of B cells. TLS fail to exclude autoreactive B cells from entering the ectopic GC, leading to breach of self-tolerance and development of autoimmunity. In this context, immune-modulating viruses, such as HTLV-1 in T cells and EBV in B cells, further promote autoreactive T and B cell survival in the periphery and their preferential recruitment in the ectopic B cell follicles, whereby autoreactive EBV-infected B cells undergo plasma cell differentiation and autoantibody production.

Key Publications

Full list of publications

  1. Corsiero E, Sutcliffe N, Pitzalis C, Bombardieri M. Accumulation of Self-Reactive Naïve and Memory B Cell Reveals Sequential Defects in B Cell Tolerance Checkpoints in Sjögren's Syndrome. PLoS One. 2014 Dec 23;9(12):e114575.
  2. Pitzalis C, Jones GW, Bombardieri M, Jones SA. Ectopic lymphoid-like structures in infection, cancer and autoimmunity. Nat Rev Immunol. 2014 Jul;14(7):447-62. doi: 10.1038/nri3700. Epub 2014 Jun 20. PubMed PMID: 24948366.
  3. Croia C, Astorri E, Murray-Brown W, Willis A, Brokstad KA, Sutcliffe N, Piper K, Jonsson R, Tappuni AR, Pitzalis C, Bombardieri M. Implication of Epstein-Barr virus infection in disease-specific autoreactive B cell activation in ectopic lymphoid structures of Sjogren's syndrome. Arthritis Rheumatol. 2014 May 28. doi:10.1002/art.38726. [Epub ahead of print] PubMed PMID: 24891330.
  4. Corsiero E, Pitzalis C, Bombardieri M. Peripheral and synovial mechanisms of humoral autoimmunity in rheumatoid arthritis. Drug Discov Today. 2014 May 29. pii: S1359-6446(14)00224-4. doi: 10.1016/j.drudis.2014.05.017. [Epub ahead of print] Review. PubMed PMID: 24880103.
  5. Lucchesi D, Bombardieri M. The role of viruses in autoreactive B cell activation within tertiary lymphoid structures in autoimmune diseases. J Leukoc Biol. 2013 Dec;94(6):1191-9. doi: 10.1189/jlb.0413240. Epub 2013 Jun 28. Review. PubMed PMID: 23812327.
  6. Bombardieri M, Barone F, Lucchesi D, Nayar S, van den Berg WB, Proctor G, Buckley CD, Pitzalis C. Inducible tertiary lymphoid structures, autoimmunity, and exocrine dysfunction in a novel model of salivary gland inflammation in C57BL/6 mice. J Immunol. 2012 Oct 1;189(7):3767-76. Epub 2012 Aug 31. PubMed PMID: 22942425; PubMed Central PMCID: PMC3448973.
  7. Bombardieri M, Kam NW, Brentano F, Choi K, Filer A, Kyburz D, McInnes IB, Gay S, Buckley C, Pitzalis C. A BAFF/APRIL-dependent TLR3-stimulated pathway enhances the capacity of rheumatoid synovial fibroblasts to induce AID expression and Ig class-switching in B cells. Ann Rheum Dis. 2011 Oct;70(10):1857-65. doi: 10.1136/ard.2011.150219. Epub 2011 Jul 27. PubMed PMID: 21798884.
  8. Astorri E, Bombardieri M*, Gabba S, Peakman M, Pozzilli P, Pitzalis C. Evolution of ectopic lymphoid neogenesis and in situ autoantibody production in autoimmune nonobese diabetic mice: cellular and molecular characterization of tertiary lymphoid structures in pancreatic islets. J Immunol. 2010 Sep 15;185(6):3359-68. doi: 10.4049/jimmunol.1001836. Epub 2010 Aug 16. PubMed PMID: 20713891. *Joint first Author
  9. Humby F, Bombardieri M*, Manzo A, Kelly S, Blades MC, Kirkham B, Spencer J, Pitzalis C. Ectopic lymphoid structures support ongoing production of class-switched autoantibodies in rheumatoid synovium. PLoS Med. 2009 Jan 13;6(1):e1. doi: 10.1371/journal.pmed.0060001. PubMed PMID: 19143467; PubMed Central PMCID: PMC2621263. *Joint first Author
  10. Ciccia F, Bombardieri M, Principato A, Giardina A, Tripodo C, Porcasi R, Peralta S, Franco V, Giardina E, Craxi A, Pitzalis C, Triolo G. Overexpression of interleukin-23, but not interleukin-17, as an immunologic signature of subclinical intestinal inflammation in ankylosing spondylitis. Arthritis Rheum. 2009 Apr;60(4):955-65. doi: 10.1002/art.24389. PubMed PMID: 19333939. *Joint first Author
  11. Barone F, Bombardieri M, Rosado MM, Morgan PR, Challacombe SJ, De Vita S, Carsetti R, Spencer J, Valesini G, Pitzalis C. CXCL13, CCL21, and CXCL12 expression in salivary glands of patients with Sjogren's syndrome and MALT lymphoma: association with reactive and malignant areas of lymphoid organization. J Immunol. 2008 Apr 1;180(7):5130-40. PubMed PMID: 18354239. *Joint first Author
  12. Bombardieri M, Barone F, Humby F, Kelly S, McGurk M, Morgan P, Challacombe S, De Vita S, Valesini G, Spencer J, Pitzalis C. Activation-induced cytidine deaminase expression in follicular dendritic cell networks and interfollicular large B cells supports functionality of ectopic lymphoid neogenesis in autoimmune sialoadenitis and MALT lymphoma in Sjögren's syndrome. J Immunol. 2007 Oct 1;179(7):4929-38. PubMed PMID: 17878393.

Collaborators

Internal
Prof Mauro Perretti (WHRI)

External
Prof Guido Valesini (University of Rome); Prof Simon Jones (University of Cardiff); Prof Chris Buckley (University of Birmingham); Dr Jay Chiorini (NIH); Dr Domenico Mavilio (Humanitas Institute, Milan)

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