Dr. Jean Fletcher
Associate Prof in Translational Immunolo, Biochemistry
Associate Prof in Translational Immunolo, Clinical Medicine
Publications and Further Research Outputs
Peer-Reviewed Publications
Petrasca A, Hambly R, Kearney N, Smith CM, Pender EK, Mac Mahon J, O'Rourke AM, Ismaiel M, Boland PA, Almeida JP, Kennedy C, Zaborowski A, Murphy S, Winter D, Kirby B, Fletcher JM., Metformin has anti-inflammatory effects and induces immunometabolic reprogramming via multiple mechanisms in hidradenitis suppurativa., The British journal of dermatology, 189, (6), 2023, p730-740
Petrasca A, Hambly R, Molloy O, Kearns S, Moran B, Smith CM, Hughes R, O'Donnell M, Zaborowski A, Winter D, Fletcher JM, Kirby B, Malara A., Innate lymphoid cell (ILC) subsets are enriched in the skin of patients with hidradenitis suppurativa., PloS one, 18, (2), 2023, pe0281688
Barker BE, Hanlon MM, Marzaioli V, Smith CM, Cunningham CC, Fletcher JM, Veale DJ, Fearon U, Canavan M., The mammalian target of rapamycin contributes to synovial fibroblast pathogenicity in rheumatoid arthritis., Frontiers in medicine, 10, 2023, p1029021
Hambly R, Gatault S, Smith CM, Iglesias-Martinez LF, Kearns S, Rea H, Marasigan V, Lynam-Loane K, Kirthi S, Hughes R, Fletcher JM, Kolch W, Kirby B., B-cell and complement signature in severe hidradenitis suppurativa that does not respond to adalimumab., The British journal of dermatology, 188, (1), 2023, p52-63
Smith CM, Hambly R, Gatault S, Iglesias-Martinez LF, Kearns S, Rea H, Marasigan V, Lynam-Loane K, Kirthi S, Hughes R, Fletcher JM, Kolch W, Kirby B., B-cell-derived transforming growth factor-ß may drive the activation of inflammatory macrophages and contribute to scarring in hidradenitis suppurativa., The British journal of dermatology, 188, (2), 2023, p290-310
Gaynor N, Blanco A, Madden SF, Moran B, Fletcher JM, Kaukonen D, Ramírez JS, Eustace AJ, McDermott MSJ, Canonici A, Toomey S, Teiserskiene A, Hennessy BT, O'Donovan N, Crown J, Collins DM., Alterations in immune cell phenotype and cytotoxic capacity in HER2+ breast cancer patients receiving HER2-targeted neo-adjuvant therapy., British journal of cancer, 129, (6), 2023, p1022-1031
Moran, B. and Smith, C.M. and Zaborowski, A. and Ryan, M. and Karman, J. and Dunstan, R.W. and Smith, K.M. and Hambly, R. and Musilova, J. and Petrasca, A. and Fabre, A. and O'Donnell, M. and Hokamp, K. and Mills, K.H.G. and Housley, W.J. and Winter, D.C. and Kirby, B. and Fletcher, J.M., Targeting the NLRP3 inflammasome reduces inflammation in hidradenitis suppurativa skin, The British journal of dermatology, 189, (4), 2023, p447-458
O'Connor, C., Jordan, K., Vagg, T., Murphy, C.E., Barry, D.B., Toulouse, A., Flecther, J., Downer, E.J. , Animated teaching improves student learning of human gastrulation and neurulation., Annals of Anatomy, in press, 2023
Hambly R, Kearney N, Hughes R, Fletcher JM, Kirby B., Metformin Treatment of Hidradenitis Suppurativa: Effect on Metabolic Parameters, Inflammation, Cardiovascular Risk Biomarkers, and Immune Mediators., International journal of molecular sciences, 24, (8), 2023, p6969
Floudas A, Smith CM, Tynan O, Neto N, Krishna V, Wade SM, Hanlon M, Cunningham C, Marzaioli V, Canavan M, Fletcher JM, Mullan RH, Cole S, Hao LY, Monaghan MG, Nagpal S, Veale DJ, Fearon U., Distinct stromal and immune cell interactions shape the pathogenesis of rheumatoid and psoriatic arthritis., Annals of the rheumatic diseases, 2022, pannrheumdis-2021-221761
Fitzgerald, H.K.; O'Rourke, S.A.; Desmond, E.; Neto, N.G.B.; Monaghan, M.G.; Tosetto, M.; Doherty, J.; Ryan, E.J.; Doherty, G.A.; Nolan, D.P.; Fletcher, J.M.; Dunne, A, The Trypanosoma brucei-Derived Ketoacids, Indole Pyruvate and Hydroxyphenylpyruvate, Induce HO-1 Expression and Suppress Inflammatory Responses in Human Dendritic Cells, Antioxidants, 11, 2022, p164-
Kirby B, Fletcher JM., Mechanism of action of dimethyl fumarate: a small molecule with big effects., The British journal of dermatology, 185, (3), 2021, p483-484
MacMahon Copas AN, McComish SF, Fletcher JM, Caldwell MA., The Pathogenesis of Parkinson's Disease: A Complex Interplay Between Astrocytes, Microglia, and T Lymphocytes?, Frontiers in neurology, 12, 2021, p666737
Petrasca A, Phelan J.J., Ansboro S, Veale D.J., Fearon U., Fletcher J.M., Targeting bioenergetics prevents CD4 T cell-mediated activation of synovial fibroblasts in rheumatoid arthritis., Rheumatology, 2020
Sulaimani J, Cluxton D, Clowry J, Petrasca A, Molloy OE, Moran B, Sweeney CM, Malara A, McNicholas N, McGuigan C, Kirby B, Fletcher JM., Dimethyl fumarate modulates the Treg-Th17 cell axis in patients with psoriasis., The British journal of dermatology, 2020
Fletcher JM, Moran B, Petrasca A, Smith CM., IL-17 in inflammatory skin diseases psoriasis and hidradenitis suppurativa., Clinical and experimental immunology, 201, (2), 2020, p121-134
Cluxton D, Petrasca A, Moran B, Fletcher JM, Differential regulation of human Treg and Th17 cells by fatty acid synthesis and glycolysis, Frontiers in Immunology, 10, 2019, p115-
Campbell, N.K. and Fitzgerald, H.K. and Fletcher, J.M. and Dunne, A., Plant-derived polyphenols modulate human dendritic cell metabolism and immune function via AMPK-dependent induction of heme oxygenase-1, Frontiers in Immunology, 10, (MAR), 2019, p00345-
Moran B, Gallagher C, Tobin AM, Fletcher JM., Enrichment of polyfunctional IL-17 producing T cells in paradoxical psoriasis skin lesions., The Journal of investigative dermatology, 2019
J. Musilova, B. Moran, C.M. Sweeney, A. Malara, A. Zaborowski, R. Hughes, D.C. Winter, J.M. Fletcher, B. Kirby, Enrichment of Plasma Cells in the Peripheral Blood and Skin of Patients with Hidradenitis Suppurativa, Journal of Investigative Dermatology, 2019
Campbell, N.K. and Fitzgerald, H.K. and Malara, A. and Hambly, R. and Sweeney, C.M. and Kirby, B. and Fletcher, J.M. and Dunne, A., Naturally derived Heme-Oxygenase 1 inducers attenuate inflammatory responses in human dendritic cells and T cells: Relevance for psoriasis treatment, Scientific Reports, 8, (1), 2018, p10287 -
Canavan M, Walsh AM, Bhargava V, Wade SM, McGarry T, Marzaioli V, Moran B, Biniecka M, Convery H, Wade S, Orr C, Mullan R, Fletcher JM, Nagpal S, Veale DJ, Fearon U, Enriched CD141+ DCs in the joint are transcriptionally distinct, activated, and contribute to joint pathogenesis., JCI Insight, 3, (23), 2018, p95228-
O'Rourke M, Fearon U, Sweeney CM, Basdeo SA, Fletcher JM, Murphy CC, Canavan M, The pathogenic role of dendritic cells in non-infectious anterior uveitis., Experimental eye research, 2018, p121 - 128
Sharee A. Basdeo, Deborah Cluxton, Jamal Sulaimani, Barry Moran, Mary Canavan, Carl Orr, Douglas J. Veale, Ursula Fearon and Jean M. Fletcher, Ex-Th17 (Nonclassical Th1) Cells Are Functionally Distinct from Classical Th1 and Th17 Cells and Are Not Constrained by Regulatory T Cells., J immunology, 198 , (2), 2017, p2249 - 2259
Barry Moran, Cheryl M. Sweeney, Rosalind Hughes, Anna Malara, Shivashini Kirthi, Anne-Marie Tobin, Brian Kirby, Jean M. Fletcher, Hidradenitis Suppurativa Is Characterized by Dysregulation of the Th17:Treg Cell Axis, Which Is Corrected by Anti-TNF Therapy, Journal of Investigative Dermatology, 137, (11), 2017, p2389--2395
Neuroinflammatory Disorders in, editor(s)Orla Hardiman, Colin P. Doherty, Marwa Elami, Peter Bede , Neurodegenerative Disorders, Springer International Publishing, 2016, pp269 - 287, [Costelloe C, Fletcher JM, Fitzgerald D. Neuroinflammatory Disorders. (In Neurodegenerative Disorders).]
Dunne M, Ryan C, Tosetto M, Nolan B, Geraghty R, Winter DC, O'Connell R, Hyland J, Doherty GA, Sheahan K, Ryan EJ, Fletcher JM., Enrichment of inflammatory IL-17 and TNF-α secreting CD4+ T cells within colorectal tumours despite the presence of elevated CD39+ T regulatory cells and increased expression of the immune checkpoint molecule, PD-1., Frontiers in Oncology, 6, 2016, p50-
Basdeo S.A, Campbell N.K, Sullivan L.M, Flood B, Creagh E.M, Mantle T.J, Fletcher J.M, Dunne A, Suppression of human alloreactive T cells by linear tetrapyrroles; relevance for transplantation, Translational Research, 178, 2016, p81-94.e2
Basdeo SA, Kelly S, O'Connell K, Tubridy N, McGuigan C, Fletcher JM, Increased expression of Tbet in CD4+ T cells from clinically isolated syndrome patients at high risk of conversion to clinically definite MS. , Springer Plus, 5, 2016, p779-
Basdeo, S.A., Moran, B., Cluxton, D., (...), Fearon, U., Fletcher, J.M., Polyfunctional, pathogenic CD161+ Th17 lineage cells are resistant to regulatory T cell-mediated suppression in the context of autoimmunity, Journal of Immunology, 195, (2), 2015, p528-540
Kelly, A., Fahey, R., Fletcher, J.M., Keogh, C., Carroll, A.G., Siddachari, R., Geoghegan, J., Hegarty, J.E., Ryan, E.J., O'Farrelly, C., CD141+ myeloid dendritic cells are enriched in healthy human liver, Journal of Hepatology, 60, (1), 2014, p135-142
Fletcher, J., Hutchinson, M., Tubridy, N., Response to comment on the article by Allen et al. 'A pilot study of the immunological effects of high-dose vitamin D in healthy volunteers', Multiple Sclerosis , 19, (4), 2013, p509
O'Connell K, Kelly S, Kinsella K, Jordan S, Kenny O, Murphy D, Heffernan E, O'Laoide R, O'Shea D, McKenna C, Cassidy L, Fletcher J, Walsh C, Brady J, McGuigan C, Tubridy N, Hutchinson M, Dose-related effects of vitamin D on immune responses in patients with clinically isolated syndrome and healthy control participants: study protocol for an exploratory randomized double- blind placebo-controlled trial., Trials, 14, 2013, p272
Jean M Fletcher, Sharee A Basdeo, Aideen C Allen and Padraic J Dunne, Therapeutic use of vitamin D and its analogues in autoimmunity, Recent Patents in Inflammation Allergy Drug Discovery, 6, (1), 2012, p22 - 34
Immunology of Multiple Sclerosis in, The Biology of Multiple Sclerosis, Cambridge University Press, 2012, pp1-146 , [Fletcher JM and Mills KHG]
Allen AC, Kelly S, Basdeo SA, Kinsella K, Mulready KJ, Mills KH, Tubridy N, Walsh C, Brady JJ, Hutchinson M, Fletcher JM, A pilot study of the immunological effects of high-dose vitamin D in healthy volunteers., Multiple sclerosis (Houndmills, Basingstoke, England), 18, (12), 2012, p1797 - 1800
Cheryl M. Sweeney, Roisin Lonergan, Sharee A. Basdeo, Katie Kinsella, Lara S. Dungan, Sarah C. Higgins, Patrick J. Kelly, Lisa Costelloe, Niall Tubridy, Kingston H.G. Mills, Jean M. Fletcher, IL-27 mediates the response to IFN beta therapy in multiple sclerosis patients by inhibiting Th17 cells, Brain, Behavior and Immunity, 25, (6), 2011, p1170-1181
Lalor, S.J., Dungan, L.S., Sutton, C.E., Basdeo, S.A., Fletcher, J.M., Mills, K.H.G., Caspase-1-processed cytokines IL-1β and IL-18 promote IL-17 production by γδ and CD4 T cells that mediate autoimmunity, Journal of Immunology, 186, (10), 2011, p5738-5748
O'Brien M, Lonergan R, Costelloe L, O'Rourke K, Fletcher JM, Kinsella K, Sweeney C, Antonelli G, Mills KH, O'Farrelly C, Hutchinson M, Tubridy N. , OAS1: a multiple sclerosis susceptibility gene that influences disease severity., Neurology, 75, (5), 2010, p411 - 418
Hoare M, Gelson WT, Das A, Fletcher JM, Davies SE, Curran MD, Vowler SL, Maini MK, Akbar AN, Alexander GJ., CD4+ T-lymphocyte telomere length is related to fibrosis stage, clinical outcome and treatment response in chronic hepatitis C virus infection., Journal of Hepatology, 53, (2), 2010, p252 - 260
Fletcher, J.M., Lalor, S.J., Sweeney, C.M., Tubridy, N., Mills, K.H.G, T cells in multiple sclerosis and experimental autoimmune encephalomyelitis , Clinical and Experimental Immunology, 162, (1), 2010, p1-11
Fletcher JM, Lonergan R, Costelloe L, Kinsella K, Moran B, O'Farrelly C, Tubridy N, Mills KH, CD39+Foxp3+ regulatory T Cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis., Journal of Immunology , 183, (11), 2009, p7602-7610
IL-10 and TGF-beta-producing regulatory T cells in infection in, editor(s)Shuiping Jiang , Regulatory cells and Clinical Application, Springer Science and Business Media, LLC , 2008, pp423 - 453, [Dunne PJ, Rowan A, Fletcher JM and KHG Mills]
Jarnicki, AJ, Conroy, H. Brereton, C, Donnelly, G., Toomey, D., Walsh, K.,, Sweeney, C., Leavy, O., Fletcher, J., Lavelle, E., Dunne, P. and Mills, K.H.G., Attenuating regulatory T cell induction by TLR agonists through inhibition of p38 MAPK signaling in dendritic cells enhances their efficacy as vaccine adjuvants and cancer immunotherapeutics, Journal of Immunology, 180, (6), 2008, p3797 - 3806
Rowan AG, Fletcher JM, Ryan EJ, Moran B, Hegarty JE, O'Farrelly C and Mills KHG, Hepatitis C virus-specific Th17 cells are suppressed by virus-induced TGF-beta, Journal of Immunology, 181, (7), 2008, p4485 - 4494
Van Baarle, D., Nanlohy, N.M., Otto, S., Plunkett, F.J., Fletcher, J.M., Akbar, A.N., Progressive telomere shortening of Epstein-Barr virus-specific memory T cells during HIV infection: Contributor to exhaustion, Journal of Infectious Diseases, 198, (9), 2008, p1353-1357
Colonna-Romano G, Akbar AN, Aquino A, Bulati M, Candore G, Lio D, Ammatuna P, Fletcher JM, Caruso C, Pawelec G. , Impact of CMV and EBV seropositivity on CD8 T lymphocytes in an old population from West-Sicily., Experimental Gerontology, 42, (10), 2007, p995-1002.
Plunkett FJ, Franzese O, Finney HM, Fletcher JM, Belaramani LL, Salmon M, Dokal I, Webster D, Lawson AD, Akbar AN., The loss of telomerase activity in highly differentiated CD8+CD28-CD27- T cells is associated with decreased Akt (Ser473) phosphorylation., Journal of Immunology , 178, (12), 2007, p7710-7719
Vukmanovic-Stejic M, Zhang Y, Cook JE, Fletcher JM, McQuaid A, Masters JE, Rustin MH, Taams LS, Beverley PC, Macallan DC, Akbar AN., Human CD4+ CD25hi Foxp3+ regulatory T cells are derived by rapid turnover of memory populations in vivo., Journal of Clinical Investigation, 116, (9), 2006, p2423-2433.
Fletcher JM, Vukmanovic-Stejic M, Dunne PJ, Birch KE, Cook JE, Jackson SE, Salmon M, Rustin MH, Akbar AN., Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion., Journal of Immunology , 175, (12), 2005, p8218-8225
Akbar AN, Fletcher JM., Memory T cell homeostasis and senescence during aging., Current Opinion in Immunology, 17, (5), 2005, p480-485
Dunne PJ, Belaramani L, Fletcher JM, Fernandez de Mattos S, Lawrenz M, Soares MV, Rustin MH, Lam EW, Salmon M, Akbar AN, Quiescence and functional reprogramming of Epstein-Barr virus (EBV)-specific CD8+ T cells during persistent infection. , Blood, 106, (2), 2005, p558-565
Plunkett FJ, Franzese O, Belaramani LL, Fletcher JM, Gilmour KC, Sharifi R, Khan N, Hislop AD, Cara A, Salmon M, Gaspar HB, Rustin MH, Webster D, Akbar AN. , The impact of telomere erosion on memory CD8+ T cells in patients with X-linked lymphoproliferative syndrome., Mechanisms of Ageing and Development, 126, (8), 2005, p855-865
Reed JR, Vukmanovic-Stejic M, Fletcher JM, Soares MV, Cook JE, Orteu CH, Jackson SE, Birch KE, Foster GR, Salmon M, Beverley PC, Rustin MH, Akbar AN. , Telomere erosion in memory T cells induced by telomerase inhibition at the site of antigenic challenge in vivo., Journal of Experimental Medicine, 199, (10), 2004, p1433-1443
Soares MV, Plunkett FJ, Verbeke CS, Cook JE, Faint JM, Belaramani LL, Fletcher JM, Hammerschmitt N, Rustin M, Bergler W, Beverley PC, Salmon M, Akbar AN., Integration of apoptosis and telomere erosion in virus-specific CD8+ T cells from blood and tonsils during primary infection., Blood., 103, (1), 2004, p162-167
Lantto J, Fletcher JM, Ohlin M., Binding characteristics determine the neutralizing potential of antibody fragments specific for antigenic domain 2 on glycoprotein B of human cytomegalovirus, Virology., 305, (1), 2003, p201-209
Taams, L.S., Vukmanovic-Stejic, M., Smith, J., Dunne, P.J., Fletcher, J.M., Plunkett, F.J., Ebeling, S.B., (...), Akbar, A.N., 17. Taams LS, Vukmanovic-Stejic M, Smith J, Dunne PJ, Fletcher JM, Plunkett FJ, Ebeling SB, Lombardi G, Rustin MH, Bijlsma JW, Lafeber FP, Salmon M, Akbar AN. Antigen-specific T cell suppression by human CD4+CD25+ regulatory T cells., European Journal of Immunology, 32, (6), 2002, p1621-1630
Dunne PJ, Faint JM, Gudgeon NH, Fletcher JM, Plunkett FJ, Soares MV, Hislop AD, Annels NE, Rickinson AB, Salmon M, Akbar AN., Epstein-Barr virus-specific CD8(+) T cells that re-express CD45RA are apoptosis-resistant memory cells that retain replicative potential., Blood, 100, (3), 2002, p933-940.
*Lantto J, *Fletcher JM, Ohlin M. , A divalent antibody format is required for neutralization of human cytomegalovirus via antigenic domain 2 on glycoprotein B, Journal of General Virology, 83, (8), 2002, p2001-2005
Marais, G.I., Fletcher, J.M., Potter, P.C., In vivo and in vitro diagnosis of latex allergy at Groote Schuur Hospital , Ugeskrift for Laeger , 161, (29), 1999, p1004-1008
Fletcher JM, Prentice HG, Grundy JE., Natural killer cell lysis of cytomegalovirus (CMV)-infected cells correlates with virally induced changes in cell surface lymphocyte function-associated antigen-3 (LFA-3) expression and not with the CMV-induced down-regulation of cell surface class I HLA. , Journal of Immunology, 161, (5), 1998, p2365-2374
Grundy JE, Lawson KM, MacCormac LP, Fletcher JM, Yong KL., Cytomegalovirus-infected endothelial cells recruit neutrophils by the secretion of C-X-C chemokines and transmit virus by direct neutrophil-endothelial cell contact and during neutrophil transendothelial migration, Journal of Infectious Diseases, 177, (6), 1998, p1465-1474.
Research Expertise
Description
Th17 cells are key players in autoimmune disease and an important therapeutic target. My independent research career has focused on understanding the role and regulation of Th17 cells in human diseases including multiple sclerosis (MS), rheumatoid arthritis (RA), psoriasis, cancer and hidradenitis suppurativa (HS). I have established a niche in this area within Ireland and made a significant contribution to the field internationally through my publications. Over 19 of my articles have been cited 100+ times, indicating that my research has made a significant impact. I have also attracted significant grant funding to support my research (over €5 million over 15 grants). Furthermore, I have established important clinical collaborations which have underpinned the translational aspects of my work. My overarching research aim is to understand the role of Th17 cells in human disease and how they can be targeted to develop new or improved therapies. " My early work into the role of Th17 cells in MS made a significant impact by dissecting the regulation of IL-17 by different types of Treg cells and demonstrated defective regulation in MS patients (2009, DOI: 10.4049/jimmunol.0901881, 578 citations, open access, featured `In This Issue"). Subsequent work showed how pathogenic Th17 cells in MS patients were inhibited by IFN-ß therapy (2011, DOI: 10.1016/j.bbi.2011.03.007, >177 citations). This work was funded by my HRB Postdoctoral Fellowship (€226,000). " My research into Th17 cells in RA has demonstrated that in certain situations such as the inflamed RA joint, Th17 cells are unstable and switch into an ex-Th17 cell (2015, DOI: 10.4049/jimmunol.1402990, 97 citations, open access). Our novel finding was that ex-Th17 cells were highly pathogenic and resistant to regulation by Treg cells (2017, DOI: 10.4049/jimmunol.1600737, 152 citations, open access). The switch to this pathogenic phenotype that lacks IL-17 production may explain the lack of success of IL-17 targeted therapies in RA. This work was funded by my SFI Starting Investigator Grant (€441,000). " As part of an SFI Strategic Partnership grant with AbbVie (€2.5M) we recently demonstrated differential regulation of Th17 vs Treg cells by metabolic pathways (2019, DOI: 10.3389/fimmu.2019.00115, 159 citations, open access). We have also investigated the role of metabolism in RA joint inflammation. We showed that T cells induced a switch towards glycolysis in RA synovial fibroblasts and that targeting glycolysis could reverse the inflammatory effects of T cells (2020, DOI: 10.1093/rheumatology/kez682, 50 citations, open access). This work was funded by a HRB grant as PI (€329,000). " My group"s research into HS has revealed several therapeutic targets which can reduce inflammation in HS, including Th17 cells (2017, DOI: 10.1016/j.jid.2017.05.033, 165 citations, open access, Editor"s Choice in Science Translational Medicine), cellular metabolism (2023, DOI: 10.1093/bjd/ljad305, 2 citations, open access) and NLRP3 inflammasome (2023, DOI: 10.1093/bjd/ljad184, 7 citations, open access). These studies were funded by an IRC postdoctoral fellowship which I mentored (€97,000), City of Dublin Skin and Cancer Hospital Charity (CDSCHC, €164,000), British Skin Foundation (BSF, €11,000) and a Provost"s PhD Award.Projects
- Title
- Dysregulation of pathogenic T cells in multiple sclerosis
- Funding Agency
- HRB
- Date From
- 2006
- Date To
- 2009
- Title
- The role of CD39+ regulatory T cells in autoimmune disease
- Funding Agency
- SFI
- Date From
- 2009
- Date To
- 2014
Recognition
Awards and Honours
First prize for the best oral presentation at the Irish Society for Immunology 2008 Annual Congress.
Fellow of Trinity College Dublin
Memberships
British Society for Immunology
Irish Society for Immunology
Biochemical Society