Research Interests

The Clatworthy lab is interested in understanding how B cell activation and IgG antibody effector function is regulated in different tissues, particularly in the kidney and the gut using cellular and molecular immunology, single cells RNA Sequencing and two-photon microscopy.

How can we regulate B cell activation and antibody generation in human disease?

We are interested in understanding humoral immunity in humans, how this goes wrong in disease and how this can be manipulated therapeutically using experimental medicine studies. We have recently completed a study investigating how belimumab, an anti-BAFF antibody, affects the B cell compartment in renal transplant recipients, in collaboration with Glaxo-Smith-Kline. We found that belimumab suppressed new antibody formation and skewed residual B cells to an IL10-producing, regulatory phenotype.

Which immune cells are capable of responding to IgG in the kidneys, and how are their position and function influenced by the kidney microenvironment and cross-talk with other resident immune cells?

Autoantibodies are associated with a number of kidney diseases, and antibody-mediated rejection has a negative impact on transplant outcomes. We are using human kidney tissue to profile resident immune cells using multiparameter flow cytometry, mass cytometry, and RNA sequencing, as well as complementary mouse models to understand function. We have recently shown how the intrarenal sodium gradient can influence mononuclear phagocyte position and function to optimize defence against ascending infection (Berry et al. 2017).

What role do IgG and FcgR play in the gastrointestinal tract?

Although IgA is the dominant antibody isotype found at mucosal surfaces during health, genetic variation in FcgRs can influence susceptibility to inflammatory bowel disease (IBD), suggesting that IgG may be important during inflammation. We are currently investigating how the induction of IgG in the gastrointestinal tract can activate gut-resident cells, how this is regulated, and whether this is important in IBD.

How does FcgR-crosslinking by IgG affect immune cell metabolism?
There is increasing evidence that immune cells change their metabolism in response to activation signals and that some of these changes may be required for their function. We are investigating how IgG immune complexes affect macrophage metabolism and influence IgG-associated tissue inflammation.

Key Publications

Recent

1. Stephenson E^*, Reynolds G^*, Botting RA^*, Calero-Nieto FJ^*, Morgan M^*, Tuong ZK^*, Bach K^*, Sungnak W^*, Worlock KB, Yoshida M, Kumasaka N, Kania K, Engelbert J, Olabi B, Spegarova JS, Wilson NK, Mende N, Jardine L, Gardner LCS, Goh I, Horsfall D, McGrath J, Webb S, Mather MW, Lindeboom RGH, Dann E, Huang N, Polanski K, Prigmore E, Gothe F, Scott J, Payne RP, Baker KF, Hanrath AT, Schim van der Loeff ICD, Barr AS, Sanchez-Gonzalez A, Bergamaschi L, Mescia F, Barnes JL, Kilich E, de Wilton A, Saigal A, Saleh A, Janes SM, Smith CM, Gopee N, Wilson C, Coupland P, Coxhead JM, Kiselev VY, van Dongen S, Bacardit J, King HW; Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID-19 BioResource Collaboration, Rostron AJ, Simpson AJ, Hambleton S, Laurenti E, Lyons PA, Meyer KB, Nikolić MZ, Duncan CJA, Smith KGC, Teichmann SA^†, Clatworthy MR^†, Marioni JC^†, Gottgens B^†, Haniffa M^† . The cellular immune response to COVID-19 deciphered by single cell multi-omics across three UK centres. Nat Medicine 2021; 27(5):904-916. ^† co-corresponding.
2. Lynall ME, Kigar SL, Lehmann ML, DePuyt AE, Tuong ZK, Listwak SJ, Elkahloun AG, Bullmore ET, Herkenham M, Clatworthy MR. B-cells are abnormal in psychosocial stress and regulate meningeal myeloid cell activation. Brain Behav Immun. 2021:226-238.
3. Fitzpatrick Z, Frazer G, Ferro A, Clare S, Bouladoux N, Ferdinand JR, Tuong ZW, Negro-Demontel ML, Suchanek O, Tajsic T, Harcourt K, Scott K, Bashford-Rogers R, Helmy A, Reich DS, Belkaid Y, Lawley T, McGavern DB*, Clatworthy MR*. Gut-educated IgA plasma cells defend meningeal venous sinuses. 2020; Nov;587(7834):472-476.

 

Top 3, in addition to the above

1. Stewart BS, Ferdinand JR, Young MD, Mitchell TJ, Loudon KW, Riding AM, Richoz N, Frazer GL, Staniforth JU, Vieira Braga FA, Botting R, Popescu DM, Vento-Tormo R, Stephenson E, Cagan A, Farndon SJ, Polanski K, Efremova M, Green K, Velasco-Herrera M, Guzzo C, CollorD G, Mamanova L, Aho T, Armitage JN, Riddick AC, Mushtaq I, Farrell S, Rampling D, Nicholson J, Filby A, Burge J, Lisgo S, Lindsay S, Bajenoff M, Warren AY, Stewart GD, Sebire N, Coleman N, Haniffa M*, Teichmann SA*, Behjati S*, Clatworthy MR*. Spatio-temporal immune zonation of the human kidney.  Science 2019;365(6460):1461-1466.
2. Castro-Dopico T, Dennison TW, Ferdinand JR, Mathews RJ, Fleming A, Clift D, Stewart BJ, Jing C, Strongili K, Labzin LI, Monk EJM, Saeb-Parsy K, Bryant CE, Clare S, Parkes M, Clatworthy MR. Anti-commensal IgG drives intestinal inflammation and type 17 immunity. Immunity Apr 16;50(4):1099-1114.
3. Berry MR, Mathews RJ, Ferdinand JR, Jing C, Loudon KW, Wlodek E, Dennison TW, Kuper C, Neuhofer W, Clatworthy MR. Renal Sodium Gradient Orchestrates a Dynamic Antibacterial Defense Zone. Cell. 2017;170(5):860-74.

 

 

 

All publications 2020-2021

1. Ferdinand JR, Hosgood SA, Moore T, Ferro A, Ward CJ, Castro-Dopico T, Nicholson ML*, Clatworthy MR*. Cytokine absorption during human kidney perfusion reduces delayed graft function-associated inflammatory gene signature. Am J Transplant. 2021;21(6):2188-2199
2. Hamed M, Logan A, Gruszczyk AV, Beach TE, James AM, Dare AJ, Barlow A, Martin J, Georgakopoulos N, Gane AM, Crick K, Fouto D, Fear C, Thiru S, Dolezalova N, Ferdinand JR, Clatworthy MR, Hosgood SA, Nicholson ML, Murphy MP, Saeb-Parsy K. Mitochondria-targeted antioxidant MitoQ ameliorates ischaemia-reperfusion injury in kidney transplantation models. Br J Surg. 2021 May 8:znab108.
3. Wlodek E, Kirkpatrick RB, Andrews S, Noble R, Schroyer R, Scott J, Watson CJE, Clatworthy MR, Harrison EM, Wigmore SJ, Stevenson K, Kingsmore D, Sheerin NS, Bestard O, Stirnadel-Farrant HA, Abberley L, Busz M, DeWall S, Birchler M, Krull D, Thorneloe KS, Weber A, Devey L. A pilot study evaluating GSK1070806 inhibition of interleukin-18 in renal transplant delayed graft function. PLoS One. 2021 Mar 8;16(3):e0247972.
4. Cimino I, Kim H, Tung YCL, Pedersen K, Rimmington D, Tadross JA, Kohnke SN, Neves-Costa A, Barros A, Joaquim S, Bennett D, Melvin A, Lockhart SM, Rostron AJ, Scott J, Liu H, Burling K, Barker P, Clatworthy MR, Lee EC, Simpson AJ, Yeo GSH, Moita LF, Bence KK, Jørgensen SB, Coll AP, Breen DM, O’Rahilly S. Activation of the hypothalamic-pituitary-adrenal axis by exogenous and endogenous GDF15. Proc Natl Acad Sci U S A. 2021 Jul 6;118(27):e2106868118

5. Hosgood SA, Reschke M, Albert C, Bracaglia LG, Ferdinand JR, Stewart BJ, Edwards CM, Vaish AG5, Thiru S, Mulligan DC, Haakinson DJ, Clatworthy MR, Saltzman WM, Pober JS, Nicholson ML, Tietjen GT. Lysis of cold-storage-induced microvascular obstructions for ex vivo revitalization of marginal human kidneys.  Am J Transplant. 2021, 21(1):161-173.
6. Georgiades F, Summers DM, Butler AJ, Russell NKI, Clatworthy MR, Torpey NP. Renal transplantation during the SARS-CoV-2 pandemic in the UK: Experience from a large-volume center. Transplant International. 2021 Jan;35(1):e14150.
7. Suchanek O, Clatworthy MR. Novel strategies to target the humoral alloimmune response. HLA. 2020 Dec;96(6):667-680.
8. Dutcher EG, Pama EAC, Lynall ME, Khan S, Clatworthy MR, Robbins TW, Bullmore ET, Dalley JW. Early-life stress and inflammation: A systematic review of a key experimental approach in rodents. Brain Neurosci Adv. 2020 Dec 28;4:2398212820978049
9. Burrows N*, Bashford-Rogers RJM, Bhute VJ, Peñalver A, Ferdinand JR, Stewart BS, Smith JEG, Deobagkar-Lele M, Giudice G, Connor TM, Inaba A, Bergamaschi L, Smith S, Tran MGB, Petsalaki E, Lyons PA, Espeli M, Huntly BJP, Smith KGC, Cornall RJ, Clatworthy MR, Maxwell PH. Dynamic regulation of HIF-1 activity is essential for normal B cell development. Nat Immunol. 2020;21(11):1408-1420.
10. Castro-Dopico T, Fleming A, Dennison TW, Ferdinand JR, Harcourt K, Stewart BJ, Cader Z, Tuong ZK, Jing C, Lok LSC, Mathews RJ, Portet A, Kaser A, Clare S, Clatworthy MR. GM-CSF calibrates macrophage defence and wound healing programmes during intestinal infection and inflammation. Cell Reports. 2020;32(1):107857.
11. Tuong ZK, Clatworthy MR. Organ Immune Responses – Don’t forget the structural cells. Nat Rev Nephrol. 2020 Oct;16(10):570-571.
12. Jing C, Castro-Dopico T, Richoz N, Tuong ZK, Ferdinand JR, Lok LSC, Loudon KW, Banham GD, Mathews RJ, Cader Z, Fitzpatrick S, Bashant KR, Kaplan MJ, Kaser A, Johnson RS, Murphy MP, Siegel RM, Clatworthy MR. Macrophage Metabolic Reprogramming Presents a Therapeutic Target in Lupus Nephritis. Proc Natl Acad Sci U S A. 2020 Jun 15:202000943.

13. Bellomo A, Mondor I, Spinelli L, Lagueyrie M, Stewart BJ, Brouilly N, Malissen B,Clatworthy MR, Bajénoff M. Reticular Fibroblasts Expressing the Transcription Factor WT1 Define a Stromal Niche That Maintains and Replenishes Splenic Red Pulp Macrophages. Immunity. 2020 Jun 17:S1074-7613(20)30238-7.
14. Stewart BJ,Clatworthy MR. Applying single-cell technologies to clinical pathology: progress in nephropathology. J Pathol. 2020 Mar 3. doi: 10.1002/path.5417. PMID:32125696
15. Park JE, Botting RA, Domínguez Conde C, Popescu DM, Lavaert M, Kunz DJ, Goh I, Stephenson E, Ragazzini R, Tuck E, Wilbrey-Clark A, Roberts K, Kedlian VR, Ferdinand JR, He X, Webb S, Maunder D, Vandamme N, Mahbubani KT, Polanski K, Mamanova L, Bolt L, Crossland D, de Rita F, Fuller A, Filby A, Reynolds G, Dixon D, Saeb-Parsy K, Lisgo S, Henderson D, Vento-Tormo R, Bayraktar OA, Barker RA, Meyer KB, Saeys Y, Bonfanti P, Behjati S,Clatworthy MR, Taghon T, Haniffa M, Teichmann SA. A cell atlas of human thymic development defines T cell repertoire formation. Science. 2020 Feb 21;367(6480). PMID:32079746
16. James KR, Gomes T, Elmentaite R, Kumar N, Gulliver EL, King HW, Stares MD, Bareham BR, Ferdinand JR, Petrova VN, Polański K, Forster SC, Jarvis LB, Suchanek O, Howlett S, James LK, Jones JL, Meyer KB,Clatworthy MR, Saeb-Parsy K, Lawley TD, Teichmann SA. Distinct microbial and immune niches of the human colon. Nat Immunol. 2020 Mar;21(3):343-353. PMID:32066951
17. Wijeyekoon RS, Kronenberg-Versteeg D, Scott KM, Hayat S, Kuan WL, Evans JR, Breen DP, Cummins G, Jones JL,Clatworthy MR, Floto RA, Barker RA, Williams-Gray CH. Peripheral innate immune and bacterial signals relate to clinical heterogeity in Parkinson’s disease. Brain Behav Immun. 2020 Jan 30. pii: S0889-1591(19)31261-9. PMID:32006615.