My group "The Lectin Biology Group" is considered 'the mannose receptor hub' and we have numerous collaborations with other researchers interested in investigating the role of this receptor in homeostasis and immunity. Recently examples led to publications in J. Allergy Clin Immunol. 2011. 129:501-509; Int J Parasitol. 2011. 4:1335-45 and Blood. 2012. 119:3828-35.
In addition to continuing my work on lectin receptors and providing the platform technology underpinning lectin receptor research, I have also successfully redirected my research towards more clinically-oriented topics. Since 2009 my laboratory has established experimental models to investigate pathogen recognition by human immune cells. In collaboration with Prof. P. Williams and Prof. M. Camara (University of Nottingham) we are studying the interaction of differentiated lung epithelial cells, macrophages, monocytes and neutrophils with P. aeruginosa (both planktonic and biofilm cultures) and how it is affected by key virulence factors and inflammatory conditions (PLoS One 10(2) e0117447). We are also analysing immune responses in Cystic Fibrosis and Idiopathic Pulmonary Fibrosis patients using PBMC cultures in collaboration with Dr A. Fogarty, Prof Alan Knox and Prof R. Hubbard (University of Nottingham). In these studies we are interest in defining cytokine profiles that can be correlated with clinical characteristics. They are generating novel hypotheses, that will be tested experimentally using our expertise in human and mouse immune cells.
An additional interest of the group is the role of mannose receptor in the presentation of antigens to cells of the acquired immune system following our identification of mannose receptor-expressing dendritic cells in murine peripheral lymph nodes (J. Immunol. 2007. 178:4975-83, funded by the Arthritis Research Campaign, PhD fellowship). Towards this aim, we are collaborating with Dr G. Mantovani, School of Pharmacy, University of Nottingham, to exploit the use of glycopolymers to target antigens to lectin receptors expressed by antigen presenting cells.
Recent work in my laboratory (since 2006) involved, among others, an exciting collaborative project with the Allergy Research Group (University of Nottingham) on the role of the mannose receptor in the recognition of allergens and in the development of allergic sensitisation (funded by Asthma UK, J. Immunol. 2010.185:1522-31 and J. Biol. Chem. 2011. 286:13033-40) and promoted by the Consortium for Functional Glycomics Gateway). Similarly, collaborative work with Prof F. Stevenson (Southampton University), funded by Cancer Research UK, unveiled a unique role for mannose-specific lectins (mannose receptor and DC-SIGN) in promoting the survival of Follicular Lymphoma cells (Proc. Natl. Acad. Sci. U S A. 2010. 107(43):18587-92). We have also discovered an interesting interplay between the mannose receptor and the beta-glucan receptor that suggests that the beta-glucan receptor could control the contribution of the mannose receptor to the responses to fungal (J. Biol. Chem. 2011 286:7822-9) and a key role for mannose receptor in glomerulonephritis (J. Clin. Inv. 2010. 120:1469-1478).
I trained as a virologist in Dr. Eladio Vinuela's laboratory at the Universidad Autonoma de Madrid where I characterised one of the structural proteins of African Swine Fever virus (1). I became interested in the interaction of viruses with the immune system during my stay as a Fulbright Fellow in Professor R. W. Moyer's laboratory at the University of Florida (2, 3). During my stay at the Sir William Dunn School of Pathology, University of Oxford I worked in the field of mannose receptor (MR) in relation to innate and acquired immunity and became familiar with the biology of macrophages (Mf) and dendritic cells (DC) in vivo and in vitro. The MR contains two distinct lectin domains in its extracellular region. The cysteine-rich domain (CR) recognises sulphated sugars, while mannose (together with fucose and N-acetyl-glucosamine) recognition is mediated by one of its eight C-type lectin-like recognition domains (CTLDs), CTLD4. A fibronectin type II domain (FNII) is located between the CR and CTLDs.
When I joined the laboratory, the general view was that the MR was a pathogen-associated molecular pattern receptor used by the immune system in general, to recognise non-self and by DC in particular, to enhance antigen uptake and presentation to T cells. By using a combined approach involving the analysis of the distribution of mannose receptor and its ligands in situ and their biochemical characterisation, my work has contributed to modify this perception and to illustrate the complexity behind MR biology. Self-recognition by this receptor is now perceived as one of its major functions. Our working hypothesis is that, in the absence of inflammatory stimuli, MR recognition leads to clearance and immune ignorance but a different scenario emerges during inflammation; under these conditions the expression pattern of the MR is altered and MR-mediated recognition leads to enhanced immunogenicity (see (4) for review). Specific examples of my contribution to the MR area are:
(1) My PhD student S. A. Linehan described the distribution of the mannose receptor in situ and investigated where ligands for its CTLDs can be detected in situ. We identified thyroglobulin, often a target of autoantibodies in thyroid disease, as a novel MR ligand (5, 6).
(2) Trying to determine under which conditions ligands for MR are "seen" by the acquired immune system, my PhD student Emma McKenzie identified a population of DC that expresses MR. These cells are restricted to peripheral lymphoid organs and are increased in numbers in the presence of endotoxin. Furthermore, these MR+DC can be targeted using anti-MR monoclonal antibodies and this targeting leads to increased immunogenicity (E. J. McKenzie et al. manuscript in preparation).
(3) I discovered a soluble form of the MR (7) and ligands for the CR. These CR-ligands are present in specialised cells in secondary lymphoid organs that seem to be involved in antigen clearance (in naïve animals) or in antigen transport and retention in B cell follicles (in stimulated animals) (8, 9). These results inspired the "soluble mannose receptor-mediated antigen delivery hypothesis" (See below). I identified two of the CR ligands in lymphoid organs as sulphated glycoforms of sialoadhesin and CD45 (10). Together with Dr P. R. Taylor (a postdoctoral researcher funded by a project grant awarded to me by the Wellcome Trust), I demonstrated that these CR ligands are exposed to the circulation and lymph and mediate binding of CR containing proteins in vivo (11). The antibody responses obtained against CR-containing proteins in the absence and presence of innate stimulation are consistent, again, with the idea that we are dealing with a non-immunogenic clearance system that can lead to enhanced immunogenicity under some circumstances (P. R. Taylor et al, manuscript in preparation). During the course of these studies we identified the FDC-M2 marker as complement component C4 (12).
(4) I determined that in human spleen MR expression is restricted to venous sinuses where co-localises with its sulphated ligands. These results open the possibility of a major role for MR in blood homeostasis (13).
(5) Together with Dr. S. Zamze and Dr. S. Wong, I obtained the first panel of monoclonal antibodies that specifically recognise the murine form of the MR and developed a novel binding assay using full-length soluble MR. This assay has been exploited to investigate direct binding of the MR to capsular polysaccharides from several bacteria (14).
(6) My PhD student Yunpeng Su (co-supervised by Dr P. Rudd, Glycobiology Institute, Oxford University) demonstrated that MR glycoforms lacking sialic acid have drastically reduced ability to bind and internalise mannosylated ligands and that MR is differentially glycosylated in vivo (15).
(7) Together with Dr Oscar Llorca (CIB, Madrid), I studied the three dimensional structure of the MR by electron microscopy. Our results demonstrate that MR adopts a bent conformation under physiological conditions. In this conformation the three binding sites of the MR (CR, FNII and CTLD4) are in close proximity indicating that interference between binding sites is very likely (J. Boskovic et al. J. Biol. Chem. In press).
I have also been involved in the study of other lectin receptors and together with Drs G.R. Brown and P.R. Taylor I have contributed to the characterisation of Dectin-1 as the major beta-glucan receptor in Mf, and in the identification of the cells expressing this molecule in vivo (16, 17). I have also been involved in the characterisation of the mAb 7/4 as a useful marker for monocytes (18) and in the characterisation of the binding properties of Dectin-2 (E. McGreal et al. Glycobiology. In press).
1. Martinez-Pomares, L., Simon-Mateo, C., Lopez-Otin, C. & Vinuela, E. (1997) Virology 229, 201-11.
2. Martinez-Pomares, L., Stern, R. J. & Moyer, R. W. (1993) J Virol 67, 5450-62.
3. Martinez-Pomares, L., Thompson, J. P. & Moyer, R. W. (1995) Virology 206, 591-600.
4. Taylor, P. R., Gordon, S. & Martinez-Pomares, L. (2005) Trends Immunol 26, 104-10.
5. Linehan, S. A., Martinez-Pomares, L., da Silva, R. P. & Gordon, S. (2001) Eur J Immunol 31, 1857-66.
6. Linehan, S. A., Martinez-Pomares, L. & Gordon, S. (2000) Adv Exp Med Biol 479, 1-14.
7. Martinez-Pomares, L., Mahoney, J. A., Kaposzta, R., Linehan, S. A., Stahl, P. D. & Gordon, S. (1998) J Biol Chem 273, 23376-80.
8. Berney, C., Herren, S., Power, C. A., Gordon, S., Martinez-Pomares, L. & Kosco-Vilbois, M. H. (1999) J Exp Med 190, 851-60.
9. Martinez-Pomares, L., Kosco-Vilbois, M., Darley, E., Tree, P., Herren, S., Bonnefoy, J. Y. & Gordon, S. (1996) J Exp Med 184, 1927-37.
10. Martinez-Pomares, L., Crocker, P. R., Da Silva, R., Holmes, N., Colominas, C., Rudd, P., Dwek, R. & Gordon, S. (1999) J Biol Chem 274, 35211-8.
11. Taylor, P. R., Zamze, S., Stillion, R. J., Wong, S. Y., Gordon, S. & Martinez-Pomares, L. (2004) Proc Natl Acad Sci U S A 101, 1963-8.
12. Taylor, P. R., Pickering, M. C., Kosco-Vilbois, M. H., Walport, M. J., Botto, M., Gordon, S. & Martinez-Pomares, L. (2002) Eur J Immunol 32, 1888-96.
13. Martinez-Pomares, L., Hanitsch, L. G., Stillion, R., Keshav, S. & Gordon, S. (2005) Lab Invest 85, 1238-49.
14. Zamze, S., Martinez-Pomares, L., Jones, H., Taylor, P. R., Stillion, R. J., Gordon, S. & Wong, S. Y. (2002) J Biol Chem 277, 41613-23.
15. Su, Y., Bakker, T., Harris, J., Tsang, C., Brown, G. D., Wormald, M. R., Gordon, S., Dwek, R. A., Rudd, P. M. & Martinez-Pomares, L. (2005) J Biol Chem 280, 32811-20.
16. Brown, G. D., Taylor, P. R., Reid, D. M., Willment, J. A., Williams, D. L., Martinez-Pomares, L., Wong, S. Y. & Gordon, S. (2002) J Exp Med 196, 407-12.
17. Taylor, P. R., Brown, G. D., Reid, D. M., Willment, J. A., Martinez-Pomares, L., Gordon, S. & Wong, S. Y. (2002) J Immunol 169, 3876-82.
18. Taylor, P. R., Brown, G. D., Geldhof, A. B., Martinez-Pomares, L. & Gordon, S. (2003) Eur J Immunol 33, 2090-7.
We have worked on the following topics since my arrival at Nottingham in 2005.
- The role of mannose receptor in antigen presentation by studying mannose receptor expression and function in dendritic cells and through the use of chimaeric mAbs and glyco-conjugates to target Ag to MR+ cells.
- Possible cross-talk between two lectin receptors, mannose receptor and the beta-glucan receptor (funded by the Mizutani Foundation for Glycoscience). We have demonstrated that engagement of the beta-glucan receptor enhances mannose receptor shedding.
- We enjoy successful collaborations with the Asthma Research Group (University of Nottingham) and together we are investigating the role of MR in promoting the allergenicity of major glyco-allergens such as Der p 1 and Fel d 1 (initially funded by Asthma, UK). During the course of this collaboration we have developed an allergy model that has allowed has to demonstrate the key contribution of the mannose receptor to allergen recognition in vivo.
- With the Genetic Vaccine Group (University of Southampton) we have been involved on the study of the functional role of unusual oligomannose glycans expressed by the surface Ig of malignant germinal center B-cells (funded by CR,UK).
I am interested in exploiting my expertise in innate immunity to investigate the contribution of macrophages to inflammation. Going beyond the mannose receptor, I want to look at macrophage activation during different inflammatory processes in order to identify pathways that could affect the resolution phase and that, when uncontrolled could lead to fibrosis and organ failure.