Chris Buckley

MRC Senior Clinical Fellow.

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Rheumatology Research Training and Experience

Biochemistry from University of Oxford (1985). MBBS Royal Free Hospital, London (1990). MRCP (1993) during subsequent training in General Medicine at Hammersmith Hospital, London and John Radcliffe Hospital, Oxford. DPhil (1996) arising from Wellcome Training Fellowship with Professor J Bell and Dr D Simmons at the Institute of Molecular Medicine, Oxford. Rheumatology training with Dr A Mowatt and Dr P Wordsworth at the Nuffield Orthopaedic Hospital, Oxford 1996 - Wellcome Clinician Scientist Fellowship and joined the Department of Rheumatology in Birmingham. 2000 - Senior Lecturer (MRC Senior Clinical Fellow)

Research Interests

I work in close collaboration with Mike Salmon and my clinical colleagues at City Hospital (Caroline Gordon, Deva Situnayake, David Carruthers, Karim Raza). Our research interests are focused on the molecular basis of leukocyte accumulation and retention at sites of chronic inflammation, in particular within the inflamed synovium. These studies are particularly aimed at:

1. Defining the adhesive mechanisms involved in selective transendothelial migration.
2. The role of adhesion dependent signals in modifying leukocyte migration and behaviour.
3. Adhesive mechanisms regulating leukocyte retention and apoptosis within the chronically inflamed synovium.
4. Molecular analysis of leukocyte accumulation and retention in chronic inflammation.

In addition, we also study the biology of an adhesion receptor CD31(PECAM-1) involved in leucocyte transendothelial migration. This is part of a long standing collaboration with Professor Gerard Nash and Ed Rainger in the Department of Physiology at Birmingham.

The Role of Fibroblasts in Chronic Inflammation

During immune responses, peripheral blood leukocyte numbers are tightly regulated. However little is known about how leukocyte numbers are regulated during inflammatory responses within tissues. Although there is considerable evidence that preferential recruitment of cells to inflammatory lesions occurs during the initial stages of an inflammatory response, the mechanisms regulating their retention within inflamed tissue remain largely unexplored.

The molecular basis of leukocyte accumulation in chronic inflammation remains unclear but altered leukocyte adhesive mechanisms as well as changes in cytokine and chemokine receptor expression appear to play important roles. A longstanding observation has been that tissues undergoing chronic inflammatory reactions contain infiltrates of distinct subsets of leukocytes that are often organised into well defined lymphoid like structures. For example, within the rheumatoid synovium, B cells organised in clusters are in close contact with macrophages, synoviocytes and CD8 T cells at the periphery of a lymphocyte-rich area composed predominantly of CD4 T cells aggregated around post capillary venules. How this characteristic pattern of leukocyte accumulation occurs remains unclear, but it is likely that cytokines such as TNF-a and lymphotoxin and chemokines such as SDF-1 play an important role in defining this architectural structure.

The paradigm for tissue specific homing of leukocytes is the "area code" hypothesis, which predicts that a specific combination of adhesive interactions and chemokine signals from the endothelium directs leukocyte migration into specific tissue sites. In addition to this endothelial "area code" it appears that similar area codes exist within tissues. The best defined precedent for such stromal cell "area coding" comes from studies of leukocyte homing to the gut mucosa where leukocytes use aEb7/E-cadherin interactions in order to adhere to and become retained within the gut epithelial lining. In addition a clear haemopoietic "stem cell area code" comprising the chemnokine SDF-1 and the adhesion receptor VCAM-1 has been shown to define the stem cell niche within bone marrow. Whether such stromal area codes exist and are disordered at sites of chronic inflation leading to abnormal leukocyte accumulation remains unclear, but is the main focus of our work.

In addition to their role in regulating leukocyte recruitment from flowing blood, there is now accumulating evidence that chemokines are involved in regulating the pattern and distribution of leukocyte subsets within immune organs such as the bone marrow, thymus and lymph node. During the development of an immune response, immune cells have to be appropriately positioned within lymph nodes and tissues, such that appropriate cognate interactions can occur. This movement of cells to appropriate niches within immune organs is driven by chemokines and their receptors. In fact it is now clear that in addition to their role in positioning immune cells during immune responses, abnormal expression of chemokines and their receptors can lead to the inappropriate retention and accumulation of leukocytes within tissues and organs leading to disordered immune function.

We are examining the hypothesis that leukocyte accumulation at sites of chronic inflammation occurs primarily because of a disordered stromal cell microenvironment, supporting inappropriate leukocyte retention, proliferation and survival. The interaction between leukocytes and stromal cells during an acute inflammatory response ultimately leads to resolution of the inflammatory focus. However leukocyte interactions with stromal cells at sites of chronic inflammation appear to lead to sustained leukocyte accumulation and retention with persistence of the inflammatory lesion. A key point to emphasise in this hypothesis is that aberrant temporal and spatial expression of adhesion molecules, chemokines/cytokines and their receptors leads to persistent leukocyte retention and survival in these inappropriately stable stromal cell microenvironments. While normal homeostasis and resolution of acute inflammation depends on the right cell being in the right place at the right time, it is likely that chronic inflammation involves immune cells being positioned in the wrong place at the wrong time.

The dynamic balance of cell accumulation in any tissue compartment depends on the balance of cell recruitment, division, emigration and death. Homeostasis is maintained during normal inflammatory responses, leading to resolution. In chronic inflammation, inappropriate accumulation of leukocytes is caused by the inappropriate production of pro-retentive [e.g. (SDF-1)] and pro-survival [e.g. interferon B (IFN-B)] factors by fibroblasts.

CD31 is more than just glue. Structure function and distribution of CD31.

CD31 (PECAM-1) is a 130-kDa member of the immunoglobulin superfamily (IgSF) expressed on the surface of circulating platelets, monocytes, neutrophils and T-cell subsets. It also is a major constituent of the endothelial cell intercellular junction, where up a million molecules are concentrated. We have shown that CD31 is capable of mediating both homophilic (CD31-CD31) as well as heterophilic interactions (Fawcett et al 1995 J. Cell Biol. 128: 1229-1241, Buckley CD et al 1996 J. Cell Sci 109:437-445 ). Proposed heterophilic ligands include the integrin avb3 and as yet uncharacterised molecules on activated T cells and red blood cells that have been parasitised by Plasmodium falciparum (Prager E et al 1996 J. Exp. Med. 184:41-50, Treutiger CJ et al 1997 Nat. Med 3:1405-1411 ). We have mapped the homophilic binding site in CD31 to the N terminal domain of CD31 and shown that CD31 exists in vivo as a dimer suggesting a "zipper model" for CD31 mediated homophilic adhesion (Newton JP et al 1997 J. Biol. Chem. 272:20555-20563, Newton JP et al Biochem. Biophys. Res. Com. 261:283-291). While its role as a homophilic adhesion receptor is well established, it is now clear that like a growing number of leucocyte and endothelial adhesion molecules, CD31 functions as an adhesion-dependent signalling receptor (Buckley CD et al 1998 Mol. Memb. Biol 15:167-176). For example we have shown that homophilic CD31 interactions regulate integrin-mediated cell adhesion, the rate and direction of b2 integrin-mediated neutrophil migration, and rescues endothelial cells from serum deprivation induced apoptosis (Bird IN et al 1999 J. Cell Sci. 112:1989-1997, Rainger GE et al 1997 Cur. Biol 7: 316-325, Rainger GE et al 1999 Am. J. Physiol. 276:858-864). Furthermore our studies have suggested that CD31 plays an important role in determining contact-dependent growth inhibition when endothelial cells reach confluency (Fawcett et al 1995 J. Cell Biol. 128: 1229-1241). Therefore it appears that the primary role of CD31 is not simply to support strong adhesive interactions, but to act as a critical component of the physical sensing and junctional signalling complex between vascular cells that express CD31. Current work in our laboratory is addressing the role that the cytoplasmic domain of CD31 plays in this process.

Clinical Interests

Our clinical interests focus around the pathogenesis of rheumatoid arthritis. We (Karim Raza, Caroline Gordon, Deva Situnayake, David Carruthers, Mike Salmon) are particularly interested in the mechanisms of persistence in rhematoid arthritis. We are currently examining a cohort of patients with early arthritis to determine at what point the switch from acute resolving to chronic persistent inflammation might occur.

Current Publications

Papers and Publications (files in .PDF format, acrobat reader required)

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• Rap1 Mediates CD31-induced Integrin Adhesion
• The Small GTPase, Rap1, Mediates CD31-induced Integrin Adhesion
• New Way to Activate Caspases
• RGD Peptides Induce Apoptosis by Direct Caspase-3 Activation
• Fibroblasts Regulate the Switch from Acute Resolving to Chronic Persistient Inflammation
• Persistent Induction of the Chemokine Receptor CXCR4 by TGF-b1 on Synovial T Cells Contributes to Their Accumulation Within the Rheumatoid Synovium
• Residues on Both Faces of the First Immunoglobulin Fold Contribute to Homophilic Binding Sites of PECAM-1/CD31
• Memory T Cells Constitute a Subset of the Human CD8+ CD45RA+ Pool with Distinct Phenotypic and Migratory Characteristics
• CD31 (PECAM-1) Exists as a Dimer and Is Heavily N-Glycosylated
• Homophilic PECAM-1(CD31) interactions prevent endothelial cell apoptosis but do not support cell spreading or migration
• Cross-talk between cell adhesion molecules regulates the migration velocity of neutrophils

Email: c.d.buckley@bham.ac.uk

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Members of the Research Team

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• Ewan Ross

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Ewan Ross

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Collaborators

• Cardio Vascular Rheumatology

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