Professor Deborah Dunn-Walters

Research Collaborations

  • Professor David Kipling, University of Cardiff
  • Professors Franca Fraternali, Ton Coolen, Stuart Neil, Michael Malim, Andrew Tutt, Dr Katie Doores, Sophia Karagiannis, Anita Grigoriadis, King’s College London
  • Dr Angray Kang, Queen Mary
  • Professor Claudia Mauri, UCL
  • Ebola research collaborators: Alain Townsend, Oxford; Kenny Bailey, Edinburgh; Calum Semple, Liverpool; Miles Carroll, Porton Down; Colin Brown, UCL.
  • Professor Ramit Mehr, Bar-Ilan University, Israel
  • Dr Iris Barshack, Sheba Medical Centre Tel Aviv, Israel
  • Professor Qiang Pan Hammarstrom, Karolinska Institute Sweden
  • Professor Chris Goodnow, Australia National University Canberra
  • Professor Claude Agnes Reynaud, Paris Necker, France
  • Professor Nico Bos, Groningen, NL
  • Professor Katja Fink, SIGN Singapore
  • Dr Jessica Strid, Imperial College London
  • Medimmune Cambridge

Contact Me

E-mail:
Phone: 01483 68 2564

Find me on campus
Room: 04 AY 02


My office hours

0900 - 1700 by appointment 

Publications

Journal articles

  • Sáez de Guinoa J, Jimeno R, Gaya M, Kipling D, Garzón M, Dunn-Walters D, Ubeda C, Barral P. (2018) 'CD1d-mediated lipid presentation by CD11c+ cells regulates intestinal homeostasis'. EMBO Press The EMBO Journal,
    [ Status: Accepted ]

    Abstract

    Intestinal homeostasis relies on a continuous dialogue between the commensal bacteria and the immune system. Natural killer T (NKT) cells, which recognize CD1d-restricted microbial lipids and self-lipids, contribute to the regulation of mucosal immunity, yet the mechanisms underlying their functions remain poorly understood. Here, we demonstrate that NKT cells respond to intestinal lipids and CD11c+ cells (including dendritic cells (DCs) and macrophages) are essential to mediate lipid presentation within the gut ultimately controlling intestinal NKT cell homeostasis and activation. Conversely, CD1d and NKT cells participate in the control of the intestinal bacteria composition and compartmentalization, in the regulation of the IgA repertoire and in the induction of regulatory T cells within the gut. These changes in intestinal homeostasis require CD1d expression on DC/macrophage populations as mice with conditional deletion of CD1d on CD11c+ cells exhibit dysbiosis and altered immune homeostasis. These results unveil the importance of CD11c+ cells in controlling lipid-dependent immunity in the intestinal compartment and reveal an NKT cell–DC crosstalk as a key mechanism for the regulation of gut homeostasis.

  • Moody S, Escudero-Ibarz L, Wang M, Clipson A, Ochoa Ruiz E, Dunn-Walters D, Xue X, Zeng N, Robson A, Chuang S, Cogliatti S, Liu H, Goodlad J, Ashton-Key M, Raderer M, Bi Y, Du M. (2017) 'Significant association between TNFAIP3 inactivation and biased IGHV4-34 usage in MALT lymphoma'. Wiley Journal of Pathology, 243 (1), pp. 3-8.

    Abstract

    Both antigenic drive and genetic change play a critical role in the development of MALT lymphoma, but neither alone is sufficient for malignant transformation, and lymphoma development critically depends on their cooperation. However, which of these different events concur and how they cooperate in MALT lymphomagenesis is totally unknown. To explore this, we investigated somatic mutations of 17 genes and IGHV usage in 179 MALT lymphomas from various sites. We showed that: 1) there was a significant association between the biased usage of IGHV4-34 (binds to the carbohydrate I/i antigens) and inactivating mutation of TNFAIP3 (encoding a global negative regulator of the canonical NF-B pathway) in ocular adnexal MALT lymphoma; 2) IGHV1-69 was significantly overrepresented (54%) in MALT lymphoma of salivary gland, but not associated with mutation in any of the 17 genes investigated; and 3) MALT lymphoma lacked mutations frequently seen in other B-cell lymphomas characterised by constitutive NF-B activities, including CD79B, CARD11, MYD88, TNFRSF11A and TRAF3. Our findings show for the first time a significant association between biased usage of autoreactive IGHV and somatic mutation of NF-B regulators in MALT lymphoma, arguing for their cooperation in sustaining chronic BCR signalling and driving oncogenesis in lymphoma development.

  • Björkman A, Du L, van der Burg M, Cormier-Daire V, Borck G, Pié J, Anderlid B, Hammarström L, Ström L, de Villartay J, Kipling D, Dunn-Walters D, Pan-Hammarström Q. (2017) 'Reduced immunoglobulin gene diversity in patients with Cornelia de Lange syndrome'. Elsevier Journal of Allergy and Clinical Immunology, 141 (1), pp. 408-411.e8.

    Abstract

    B cells rely on a broad receptor repertoire to provide protection against a wide range of pathogens. This is in part achieved through V(D)J recombination, which, by assembling various combinations of variable (V), diversity (D), and joining (J) genes, creates different IgV regions.1 The recombination processes is initiated by recombination-activating gene (RAG) 1/RAG2 enzymes and requires a functional nonhomologous end-joining (NHEJ) machinery. B cells can further diversify their IgV regions through somatic hypermutation (SHM) to improve affinity between the antibody and antigen and switch the isotype of antibody produced by class-switch recombination (CSR).

  • Martin V, Wu Y, Townsend C, Lu G, O'Hare J, Mozeika A, Coolen A, Kipling D, Fraternali F, Dunn-Walters D . (2016) 'Transitional B cells in early human B cell development - time to revisit the paradigm?'. Frontiers Media Frontiers in Immunology, 7 Article number 546

    Abstract

    The B cell repertoire is generated in the adult bone marrow by an ordered series of gene rearrangement processes that result in massive diversity of immunoglobulin (Ig) genes, and consequently an equally large number of potential specificities for antigen. As the process is essentially random, then cells exhibiting excess reactivity with self-antigens are generated and need to be removed from the repertoire before the cells are fully mature. Some of the cells are deleted, and some will undergo receptor editing to see if changing the light chain can rescue an autoreactive antibody. As a consequence, the binding properties of the B cell receptor are changed as development progresses through pre- B>>immature>>transitional>>naïve phenotypes. Using long-read, high-throughput, sequencing we have produced a unique set of sequences from these four cell types in human bone marrow and matched peripheral blood and our results describe the effects of tolerance selection on the B cell repertoire at the Ig gene level. Most strong effects of selection are seen within the heavy chain repertoire, and can be seen both in gene usage and in CDR-H3 characteristics. Age-related changes are small and only the size of the CDR-H3 shows constant and significant change in these data. The paucity of significant changes in either kappa or lambda light chain repertoires implies that either the heavy chain has more influence over autoreactivity than light chain and/or that switching between kappa and lambda light chains, as opposed to switching within the light chain loci, may effect a more successful autoreactive rescue by receptor editing. Our results show that the transitional cell population contains cells other than those that are part of the pre-B>>immature>>transitional>>naïve development pathway, since the population often shows a repertoire that is outside the trajectory of gene loss/gain between pre-B and naïve stages.

  • Townsend C, Laffy J, Wu Y, O’Hare J, Martin V, Kipling D, Fraternali F, Dunn-Walters D . (2016) 'Significant differences in physicochemical properties of human immunoglobulin kappa and lambda CDR3 regions'. Frontiers Media Frontiers in Immunology, 216

    Abstract

    Antibody variable regions are composed of a heavy and a light chain and in humans there are two light chain isotypes: kappa and lambda. Despite their importance in receptor editing, the light chain is often overlooked in the antibody literature, with the focus being on the heavy chain CDR-H3 region. In this paper, we set out to investigate the physicochemical and structural differences between human kappa and lambda light chain CDR regions. We constructed a dataset containing over 29,000 - light chain variable region sequences from IgM-transcribing, newly formed B cells isolated from human bone marrow and peripheral blood. We also used a published human naïve dataset to investigate the CDR-H3 properties of heavy chains paired with kappa and lambda light chains, and probed the Protein Data Bank (PDB) to investigate the structural differences between kappa and lambda antibody CDR regions. We found that kappa and lambda light chains have very different CDR physicochemical and structural properties, whereas the heavy chains with which they are paired do not differ significantly. We also observed that the mean CDR3 N nucleotide addition in the kappa, lambda and heavy chain gene rearrangements are correlated within donors, but can differ between donors. This indicates that TdT may work with differing efficiencies between different people, but the same efficiency in the different classes of immunoglobulin chain within one person. We have observed large differences in the physicochemical and structural properties of kappa and lambda light chain CDR regions. This may reflect different roles in the humoral immune response.

  • Laffy J, Dodev T, Macpherson J, Townsend C, Lu H, Dunn-Walters D, Fraternali F. (2016) 'Promiscuous antibodies characterised by their physico-chemical properties: From sequence to structure and back'. Elsevier Progress in Biophysics and Molecular Biology, 128, pp. 47-56.

    Abstract

    Human B cells produce antibodies, which bind to their cognate antigen based on distinct molecular properties of the antibody CDR loop. We have analysed a set of 10 antibodies showing a clear difference in their binding properties to a panel of antigens, resulting in two subsets of antibodies with a distinct binding phenotype. We call the observed binding multiplicity ‘promiscuous’ and selected physico-chemical CDRH3 characteristics and conformational preferences may characterise these promiscuous antibodies. To classify CDRH3 physico-chemical properties playing a role in their binding properties, we used statistical analyses of the sequences annotated by Kidera factors. To characterise structure-function requirements for antigen binding multiplicity we employed Molecular Modelling and Monte Carlo based coarse-grained simulations. The ability to predict the molecular causes of promiscuous, multi-binding behaviour would greatly improve the efficiency of the therapeutic antibody discovery process.

  • Fraser LD, Zhao Y, Lutalo PMK, D’Cruz DP, Cason J, Silva JS, Dunn-Walters D, Nayar S, Cope AP, Spencer J. (2016) 'Immunoglobulin light chain allelic inclusion in systemic lupus erythematosus'. Wiley European Journal of Immunology, 45 (8), pp. 2409-2419.
  • Dunn-Walters D. (2015) 'The ageing human B cell repertoire: A failure of selection?'. Wiley Clinical & Experimental Immunology, 183 (1), pp. 50-56.
  • Tabibian-Keissar∗ H, Hazanov L, Schiby G, Rosenthal N, Rakovsky A, Michaeli M, Shahaf GL, Pickman Y, Rosenblatt K, Melamed D, Dunn-Walters D, Mehr R, Barshack I. (2015) 'Aging affects B-cell antigen receptor repertoire diversity in primary and secondary lymphoid tissues'. 2015 WILEY-VCH Verlag GmbH & Co European Journal of Immunology, 46 (2), pp. 480-492.
  • Bagnara D, Squillario M, Kipling D, Mora T, Walczak AM, Da Silva L, Weller S, Dunn-Walters D, Weill J-C, Reynaud C-A. (2015) 'A reassessment of IgM memory subsets in humans'. American Association of Immunologists Journal of Immunology, 195 (8), pp. 3716-3724.

    Abstract

    From paired blood and spleen samples from three adult donors, we performed high-throughput VH sequencing of human B cell subsets defined by IgD and CD27 expression: IgD+CD27+ (“marginal zone [MZ]”), IgD−CD27+ (“memory,” including IgM [“IgM-only”], IgG and IgA) and IgD−CD27− cells (“double-negative,” including IgM, IgG, and IgA). A total of 91,294 unique sequences clustered in 42,670 clones, revealing major clonal expansions in each of these subsets. Among these clones, we further analyzed those shared sequences from different subsets or tissues for VH gene mutation, H-CDR3-length, and VH/JH usage, comparing these different characteristics with all sequences from their subset of origin for which these parameters constitute a distinct signature. The IgM-only repertoire profile differed notably from that of MZ B cells by a higher mutation frequency and lower VH4 and higher JH6 gene usage. Strikingly, IgM sequences from clones shared between the MZ and the memory IgG/IgA compartments showed a mutation and repertoire profile of IgM-only and not of MZ B cells. Similarly, all IgM clonal relationships (among MZ, IgM-only, and double-negative compartments) involved sequences with the characteristics of IgM-only B cells. Finally, clonal relationships between tissues suggested distinct recirculation characteristics between MZ and switched B cells. The “IgM-only” subset (including cells with its repertoire signature but higher IgD or lower CD27 expression levels) thus appear as the only subset showing precursor–product relationships with CD27+ switched memory B cells, indicating that they represent germinal center–derived IgM memory B cells and that IgM memory and MZ B cells constitute two distinct entities.

  • Martin V, Wu Y-C, Kipling D, Dunn-Walters D. (2015) 'Ageing of the B-cell repertoire'. The Royal Society Publishing Philosophical Transactions of the Royal Society B, 370 (1676)

    Abstract

    Older people are more susceptible to infection, less responsive to vaccination and have a more inflammatory immune environment. Using spectratype analysis, we have previously shown that the B-cell repertoire of older people shows evidence of inappropriate clonal expansions in the absence of challenge, and that this loss of B-cell diversity correlates with poor health. Studies on response to vaccination, using both spectratyping and high-throughput sequencing of the repertoire, indicate that older responses to challenge are lacking in magnitude and/or delayed significantly. Also that some of the biologically significant differences may be in different classes of antibody. We have also previously shown that normal young B-cell repertoires can vary between different phenotypic subsets of B cells. In this paper, we present an analysis of immunoglobulin repertoire in different subclasses of antibody in five different populations of B cell, and show how the repertoire in these different groups changes with age. Although some age-related repertoire differences occur in naive cells, before exogenous antigen exposure, we see indications that there is a general dysregulation of the selective forces that shape memory B-cell populations in older people.

  • Martin V, Wu Y-C, Kipling D, Dunn-Walters D. (2015) 'Age-related aspects of human IgM+ B cell heterogeneity'. Wiley Annals of the New York Academy of Sciences, 1362 (B-1 Cell Development and Function), pp. 153-163.

    Abstract

    The CD27+IgD+ B cell population, known as IgM memory, reduces with age. It is thought that this population is responsible for pneumococcal polysaccharide T-independent responses, and that the age-related reduction might be partially responsible for the increased susceptibility of older people to bacterial pathogens. There are other IgM+ B cell populations that do not express IgD. We compared the different IgM populations using high-throughput sequencing of the immunoglobulin (Ig) gene repertoire and multidimensional cell phenotyping and found that the different populations of IgM cells, defined by CD27 and IgD expression, have repertoire differences. Some of these differences are likely indicative of different selection pressures in an immune response, although the older individuals were found to have a changed repertoire in naive B cells, which may contribute to some of the changes seen in memory cells. In addition, even within the CD27+IgD+ IgM memory population there are multiple cell types. We show that the level of IgM expression varies substantially and hypothesize that this distinguishes between T-dependent and T-independent types of IgM memory cells. Significant age-related changes in the relative proportions of these populations may exacerbate the reduction in T-independent responders in old age.

  • Tete SM, Kipling D, Westra J, de Haan A, Bijl M, Dunn-Walters D, Sahota SS, Bos NA. (2015) 'Monoclonal paraprotein influences baseline B-cell repertoire diversity and perturbates influenza vaccination-induced B-cell response'. Elsevier Experimental Hematology, 43 (6), pp. 439-447.
  • Wu Y-C, Kipling D, Dunn-Walters D. (2015) 'Assessment of B cell repertoire in humans'. Humana Press Methods in Molecular Biology, 1343, pp. 199-218.
  • Michaeli M, Tabibian-Keissar H, Schiby G, Shahaf G, Pickman Y, Hazanov L, Rosenblatt K, Dunn-Walters D, Barshack I, Mehr R. (2014) 'Immunoglobulin gene repertoire diversification and selection in the stomach – from gastritis to gastric lymphomas'. Frontiers Media Frontiers in Immunology, 5 Article number 264 , pp. 1-14.
  • Sabouria Z, Schofield P, Horikawa K, Spierings E, Kipling D, Randall KL, Langley D, Roome B, Vazquez-Lombardi R, Rouet R, Hermes J, Chan TD, Brink R, Dunn-Walters D, Christ D, Goodnow CC. (2014) 'Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity'. National Academy of Sciences PNAS, 111 (25), pp. E2567-E2575.

    Abstract

    The best-understood mechanisms for achieving antibody self/nonself discrimination discard self-reactive antibodies before they can be tested for binding microbial antigens, potentially creating holes in the repertoire. Here we provide evidence for a complementary mechanism: retaining autoantibodies in the repertoire displayed as low levels of IgM and high IgD on anergic B cells, masking a varying proportion of autoantibody-binding sites with carbohydrates, and removing their self-reactivity by somatic hypermutation and selection in germinal centers (GCs). Analysis of human antibody sequences by deep sequencing of isotype-switched memory B cells or in IgG antibodies elicited against allogeneic RhD+ erythrocytes, vaccinia virus, rotavirus, or tetanus toxoid provides evidence for reactivation of anergic IgMlow IgD+ IGHV4-34+ B cells and removal of cold agglutinin self-reactivity by hypermutation, often accompanied by mutations that inactivated an N-linked glycosylation sequon in complementarity-determining region 2 (CDR2). In a Hy10 antibody transgenic model where anergic B cells respond to a biophysically defined lysozyme epitope displayed on both foreign and self-antigens, cell transfers revealed that anergic IgMlow IgD+ B cells form twice as many GC progeny as naïve IgMhi IgD+ counterparts. Their GC progeny were rapidly selected for CDR2 mutations that blocked 72% of antigen-binding sites with N-linked glycan, decreased affinity 100-fold, and then cleared the binding sites of blocking glycan. These results provide evidence for a mechanism to acquire self/non-self discrimination by somatic mutation away from self-reactivity, and reveal how varying the efficiency of N-glycosylation provides a mechanism to modulate antibody avidity.

Book chapters

  • Pawelec G, Müller L, Fülöp T, Dunn-Walters D. (2017) 'Immune system changes and immunosenescence'. in Michel J, Beattie B, Martin F, Walston J (eds.) Oxford Textbook of Geriatric Medicine 3rd Edition. Oxford, UK : Oxford University Press

    Abstract

    The immune system defends against infection, but older people paradoxically suffer not only from failing immunity resulting in increased susceptibility to infections and decreased responsiveness to vaccination, but at the same time increased inflammation and immunopathology accompanying immune responses. Interventions to reduce such deleterious effects while enhancing protective immunity are challenging but need to be confronted if we are to deal successfully with the increasing numbers of elderly and frail people in modern societies. To do this, we need to understand the mechanisms responsible for age-associated increased susceptibility to infections and immune-influenced chronic degenerative diseases of ageing. Defining relevant age-associated alterations and identifying reliable biomarkers for monitoring clinically-relevant immune status in the elderly population is crucial to overcoming these problems. Here, we briefly outline age-associated changes to immunity collectively termed ‘immunosenescence’

  • Dunn-Walters D, O’Hare J. (2017) 'Older Human B Cells and Antibodies'. in Fulop T, Franceschi C, Hirokawa K, Pawelec G (eds.) Handbook of Immunosenescence Springer International Publishing Handbook of Immunosenescence, , pp. 1-34.

    Abstract

    B cells have a number of different roles in the immune response. Their excellent antigen presentation potential can contribute to the activation of other cells of the immune system, and evidence is emerging that specialized subsets of these cells, that may be increased with age, can influence the cell-mediated immune system in antitumor responses. They can also regulate immune responses, to avoid autoreactivity and excessive inflammation. Deficiencies in regulatory B cells may be beneficial in cancer but will only exacerbate the inflammatory environment that is a hallmark of aging. The B cell role as antibody producers is particularly important, since antibodies perform numerous different functions in different environments. Although studying tissue responses in humans is not as easy as in mice, we do know that certain classes of antibodies are more suited to protecting the mucosal tissues (IgA) or responding to T-independent bacterial polysaccharide antigens (IgG2) so we can make some inference with respect to tissue-specific immunity from a study of peripheral blood. We can also make inferences about changes in B cell development with age by looking at the repertoire of different B cell populations to see how age affects the selection events that would normally occur to avoid autoreactivity, or increase specificity, to antigen.

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