Anne Cooke

University of Cambridge | Cam · Department of Pathology

In this article from our Women in Immunology series, Anne Cooke highlights the pioneering work of Deborah Doniach in the field of autoimmunity.

Glucagon-like peptide 1 (GLP-1) is produced by L cells in the small intestine in response to ingested glucose and increases insulin release from pancreatic beta cells by activation of its cognate receptor (GLP-1R). Stimulation of this receptor also contributes to increased beta cell survival and regeneration. We have found that pancreatic beta cell...

These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell ty...

Objective: Despite progress in treating relapsing multiple sclerosis (MS), effective inhibition of nonrelapsing progressive MS is an urgent, unmet, clinical need. Animal models of MS, such as experimental autoimmune encephalomyelitis (EAE), provide valuable tools to examine the mechanisms contributing to disease and may be important for developing...

We report the restoration of euglycaemia in chemically induced diabetic C57BL/6 mice and spontaneously diabetic Non Obese Diabetic (NOD) mice by intravenous systemic administration of a single-stranded adeno-associated virus (ssAAV2/8) codon optimised (co) vector encoding furin cleavable human proinsulin under a liver-specific promoter. There were...

Parasitic helminths and their isolated secreted products show promise as novel treatments for allergic and autoimmune conditions in humans. Foremost amongst the secreted products is ES-62, a glycoprotein derived from Acanthocheilonema viteae, a filarial nematode parasite of gerbils, which is anti-inflammatory by virtue of covalently-attached phosph...

We present a novel and readily accessible method facilitating cellular time-resolved imaging of transplanted pancreatic islets. Grafting of islets to the mouse ear pinna allows non-invasive, in vivo longitudinal imaging of events in the islets and enables improved acquisition of experimental data and use of fewer experimental animals than is possib...

Kaede-C57BL/6 fluorescent islets transplanted into the pinna of the ear of a wt C57BL/6 mouse. Image capture starts at the bottom of the Z stack (middle of the ear) and moves to the top (up through the dermis to the epidermis). The movie shows the Kaede transplanted islets in green, vasculature in red (Qdot tracer given i.v. prior to imaging), and...

24-min capture of pinna with NOD scid islets transplanted into a NOD-hCD2-GFP recipient. T cells are green (GFP), blood vessels are white (Q-dots), and collagen is blue (secondary harmonic signal), while dead cells become red through uptake of Sytox dye.

15-min capture of pinna with NOD scid islets transplanted into a NOD-hCD2-GFP recipient (depicted in Figure S1 in Supplementary Material) before injection of antibody. T cells are green (GFP), blood vessels are red (Q-dots), and collagen is blue (secondary harmonic signal).

13-min capture of pinna with NOD scid islets transplanted into a NOD-Foxp3-GFP recipient. Foxp3+ T cells are green (GFP), blood vessels are red (Q-dots), and collagen is blue (secondary harmonic signal).

32-min capture of pinna with NOD scid islets transplanted into a NOD-hCD2-GFP recipient after injection of agly anti-CD3 antibody. T cells are green (GFP), blood vessels are red (Q-dots), and collagen is blue (secondary harmonic signal).

16-min capture of pinna with NOD scid islets transplanted into a NOD-hCD2-GFP recipient. T cells are green (GFP), blood vessels are red (Q-dots), and collagen is blue (secondary harmonic signal).

15-min capture of pinna with NOD scid islets transplanted into a NOD-hCD2-GFP recipient (depicted in Figure S1 in Supplementary Material) after injection of isotype control antibody. T cells are green (GFP), blood vessels are red (Q-dots), and collagen is blue (secondary harmonic signal).

29-min capture of pinna with NOD scid islets transplanted into a NOD-hCD2-GFP recipient (depicted in Figure S1 in Supplementary Material) after injection of agly anti-CD3 antibody. T cells are green (GFP), blood vessels are red (Q-dots), and collagen is blue (secondary harmonic signal).

29-min capture of pinna with NOD scid islets transplanted into a NOD-hCD2-GFP recipient before injection of agly anti-CD3 antibody. T cells are green (GFP), blood vessels are red (Q-dots), and collagen is blue (secondary harmonic signal).

59-min capture of a pancreatic islet with immune cell infiltrate in a NOD-hCD2-GFP mouse before injection of antibody. T cells are green (GFP), blood vessels are red (Q-dots), and collagen is blue (secondary harmonic signal).

59-min capture of a pancreatic islet with immune cell infiltrate in a NOD-hCD2-GFP mouse after injection of agly anti-CD3 antibody. T cells are green (GFP), blood vessels are red (Q-dots), and collagen is blue (secondary harmonic signal).

With the increase in incidence of type 1 diabetes (T1DM), particularly in Westernised societies, there is an urgent need to understand the early molecular and metabolic alterations that accompany the autoimmune disease. This is not least because in murine models early intervention can prevent the development of overt disease. In this study we have...

Metabolism is of central importance to T cell survival and differentiation. It is well known that T cells cannot function in the absence of glucose, but it is less clear how they respond to excessive levels of glucose. In this study we investigated how increasing levels of glucose affect T cell-mediated immune responses. We examined the effects of...

Metabolism is of central importance to T cell survival and differentiation. It is well known that T cells cannot function in the absence of glucose, but it is less clear how they respond to excessive levels of glucose. In this study we investigated how increasing levels of glucose affect T cell-mediated immune responses. We examined the effects of...

Microbes, including viruses, influence type 1 diabetes (T1D) development, but many such influences remain undefined. Previous work on underlying immune mechanisms has focussed on cytokines and T cells. Here, we compared two nonobese diabetic (NOD) mouse colonies, NODlow and NODhigh, differing markedly in their cumulative T1D incidence (22% vs. 90%...

Further experiments on the possibility of a diabetogenic effect of MNV. Contains brief introduction, methods, results and discussion of experiments showing that MNV infection of NODlow mice fails to raise their low T1D incidence. (PDF)

Increased BAFF levels in the serum of NODhigh mice. BAFF concentrations in the sera of NODlow (closed circles) and NODhigh (open circles) assessed by ELISA. Sera from individual mice are shown, and means were compared by Student’s t test. (PDF)

Similar IL-10 secretion by LPS-stimulated splenic B cells from NODlow and NODhigh mice. Splenocytes were obtained from six-week-old female mice from both colonies and used for immunomagnetic (MACS) enrichment of B cells to high purity (> 97% CD19+B220+; (A)). IL-10 release following stimulation with LPS (10 μg/ml) was quantified by ELISA (B). Data...

Abundance of selected intestinal bacteria in individual mice assessed by high-throughput sequencing. Counts for specific bacterial 16S rRNA gene sequences were normalized by sequencing depth, showing significant differences in any pairwise comparisons of intestinal bacterial composition between 5-week-old female NODhigh mice (green open squares), N...

Three-week-old NODlow female weanlings acquire H. hepaticus following oral gavage. Gel electrophoresis showing PCR amplification of H. hepaticus genomic DNA isolated from feces of NODlow mice orally gavaged at weaning (3 weeks old) with a fecal suspension obtained from 12-week-old pre-diabetic NODhigh females. Lane 1: DNA marker; lane 2: negative c...

Similar T-cell frequencies and absolute counts in splenocytes from NODlow and NODhigh mice. Splenocytes were obtained from six-week-old female mice from both colonies (n = 8 each), counted, stained for CD3, and analysed by flow cytometry. Percentages (left) and absolute counts (right) of CD3+ T cells are shown for individual NODlow (black circles)...

Figure S1. Properties of agly‐anti‐CD3. Figure S2. Injection of agly‐anti‐CD3 reverses diabetes in non‐obese diabetic mice in a dose‐dependent manner. Figure S3. Agly‐anti‐CD3 treatment increases the percentage of Foxp3+ regulatory T (T reg) cells through selectively sparing this population. Figure S4. Treatment with agly‐anti‐CD3 does not cause...

G1 phase cell cycle proteins, such as cyclin-dependent kinase 6 (Cdk6) and its activating partners, the D-type cyclins, are important regulators of T-cell development and function. An F-box protein, called F-box only protein 7 (Fbxo7), acts as a cell cycle regulator by enhancing cyclin D-Cdk6 complex formation and stabilising levels of p27, a cycli...

T cells play a key role in the pathogenesis of type 1 diabetes, and targeting the CD3 component of the T-cell receptor complex provides one therapeutic approach. Anti-CD3 treatment can reverse overt disease in spontaneously diabetic non-obese diabetic mice, an effect proposed to, at least in part, be caused by a selective depletion of pathogenic ce...

T cells play a key role in the pathogenesis of type 1 diabetes, and targeting the CD3 component of the TCR complex provides one therapeutic approach. Anti-CD3 treatment can reverse overt disease in spontaneously diabetic non-obese diabetic mice, an effect proposed to, at least in part, be caused by a selective depletion of pathogenic cells. We have...

G₁ phase cell cycle proteins, such as cyclin-dependent kinase 6 (Cdk6) and its activating partners, the D-type cyclins, are important regulators of T-cell development and function. An F-box protein, called F-box only protein 7 (Fbxo7), acts as a cell cycle regulator by enhancing cyclin D-Cdk6 complex formation and stabilising levels of p27, a cycli...

Type 1 diabetes is caused by the destruction of insulin producing beta cells by the immune system. The p110δ isoform of PI3K is expressed primarily in cells of haematopoietic origin and the catalytic activity of p110δ is important for the activation of these cells. Targeting of this pathway offers an opportunity to reduce immune cell activity witho...

CTLA-4 is a critical 'checkpoint' regulator in autoimmunity. Variation in CTLA-4 isoform expression has been linked to type 1 diabetes development in human and NOD mouse studies. In the NOD mouse, a causative link between increased expression of the minor isoform, ligand-independent CTLA-4, and a reduction in diabetes has become widely accepted. Al...

CTLA-4 is a critical ‘checkpoint’ regulator in autoimmunity. Variation in CTLA-4 isoform expression has been linked to type 1 diabetes development in human and NOD mouse studies. In the NOD mouse, a causative link between increased expression of the minor isoform, ligand-independent CTLA-4, and a reduction in diabetes has become widely accepted. Al...

The T2 ribonuclease omega-1 is a powerful Th2-inducing factor secreted by the eggs of the blood fluke Schistosoma mansoni. Omega-1 can modulate pattern recognition receptor -induced inflammatory signatures and alter antigen presentation by dendritic cells. Recent findings have suggested that component(s) contained in or secreted by S. mansoni eggs...

There are three prerequisites for development of the autoimmune disease type 1 diabetes (T1D). First, β cell-reactive T cells need to be activated; second, the response needs to be proinflammatory; and finally, immune regulation of autoreactive responses must fail. Here, we describe our current understanding of the cell types and immune mechanisms...

The glycoprotein CD52 is an important target for clinical antibodies, but its receptor and function have remained a mystery. However, it now seems that CD52 may be released in soluble form by a subpopulation of human T cells and may thereby exert an as-yet-unrecognized regulatory function via the inhibitory molecule Siglec-10.

The H2-A(g7) (A(g7)) MHC class II (MHCII) allele is required for type 1 diabetes (T1D) in NOD mice. A(g7) not only has a unique peptide-binding profile, it was reported to exhibit biochemical defects, including accelerated protein turnover. Such defects were proposed to impair Ag presentation and, thus, self-tolerance. Here, we report measurements...

The butyrophilin-related protein Btn2a2 was upregulated on murine APC including CD19(+) B cells, CD11b(+)F4/80(+) peritoneal macrophages, and CD11c(+) bone marrow-derived dendritic cells after activation with LPS or Pam3CysK4, suggesting a role in modulation of T lymphocytes. Consistent with this, binding of mouse Btn2a2-Fc to CD3(+) primary mouse...

Bacterial-induced intestinal inflammation is crucially dependent on interleukin (IL)-23 and is associated with CD4+ T helper type 1 (Th1) and Th17 responses. However, the relative contributions of these subsets during the induction and resolution of colitis in T-cell-sufficient hosts remain unknown. We report that Helicobacter hepaticus-induced typ...

Type 1 diabetes (T1D) remains an important health problem, particularly in western countries, where the incidence has been increasing in younger children. In 1986, Eisenbarth described T1D as a chronic autoimmune disease. Work over the past three-and-a-half decades has identified many of the genetic, immunological and environmental factors that are...

The spontaneous destruction of insulin producing pancreatic beta cells in non-obese diabetic (NOD) mice provides a valuable model of type 1 diabetes. As in humans, disease susceptibility is controlled by the classical MHC class II genes that guide CD4(+) T cell responses to self and foreign antigens. It has long been suspected that the dedicated cl...

Type 1 diabetes is increasing dramatically in incidence in the developed world. While there may be several reasons for this, improved sanitation and public health measures have altered our interactions with certain infectious agents such as helminths. There is increasing interest in the use of helminths or their products to alleviate inflammatory o...

Type 1 diabetes (T1D) is an autoimmune disease where the immune system selectively targets the pancreatic insulin-producing beta cell. This disease is increasing in incidence faster than can be accounted for by genetic change thus highlighting the importance of environmental modifiers. The environmental modifiers of disease onset can vary from agen...

Parasitic worms have evolved strategies to manipulate the host immune system, some of which may lead to a reduction in inflammation. Characterisation of the ways in which these organisms mediate an anti-inflammatory response and identification of parasite-derived molecules involved in immune modulation paves the way to novel therapeutic approaches...

Type one diabetes (T1D) is a complex T cell-mediated autoimmune disease, the defining feature of which is the destruction of the insulin-secreting beta- (β)- cell. Both genetic and environmental factors combine to precipitate disease, and the outcome of the pathological process is dependent on multiple inter-related factors. In this review, the mec...

The nonobese diabetic (NOD) mouse has provided an important animal model for studying the mechanism and genetics of type 1 diabetes over the past 30 years. Arguably, the bio-breeding (BB) rat model may be an even closer phenotypic mimic of the typical human disease. A large number of distinct genetic traits which influence diabetes development have...

Increasingly, evidence suggests that there is a strong environmental component to the development of the autoimmune disease type 1 diabetes. Our previous data showed that NOD mice are protected from developing diabetes after infection with Salmonella typhimurium and there is some evidence that changes within the DC compartment play a crucial role i...

Pathogenesis of type 1 diabetes (T1D) is mediated by effector T cells and CD4 Th1 and Th17T cells have important roles in this process. While effector function of Th1 cells is well established, because of their inherent plasticity Th17 cells have been more controversial. Th17 cells contribute to pathogenicity, but several studies indicate that Th17...

Immunization with Schistosoma mansoni soluble antigen preparations protects non-obese diabetic (NOD) mice against the development of type 1 diabetes. These preparations have long been known to induce Th2 responses in vitro and in vivo. Recently, two separate groups have reported that ω-1, a well-characterized glycoprotein in S. mansoni soluble egg...

Autoimmune and inflammatory diseases, including type 1 diabetes, multiple sclerosis, inflammatory bowel disease, and rheumatoid arthritis, constitute an important and growing public health burden. However, in many cases our understanding of disease biology is limited and available therapies vary greatly in their efficacy and safety. Animal models o...

Some infectious diseases have been shown to halt the onset of autoimmune disease in animal models and have been suggested to also influence autoimmune pathology in humans. The isolation and study of small molecules and proteins from the infectious agents responsible for the protective effect will enable a mechanistic understanding of how these comp...

While some infectious agents have been linked to onset of autoimmune disease there is also other evidence suggesting that certain infectious agents might inhibit autoimmune pathology. This review focuses on the ways in which infectious agents or their products might intervene in an autoimmune response.

Plasticity within Th cell populations may play a role in enabling site-specific immune responses to infections while limiting tissue destruction. Epigenetic processes are fundamental to such plasticity; however, to date, most investigations have focused on in vitro-generated T cells. In this study, we have examined the molecular mechanisms underpin...

Zymosan is a complex fungal component shown to be capable of both promoting and suppressing the development of autoimmune disorders in mice. In this study, we show that a single injection of zymosan just prior to diabetes onset can significantly delay the progression of disease in NOD mice. Zymosan treatment of NOD mice induced the production of bi...

The immunomodulatory effect of Schistosoma mansoni antigens has often been attributed to interaction with PRR expressed on APC. Our previous work has shown that S. mansoni-soluble egg antigen (SEA) can induce, together with a Th2 response, TGF-β-dependent Foxp3 expression in naïve CD4(+) T cells from NOD mice. We found that SEA can directly upregul...

The development of type 1 diabetes involves a complex interaction between pancreatic beta-cells and cells of both the innate and adaptive immune systems. Analyses of the interactions between natural killer (NK) cells, NKT cells, different dendritic cell populations and T cells have highlighted how these different cell populations can influence the...

In this issue of Immunity, Tsai et al. (2010) demonstrate that low-avidity autoantigen-specific regulatory CD8(+) T cells can reverse ongoing autoimmune disease and provide insight into the mechanism by which this is achieved.

We have shown that Schistosoma mansoni egg soluble antigen (SEA) prevents diabetes in the nonobese diabetic (NOD) mouse inducing functional changes in antigen presenting cells (APCs) and expanding T helper (Th) 2 and regulatory T cell (Treg) responses. A Th2 response to S. mansoni infection or its antigens is key to both the establishment of tolera...

The incidence of some autoimmune diseases is increasing dramatically in the developed world. For example, the incidence of the autoimmune disease, Type 1 diabetes (T1D), is increasing in the UK at a rate of 4% per annum; faster than can be accounted for by genetic change. In the case of T1D, as for many autoimmune diseases, the development of the d...

Type 1 diabetes (T1D) is an autoimmune disease where insulin producing pancreatic beta cells are progressively destroyed. In the absence of a cure, exogenous insulin is given to maintain glucose homeostasis. Tolerogenic strategies to halt destruction and facilitate recovery of beta cells are being explored. This disease is under polygenic control;...

Nonobese diabetic (NOD) mice provide an excellent model of type 1 diabetes. The genetic contribution to this disease is complex, with more than 20 loci implicated in diabetes onset. One of the challenges for researchers using the NOD mouse model (and, indeed, other models of spontaneous autoimmune disease) has been the high density of sequence vari...

Type 1 diabetes development in NOD mice appears to require both CD4(+) and CD8(+) T cells. However, there are some situations where it has been suggested that either CD4(+) or CD8(+) T cells are able to mediate diabetes in the absence of the other population. In the case of transgenic mice, this may reflect the numbers of antigen-specific T cells a...

It has often been suggested that autoimmune diseases are initiated by certain infectious agents that mimic self-antigens or polyclonally activated autoreactive lymphocytes. An alternative, and not necessarily mutually exclusive, hypothesis that some infections might inhibit the onset of some autoimmune conditions has more recently been explored. In...