53 results found
Hayes MD, Ward S, Crawford G, et al., 2019, Natural IgE promotes epithelial hyperplasia and inflammation-driven tumour growth
<jats:title>Abstract</jats:title><jats:p>IgE is the least abundant circulating antibody class but is constitutively present in healthy tissues bound to resident cells via its high-affinity receptor, FcεRI. The physiological role of endogenous IgE is unclear but it is suggested to provide host protection against a variety of noxious environmental substances and parasitic infections at epithelial barrier surfaces. Here we show that skin inflammation enhances levels of IgE with natural specificities and with a similar repertoire, VDJ rearrangements and CDRH3 characteristics as in healthy tissue. IgE-bearing basophils are recruited to inflamed skin via CXCL12 and TSLP/IL-3-dependent upregulation of CXCR4. In the inflamed skin, IgE/FcεRI-signalling in basophils promotes epithelial cell growth and differentiation, partly through histamine engagement of H<jats:sub>1</jats:sub>R and H<jats:sub>4</jats:sub>R. Furthermore, this natural IgE response strongly drives tumour outgrowth of epithelial cells harbouring oncogenic mutation. These findings indicate that natural IgE support skin barrier defences however during chronic tissue inflammation this may be subverted to promote tumour growth.</jats:p>
Ferrer IR, West HC, Henderson S, et al., 2019, A wave of monocytes is recruited to replenish the long-term Langerhans cell network after immune injury, Science Immunology, Vol: 4, Pages: 1-14, ISSN: 2470-9468
A dense population of embryo-derived Langerhans cells (eLCs) is maintained within the sealed epidermis without contribution from circulating cells. When this network is perturbed by transient exposure to ultraviolet light, short-term LCs are temporarily reconstituted from an initial wave of monocytes but thought to be superseded by more permanent repopulation with undefined LC precursors. However, the extent to which this process is relevant to immunopathological processes that damage LC population integrity is not known. Using a model of allogeneic hematopoietic stem cell transplantation, where alloreactive T cells directly target eLCs, we have asked whether and how the original LC network is ultimately restored. We find that donor monocytes, but not dendritic cells, are the precursors of long-term LCs in this context. Destruction of eLCs leads to recruitment of a wave of monocytes that engraft in the epidermis and undergo a sequential pathway of differentiation via transcriptionally distinct EpCAM+ precursors. Monocyte-derived LCs acquire the capacity of self-renewal, and proliferation in the epidermis matched that of steady-state eLCs. However, we identified a bottleneck in the differentiation and survival of epidermal monocytes, which, together with the slow rate of renewal of mature LCs, limits repair of the network. Furthermore, replenishment of the LC network leads to constitutive entry of cells into the epidermal compartment. Thus, immune injury triggers functional adaptation of mechanisms used to maintain tissue-resident macrophages at other sites, but this process is highly inefficient in the skin.
Crawford G, Hayes MD, Seoane RC, et al., 2018, Epithelial damage and tissue gamma delta T cells promote a unique tumor-protective IgE response, NATURE IMMUNOLOGY, Vol: 19, Pages: 859-870, ISSN: 1529-2908
IgE is an ancient and conserved immunoglobulin isotype with potent immunological function. Nevertheless, the regulation of IgE responses remains an enigma, and evidence of a role for IgE in host defense is limited. Here we report that topical exposure to a common environmental DNA-damaging xenobiotic initiated stress surveillance by γδTCR+ intraepithelial lymphocytes that resulted in class switching to IgE in B cells and the accumulation of autoreactive IgE. High-throughput antibody sequencing revealed that γδ T cells shaped the IgE repertoire by supporting specific variable-diversity-joining (VDJ) rearrangements with unique characteristics of the complementarity-determining region CDRH3. This endogenous IgE response, via the IgE receptor FcεRI, provided protection against epithelial carcinogenesis, and expression of the gene encoding FcεRI in human squamous-cell carcinoma correlated with good disease prognosis. These data indicate a joint role for immunosurveillance by T cells and by B cells in epithelial tissues and suggest that IgE is part of the host defense against epithelial damage and tumor development.
Ling GS, Crawford G, Buang N, et al., 2018, C1q restrains autoimmunity and viral infection by regulating CD8+ T cell metabolism, Science, Vol: 360, Pages: 558-563, ISSN: 0036-8075
Deficiency of C1q, the initiator of the complement classical pathway, is associated with the development of systemic lupus erythematosus (SLE). Explaining this association in terms of abnormalities in the classical pathway alone remains problematic because C3 deficiency does not predispose to SLE. Here, using a mouse model of SLE, we demonstrate that C1q, but not C3, restrains the response to self-antigens by modulating the mitochondrial metabolism of CD8+ T cells, which can themselves propagate autoimmunity. C1q deficiency also triggers an exuberant effector CD8+ T cell response to chronic viral infection leading to lethal immunopathology. These data establish a link between C1q and CD8+ T cell metabolism and may explain how C1q protects against lupus, with implications for the role of viral infections in the perpetuation of autoimmunity.
Silva-Santos B, Strid J, 2018, Working in "NK Mode": Natural Killer Group 2 Member D and Natural Cytotoxicity Receptors in Stress-Surveillance by gamma delta T Cells, FRONTIERS IN IMMUNOLOGY, Vol: 9, ISSN: 1664-3224
Natural killer cell receptors (NKRs) are germline-encoded transmembrane proteins that regulate the activation and homeostasis of NK cells as well as other lymphocytes. For γδ T cells, NKRs play critical roles in discriminating stressed (transformed or infected) cells from their healthy counterparts, as proposed in the “lymphoid stress-surveillance” theory. Whereas the main physiologic role is seemingly fulfilled by natural killer group 2 member D, constitutively expressed by γδ T cells, enhancement of their therapeutic potential may rely on natural cytotoxicity receptors (NCRs), like NKp30 or NKp44, that can be induced selectively on human Vδ1+ T cells. Here, we review the contributions of NCRs, NKG2D, and their multiple ligands, to γδ T cell biology in mouse and human.
Duggan SP, Garry C, Behan FM, et al., 2018, siRNA library screening identifies a druggable immune-signature driving esophageal adenocarcinoma cell growth, Cellular and Molecular Gastroenterology and Hepatology, Vol: 5, Pages: 569-590, ISSN: 2352-345X
Background & Aims: Effective therapeutic approaches are urgently required to tackle the alarmingly poor survival outcomes in esophageal adenocarcinoma (EAC) patients. EAC originates from within the intestinal-type metaplasia, Barrett’s esophagus, a condition arising on a background of gastroesophageal reflux disease and associated inflammation.Methods:This study used a druggable genome small interfering RNA (siRNA) screening library of 6022 siRNAs in conjunction with bioinformatics platforms, genomic studies of EAC tissues, somatic variation data of EAC from The Cancer Genome Atlas data of EAC, and pathologic and functional studies to define novel EAC-associated, and targetable, immune factors.Results:By using a druggable genome library we defined genes that sustain EAC cell growth, which included an unexpected immunologic signature. Integrating Cancer Genome Atlas data with druggable siRNA targets showed a striking concordance and an EAC-specific gene amplification event associated with 7 druggable targets co-encoded at Chr6p21.1. Over-representation of immune pathway–associated genes supporting EAC cell growth included leukemia inhibitory factor, complement component 1, q subcomponent A chain (C1QA), and triggering receptor expressed on myeloid cells 2 (TREM2), which were validated further as targets sharing downstream signaling pathways through genomic and pathologic studies. Finally, targeting the triggering receptor expressed on myeloid cells 2-, C1q-, and leukemia inhibitory factor–activated signaling pathways (TYROBP–spleen tyrosine kinase and JAK-STAT3) with spleen tyrosine kinase and Janus-activated kinase inhibitor fostamatinib R788 triggered EAC cell death, growth arrest, and reduced tumor burden in NOD scid gamma mice.Conclusions:These data highlight a subset of genes co-identified through siRNA targeting and genomic studies of expression and somatic variation, specifically highlighting the contribution that immune-related fac
Gaya M, Barral P, Burbage M, et al., 2017, Initiation of Antiviral B Cell Immunity Relies on Innate Signals from Spatially Positioned NKT Cells., Cell, Vol: 172, Pages: 517-533.e20, ISSN: 0092-8674
B cells constitute an essential line of defense from pathogenic infections through the generation of class-switched antibody-secreting cells (ASCs) in germinal centers. Although this process is known to be regulated by follicular helper T (TfH) cells, the mechanism by which B cells initially seed germinal center reactions remains elusive. We found that NKT cells, a population of innate-like T lymphocytes, are critical for the induction of B cell immunity upon viral infection. The positioning of NKT cells at the interfollicular areas of lymph nodes facilitates both their direct priming by resident macrophages and the localized delivery of innate signals to antigen-experienced B cells. Indeed, NKT cells secrete an early wave of IL-4 and constitute up to 70% of the total IL-4-producing cells during the initial stages of infection. Importantly, the requirement of this innate immunity arm appears to be evolutionarily conserved because early NKT and IL-4 gene signatures also positively correlate with the levels of neutralizing antibodies in Zika-virus-infected macaques. In conclusion, our data support a model wherein a pre-TfH wave of IL-4 secreted by interfollicular NKT cells triggers the seeding of germinal center cells and serves as an innate link between viral infection and B cell immunity.
Silva-Santos B, Strid J, 2017, γδ T cells get adaptive., Nature Immunology, Vol: 18, Pages: 370-372, ISSN: 1529-2916
Throughout ontogeny, the γδ TCR repertoire in human blood becomes less diverse and more focused, yet is private in nature, and specific adult γδ T cell subsets undergo substantial clonal expansion after challenge with cytomegalovirus.
Giacomassi C, Buang N, Ling GS, et al., 2016, Complement C3 exacerbates imiquimod-induced skin inflammation and psoriasiform dermatitis, Journal of Investigative Dermatology, Vol: 137, Pages: 760-763, ISSN: 1523-1747
The complement system is pivotal in protection against pathogens, but also plays important roles in bridging innate and adaptive immune responses (Scott and Botto, 2015) and in modulating local and systemic inflammation (Markiewski and Lambris, 2007). Activation of complement occurs through three different pathways (classical, alternative and lectin), converges at C3 cleavage and culminates in the formation of the membrane attack complex. The anaphylotoxic fragments, C3a and C5a, generated during the proteolytic cascade, recruit immune cells that can promote the removal of debris and pathogens, but can also cause tissue damage (Markiewski and Lambris, 2007).
Giacomassi C, Ling GS, Buang N, et al., 2016, Complement C3 Exacerbates TLR7-Mediated Skin Inflammation but Not Systemic Autoimmunity, Annual European Congress of Rheumatology (EULAR), Publisher: BMJ Publishing Group, Pages: 280-281, ISSN: 0003-4967
Hayes MD, Crawford G, Castro-Seoane R, et al., 2016, IgE strongly promotes inflammation-driven skin carcinogenesis, Annual Meeting of the European-Society-for-Dermatological-Research (ESDR), Publisher: Elsevier, Pages: S211-S211, ISSN: 0022-202X
Dalessandri T, Crawford G, Hayes M, et al., 2016, IL-13 from intraepithelial lymphocytes regulates tissue homeostasis and protects against carcinogenesis in the skin, Nature Communications, Vol: 7, ISSN: 2041-1723
The skin is under constant renewal and exposure to environmental challenges. Howhomeostasis is maintained alongside protective mechanisms against damage is unclear.Among the basal epithelial cells (ECs) is a population of resident intraepithelial lymphocytes(IELs) that provide host-protective immune surveillance. Here we show that IELscross-communicate with ECs via the production of IL-13. Skin ECs are activated by IEL-derivedIL-13, enabling a canonical EC stress response. In the absence of IL-13, or canonical IEL, theskin has decreased ability to repair its barrier and increased susceptibility to cutaneouscarcinogenesis. IL-13 controls the rate of EC movement through the epidermis, which mightexplain the importance of IL-13 for epidermal integrity and its suppressive effect on skincarcinogenesis. These findings show that IL-13 acts as a molecular bridge between IELs andECs, and reveal a critical host-defensive role for type-2 immunity in regulating EC tissuehomeostasis and carcinogenesis.
Strid J, McLean WH, Irvine AD, 2016, Too Much, Too Little or Just Enough: A Goldilocks Effect for IL-13 and Skin Barrier Regulation?, Journal of Investigative Dermatology, Vol: 136, Pages: 561-564, ISSN: 1523-1747
The mechanistic relationship between IL-4/IL-13 and skin barrier function has been of interest since the filaggrin discovery and the subsequent in vitro demonstration that IL-4 and IL-13 downregulate filaggrin expression in cultured keratinocytes. Hönzke and colleagues explore these interactions further. The effects of IL-4/ll-13 may be context dependent, with differing roles in homeostasis and in disease.
Strid J, McLean WHI, Irvine AD, 2016, Too Much, Too Little or Just Enough: A Goldilocks Effect for IL-13 and Skin Barrier Regulation?, JOURNAL OF INVESTIGATIVE DERMATOLOGY, Vol: 136, Pages: 561-564, ISSN: 0022-202X
Strid J, 2015, Skin perturbations, stress surveillance and atopy, 51st Congress of the European-Societies-of-Toxicology (EUROTOX), Publisher: Elsevier, Pages: S42-S42, ISSN: 0378-4274
Crawford GH, Seoane RC, Strid J, 2014, Lymphoid stress-surveillance promotes protective IgE responses in the skin, IMMUNOLOGY, Vol: 143, Pages: 78-78, ISSN: 0019-2805
Dalessandri T, Seoane RC, Strid J, 2014, IL-13 has prominent effects on skin epithelia and significantly protects against cutaneous carcinogenesis, IMMUNOLOGY, Vol: 143, Pages: 109-109, ISSN: 0019-2805
Hayes M, Strid J, 2014, IgE effector cells accumulate in inflamed skin and IgE strongly promotes inflammation-driven skin carcinogenesis, IMMUNOLOGY, Vol: 143, Pages: 169-169, ISSN: 0019-2805
Seoane RC, Crawford G, Strid J, 2014, The scope of skin-induced lymphoid stress-surveillance, IMMUNOLOGY, Vol: 143, Pages: 171-171, ISSN: 0019-2805
Giacomassi C, Ling GS, Strid J, et al., 2014, Complement C3 exacerbates skin inflammation in a murine model of imiquimod-induced psoriasis, IMMUNOLOGY, Vol: 143, Pages: 120-120, ISSN: 0019-2805
Strid KJ, Dalessandri T, 2014, Beneficial autoimmunity at body surfaces – immune surveillance and rapid type 2 immunity regulate tissue homeostasis and cancer, Frontiers in Immunology, Vol: 5, ISSN: 1664-3224
Dalessandri T, Strid J, 2013, Epithelial stress and DNA- damage induce a rapid Type 2 immune response with high levels of IgE, Annual Congress of the British-Society-for-Immunology, Publisher: WILEY-BLACKWELL, Pages: 31-31, ISSN: 0019-2805
Strid J, Sobolev O, Filler R, et al., 2012, Integration of pathways initiating early tumour-surveillance with atopic IgE responses, European Congress of Immunology, Publisher: WILEY-BLACKWELL, Pages: 169-169, ISSN: 0019-2805
Strid J, 2012, The intraepithelial T cell response to NKG2D-ligands links lymphoid stress surveillance to atopy (December, pg 1293, 2011), SCIENCE, Vol: 335, Pages: 538-538, ISSN: 0036-8075
Strid J, Sobolev O, Zafirova B, et al., 2011, The intraepithelial T cell response to NKG2D-ligands links lymphoid stress surveillance to atopy, Science, Vol: 334, Pages: 1293-1297
Hunt B, Woolf R, Strid J, et al., 2011, Defining novel afferent signals in the lymphoid stress surveillance response, Annual Congress of the British-Society-for-Immunology, Publisher: WILEY-BLACKWELL, Pages: 132-132, ISSN: 0019-2805
Hayday A, Turchinovich G, Michel M-L, et al., 2010, The construction and operation of lymphoid stress-surveillance, Annual Congress of the British-Society-for-Immunology, Publisher: WILEY-BLACKWELL PUBLISHING, INC, Pages: 27-27, ISSN: 0019-2805
Sobolev O, Strid J, Hayday A, 2010, Local and systemic consequences of lymphoid stress-surveillance by gd T cells, Annual Congress of the British-Society-for-Immunology, Publisher: WILEY-BLACKWELL PUBLISHING, INC, Pages: 151-151, ISSN: 0019-2805
Thompson RL, Miles LM, Lunn J, et al., 2010, Peanut sensitisation and allergy: influence of early life exposure to peanuts, BRITISH JOURNAL OF NUTRITION, Vol: 103, Pages: 1278-1286, ISSN: 0007-1145
Thompson RL, Miles LM, Lunn J, et al., 2010, The impact of early-life exposure to food allergens on the subsequent development of sensitisation and allergy to foods, PROCEEDINGS OF THE NUTRITION SOCIETY, Vol: 69, Pages: E118-E118, ISSN: 0029-6651
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.