ORCID Profile
0000-0002-8401-7293
Current Organisations
Trinity College Dublin
,
University of Dublin Trinity College School of Medicine
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Publisher: Elsevier BV
Date: 05-2010
DOI: 10.1016/J.JACI.2010.01.018
Abstract: Parasitic helminth infections of humans have been shown to suppress the immune response to allergens. Experimentally, infection of mice with the helminth Schistosoma mansoni prevents allergic airway inflammation and anaphylaxis via IL-10 and B cells. To identify and characterize the specific helminth-induced regulatory B-cell subpopulation and determine the mechanism by which these regulatory B cells suppress allergic airway inflammation. IL-10-producing B cells from the spleens of helminth-infected mice were phenotyped, isolated, and transferred to ovalbumin-sensitized mice, and their ability to modulate allergic airway inflammation was analyzed. S mansoni infection induced IL-10-producing CD1d(high) regulatory B cells that could prevent ovalbumin-induced allergic airway inflammation following passive transfer to ovalbumin-sensitized recipients. The capacity of regulatory B cells to suppress allergic airway inflammation was dependent on the expression of CD1d, and they functioned via an IL-10-mediated mechanism. Regulatory B cells induced pulmonary infiltration of CD4(+)CD25(+) forkhead box protein 3(+) regulatory T cells, independent of TGF-beta, thereby suppressing allergic airway inflammation. Regulatory B cells that were generated ex vivo also suppressed the development of allergic airway inflammation. Furthermore, the transfer of regulatory B cells reversed established airway inflammation in ovalbumin-sensitized mice. We have generated in vivo and ex vivo a regulatory B cell that can prevent or reverse allergen-induced airway inflammation via regulatory T cells.
Publisher: Springer Science and Business Media LLC
Date: 20-07-2023
Publisher: Oxford University Press (OUP)
Date: 08-12-2004
DOI: 10.1093/HMG/DDI030
Abstract: Netherton syndrome is an autosomal recessive multisystemic disorder characterized by congenital ichthyosiform erythroderma, hair shaft defects and atopy, caused by mutations within the human SPINK5 gene. To investigate the development of this disease, we have cloned mouse spink5 and created mice with a mutated premature stop codon at amino acid R820X, to produce an allele that closely mimics a point mutation (E827X) in human SPINK5. Newborn spink5(R820X/R820X) mice develop a lethal, severe ichthyosis with a loss of skin barrier function and dehydration, resulting in death within a few hours of birth, similar to that observed in patients with severe Netherton syndrome. Epidermal barrier function is compromised because of the stratum corneum becoming spontaneously detached in the newborn mice, and this is probably compounded by the reduced mechanical strength detected in the cornified envelopes. Biochemical analysis of skin from newborn wild-type and spink5(R820X/R820X) mice revealed a substantial increase in the proteolytic processing of profilaggrin into its constituent filaggrin monomers. Filaggrin functions to organize keratin filaments into highly ordered macrofibrils that crisscross the cornified cells of the stratum corneum imparting structural integrity, and defects in filaggrin processing occur in a number of forms of congenital ichthyosis. These data suggest that in the absence of the serine protease inhibitor spink5, there is an abnormal increase in the processing of profilaggrin, resulting in an overabundance of filaggrin monomers, and that this may play a direct role in the observed deficit in the adhesion of the stratum corneum and the severely compromised epidermal barrier function.
Publisher: The American Association of Immunologists
Date: 15-04-2011
Abstract: Parasitic-infection studies on rhesus macaque monkeys have shown juvenile animals to be more susceptible to infection than adults, but the immunological mechanism for this is not known. In this study, we investigated the age-dependent genesis of helminth-induced type 2 immune responses using adult (6–8-wk-old) and juvenile (21–28-d-old) mice. Following infection with the parasitic nematode Nippostrongylus brasiliensis, juvenile mice had increased susceptibility to infection relative to adult mice. Juvenile mice developed a delayed type 2 immune response with decreased Th2 cytokine production, IgE Ab responses, mouse mast cell protease 1 levels, and intestinal goblet cell induction. This innate immune defect in juvenile mice was independent of TLR signaling, dendritic cells, or CD4+ cell function. Using IL-4–eGFP mice, it was demonstrated that the numbers of IL-4–producing basophil and eosinophils were comparable in young and adult naive mice however, following helminth infection, the early induction of these cells was impaired in juvenile mice relative to older animals. In nonhelminth models, there was an innate in vivo defect in activation of basophils, but not eosinophils, in juvenile mice compared with adult animals. The specific role for basophils in this innate defect in helminth-induced type 2 immunity was confirmed by the capacity of adoptively transferred adult-derived basophils, but not eosinophils, to restore the ability of juvenile mice to expel N. brasiliensis. The defect in juvenile mice with regard to helminth-induced innate basophil-mediated type 2 response is relevant to allergic conditions.
Publisher: Rockefeller University Press
Date: 21-11-2005
DOI: 10.1084/JEM.20050955
Abstract: The coevolution of humans and infectious agents has exerted selective pressure on the immune system to control potentially lethal infections. Correspondingly, pathogens have evolved with various strategies to modulate and circumvent the host's innate and adaptive immune response. Schistosoma species are helminth parasites with genes that have been selected to modulate the host to tolerate chronic worm infections, often for decades, without overt morbidity. The modulation of immunity by schistosomes has been shown to prevent a range of immune-mediated diseases, including allergies and autoimmunity. In idual immune-modulating schistosome molecules have, therefore, therapeutic potential as selective manipulators of the immune system to prevent unrelated diseases. Here we show that S. mansoni eggs secrete a protein into host tissues that binds certain chemokines and inhibits their interaction with host chemokine receptors and their biological activity. The purified recombinant S. mansoni chemokine binding protein (smCKBP) suppressed inflammation in several disease models. smCKBP is unrelated to host proteins and is the first described chemokine binding protein encoded by a pathogenic human parasite and may have potential as an antiinflammatory agent.
Publisher: Rockefeller University Press
Date: 10-04-2006
DOI: 10.1084/JEM.20051615
Abstract: Type 2 immunity, which involves coordinated regulation of innate and adaptive immune responses, can protect against helminth parasite infection, but may lead to allergy and asthma after inappropriate activation. We demonstrate that il25−/− mice display inefficient Nippostrongylus brasiliensis expulsion and delayed cytokine production by T helper 2 cells. We further establish a key role for interleukin (IL)-25 in regulating a novel population of IL-4–, IL-5–, IL-13–producing non–B/non–T (NBNT), c-kit+, FcεR1− cells during helminth infection. A deficit in this population in il25−/− mice correlates with inefficient N. brasiliensis expulsion. In contrast, administration of recombinant IL-25 in vivo induces the appearance of NBNT, c-kit+, FcεR1− cells and leads to rapid worm expulsion that is T and B cell independent, but type 2 cytokine dependent. We demonstrate that these IL-25–regulated cells appear rapidly in the draining lymph nodes, implicating them as a source of type 2 cytokines during initiation of worm expulsion.
Publisher: Elsevier BV
Date: 11-2013
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.CMET.2022.02.002
Abstract: The Krebs cycle-derived metabolite itaconate and its derivatives suppress the inflammatory response in pro-inflammatory "M1" macrophages. However, alternatively activated "M2" macrophages can take up itaconate. We therefore examined the effect of itaconate and 4-octyl itaconate (OI) on M2 macrophage activation. We demonstrate that itaconate and OI inhibit M2 polarization and metabolic remodeling. Examination of IL-4 signaling revealed inhibition of JAK1 and STAT6 phosphorylation by both itaconate and OI. JAK1 activation was also inhibited by OI in response to IL-13, interferon-β, and interferon-γ in macrophages and in T helper 2 (Th2) cells. Importantly, JAK1 was directly modified by itaconate derivatives at multiple residues, including cysteines 715, 816, 943, and 1130. Itaconate and OI also inhibited JAK1 kinase activity. Finally, OI treatment suppressed M2 macrophage polarization and JAK1 phosphorylation in vivo. We therefore identify itaconate and OI as JAK1 inhibitors, suggesting a new strategy to inhibit JAK1 in M2 macrophage-driven diseases.
Publisher: Public Library of Science (PLoS)
Date: 30-06-2011
Publisher: Springer Science and Business Media LLC
Date: 20-02-2015
Publisher: Elsevier BV
Date: 2008
DOI: 10.1053/J.GASTRO.2007.10.012
Abstract: Prolyl and asparaginyl hydroxylases are key oxygen-sensing enzymes that confer hypoxic sensitivity to transcriptional regulatory pathways including the hypoxia inducible factor 1 (HIF-1) and nuclear factor-kappaB (NF-kappaB). Knockout of either HIF-1 or (IKKbeta-dependent) NF-kappaB pathways in intestinal epithelial cells promotes inflammatory disease in murine models of colitis. Both HIF-1 and NF-kappaB pathways are repressed by the action of hydroxylases through the hydroxylation of key regulatory molecules. In this study we have investigated the effects of the hydroxylase inhibitor dimethyloxalylglycine (DMOG) on Caco-2 intestinal epithelial cells in vitro and in a dextran sodium sulfate-induced model of murine colitis. DMOG induces both HIF-1 and NF-kappaB activity in cultured intestinal epithelial cells, and is profoundly protective in dextran-sodium sulfate colitis in a manner that is at least in part reflected by the development of an anti-apoptotic phenotype in intestinal epithelial cells, which we propose reduces epithelial barrier dysfunction. These data show that hydroxylase inhibitors such as DMOG represent a new strategy for the treatment of inflammatory bowel disease.
Publisher: Springer Science and Business Media LLC
Date: 03-2007
DOI: 10.1038/NRI2039
Abstract: There is no immunological mechanism to adequately explain the sudden epidemic in allergies noted in the last 30 years in developed countries. The reduction in the development of allergic disorders observed in in iduals infected with parasitic helminths, however, supports a possible role for worms in suppressing allergies. Helminths regulate the immunity of the host to ensure a mutually beneficial environment for the survival of both the parasite and the host. This interplay between helminths and allergic responses raises fundamental questions in immunobiology. Harnessing current mechanistic studies for translational research into helminth infections and atopy might have potential for the identification of novel biomarkers, and even therapeutics, in allergic diseases.
Publisher: The American Association of Immunologists
Date: 30-06-2023
Abstract: The transcription factor retinoic acid–related orphan receptor α (RORα) is important in regulating several physiological functions, such as cellular development, circadian rhythm, metabolism, and immunity. In two in vivo animal models of type 2 lung inflammation, Nippostrongylus brasiliensis infection and house dust mite (HDM) sensitization, we show a role for Rora in Th2 cellular development during pulmonary inflammation. N. brasiliensis infection and HDM challenge induced an increase in frequency of Rora-expressing GATA3+CD4 T cells in the lung. Using staggerer mice, which have a ubiquitous deletion of functional RORα, we generated bone marrow chimera mice, and we observed a delayed worm expulsion and reduced frequency in the expansion of Th2 cells and innate lymphoid type 2 cells (ILC2s) in the lungs after N. brasiliensis infection. ILC2-deficient mouse (Rorafl/flIl7raCre) also had delayed worm expulsion with associated reduced frequency of Th2 cells and ILC2s in the lungs after N. brasiliensis infection. To further define the role for Rora-expressing Th2 cells, we used a CD4-specific Rora-deficient mouse (Rorafl/flCD4Cre), with significantly reduced frequency of lung Th2 cells, but not ILC2, after N. brasiliensis infection and HDM challenge. Interestingly, despite the reduction in pulmonary Th2 cells in Rorafl/flCD4Cre mice, this did not impact the expulsion of N. brasiliensis after primary and secondary infection, or the generation of lung inflammation after HDM challenge. This study demonstrates a role for RORα in Th2 cellular development during pulmonary inflammation that could be relevant to the range of inflammatory diseases in which RORα is implicated.
Publisher: Wiley
Date: 19-04-2007
Abstract: The transmembrane form of T1/ST2 (ST2) is a specific marker on murine Th2 cells that have been generated in vitro, or isolated from sites of allergic type 2 inflammation. Despite the association of ST2 with Th2 cells, to date no obligate role for ST2 in type 2 responses in vivo has been described. We have specifically addressed the role of ST2 on T cells by generation of ST2(-/-) mice crossed with ovalbumin (OVA) T cell receptor-transgenic mice. OVA-specific ST2(-/-) cells had normal cytokine responses to T cell activation after in vitro Th2 differentiation, but OVA stimulation of IL-5 was increased. Transfer of OVA-specific ST2(-/-) Th2 cells into BALB/c mice caused exacerbated pulmonary inflammation with occluded airways, elevated airway hyper-responsiveness and increased susceptibility to methacholine challenge that was associated with mortalities of recipient mice. The increased pulmonary inflammation in OVA-specific ST2(-/-) Th2 cell recipients was associated with selective differences in pulmonary levels of Th2 cytokines compared with OVA-specific ST2(+) Th2 cell recipients. Recipients of OVA-specific ST2(-/-) Th2 cells had a significant increase in eosinophils and a significant reduction in F4/80(hi) macrophages in the lungs. This is the first demonstration of a role for ST2 expression on Th2 cells down-regulating pulmonary inflammation. These data have major implications for the targeting of ST2 as a therapy for allergic airway disorders.
Publisher: The American Association of Immunologists
Date: 12-2018
Abstract: The A20-binding inhibitor of NF-κB 2 (ABIN2) interacts with Met1-linked ubiquitin chains and is an integral component of the tumor progression locus 2 (Tpl2) kinase complex. We generated a knock-in mouse expressing the ubiquitin-binding–defective mutant ABIN2[D310N]. The expression of Tpl2 and its activation by TLR agonists in macrophages or by IL-1β in fibroblasts from these mice was unimpaired, indicating that the interaction of ABIN2 with ubiquitin oligomers is not required for the stability or activation of Tpl2. The ABIN2[D310N] mice displayed intestinal inflammation and hypersensitivity to dextran sodium sulfate–induced colitis, an effect that was mediated by radiation-resistant cells rather than by hematopioetic cells. The IL-1β–dependent induction of cyclooxygenase 2 (COX2) and the secretion of PGE2 was reduced in mouse embryonic fibroblasts and intestinal myofibroblasts (IMFs) from ABIN2[D310N] mice. These observations are similar to those reported for the Tpl2 knockout (KO) mice (Roulis et al. 2014. Proc. Natl. Acad. Sci. USA 111: E4658–E4667), but the IL-1β–dependent production of COX2 and PGE2 in mouse embryonic fibroblasts or IMFs was unaffected by pharmacological inhibition of Tpl2 in wild-type mice. The expression of ABIN2 is decreased drastically in Tpl2 KO mice. These and other lines of evidence suggest that the hypersensitivity of Tpl2 KO mice to dextran sodium sulfate–induced colitis is not caused by the loss of Tpl2 catalytic activity but by the loss of ABIN2, which impairs COX2 and PGE2 production in IMFs by a Tpl2 kinase–independent pathway.
Publisher: Public Library of Science (PLoS)
Date: 02-02-2012
Publisher: Rockefeller University Press
Date: 11-05-2015
DOI: 10.1084/JEM.20142224
Abstract: Group 2 innate lymphoid cells (ILC2s) are often found associated with mucosal surfaces where they contribute to protective immunity, inappropriate allergic responses, and tissue repair. Although we know they develop from a common lymphoid progenitor in the bone marrow (BM), the specific lineage path and transcriptional regulators that are involved are only starting to emerge. After ILC2 gene expression analysis we investigated the role of Bcl11b, a factor previously linked to T cell commitment, in ILC2 development. Using combined Bcl11b-tom and Id2-gfp reporter mice, we show that Bcl11b is expressed in ILC2 precursors in the BM and maintained in mature ILC2s. In vivo deletion of Bcl11b, by conditional tamoxifen-induced depletion or by Bcl11b−/− fetal liver chimera reconstitution, demonstrates that ILC2s are wholly dependent on Bcl11b for their development. Notably, in the absence of Bcl11b there is a concomitant expansion of the RORγt+ ILC3 population, suggesting that Bcl11b may negatively regulate this lineage. Using Nippostrongylus brasiliensis infection, we reveal that the absence of Bcl11b leads to impaired worm expulsion, caused by a deficit in ILC2s, whereas Citrobacter rodentium infection is cleared efficiently. These data clearly establish Bcl11b as a new factor in the differentiation of ILC2s.
Publisher: American Society for Microbiology
Date: 2009
DOI: 10.1128/IAI.00762-08
Abstract: The de novo immune response to infectious organisms arises from the innate recognition of pathogen-associated molecular patterns (PAMPs) by the host's pattern recognition receptors (PRRs). As the generation of type 2 cytokine responses by the human trematode parasite Schistosoma mansoni is glycan mediated, there is a particular potential role for a C-type lectin receptor (CLR) to mediate the innate recognition of schistosome PAMPs. One such CLR, dendritic cell-specific intracellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN CD209), has been shown to recognize glycans expressed by S. mansoni eggs. We show that SIGNR1 (SIGN-related 1 CD209b), a murine homologue of DC-SIGN that is expressed on macrophages, also binds both schistosome-soluble egg antigens and worm antigens in vitro. The generation of schistosome egg-induced pulmonary egg granulomas was not altered in SIGNR1-deficient mice. Following S. mansoni infection, the SIGNR1-deficient mice had an unaltered phenotype with an intact immunological response and no difference in pathology. In this study we demonstrate that although SIGNR1 recognizes S. mansoni antigens in vitro, this CLR is redundant during infection. This study highlights the finding that although there was binding of SIGNR1 to immunogenic factors produced in the S. mansoni life cycle, this recognition does not translate to a functional in vivo role for the PRR during infection.
Publisher: Frontiers Media SA
Date: 07-05-2021
DOI: 10.3389/FIMMU.2021.676932
Abstract: The immunological and inflammatory changes following acute COVID-19 are hugely variable. Persistent clinical symptoms following resolution of initial infection, termed long COVID , are also hugely variable, but association with immunological changes has not been described. We investigate changing immunological parameters in convalescent COVID-19 and interrogate their potential relationships with persistent symptoms. We performed paired immunophenotyping at initial SARS-CoV-2 infection and convalescence (n=40, median 68 days) and validated findings in 71 further patients at median 101 days convalescence. Results were compared to 40 pre-pandemic controls. Fatigue and exercise tolerance were assessed as cardinal features of long COVID using the Chalder Fatigue Scale and 6-minute-walk test. The relationships between these clinical outcomes and convalescent immunological results were investigated. We identify persistent expansion of intermediate monocytes, effector CD8+, activated CD4+ and CD8+ T cells, and reduced naïve CD4+ and CD8+ T cells at 68 days, with activated CD8+ T cells remaining increased at 101 days. Patients & years also demonstrate reduced naïve CD4+ and CD8+ T cells and expanded activated CD4+ T cells at 101 days. Ill-health, fatigue, and reduced exercise tolerance were common in this cohort. These symptoms were not associated with immune cell populations or circulating inflammatory cytokines. We demonstrate myeloid recovery but persistent T cell abnormalities in convalescent COVID-19 patients more than three months after initial infection. These changes are more marked with age and are independent of ongoing subjective ill-health, fatigue and reduced exercise tolerance.
Publisher: Springer Science and Business Media LLC
Date: 14-06-2023
DOI: 10.1038/S41467-023-39174-1
Abstract: Excessive inflammation-associated coagulation is a feature of infectious diseases, occurring in such conditions as bacterial sepsis and COVID-19. It can lead to disseminated intravascular coagulation, one of the leading causes of mortality worldwide. Recently, type I interferon (IFN) signaling has been shown to be required for tissue factor (TF gene name F3 ) release from macrophages, a critical initiator of coagulation, providing an important mechanistic link between innate immunity and coagulation. The mechanism of release involves type I IFN-induced caspase-11 which promotes macrophage pyroptosis. Here we find that F3 is a type I IFN-stimulated gene. Furthermore, F3 induction by lipopolysaccharide (LPS) is inhibited by the anti-inflammatory agents dimethyl fumarate (DMF) and 4-octyl itaconate (4-OI). Mechanistically, inhibition of F3 by DMF and 4-OI involves suppression of Ifnb1 expression. Additionally, they block type I IFN- and caspase-11-mediated macrophage pyroptosis, and subsequent TF release. Thereby, DMF and 4-OI inhibit TF-dependent thrombin generation. In vivo, DMF and 4-OI suppress TF-dependent thrombin generation, pulmonary thromboinflammation, and lethality induced by LPS, E. coli , and S. aureus , with 4-OI additionally attenuating inflammation-associated coagulation in a model of SARS-CoV-2 infection. Our results identify the clinically approved drug DMF and the pre-clinical tool compound 4-OI as anticoagulants that inhibit TF-mediated coagulopathy via inhibition of the macrophage type I IFN-TF axis.
Publisher: Humana Press
Date: 2009
DOI: 10.1007/978-1-59745-541-1_24
Abstract: Pathogen recognition is a central activity of the Toll-like receptor (TLR) family. Molecules from various pathogens have been widely used in TLR research as natural ligands for the receptors. TLR ligands from bacteria, viruses, and fungi are widely available from commercial companies and are increasingly being manufactured with high purity specifically for use in TLR research. Although increasingly used in TLR research, extracts from many parasites with potential TLR ligands are not generally produced commercially. Historically, parasite extracts were produced in academic laboratories for diagnostic or vaccination research, often without an emphasis on quality control. Here we describe methods for isolation of eggs from the human parasite Schistosoma mansoni. We also describe a protocol for generation of S. mansoni soluble egg antigens (SEA), which are commonly used in TLR research. This protocol has application for the isolation of extract from other parasites or pathogens as it is intended to reduce contamination that may cause spurious data in TLR research.
Location: United Kingdom of Great Britain and Northern Ireland
Location: Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Padraic Fallon.