The skin is an important bulwark of acquired immunity against intestinal helminths

Once animals have experienced a helminthic infection, they often show stronger protective immunity against subsequent infections. Although helminthic infections are well known to elicit Th2-type immune responses, it remains ill-defined where and how acquired protection is executed. Here we show that skin-invading larvae of the intestinal helminth Nippostrongylus brasiliensis are surrounded by skin-infiltrating cells and are prevented from migrating out of infected skin during the second but not the first infection. B cell– or IgE receptor FcεRI–deficient mice showed impaired larval trapping in the skin. Selective ablation of basophils, but not mast cells, abolished the larval trapping, leading to increased worm burden in the lung and hence severe lung injury. Skin-infiltrating basophils produced IL-4 that in turn promoted the generation of M2-type macrophages, leading to the larval trapping in the skin through arginase-1 production. Basophils had no apparent contribution to worm expulsion from the intestine. This study thus reveals a novel mode of acquired antihelminth immunity, in which IgE-armed basophils mediate skin trapping of larvae, thereby limiting lung injury caused by larval migration.

Download Full-text

Preexisting helminth infection induces inhibition of innate pulmonary anti-tuberculosis defense by engaging the IL-4 receptor pathway

Journal of Experimental Medicine ◽

10.1084/jem.20091473 ◽

2011 ◽

Vol 208 (9) ◽

pp. 1863-1874 ◽

Cited By ~ 124

Author(s):

Julius A. Potian ◽

Wasiulla Rafi ◽

Kamlesh Bhatt ◽

Amanda McBride ◽

William C. Gause ◽

...

Keyword(s):

Alternative Activation ◽

Intestinal Helminth ◽

Nippostrongylus Brasiliensis ◽

Th2 Response ◽

Alternatively Activated Macrophages ◽

Cellular Immune Responses ◽

Helminthic Infections ◽

Cellular Immune ◽

The Impact ◽

Alternatively Activated

Tuberculosis and helminthic infections coexist in many parts of the world, yet the impact of helminth-elicited Th2 responses on the ability of the host to control Mycobacterium tuberculosis (Mtb) infection has not been fully explored. We show that mice infected with the intestinal helminth Nippostrongylus brasiliensis (Nb) exhibit a transitory impairment of resistance to airborne Mtb infection. Furthermore, a second dose of Nb infection substantially increases the bacterial burden in the lungs of co-infected mice. Interestingly, the Th2 response in the co-infected animals did not impair the onset and development of the protective Mtb-specific Th1 cellular immune responses. However, the helminth-induced Th2 environment resulted in the accumulation of alternatively activated macrophages (AAMs) in the lung. Co-infected mice lacking interleukin (IL) 4Rα exhibited improved ability to control Mtb infection, which was accompanied by significantly reduced accumulation of AAMs. Moreover, IL-4Rα−/− mice adoptively transferred with wild-type macrophages had a significantly higher Mtb load in their lungs compared with those that received IL-4Rα−/− macrophages, suggesting a direct contribution for the IL-4R pathway to the heightened susceptibility of co-infected animals. The Th2 response can thus enhance the intracellular persistence of Mtb, in part by mediating the alternative activation of macrophages via the IL-4Rα signaling pathway.

Download Full-text

Mast cell deficiency in mice results in biomass overgrowth and delayed expulsion of the rat tapeworm Hymenolepis diminuta

Bioscience Reports ◽

10.1042/bsr20180687 ◽

2018 ◽

Vol 38 (6) ◽

Cited By ~ 3

Author(s):

Marisol I. González ◽

Fernando Lopes ◽

Derek M. McKay ◽

José L. Reyes

Keyword(s):

Cellular Response ◽

In Vitro Release ◽

Hymenolepis Diminuta ◽

Mouse Strains ◽

Helminth Parasites ◽

Th2 Response ◽

Helminthic Infections ◽

Worm Expulsion ◽

Deficient Mice

Infection with helminth parasites evokes a complex cellular response in the host, where granulocytes (i.e. eosinophils, basophils and mast cells (MCs)) feature prominently. In addition to being used as markers of helminthic infections, MCs have been implicated in worm expulsion since animals defective in c-kit signaling, which results in diminished MC numbers, can have delayed worm expulsion. The role of MCs in the rejection of the rat tapeworm, Hymenolepsis diminuta, from the non-permissive mouse host is not known. MC-deficient mice display a delay in the expulsion of H. diminuta that is accompanied by a less intense splenic Th2 response, as determined by in vitro release of interleukin (IL)-4, IL-5 and IL-13 cytokines. Moreover, worms retrieved from MC-deficient mice were larger than those from wild-type (WT) mice. Assessment of gut-derived IL-25, IL-33, thymic stromal lymphopoietin revealed lower levels in uninfected MC-deficient mice compared with WT, suggesting a role for MCs in homeostatic control of these cytokines: differences in these gut cytokines between the mouse strains were not observed after infection with H. diminuta. Finally, mice infected with H. diminuta display less severe dinitrobenzene sulphonic acid (DNBS)-induced colitis, and this beneficial effect of the worm was unaltered in MC-deficient mice challenged with DNBS, as assessed by a macroscopic disease score. Thus, while MCs are not essential for rejection of H. diminuta from mice, their absence slows the kinetics of expulsion allowing the development of greater worm biomass prior to successful rejection of the parasitic burden.

Download Full-text

Cholestatic IL-6 deficient mice show increased susceptibility to endotoxin-induced lethality in association with increased liver and lung injury

Gastroenterology ◽

10.1016/s0016-5085(01)81807-2 ◽

2001 ◽

Vol 120 (5) ◽

pp. A363-A363

Author(s):

M SEWNATH ◽

T POLL ◽

F KATE ◽

D GOUMA

Keyword(s):

Lung Injury ◽

Deficient Mice ◽

Increased Susceptibility

Download Full-text

Mesenchymal Stromal (stem) Cell (MSC) therapy modulates miR-193b-5p expression to attenuate sepsis-induced acute lung injury

European Respiratory Journal ◽

10.1183/13993003.04216-2020 ◽

2021 ◽

pp. 2004216

Author(s):

Claudia C. dos Santos ◽

Hajera Amatullah ◽

Chirag M. Vaswani ◽

Tatiana Maron-Gutierrez ◽

Michael Kim ◽

...

Keyword(s):

Stem Cell ◽

Lung Injury ◽

Conditioned Media ◽

Therapeutic Effects ◽

Host Immune System ◽

Gene And Protein Expression ◽

Stromal Stem Cell ◽

Mesenchymal Stromal Stem Cell ◽

Deficient Mice

Although mesenchymal stromal (stem) cell (MSC) administration attenuates sepsis-induced lung injury in pre-clinical models, the mechanism(s) of action and host immune system contributions to its therapeutic effects, remain elusive. We show that treatment with MSCs decreased expression of host-derived microRNA (miR)-193b-5p and increased expression of its target gene, the tight junctional protein occludin (Ocln), in lungs from septic mice. Mutating the Ocln 3′ UTR miR-193b-5p binding sequence impaired binding to Ocln mRNA. Inhibition of miR-193b-5p in human primary pulmonary microvascular endothelial cells (HPMECs) prevents tumor necrosis factor (TNF)-induced decrease in Ocln gene and protein expression and loss of barrier function. MSC conditioned media mitigated TNF-induced miR-193b-5p upregulation and Ocln downregulation in vitro. When administered in vivo, MSC conditioned media recapitulated the effects of MSC administration on pulmonary miR-193b-5p and Ocln expression. MiR-193b deficient mice were resistant to pulmonary inflammation and injury induced by LPS instillation. Silencing of Ocln in miR-193b deficient mice partially recovered the susceptibility to LPS-induced lung injury. In vivo inhibition of miR-193b-5p protected mice from endotoxin-induced lung injury. Finally, the clinical significance of these results was supported by the finding of increased miR-193b-5p expression levels in lung autopsy samples from Acute Respiratory Distress Syndrome patients who died with diffuse alveolar damage.

Download Full-text

Complement-dependent immune complex-induced bronchial inflammation and hyperreactivity

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2001.280.3.l512 ◽

2001 ◽

Vol 280 (3) ◽

pp. L512-L518 ◽

Cited By ~ 24

Author(s):

Nicholas W. Lukacs ◽

M. Michael Glovsky ◽

Peter A. Ward

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Bronchoalveolar Lavage ◽

Immune Complex ◽

Airway Hyperreactivity ◽

Lung Model ◽

Bronchial Inflammation ◽

Lung Injury Model ◽

Airway Responses ◽

Deficient Mice

Bronchoconstriction responses in the airway are caused by multiple insults and are the hallmark symptom in asthma. In an acute lung injury model in mice, IgG immune complex deposition elicited severe airway hyperreactivity that peaked by 1 h, was maintained at 4 h, and was resolved by 24 h. The depletion of complement with cobra venom factor (CVF) markedly reduced the hyperreactive airway responses, suggesting that complement played an important role in the response. Blockade of C5a with specific antisera also significantly reduced airway hyperreactivity in this acute lung model. Complement depletion by CVF treatment significantly reduced tumor necrosis factor and histamine levels in bronchoalveolar lavage fluids, correlating with reductions in airway hyperreactivity. To further examine the role of specific complement requirement, we initiated the immune complex response in C5-sufficient and C5-deficient congenic animals. The airway hyperreactivity response was partially reduced in the C5-deficient mice. Complement depletion with CVF attenuated airway hyperreactivity in the C5-sufficient mice but had a lesser effect on the airway hyperreactive response and histamine release in bronchoalveolar lavage fluids in C5-deficient mice. These data indicate that acute lung injury in mice after deposition of IgG immune complexes induced airway hyperreactivity that is C5 and C5a dependent.

Download Full-text

Nippostrongylus brasiliensis: further properties of antibody-damaged worms and induction of comparable damage by maintaining worms in vitro

Parasitology ◽

10.1017/s0031182000046710 ◽

1975 ◽

Vol 71 (2) ◽

pp. 275-283 ◽

Cited By ~ 18

Author(s):

R. J. Love ◽

Bridget M. Ogilvie ◽

Diane J. McLaren

Keyword(s):

Immune Response ◽

Isoenzyme Pattern ◽

Nippostrongylus Brasiliensis ◽

Ultrastructural Morphology ◽

Immature Rats ◽

Normal Rat ◽

Worm Expulsion ◽

Anterior Migration

When adult Nippostrongylus brasiliensis were maintained in vitro they became damaged. Using the criteria of ultrastructural morphology, acetylcholinesterase isoenzyme pattern and the behaviour of the worms after transfer to a normal rat, this damage appeared to be similar to that produced by the in vivo action of antibodies.Antibodies were shown to be responsible for the anterior migration of adult worms which occurs during primary infections in mature rats and in the prolonged infections seen in lactating and immature rats.Antibody damaged worms and worms unaffected by antibodies were equally able to stimulate the immune response required for worm expulsion. Apparently antibody damage is not required for the initiation of the second immune component necessary for expulsion of this parasite.

Download Full-text

Fas-deficient mice have impaired alveolar neutrophil recruitment and decreased expression of anti-KC autoantibody:KC complexes in a model of acute lung injury

Respiratory Research ◽

10.1186/1465-9921-13-91 ◽

2012 ◽

Vol 13 (1) ◽

pp. 91 ◽

Cited By ~ 3

Author(s):

Sucheol Gil ◽

Alex W Farnand ◽

William A Altemeier ◽

Sean E Gill ◽

Anna Kurdowska ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Neutrophil Recruitment ◽

Deficient Mice

Download Full-text

CHOP Deficient Mice Have Augmented Lung Injury with Hyperoxia.

10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a4168 ◽

2009 ◽

Author(s):

TI Lozon ◽

WA Altemeier

Keyword(s):

Lung Injury ◽

Deficient Mice

Download Full-text

Host–parasite interactions in rodent nematode infections

Journal of Helminthology ◽

10.1079/joh2003172 ◽

2003 ◽

Vol 77 (2) ◽

pp. 125-131 ◽

Cited By ~ 11

Author(s):

Y.R. Mahida

Keyword(s):

Neutralizing Antibodies ◽

Host Response ◽

Trichinella Spiralis ◽

Host Responses ◽

Nippostrongylus Brasiliensis ◽

Trichuris Muris ◽

Epithelial Phenotype ◽

Worm Expulsion ◽

Genetically Manipulated ◽

Host Parasite

AbstractIn rodents,Trichinella spiralisandNippostrongylus brasiliensisinfect the small intestine andTrichuris murisresides in the colon. The intestinal host response in these animals is characterized by changes in mucosal architecture and inflammation and is associated with worm expulsion. The requirement of T cell-mediated host response in worm expulsion has been demonstrated over many years. Subsequent studies have shown that Th2-type, but not Th1-type, responses mediate resistance to the nematodes. Investigations using neutralizing antibodies and genetically manipulated mice have characterized the contribution of individual Th2-type cytokines in not only worm expulsion, but also specific cellular changes that occur in the mucosa, such as alterations in epithelial phenotype and smooth muscle. There is also increasing appreciation of the contribution of non-bone marrow-derived cells in innate and adaptive host responses in these models.

Download Full-text