Papers by De'Broski Herbert
Journal of Allergy and Clinical Immunology
The involvement of allergen-specific IgE (sIgE) in the pathophysiology of local allergic rhinitis... more The involvement of allergen-specific IgE (sIgE) in the pathophysiology of local allergic rhinitis (LAR) has been challenged, especially due to the low proportion of LAR patients with detectable sIgE in the nasal secretions. In this study we investigate the production of IgE in the nasal mucosa of LAR patients METHODS: 8 LAR, 5 allergic rhinitis (AR), and 5 non-atopic control individuals underwent a nasal allergen challenge (NAC). Before and after the NAC a blood sample and a mucosal biopsy were obtained. Immunostaining was performed in the biopsy whereas the blood sample was used for basophil activation test (BAT). RESULTS: The NAC induced rhinitis symptoms and increased nasal eosinophils in LAR and AR individuals, but not in controls. The BAT was positive in all AR patients, in 38% of LAR subjects, and in none of the controls. The number of mucosal CD38+plasma cells (PC) was similar in the three study groups before and after the provocation. The NAC induced an increase in the number of mucosal IgE+CD38+PC in LAR subjects (p50.006), but not in AR or control individuals. After the NAC, mucosal IgE+CD38+PC were more abundant in AR and LAR patients than in controls (p50.05 and p50.01, respectively). The NAC did not induce significant increases of mucosal IgE+ or IgA+ CD20+B cells in any of the study groups. CONCLUSIONS: These results suggests that the allergen exposure drives the production of IgE in the nasal mucosa of LAR patients. The IgE might be partially allergen-specific, as suggested by the BAT results.
International Forum of Allergy & Rhinology
American Journal of Physiology-Lung Cellular and Molecular Physiology
H1N1 influenza virus infection induces dramatic and permanent alveolar remodeling mediated by p63... more H1N1 influenza virus infection induces dramatic and permanent alveolar remodeling mediated by p63+ progenitor cell expansion in both mice and some patients with acute respiratory distress syndrome. This persistent lung epithelial dysplasia is accompanied by chronic inflammation, but the driver(s) of this pathology are unknown. This work identified de novo appearance of solitary chemosensory cells (SCCs), as defined by the tuft cell marker doublecortin-like kinase 1, in post-influenza lungs, arising in close proximity with the dysplastic epithelium, whereas uninjured lungs are devoid of SCCs. Interestingly, fate mapping demonstrated that these cells are derived from p63-expressing lineage-negative progenitors, the same cell of origin as the dysplastic epithelium. Direct activation of SCCs with denatonium + succinate increased plasma extravasation specifically in post-influenza virus-injured lungs. Thus we demonstrate the previously unrecognized development and activity of SCCs in the...
Whether conventional dendritic cell (cDC) precursors acquire lineage-specific identity under dire... more Whether conventional dendritic cell (cDC) precursors acquire lineage-specific identity under direction of regenerative secreted glycoproteins within bone marrow niches is entirely unknown. Herein, we demonstrate that Wnt4, a beta-catenin independent Wnt ligand, is both necessary and sufficient for necessary for the full extent of pre-cDC1 specification within bone marrow. Cell-intrinsic Wnt4 deficiency in CD11c+ cells reduced mature cDC1 numbers in BM, spleen, lung, and intestine and, reciprocally, rWnt4 treatment promoted pJNK activation and cDC1 expansion. Lack of cell-intrinsic Wnt4 in mice CD11cCreWnt4flox/flox impaired stabilization of IRF8/cJun complexes in BM and increased the basal frequency of both cDC2 and ILC2 populations in the periphery. Accordingly, CD11c-restricted Wnt4 augmented Type 2 immunity against the hookworm parasite Nippostrongylus brasiliensis accompanied by increased interleukin 5 production relative to CD11cCre controls. Collectively, these data show previ...
Intestinal epithelial cells (IEC) comprise diverse lineages that serve distinct roles necessary f... more Intestinal epithelial cells (IEC) comprise diverse lineages that serve distinct roles necessary for regulation of nutrient absorption, regeneration, immunity, and homeostasis. Goblet cells secrete Trefoil factor 3 (TFF3) to maintain mucus viscosity and drive mucosal healing by inhibiting cell death and influencing tight junction protein expression3. However, whether TFF3 signaling relies upon conventional ligand-receptor interactions has been unclear for decades. This study demonstrates that the orphan transmembrane protein leucine rich repeat receptor and nogo-interacting protein 2 (LINGO2) immunoprecipitates with TFF3, that LINGO2 and TFF3 co-localize at the IEC cell surface, and that TFF3/LINGO2 interactions block IEC apoptosis. Loss of function studies show that TFF3-driven STAT3 and EGFR activation are both LINGO2 dependent. Importantly, we demonstrate that TFF3 disrupts LINGO2/EGFR interactions that normally restrict EGFR activity, resulting in enhanced EGFR signaling. Excessi...
International forum of allergy & rhinology, Jan 10, 2018
Recent evidence has demonstrated an expanding role of respiratory epithelial cells in immune surv... more Recent evidence has demonstrated an expanding role of respiratory epithelial cells in immune surveillance and modulation. Studies have been focusing on the earliest events that link epithelial injury to downstream inflammatory responses. Cytokines produced by and released from respiratory epithelial cells are among these early trigger signals. Epithelial-derived cytokines, namely thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, and IL-33, have come to the forefront of recent investigations. Each of these 3 cytokines has been implicated in chronic rhinosinusitis (CRS), asthma, and atopy. Herein we review studies elucidating the roles of epithelial-derived cytokines in the pathobiology of upper airway disease, with particular emphasis on type 2 inflammatory conditions.
International forum of allergy & rhinology, Jan 9, 2018
Chronic rhinosinusitis with nasal polyps (CRSwNP) is commonly characterized by type-2 inflammatio... more Chronic rhinosinusitis with nasal polyps (CRSwNP) is commonly characterized by type-2 inflammation. It is established that group-2 innate lymphoid cells (ILC2s) are a subset of immune cells important in orchestrating mucosal type-2 response. IL-25 is an epithelial-derived cytokine that is a critical activator of ILC2s. Recent evidence demonstrates that specialized taster epithelial cells, such as solitary chemosensory cells (SCCs), may be producers of IL-25. To elucidate the relationship between SCCs and ILC2s in CRSwNP, we sought to quantify ILC2s and SCCs to determine if these cell types are enriched in nasal polyps compared to healthy sinonasal mucosa. We quantified SCCs and ILC2s using multicolor flow cytometry in nasal polyps and non-inflamed turbinate mucosa from seven patients and investigated the role of IL-13 and dexamethasone on SCC frequency using tissue explants of nasal polyps and turbinate mucosa. SCCs were found to be the primary source of IL-25. Nasal polyps demonstr...
The Journal of allergy and clinical immunology, Jan 17, 2018
IL-25 can function as an early signal for the respiratory Type 2 response characteristic of aller... more IL-25 can function as an early signal for the respiratory Type 2 response characteristic of allergic asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). In the mouse gut, tuft cells are the epithelial source of IL-25. However, the source of human airway epithelial IL-25 has remained elusive. In this study, we sought to determine if the solitary chemosensory cell (SCC) is the predominant source of IL-25 in the sinonasal epithelium. Flow cytometry and immunofluorescence for SCCs and IL-25 were used to interrogate polyp and turbinate tissue from patients with chronic rhinosinusitis with nasal polyps (CRSwNP). Mucus was collected during acute inflammatory exacerbations from patients with CRSwNP or CRS without nasal polyps and IL-25 levels determined by Enzyme Linked Immuno-Sorbent Assay (ELISA). Lastly, sinonasal epithelial cultures derived from polyp and turbinate tissue were stimulated with IL-13 and analyzed for SCC proliferation and IL-25 production. This study demonstrate...
The Journal of Immunology, 2016
Immunology, Jun 29, 2016
Cellular and molecular investigation of parasitic helminth infections has greatly accelerated the... more Cellular and molecular investigation of parasitic helminth infections has greatly accelerated the understanding of Type 2 immune responses. However, there remains considerable debate regarding the specific leukocytes that kill parasites and whether these mechanisms are distinct from those responsible for tissue repair. Herein, we chronicle discoveries over the past decade highlighting current paradigms in Type 2 immunity with a particular emphasis upon how CD4(+) T helper 2 cells (TH 2), type 2 innate lymphoid cells (ILC2), and alternatively activated macrophages (M2) coordinately control helminth-induced parasitism. Primarily, this review will draw from studies of the murine nematode parasite Nippostrongylus brasiliensis, which bears important similarities to the human hookworms Ancylostoma duodenale and Necator americanus. Given that one or more hookworm species currently infect millions of individuals across the globe, we propose that vaccine and/or pharmaceutical-based cure stra...
Journal of immunology (Baltimore, Md. : 1950), Jan 15, 2008
The cytokines IL-10 and TGF-beta regulate immunity and inflammation. IL-10 is known to suppress t... more The cytokines IL-10 and TGF-beta regulate immunity and inflammation. IL-10 is known to suppress the extent of hepatic damage caused by parasite ova during natural infection with Schistosoma mansoni, but the role of TGF-beta is less clear. Cytokine blockade studies in mice revealed that anti-IL-10R mAb treatment during acute infection modestly increased cytokine production and liver damage, whereas selective anti-TGF-beta mAb treatment had marginal effects. In contrast, mice administered both mAbs developed severe hepatic inflammation, with enlarged, necrotic liver granulomas, cachexia, and >80% mortality by 8 wk postinfection, despite increased numbers of CD4(+)CD25(+)Foxp3(+) T regulatory cells. Blocking both IL-10 and TGF-beta at the onset of egg production also significantly increased IL-4, IL-6, TNF, IFN-gamma, and IL-17 production and markedly increased hepatic, peritoneal, and splenic neutrophilia. In contrast, coadministration of anti-IL-10R and TGF-beta mAbs had little ef...
Medical Microbiology and Immunology, 2014
Pneumonia is the leading killer of children worldwide. Here, we report that helminth-infected mic... more Pneumonia is the leading killer of children worldwide. Here, we report that helminth-infected mice develop fatal pneumonia when challenged with Streptococcus pneumoniae. Mice were chronically infected with either the flatworm Taenia crassiceps or the roundworm Heligmosomoides polygyrus. Upon challenge with a pneumonic type 3 strain of S. pneumoniae (A66.1), the worm-infected mice developed pneumonia at a rate and to a degree higher than age-matched control mice as measured by bioluminescent imaging and lung titers. This predisposition to pneumonia appears to be specific to S. pneumoniae, as worm-infected mice did not show evidence of increased morbidity when challenged with a lethal dose of influenza virus or sublethal doses of Staphylococcus aureus or Listeria monocytogenes. The defect was also present when worm-infected mice were challenged with a type 2 sepsis-causing strain (D39); an increased rate of pneumonia, decreased survival, and increased lung and blood titers were found. Pneumococcal colonization and immunity against acute otitis media were unaffected. Anti-helminthic treatment in the H. polygyrus model reversed this susceptibility. We conclude that helminth coinfection predisposes mice to fatal pneumococcal pneumonia by promoting increased outgrowth of bacteria in the lungs and blood. These data have broad implications for the prevention and treatment for pneumonia in the developing world, where helminth infections are endemic and pneumococcal pneumonia is common.
Nature Medicine, 2014
read "Gene expression analysis identified higher expression of JAK-STAT signaling targets in 3-we... more read "Gene expression analysis identified higher expression of JAK-STAT signaling targets in 3-week-old relative to 18-month-old mice, " when it should have read "Gene expression analysis identified higher expression of JAK-STAT signaling targets in 18-month-old relative to 3-week-old mice. " The error has been corrected for the print, PDF and HTML versions of this article.
Nature Medicine, 2013
CD4(+) type 1 T regulatory (Tr1) cells are induced in the periphery and have a pivotal role in pr... more CD4(+) type 1 T regulatory (Tr1) cells are induced in the periphery and have a pivotal role in promoting and maintaining tolerance. The absence of surface markers that uniquely identify Tr1 cells has limited their study and clinical applications. By gene expression profiling of human Tr1 cell clones, we identified the surface markers CD49b and lymphocyte activation gene 3 (LAG-3) as being stably and selectively coexpressed on mouse and human Tr1 cells. We showed the specificity of these markers in mouse models of intestinal inflammation and helminth infection and in the peripheral blood of healthy volunteers. The coexpression of CD49b and LAG-3 enables the isolation of highly suppressive human Tr1 cells from in vitro anergized cultures and allows the tracking of Tr1 cells in the peripheral blood of subjects who developed tolerance after allogeneic hematopoietic stem cell transplantation. The use of these markers makes it feasible to track Tr1 cells in vivo and purify Tr1 cells for cell therapy to induce or restore tolerance in subjects with immune-mediated diseases.
Journal of Leukocyte Biology, 2013
RSV is the major cause of severe bronchiolitis in infants, and severe bronchiolitis as a result o... more RSV is the major cause of severe bronchiolitis in infants, and severe bronchiolitis as a result of RSV is associated with subsequent asthma development. A biased Th2 immune response is thought to be responsible for neonatal RSV pathogenesis; however, molecular mechanisms remain elusive. Our data demonstrate, for the first time, that IL-4Rα is up-regulated in vitro on human CD4(+) T cells from cord blood following RSV stimulation and in vivo on mouse pulmonary CD4(+) T cells upon reinfection of mice, initially infected as neonates. Th cell-specific deletion of Il4ra attenuated Th2 responses and abolished the immunopathophysiology upon reinfection, including airway hyper-reactivity, eosinophilia, and mucus hyperproduction in mice infected initially as neonates. These findings support a pathogenic role for IL-4Rα on Th cells following RSV reinfection of mice initially infected as neonates; more importantly, our data from human cells suggest that the same mechanism occurs in humans.
Immunity, 2013
Type 2 inflammatory cytokines, including interleukin-4 (IL-4), IL-5, IL-9, and IL-13, drive the c... more Type 2 inflammatory cytokines, including interleukin-4 (IL-4), IL-5, IL-9, and IL-13, drive the characteristic features of immunity against parasitic worms and allergens. Whether IL-9 serves an essential role in the initiation of host-protective responses is controversial, and the importance of IL-9-versus IL-4-producing CD4 + effector T cells in type 2 immunity is incompletely defined. Herein, we generated IL-9deficient and IL-9-fluorescent reporter mice that demonstrated an essential role for this cytokine in the early type 2 immunity against Nippostrongylus brasiliensis. Whereas T helper 9 (Th9) cells and type 2 innate lymphoid cells (ILC2s) were major sources of infection-induced IL-9 production, the adoptive transfer of Th9 cells, but not Th2 cells, caused rapid worm expulsion, marked basophilia, and increased mast cell numbers in Rag2-deficient hosts. Taken together, our data show a critical and nonredundant role for Th9 cells and IL-9 in host-protective type 2 immunity against parasitic worm infection. Immunity Th9 Cells Promote Anti-helminth Immunity
The American Journal of Pathology, 2012
Transforming growth factor β (TGF-β) regulates inflammation, immunosuppression, and wound-healing... more Transforming growth factor β (TGF-β) regulates inflammation, immunosuppression, and wound-healing cascades, but it remains unclear whether any of these functions involve regulation of myeloid cell function. The present study demonstrates that selective deletion of TGF-βRII expression in myeloid phagocytes i) impairs macrophage-mediated suppressor activity, ii) increases baseline mRNA expression of proinflammatory chemokines/cytokines in the lung, and iii) enhances type 2 immunity against the hookworm parasite Nippostrongylus brasiliensis. Strikingly, TGF-β-responsive myeloid cells promote repair of hookworm-damaged lung tissue, because LysM(Cre)TGF-βRII(flox/flox) mice develop emphysema more rapidly than wild-type littermate controls. Emphysematous pathology in LysM(Cre)TGF-βRII(flox/flox) mice is characterized by excessive matrix metalloprotease (MMP) activity, reduced lung elasticity, increased total lung capacity, and dysregulated respiration. Thus, TGF-β effects on myeloid cells suppress helminth immunity as a consequence of restoring lung function after infection.
The American Journal of Pathology, 2012
Supported by grants R01HL091769 (M.B.J.) and R01 GM 083204 and R01 AI 095289 (D.R.H.) from the NIH.
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Papers by De'Broski Herbert