The Journal of Heart and Lung Transplantation, 2013
Antibody-mediated rejection (AMR) after lung transplantation remains enigmatic, and there is no c... more Antibody-mediated rejection (AMR) after lung transplantation remains enigmatic, and there is no consensus on the characteristic clinical, immunologic and histologic features. We performed a retrospective, single-center cohort study and identified cases of acute AMR based on the presence of circulating donor-specific human leukocyte antigen (HLA) antibodies (DSA), histologic evidence of acute lung injury, C4d deposition and clinical allograft dysfunction. We identified 21 recipients with acute AMR based on the aforementioned criteria. AMR occurred a median 258 days after transplantation; 7 recipients developed AMR within 45 days of transplantation. All patients had clinical allograft dysfunction, DSA, histology of acute lung injury and capillary endothelial C4d deposition. Fifteen recipients improved clinically and survived to hospital discharge, but 6 died of refractory AMR. One survivor had bronchiolitis obliterans syndrome at the time of AMR diagnosis; 13 of the 14 remaining survivors developed chronic lung allograft dysfunction (CLAD) during follow-up. Overall, 15 recipients died during the study period, and the median survival after the diagnosis of AMR was 593 days. Acute AMR can be a fulminant form of lung rejection, and survivors are at increased risk of developing CLAD. The constellation of acute lung injury, DSA and capillary endothelial C4d deposition is compelling for acute AMR in recipients with allograft dysfunction. This clinicopathologic definition requires validation in a multicenter cohort, but may serve as a foundation for future studies to further characterize AMR.
In vitro stimulation of mouse splenocytes with hemagglutinin (HA) 173-190, a peptide derived from... more In vitro stimulation of mouse splenocytes with hemagglutinin (HA) 173-190, a peptide derived from influenza virus hemagglutinin (A/JAP/305/57, H2N2), induces CTLs that are directed to the MHC class Ib molecule, H2-M3. M3 preferably binds peptides bearing an N-terminal formylmethionine. In this study, we show that several related nonformylated peptides can induce anti-HA CTLs in vitro: MLIIW (the minimal epitope), derived from HA186-190 at the C-terminal end of HA173-190; MLIIWG; MLIIWGV; and MLIIWGI, as well as formylated MLIIW. The heptamer peptides correspond to a polymorphism of HA192 in H2 strains of influenza; they have the highest relative affinities for M3 of the nonformylated peptides and higher affinities than some formylated mitochondrial peptides. Depending on the affinity of the peptide, a range of concentrations can be used to induce CTLs. One nanomolar of the high affinity f-MLIIW peptide can induce anti-HA CTLs, whereas 100-fold more of the lower affinity MLIIW peptide is needed. Lines induced with high concentrations (1 microM or greater) of f-MLIIW recognize Ag poorly, and the most efficient CTLs are induced with the lowest concentrations of peptide. Analysis with a panel of anti-TCRVbeta Abs shows that different T cells respond to high vs low peptide; the repertoire of cells responding to higher concentrations is more diverse, consistent with the expansion of more, but less efficient, clones. Thus, peptide affinity and concentration should be considered together for generating efficient antipeptide CTLs in vitro.
The Journal of Heart and Lung Transplantation, 2015
Allosensitization can be a significant barrier to transplantation for some patients, and previous... more Allosensitization can be a significant barrier to transplantation for some patients, and previous studies suggested that pre-transplant allosensitization was associated with worse outcomes after lung transplantation. However, human leukocyte antigen (HLA) antibody testing has evolved significantly over the past 10 years, and current assays are highly sensitive and specific. We examined the impact of pre-transplant allosensitization on post-transplant outcomes in the era of solid-phase multiplex HLA antibody detection assays in this retrospective, single-center study of 304 adult transplant recipients between January 1, 2006, and December 31, 2012. We accepted donor organs for allosensitized patients if a virtual crossmatch was compatible with all previously identified antibodies. In univariate and multivariate Cox proportional hazards models, pre-transplant allosensitization, the calculated panel reactive antibody, and the number of pre-transplant HLA antibodies were not associated with the development of acute cellular rejection, lymphocytic bronchiolitis, donor-specific HLA antibodies, chronic lung allograft dysfunction, or graft failure. Pre-transplant allosensitization does not adversely affect outcomes after lung transplantation when the potentially reactive HLAs are avoided in the donor by a virtual crossmatch with the recipient.
Viral infections and type 2 immune responses are thought to be critical for the development of ch... more Viral infections and type 2 immune responses are thought to be critical for the development of chronic respiratory disease, but the link between these events needs to be better defined. Here, we study a mouse model in which infection with a mouse parainfluenza virus known as Sendai virus (SeV) leads to long-term activation of innate immune cells that drive IL-13-dependent lung disease. We find that chronic postviral disease (signified by formation of excess airway mucus and accumulation of M2-differentiating lung macrophages) requires macrophage expression of triggering receptor expressed on myeloid cells-2 (TREM-2). Analysis of mechanism shows that viral replication increases lung macrophage levels of intracellular and cell surface TREM-2, and this action prevents macrophage apoptosis that would otherwise occur during the acute illness (5-12 d after inoculation). However, the largest increases in TREM-2 levels are found as the soluble form (sTREM-2) long after clearance of infectio...
Journal of immunology (Baltimore, Md. : 1950), 2015
Surfactant protein D (SP-D) is critical for maintenance of lung homeostasis and provides a first ... more Surfactant protein D (SP-D) is critical for maintenance of lung homeostasis and provides a first line of defense to pathogens at mucosal surfaces. Polymorphisms in the SP-D-encoding gene SFTPD have been associated with chronic obstructive pulmonary disease and ulcerative colitis. Identification of the immunoreceptors that bind SP-D is essential for understanding its contribution to lung homeostasis and mucosal defense. We located a putative binding motif for the osteoclast-associated receptor (OSCAR) within the SP-D collagenous domain. An OSCAR-Fc fusion protein specifically bound to the collagenous region of recombinant SP-D and captured native SP-D from human bronchoalveolar lavage. OSCAR localized in an intracellular compartment of alveolar macrophages together with SP-D. Moreover, we found OSCAR on the surface of interstitial lung and blood CCR2(+) inflammatory monocytes, which secreted TNF-α when exposed to SP-D in an OSCAR-dependent fashion. OSCAR and SP-D did not exclusively ...
An abnormal immune response to environmental agents is generally thought to be responsible for ca... more An abnormal immune response to environmental agents is generally thought to be responsible for causing chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Based on studies of experimental models and human subjects, there is increasing evidence that the response of the innate immune system is crucial for the development of this type of airway disease. Airway epithelial cells and innate immune cells represent key components of the pathogenesis of chronic airway disease and are emerging targets for new therapies. In this Review, we summarize the innate immune mechanisms by which airway epithelial cells and innate immune cells regulate the development of chronic respiratory diseases. We also explain how these pathways are being targeted in the clinic to treat patients with these diseases.
Recurrent disease after liver transplant is a significant problem. Recurrent primary biliary cirr... more Recurrent disease after liver transplant is a significant problem. Recurrent primary biliary cirrhosis (RPBC) is a histologic diagnosis. Clinical data is unreliable in predicting or diagnosing recurrence. RPBC appears to have a changing clinical presentation in recent years. The diagnosis of RPBC after liver transplantation was made histologically. Data were obtained from our prospectively maintained liver-transplant database and evaluated statistically. Between 1985 and 1999, 1,835 liver transplants were performed, 169 for PBC. One hundred fifty-six patients were evaluated (one patient received retransplantation, and 13 were excluded). Seventeen (10.9%) experienced recurrence. Median posttransplantation follow-up time was 72.1 months. Median time to recurrence was 49.6 months. Median follow-up time after recurrence was 11.5 months. Neither acute rejection episodes (P=0.34) nor OKT3 use (P=0.36) before diagnosis of recurrence was significant. The combination of cyclosporine, azathioprine, and prednisolone demonstrated recurrence in 6 of 71 (8.4%). Six of 49 (12.2%) patients treated with cyclosporine with or without mycophenolate mofetil and prednisolone experienced recurrence. Six of 36 (16.7%) patients treated with tacrolimus and prednisolone with or without mycophenolate mofetil experienced recurrence. Patients treated with cyclosporine had numerically fewer recurrences than those treated with tacrolimus (P=0.11). Patients with RPBC demonstrated prolonged survival. Clinical factors did not aid in predicting RPBC. The clinical course of RPBC appears to be different than in the earlier years of liver transplantation. Immunosuppression may play a role. The use and type of antimetabolite drugs had no affect on recurrence. RPBC demonstrated a different clinical course with tacrolimus treatment (shorter time to recurrence) and increased incidence when compared with cyclosporine treatment. Controlled randomized studies are necessary to determine differences between tacrolimus and cyclosporine treatment, if any.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2015
Inducible nitric oxide synthase (iNOS) activity increases in acute and chronic inflammatory lung ... more Inducible nitric oxide synthase (iNOS) activity increases in acute and chronic inflammatory lung diseases. Imaging iNOS expression may be useful as an inflammation biomarker for monitoring lung disease activity. We developed a novel tracer for PET that binds to iNOS in vivo, (18)F-NOS. In this study, we tested whether (18)F-NOS could quantify iNOS expression from endotoxin-induced lung inflammation in healthy volunteers. Healthy volunteers were screened to exclude cardiopulmonary disease. Qualifying volunteers underwent a baseline, 1-h dynamic (18)F-NOS PET/CT scan. Endotoxin (4 ng/kg) was then instilled bronchoscopically in the right middle lobe. (18)F-NOS imaging was performed again approximately 16 h after endotoxin instillation. Radiolabeled metabolites were determined from blood samples. Cells recovered by bronchoalveolar lavage (BAL) after imaging were stained immunohistochemically for iNOS. (18)F-NOS uptake was quantified as the distribution volume ratio (DVR) determined by L...
Some investigators find a deficiency in IFN production from airway epithelial cells infected with... more Some investigators find a deficiency in IFN production from airway epithelial cells infected with human rhinovirus in asthma, but whether this abnormality occurs with other respiratory viruses is uncertain. To assess the effect of influenza A virus (IAV) and respiratory syncytial virus (RSV) infection on IFN production and viral level in human bronchial epithelial cells (hBECs) from subjects with and without asthma. Primary-culture hBECs from subjects with mild to severe asthma (n = 11) and controls without asthma (hBECs; n = 7) were infected with live or ultraviolet-inactivated IAV (WS/33 strain), RSV (Long strain), or RSV (A/2001/2-20 strain) with multiplicity of infection 0.01 to 1. Levels of virus along with IFN-β and IFN-λ and IFN-stimulated gene expression (tracked by 2'-5'-oligoadenylate synthetase 1 and myxovirus (influenza virus) resistance 1 mRNA) were determined up to 72 hours postinoculation. After IAV infection, viral levels were increased 2-fold in hBECs from asthmatic subjects compared with nonasthmatic control subjects…
Management of boron (B) in soils can be difficult since a narrow range exists between plant defic... more Management of boron (B) in soils can be difficult since a narrow range exists between plant deficiency and toxicity. A greenhouse study was conducted to evaluate the effectiveness of four soil-applied B fertilizers varying in solubility (Granubor, Hydroboracite, Ulexite, and Colemanite) in supplying B to alfalfa (Medicago sativa L.). Boron was incorporated at rates of 0, 1, or 2 mg
To better understand the immune basis for chronic inflammatory lung disease, we analyzed a mouse ... more To better understand the immune basis for chronic inflammatory lung disease, we analyzed a mouse model of lung disease that develops after respiratory viral infection. The disease that develops in this model is similar to asthma and chronic obstructive pulmonary disease (COPD) in humans and is manifested after the inciting virus has been cleared to trace levels. The model thereby mimics the relationship of paramyxoviral infection to the development of childhood asthma in humans. When the acute lung disease appears in this model (at 3 weeks after viral inoculation), it depends on an immune axis that is initiated by expression and activation of the high-affinity IgE receptor (FcvarepsilonRI) on conventional lung dendritic cells (cDCs) to recruit interleukin (IL)-13-producing CD4(+) T cells to the lower airways. However, when the chronic lung disease develops fully (at 7 weeks after inoculation), it is driven instead by an innate immune axis that relies on invariant natural killer T (i...
Chronic obstructive lung disease is characterized by persistent abnormalities in epithelial and i... more Chronic obstructive lung disease is characterized by persistent abnormalities in epithelial and immune cell function that are driven, at least in part, by infection. Analysis of parainfluenza virus infection in mice revealed an unexpected role for innate immune cells in IL-13-dependent chronic lung disease, but the upstream driver for the immune axis in this model and in humans with similar disease was undefined. We demonstrate here that lung levels of IL-33 are selectively increased in postviral mice with chronic obstructive lung disease and in humans with very severe chronic obstructive pulmonary disease (COPD). In the mouse model, IL-33/IL-33 receptor signaling was required for Il13 and mucin gene expression, and Il33 gene expression was localized to a virus-induced subset of airway serous cells and a constitutive subset of alveolar type 2 cells that are both linked conventionally to progenitor function. In humans with COPD, IL33 gene expression was also associated with IL13 and mucin gene expression, and IL33 induction was traceable to a subset of airway basal cells with increased capacities for pluripotency and ATP-regulated release of IL-33. Together, these findings provide a paradigm for the role of the innate immune system in chronic disease based on the influence of long-term epithelial progenitor cells programmed for excess IL-33 production.
Macrophages are the most abundant immune cell population in normal lung tissue and serve critical... more Macrophages are the most abundant immune cell population in normal lung tissue and serve critical roles in innate and adaptive immune responses as well as the development of inflammatory airway disease. Studies in a mouse model of chronic obstructive lung disease and translational studies of humans with asthma and COPD have shown that a special subset of macrophages is required for disease progression. This subset is activated by an alternative pathway that depends on production of IL-4 and IL-13, in contrast to the classic pathway driven by interferon-γ. Recent and unexpected results indicate that alternatively activated macrophages (AAMs) can also become a major source of IL-13 production and, thereby, drive the increased mucus production and airway hyperreactivity that is characteristic of airway disease. Although the normal and abnormal functions of AAMs are still being defined, it is already apparent that markers of this immune cell subset can be useful to guide stratification and treatment of patients with chronic airway diseases. Here, we review basic and clinical research studies that highlight the importance of AAMs in the pathogenesis of asthma, COPD, and other chronic airway diseases.
Recent studies have demonstrated that the Ro/SSA autoantigen is heterogeneous as is the correspon... more Recent studies have demonstrated that the Ro/SSA autoantigen is heterogeneous as is the corresponding autoimmune response. In addition the autoimmune responses is highly species specific and preferentially reactive with the human antigen. Quantitative ELISA study shows that red blood cell Ro/SSA evolves much more rapidly than lymphocyte Ro/SSA and Western Blot analysis shows that the quantitative ELISA results are mirrored by changes in the 60 kD Ro/SSA molecules but not the 52 kD and 54 kD Ro/SSA molecules. The 52 kD and 54 kD Ro/SSA molecules seem to be relatively conserved as indicated by the Western immunoblotting experiments. These studies add weight to the concept that the antigenic epitopes of these related proteins are under the control of separate genes which have undergone different rates of evolution.
The Journal of Heart and Lung Transplantation, 2013
Antibody-mediated rejection (AMR) after lung transplantation remains enigmatic, and there is no c... more Antibody-mediated rejection (AMR) after lung transplantation remains enigmatic, and there is no consensus on the characteristic clinical, immunologic and histologic features. We performed a retrospective, single-center cohort study and identified cases of acute AMR based on the presence of circulating donor-specific human leukocyte antigen (HLA) antibodies (DSA), histologic evidence of acute lung injury, C4d deposition and clinical allograft dysfunction. We identified 21 recipients with acute AMR based on the aforementioned criteria. AMR occurred a median 258 days after transplantation; 7 recipients developed AMR within 45 days of transplantation. All patients had clinical allograft dysfunction, DSA, histology of acute lung injury and capillary endothelial C4d deposition. Fifteen recipients improved clinically and survived to hospital discharge, but 6 died of refractory AMR. One survivor had bronchiolitis obliterans syndrome at the time of AMR diagnosis; 13 of the 14 remaining survivors developed chronic lung allograft dysfunction (CLAD) during follow-up. Overall, 15 recipients died during the study period, and the median survival after the diagnosis of AMR was 593 days. Acute AMR can be a fulminant form of lung rejection, and survivors are at increased risk of developing CLAD. The constellation of acute lung injury, DSA and capillary endothelial C4d deposition is compelling for acute AMR in recipients with allograft dysfunction. This clinicopathologic definition requires validation in a multicenter cohort, but may serve as a foundation for future studies to further characterize AMR.
In vitro stimulation of mouse splenocytes with hemagglutinin (HA) 173-190, a peptide derived from... more In vitro stimulation of mouse splenocytes with hemagglutinin (HA) 173-190, a peptide derived from influenza virus hemagglutinin (A/JAP/305/57, H2N2), induces CTLs that are directed to the MHC class Ib molecule, H2-M3. M3 preferably binds peptides bearing an N-terminal formylmethionine. In this study, we show that several related nonformylated peptides can induce anti-HA CTLs in vitro: MLIIW (the minimal epitope), derived from HA186-190 at the C-terminal end of HA173-190; MLIIWG; MLIIWGV; and MLIIWGI, as well as formylated MLIIW. The heptamer peptides correspond to a polymorphism of HA192 in H2 strains of influenza; they have the highest relative affinities for M3 of the nonformylated peptides and higher affinities than some formylated mitochondrial peptides. Depending on the affinity of the peptide, a range of concentrations can be used to induce CTLs. One nanomolar of the high affinity f-MLIIW peptide can induce anti-HA CTLs, whereas 100-fold more of the lower affinity MLIIW peptide is needed. Lines induced with high concentrations (1 microM or greater) of f-MLIIW recognize Ag poorly, and the most efficient CTLs are induced with the lowest concentrations of peptide. Analysis with a panel of anti-TCRVbeta Abs shows that different T cells respond to high vs low peptide; the repertoire of cells responding to higher concentrations is more diverse, consistent with the expansion of more, but less efficient, clones. Thus, peptide affinity and concentration should be considered together for generating efficient antipeptide CTLs in vitro.
The Journal of Heart and Lung Transplantation, 2015
Allosensitization can be a significant barrier to transplantation for some patients, and previous... more Allosensitization can be a significant barrier to transplantation for some patients, and previous studies suggested that pre-transplant allosensitization was associated with worse outcomes after lung transplantation. However, human leukocyte antigen (HLA) antibody testing has evolved significantly over the past 10 years, and current assays are highly sensitive and specific. We examined the impact of pre-transplant allosensitization on post-transplant outcomes in the era of solid-phase multiplex HLA antibody detection assays in this retrospective, single-center study of 304 adult transplant recipients between January 1, 2006, and December 31, 2012. We accepted donor organs for allosensitized patients if a virtual crossmatch was compatible with all previously identified antibodies. In univariate and multivariate Cox proportional hazards models, pre-transplant allosensitization, the calculated panel reactive antibody, and the number of pre-transplant HLA antibodies were not associated with the development of acute cellular rejection, lymphocytic bronchiolitis, donor-specific HLA antibodies, chronic lung allograft dysfunction, or graft failure. Pre-transplant allosensitization does not adversely affect outcomes after lung transplantation when the potentially reactive HLAs are avoided in the donor by a virtual crossmatch with the recipient.
Viral infections and type 2 immune responses are thought to be critical for the development of ch... more Viral infections and type 2 immune responses are thought to be critical for the development of chronic respiratory disease, but the link between these events needs to be better defined. Here, we study a mouse model in which infection with a mouse parainfluenza virus known as Sendai virus (SeV) leads to long-term activation of innate immune cells that drive IL-13-dependent lung disease. We find that chronic postviral disease (signified by formation of excess airway mucus and accumulation of M2-differentiating lung macrophages) requires macrophage expression of triggering receptor expressed on myeloid cells-2 (TREM-2). Analysis of mechanism shows that viral replication increases lung macrophage levels of intracellular and cell surface TREM-2, and this action prevents macrophage apoptosis that would otherwise occur during the acute illness (5-12 d after inoculation). However, the largest increases in TREM-2 levels are found as the soluble form (sTREM-2) long after clearance of infectio...
Journal of immunology (Baltimore, Md. : 1950), 2015
Surfactant protein D (SP-D) is critical for maintenance of lung homeostasis and provides a first ... more Surfactant protein D (SP-D) is critical for maintenance of lung homeostasis and provides a first line of defense to pathogens at mucosal surfaces. Polymorphisms in the SP-D-encoding gene SFTPD have been associated with chronic obstructive pulmonary disease and ulcerative colitis. Identification of the immunoreceptors that bind SP-D is essential for understanding its contribution to lung homeostasis and mucosal defense. We located a putative binding motif for the osteoclast-associated receptor (OSCAR) within the SP-D collagenous domain. An OSCAR-Fc fusion protein specifically bound to the collagenous region of recombinant SP-D and captured native SP-D from human bronchoalveolar lavage. OSCAR localized in an intracellular compartment of alveolar macrophages together with SP-D. Moreover, we found OSCAR on the surface of interstitial lung and blood CCR2(+) inflammatory monocytes, which secreted TNF-α when exposed to SP-D in an OSCAR-dependent fashion. OSCAR and SP-D did not exclusively ...
An abnormal immune response to environmental agents is generally thought to be responsible for ca... more An abnormal immune response to environmental agents is generally thought to be responsible for causing chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Based on studies of experimental models and human subjects, there is increasing evidence that the response of the innate immune system is crucial for the development of this type of airway disease. Airway epithelial cells and innate immune cells represent key components of the pathogenesis of chronic airway disease and are emerging targets for new therapies. In this Review, we summarize the innate immune mechanisms by which airway epithelial cells and innate immune cells regulate the development of chronic respiratory diseases. We also explain how these pathways are being targeted in the clinic to treat patients with these diseases.
Recurrent disease after liver transplant is a significant problem. Recurrent primary biliary cirr... more Recurrent disease after liver transplant is a significant problem. Recurrent primary biliary cirrhosis (RPBC) is a histologic diagnosis. Clinical data is unreliable in predicting or diagnosing recurrence. RPBC appears to have a changing clinical presentation in recent years. The diagnosis of RPBC after liver transplantation was made histologically. Data were obtained from our prospectively maintained liver-transplant database and evaluated statistically. Between 1985 and 1999, 1,835 liver transplants were performed, 169 for PBC. One hundred fifty-six patients were evaluated (one patient received retransplantation, and 13 were excluded). Seventeen (10.9%) experienced recurrence. Median posttransplantation follow-up time was 72.1 months. Median time to recurrence was 49.6 months. Median follow-up time after recurrence was 11.5 months. Neither acute rejection episodes (P=0.34) nor OKT3 use (P=0.36) before diagnosis of recurrence was significant. The combination of cyclosporine, azathioprine, and prednisolone demonstrated recurrence in 6 of 71 (8.4%). Six of 49 (12.2%) patients treated with cyclosporine with or without mycophenolate mofetil and prednisolone experienced recurrence. Six of 36 (16.7%) patients treated with tacrolimus and prednisolone with or without mycophenolate mofetil experienced recurrence. Patients treated with cyclosporine had numerically fewer recurrences than those treated with tacrolimus (P=0.11). Patients with RPBC demonstrated prolonged survival. Clinical factors did not aid in predicting RPBC. The clinical course of RPBC appears to be different than in the earlier years of liver transplantation. Immunosuppression may play a role. The use and type of antimetabolite drugs had no affect on recurrence. RPBC demonstrated a different clinical course with tacrolimus treatment (shorter time to recurrence) and increased incidence when compared with cyclosporine treatment. Controlled randomized studies are necessary to determine differences between tacrolimus and cyclosporine treatment, if any.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2015
Inducible nitric oxide synthase (iNOS) activity increases in acute and chronic inflammatory lung ... more Inducible nitric oxide synthase (iNOS) activity increases in acute and chronic inflammatory lung diseases. Imaging iNOS expression may be useful as an inflammation biomarker for monitoring lung disease activity. We developed a novel tracer for PET that binds to iNOS in vivo, (18)F-NOS. In this study, we tested whether (18)F-NOS could quantify iNOS expression from endotoxin-induced lung inflammation in healthy volunteers. Healthy volunteers were screened to exclude cardiopulmonary disease. Qualifying volunteers underwent a baseline, 1-h dynamic (18)F-NOS PET/CT scan. Endotoxin (4 ng/kg) was then instilled bronchoscopically in the right middle lobe. (18)F-NOS imaging was performed again approximately 16 h after endotoxin instillation. Radiolabeled metabolites were determined from blood samples. Cells recovered by bronchoalveolar lavage (BAL) after imaging were stained immunohistochemically for iNOS. (18)F-NOS uptake was quantified as the distribution volume ratio (DVR) determined by L...
Some investigators find a deficiency in IFN production from airway epithelial cells infected with... more Some investigators find a deficiency in IFN production from airway epithelial cells infected with human rhinovirus in asthma, but whether this abnormality occurs with other respiratory viruses is uncertain. To assess the effect of influenza A virus (IAV) and respiratory syncytial virus (RSV) infection on IFN production and viral level in human bronchial epithelial cells (hBECs) from subjects with and without asthma. Primary-culture hBECs from subjects with mild to severe asthma (n = 11) and controls without asthma (hBECs; n = 7) were infected with live or ultraviolet-inactivated IAV (WS/33 strain), RSV (Long strain), or RSV (A/2001/2-20 strain) with multiplicity of infection 0.01 to 1. Levels of virus along with IFN-β and IFN-λ and IFN-stimulated gene expression (tracked by 2'-5'-oligoadenylate synthetase 1 and myxovirus (influenza virus) resistance 1 mRNA) were determined up to 72 hours postinoculation. After IAV infection, viral levels were increased 2-fold in hBECs from asthmatic subjects compared with nonasthmatic control subjects…
Management of boron (B) in soils can be difficult since a narrow range exists between plant defic... more Management of boron (B) in soils can be difficult since a narrow range exists between plant deficiency and toxicity. A greenhouse study was conducted to evaluate the effectiveness of four soil-applied B fertilizers varying in solubility (Granubor, Hydroboracite, Ulexite, and Colemanite) in supplying B to alfalfa (Medicago sativa L.). Boron was incorporated at rates of 0, 1, or 2 mg
To better understand the immune basis for chronic inflammatory lung disease, we analyzed a mouse ... more To better understand the immune basis for chronic inflammatory lung disease, we analyzed a mouse model of lung disease that develops after respiratory viral infection. The disease that develops in this model is similar to asthma and chronic obstructive pulmonary disease (COPD) in humans and is manifested after the inciting virus has been cleared to trace levels. The model thereby mimics the relationship of paramyxoviral infection to the development of childhood asthma in humans. When the acute lung disease appears in this model (at 3 weeks after viral inoculation), it depends on an immune axis that is initiated by expression and activation of the high-affinity IgE receptor (FcvarepsilonRI) on conventional lung dendritic cells (cDCs) to recruit interleukin (IL)-13-producing CD4(+) T cells to the lower airways. However, when the chronic lung disease develops fully (at 7 weeks after inoculation), it is driven instead by an innate immune axis that relies on invariant natural killer T (i...
Chronic obstructive lung disease is characterized by persistent abnormalities in epithelial and i... more Chronic obstructive lung disease is characterized by persistent abnormalities in epithelial and immune cell function that are driven, at least in part, by infection. Analysis of parainfluenza virus infection in mice revealed an unexpected role for innate immune cells in IL-13-dependent chronic lung disease, but the upstream driver for the immune axis in this model and in humans with similar disease was undefined. We demonstrate here that lung levels of IL-33 are selectively increased in postviral mice with chronic obstructive lung disease and in humans with very severe chronic obstructive pulmonary disease (COPD). In the mouse model, IL-33/IL-33 receptor signaling was required for Il13 and mucin gene expression, and Il33 gene expression was localized to a virus-induced subset of airway serous cells and a constitutive subset of alveolar type 2 cells that are both linked conventionally to progenitor function. In humans with COPD, IL33 gene expression was also associated with IL13 and mucin gene expression, and IL33 induction was traceable to a subset of airway basal cells with increased capacities for pluripotency and ATP-regulated release of IL-33. Together, these findings provide a paradigm for the role of the innate immune system in chronic disease based on the influence of long-term epithelial progenitor cells programmed for excess IL-33 production.
Macrophages are the most abundant immune cell population in normal lung tissue and serve critical... more Macrophages are the most abundant immune cell population in normal lung tissue and serve critical roles in innate and adaptive immune responses as well as the development of inflammatory airway disease. Studies in a mouse model of chronic obstructive lung disease and translational studies of humans with asthma and COPD have shown that a special subset of macrophages is required for disease progression. This subset is activated by an alternative pathway that depends on production of IL-4 and IL-13, in contrast to the classic pathway driven by interferon-γ. Recent and unexpected results indicate that alternatively activated macrophages (AAMs) can also become a major source of IL-13 production and, thereby, drive the increased mucus production and airway hyperreactivity that is characteristic of airway disease. Although the normal and abnormal functions of AAMs are still being defined, it is already apparent that markers of this immune cell subset can be useful to guide stratification and treatment of patients with chronic airway diseases. Here, we review basic and clinical research studies that highlight the importance of AAMs in the pathogenesis of asthma, COPD, and other chronic airway diseases.
Recent studies have demonstrated that the Ro/SSA autoantigen is heterogeneous as is the correspon... more Recent studies have demonstrated that the Ro/SSA autoantigen is heterogeneous as is the corresponding autoimmune response. In addition the autoimmune responses is highly species specific and preferentially reactive with the human antigen. Quantitative ELISA study shows that red blood cell Ro/SSA evolves much more rapidly than lymphocyte Ro/SSA and Western Blot analysis shows that the quantitative ELISA results are mirrored by changes in the 60 kD Ro/SSA molecules but not the 52 kD and 54 kD Ro/SSA molecules. The 52 kD and 54 kD Ro/SSA molecules seem to be relatively conserved as indicated by the Western immunoblotting experiments. These studies add weight to the concept that the antigenic epitopes of these related proteins are under the control of separate genes which have undergone different rates of evolution.
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Papers by Derek Byers