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1.  Cystic Fibrosis patients have inducible IL-17+IL-22+ memory cells in lung draining lymph nodes 
Background
Interleukin (IL)-17 is an important cytokine signature of a T helper differentiation pathway, Th17. This T cell subset is crucial in mediating autoimmune disease or antimicrobial immunity in animal models, but its presence and role in human disease remains to be completely characterized.
Objective
We set out to determine the frequency of Th17 cells in cystic fibrosis (CF), a disease in which there is recurrent infection with known pathogens.
Methods
Explanted lungs from patients undergoing transplant or organ donors (CF = 18, non-CF, non-bronchiectatic = 10) were collected. Hilar nodes and parenchymal lung tissue were processed. We examined them for Th17 signature by immunofluorescence and quantitative real time PCR. T cells were isolated and stimulated with antigens from Pseudomonas aeruginosa and Aspergillus. Cytokine profiles and staining by flow cytometry were used to assess the reactivity of these cells to antigen stimulation.
Results
We found a strong IL-17 phenotype in CF compared to non-CF controls. Within this tissue, we found pathogen-antigen-responsive CD4+IL17+ cells. There were double positive IL-17+IL-22+ cells and the IL-22+ population had higher proportions of memory characteristics. Antigen-specific Th17 responses were stronger in the draining lymph nodes compared to matched parenchymal lung.
Conclusion
Inducible proliferation of Th17(22) with memory cell characteristics is seen in CF lung. The function of these individual subpopulations will require further study regarding their development. T-cells are likely not the exclusive producers of IL-17 and IL-22 and this will require further characterization.
doi:10.1016/j.jaci.2012.05.036
PMCID: PMC3488163  PMID: 22795370
Th17; Th22; IL-17; IL-22; cystic fibrosis; Pseudomonas; Aspergillus; chronic infectious disease; memory T cell response; lung transplant
2.  Role of T-lymphocytes and pro-inflammatory mediators in the pathogenesis of chronic obstructive pulmonary disease 
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the US and a major worldwide healthcare problem. The pathophysiologic mechanisms that drive development and progression of this disease are complex and only poorly understood. While tobacco smoking is the primary risk factor, other disease processes also appear to play a role. Components of the innate immune system (eg, macrophages and neutrophils) have long been believed to be important in the development of COPD. More recent evidence also suggests involvement of the adaptive immune system in pathogenesis of this disease. Here we will review the literature supporting the participation of T-cells in the development of COPD, and comment on the potential antigenic stimuli that may account for these responses. We will further explore the prospective contributions of T-cell derived mediators that could contribute to the inflammation, alveolar wall destruction, and small airway fibrosis of advanced COPD. A better understanding of these complex immune processes will lead to new insights that could result in improved preventative and/or treatment strategies.
PMCID: PMC2650590  PMID: 19281072
COPD; T-lymphocytes; adaptive immunity; cytokines
3.  The Missing Link between Smoking and COPD Autoreactivity? 
doi:10.1164/rccm.201107-1228ED
PMCID: PMC3208654  PMID: 21965008
4.  Distribution of Pneumocystis jirovecii in lungs from colonized COPD patients 
Pneumocystis jirovecii has been detected in lung tissue from patients with chronic obstructive pulmonary disease (COPD) and is associated with disease severity. The regional distribution of the organism in lungs is unknown, but differences in distribution of Pneumocystis could affect estimates of colonization prevalence. We examined the distribution of Pneumocystis in the lungs of 19 non-HIV-infected patients with COPD who were undergoing lung transplantation. DNA was extracted from explanted lungs. We found Pneumocystis colonization in lung tissue of 42.1% of patients with advanced COPD; however, there was significant regional variation in colonization between lung segments of individual patients. Colonization was detected more commonly in the lower and middle lobes than the upper lobes. These findings suggest that single samples from an individual may underestimate the prevalence of Pneumocystis colonization and future studies may obtain a higher yield of Pneumocystis colonization detection when sampling the lower lobes.
doi:10.1016/j.diagmicrobio.2011.05.008
PMCID: PMC3159032  PMID: 21851870
chronic obstructive pulmonary disease; Pneumocystis jirovecii; lung
5.  Thymic dendritic cells traffic to thymi of allogeneic recipients and prolong graft survival 
We have demonstrated that murine thymic dendritic cells (DCs) isolated from donor mice have the capability to home to thymi of fully allogeneic recipients after intravenous injections, where they induce T cell deletions and prolong donor-strain airway and skin graft survival. In contrast, infused splenic DCs immigrated poorly to thymi, and did not affect graft survival. These findings suggest that preferential homing may be an important mechanistic difference among subpopulations of DCs that mediate immune functions and illustrate a novel methodology that could have utility for induction of specific immunologic nonreactivity to allografts, or other disease-associated antigens.
doi:10.1172/JCI12142
PMCID: PMC150904  PMID: 11901184
6.  Radiographic Emphysema Predicts Low Bone Mineral Density in a Tobacco-exposed Cohort 
Rationale: Studies demonstrating an association between chronic obstructive pulmonary disease and low bone mineral density (BMD) implicate factors distinct from treatments and severity of lung disease in the pathogenesis of osteoporosis. Whereas emphysema has been independently associated with vascular disease and other comorbidities, its association with BMD has not been well studied.
Objectives: We explored the associations of BMD with computed tomography (CT) measures of emphysema and other risk factors in current and former smokers.
Methods: One hundred ninety subjects completed a CT scan, pulmonary function testing, questionnaires, and dual x-ray absorptiometry measurements of hip and lumbar spine BMD. Subjects were classified as having normal BMD, osteopenia, or osteoporosis. Demographic, physiologic, and radiographic characteristics were compared and the association of BMD with radiographic emphysema, airflow obstruction, and osteoporosis risk factors was assessed.
Measurements and Main Results: No difference existed in age, tobacco exposure, oral steroid use, or physical activity across BMD categories. Both osteopenia and osteoporosis were associated with the presence of airflow obstruction, inhaled corticosteroid use, and female sex, and demonstrated a significant relationship with the presence of visual emphysema (P = 0.0003). Quantitative emphysema, but not CT-measured indices of airway wall thickness, was inversely associated with BMD. Visual emphysema alone was a significant predictor of osteopenia/osteoporosis (odds ratio = 2.55; 95% confidence interval, 1.24–5.25) in a model including obstruction severity, age, sex, and inhaled and oral steroid use.
Conclusions: Radiographic emphysema is a strong, independent predictor of low BMD in current and former smokers. This relationship suggests a common mechanistic link between emphysema and osteopenia/osteoporosis.
doi:10.1164/rccm.201004-0666OC
PMCID: PMC3086755  PMID: 20935108
pulmonary disease, chronic obstructive; emphysema; osteoporosis
7.  Patients with Idiopathic Pulmonary Fibrosis with Antibodies to Heat Shock Protein 70 Have Poor Prognoses 
Rationale: Diverse autoantibodies are present in most patients with idiopathic pulmonary fibrosis (IPF). We hypothesized that specific autoantibodies may associate with IPF manifestations.
Objectives: To identify clinically relevant, antigen-specific immune responses in patients with IPF.
Methods: Autoantibodies were detected by immunoblots and ELISA. Intrapulmonary immune processes were evaluated by immunohistochemistry. Anti–heat shock protein 70 (HSP70) IgG was isolated from plasma by immunoaffinity. Flow cytometry was used for leukocyte functional studies.
Measurements and Main Results: HSP70 was identified as a potential IPF autoantigen in discovery assays. Anti-HSP70 IgG autoantibodies were detected by immunoblots in 3% of 60 control subjects versus 25% of a cross-sectional IPF cohort (n = 122) (P = 0.0004), one-half the patients with IPF who died (P = 0.008), and 70% of those with acute exacerbations (P = 0.0005). Anti-HSP70 autoantibodies in patients with IPF were significantly associated with HLA allele biases, greater subsequent FVC reductions (P = 0.0004), and lesser 1-year survival (40 ± 10% vs. 80 ± 5%; hazard ratio = 4.2; 95% confidence interval, 2.0–8.6; P < 0.0001). HSP70 protein, antigen–antibody complexes, and complement were prevalent in IPF lungs. HSP70 protein was an autoantigen for IPF CD4 T cells, inducing lymphocyte proliferation (P = 0.004) and IL-4 production (P = 0.01). IPF anti-HSP70 autoantibodies activated monocytes (P = 0.009) and increased monocyte IL-8 production (P = 0.049). ELISA confirmed the association between anti-HSP70 autoreactivity and IPF outcome. Anti-HSP70 autoantibodies were also found in patients with other interstitial lung diseases but were not associated with their clinical progression.
Conclusions: Patients with IPF with anti-HSP70 autoantibodies have more near-term lung function deterioration and mortality. These findings suggest antigen-specific immunoassays could provide useful clinical information in individual patients with IPF and may have implications for understanding IPF progression.
doi:10.1164/rccm.201203-0506OC
PMCID: PMC3678112  PMID: 23262513
B cells; T cells; adaptive immunity; interstitial lung disease
8.  CD28 Down-Regulation on CD4 T Cells Is a Marker for Graft Dysfunction in Lung Transplant Recipients 
Rationale: Repeated antigen-driven proliferations cause CD28 on T cells to down-regulate. We hypothesized that alloantigen-induced proliferations could cause CD28 down-regulation in lung transplant recipients.
Objectives: To ascertain if CD28 down-regulation on CD4 T cells associated with manifestations of allograft dysfunction in lung transplant recipients.
Methods: Peripheral blood CD4 T cells from 65 recipients were analyzed by flow cytometry, cytokine multiplex and proliferative assays, and correlated with clinical events.
Measurements and Main Results: Findings that CD28 was present on less than 90% of total CD4 T cells were predominantly seen among the recipients with bronchiolitis obliterans syndrome (specificity = 88%). Perforin and granzyme B were produced by >50% of the CD4+CD28null cells, but less than 6% of autologous CD4+CD28+ cells (P < 0.006). CD4+CD28null cells also had increased productions of proinflammatory cytokines, but less frequently expressed regulatory T-cell marker FoxP3 (2.1 ± 1.3%), compared with autologous CD4+CD28+ (9.5 ± 1.4; P = 0.01). Cyclosporine A (100 ng/ml) inhibited proliferation of CD4+CD28null cells by 33 ± 11% versus 68 ± 12% inhibition of CD4+CD28+ (P = 0.025). FEV1 fell 6 months later (0.35 ± 0.04 L) in recipients with CD4+CD28+/CD4total less than 90% (CD28% Low) compared with 0.08 ± 0.08 L among CD4+CD28+/CD4total (CD28% High) greater than 90% (CD28% High) recipients (P = 0.013). Two-year freedom from death or retransplantation in CD28% Low recipients was 32 ± 10% versus 78 ± 6% among the CD28% High subjects (P < 0.0001).
Conclusions: CD28 down-regulation on CD4 cells is associated with bronchiolitis obliterans syndrome and poor outcomes in lung transplantation recipients. CD4+CD28null cells have unusual, potentially pathogenic characteristics, and could be important in the progression of allograft dysfunction. These findings may illuminate a novel paradigm of transplantation immunopathogenesis, and suggest that CD28 measurements could identify recipients at risk for clinical deteriorations.
doi:10.1164/rccm.200701-013OC
PMCID: PMC2556458  PMID: 18617642
bronchiolitis obliterans syndrome; obliterative bronchiolitis; chronic allograft rejection; regulatory T cells; cyclosporine
9.  Autoantibodies in Patients with Chronic Obstructive Pulmonary Disease 
Rationale: Adaptive immune responses are present in patients with chronic obstructive pulmonary disease (COPD), and it has been postulated that these processes could be autoreactive.
Objectives: To ascertain if humoral autoimmunity could play a role in COPD pathogenesis.
Methods: Circulating IgG autoantibodies were detected by immunofluorescence and immunoprecipitation. Immunohistochemistry and immunofluorescence were used to evaluate intrapulmonary IgG and complement (C3) deposition in human lung explants. Autoantibody pathogenicity was also investigated with an antibody-dependent cell-mediated cytotoxicity assay.
Measurements and Main Results: The prevalence of anti–HEp-2 epithelial cell autoantibodies in 47 smokers/former smokers with COPD (GOLD stages 1–4) was greater than among 8 subjects with a smoking history but normal spirometry and 21 healthy control subjects who had never smoked (68 vs. 13 vs. 10%, respectively; P < 0.0001). Antibodies against primary pulmonary epithelial cells were found in 12 of 12 patients with COPD versus 3 of 12 never-smoked control subjects (P < 0.001). Self-antigens immunoprecipitated from 34 of 35 (97%) of COPD plasmas (vs. 0/12 never-smoked controls). Antibodies against a particular 130-kD autoantigen (n = 7) were associated with decreased body mass index (23.2 ± 2.1 vs. 29.5 ± 1.0 kg/m2, P = 0.007). Intrapulmonary immune complexes were present in six of six and C3 was seen in five of six COPD lung explants, unlike zero of six and one of six normals, respectively. Cytotoxicity of pulmonary epithelial cells by allogeneic mononuclear cells also increased 46% after incubation with COPD plasmas (n = 10), compared with identical treatments with eight normal specimens (P = 0.03).
Conclusions: IgG autoantibodies with avidity for pulmonary epithelium, and the potential to mediate cytotoxicity, are prevalent in patients with COPD. Autoreactive adaptive immune responses may be important in the etiology of this disease.
doi:10.1164/rccm.200701-014OC
PMCID: PMC2204079  PMID: 17975205
autoimmunity; humoral immunity; B cells; emphysema
10.  The HLA Class II Allele DRB1*1501 Is Over-Represented in Patients with Idiopathic Pulmonary Fibrosis 
PLoS ONE  2011;6(2):e14715.
Background
Idiopathic pulmonary fibrosis (IPF) is a progressive and medically refractory lung disease with a grim prognosis. Although the etiology of IPF remains perplexing, abnormal adaptive immune responses are evident in many afflicted patients. We hypothesized that perturbations of human leukocyte antigen (HLA) allele frequencies, which are often seen among patients with immunologic diseases, may also be present in IPF patients.
Methods/Principal Findings
HLA alleles were determined in subpopulations of IPF and normal subjects using molecular typing methods. HLA-DRB1*15 was over-represented in a discovery cohort of 79 Caucasian IPF subjects who had lung transplantations at the University of Pittsburgh (36.7%) compared to normal reference populations. These findings were prospectively replicated in a validation cohort of 196 additional IPF subjects from four other U.S. medical centers that included both ambulatory patients and lung transplantation recipients. High-resolution typing was used to further define specific HLA-DRB1*15 alleles. DRB1*1501 prevalence in IPF subjects was similar among the 143 ambulatory patients and 132 transplant recipients (31.5% and 34.8%, respectively, p = 0.55). The aggregate prevalence of DRB1*1501 in IPF patients was significantly greater than among 285 healthy controls (33.1% vs. 20.0%, respectively, OR 2.0; 95%CI 1.3–2.9, p = 0.0004). IPF patients with DRB1*1501 (n = 91) tended to have decreased diffusing capacities for carbon monoxide (DLCO) compared to the 184 disease subjects who lacked this allele (37.8±1.7% vs. 42.8±1.4%, p = 0.036).
Conclusions/Significance
DRB1*1501 is more prevalent among IPF patients than normal subjects, and may be associated with greater impairment of gas exchange. These data are novel evidence that immunogenetic processes can play a role in the susceptibility to and/or manifestations of IPF. Findings here of a disease association at the HLA-DR locus have broad pathogenic implications, illustrate a specific chromosomal area for incremental, targeted genomic study, and may identify a distinct clinical phenotype among patients with this enigmatic, morbid lung disease.
doi:10.1371/journal.pone.0014715
PMCID: PMC3044131  PMID: 21373184
11.  CD28 Down-Regulation on Circulating CD4 T-Cells Is Associated with Poor Prognoses of Patients with Idiopathic Pulmonary Fibrosis 
PLoS ONE  2010;5(1):e8959.
Background
Although the etiology of idiopathic pulmonary fibrosis (IPF) remains perplexing, adaptive immune activation is evident among many afflicted patients. Repeated cycles of antigen-induced proliferation cause T-cells to lose surface expression of CD28, and we hypothesized this process might also occur in IPF.
Methodology/Principal Findings
Peripheral blood CD4 T-cells from 89 IPF patients were analyzed by flow cytometry and cytokine multiplex assays, and correlated with clinical events. In comparison to autologous CD4+CD28+cells, the unusual CD4+CD28null lymphocytes seen in many IPF patients had discordant expressions of activation markers, more frequently produced cytotoxic mediators perforin (2.4±0.8% vs. 60.0±7.4%, p<0.0001) and granzyme B (4.5±2.8% vs.74.9±6.5%, p<0.0001), produced greater amounts of many pro-inflammatory cytokines, and less frequently expressed the regulatory T-cell marker FoxP3 (12.9±1.1% vs. 3.3±0.6% p<0.0001). Infiltration of CD4+CD28null T-cells in IPF lungs was confirmed by confocal microscopy. Interval changes of CD28 expression among subjects who had replicate studies were correlated with conterminous changes of their forced vital capacities (rs = 0.49, p = 0.012). Most importantly, one-year freedom from major adverse clinical events (either death or lung transplantation) was 56±6% among 78 IPF patients with CD4+CD28+/CD4total≥82%, compared to 9±9% among those with more extensive CD28 down-regulation (CD4+CD28+/CD4total<82%) (p = 0.0004). The odds ratio for major adverse events among those with the most extensive CD28 down-regulation was 13.0, with 95% confidence intervals 1.6-111.1.
Conclusions/Significance
Marked down-regulation of CD28 on circulating CD4 T-cells, a result of repeated antigen-driven proliferations, is associated with poor outcomes in IPF patients. The CD4+CD28null cells of these patients have potentially enhanced pathogenic characteristics, including increased productions of cytotoxic mediators and pro-inflammatory cytokines. These findings show proliferative T-cell responses to antigen(s) resulting in CD28 down-regulation are associated with progression and manifestations of IPF, and suggest assays of circulating CD4 T-cells may identify patients at greatest risk for clinical deterioration.
doi:10.1371/journal.pone.0008959
PMCID: PMC2813297  PMID: 20126467

Results 1-11 (11)