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Atherosclerosis prevalence is increased in chronic obstructive pulmonary disease (COPD) patients, independent of other risk factors. The etiology of the excess vascular disease in COPD is unknown, although it is presumably related to an underlying (if cryptic) systemic immune response. Autoantibodies with specificity for glucose-regulated protein 78 (GRP78), a multifunctional component of the unfolded protein response, are common in COPD patients and linked to comorbidities of this lung disease. We hypothesized anti-GRP78 autoreactivity might also be a risk factor for atherosclerosis in COPD patients. Carotid intima-medial thickness (cIMT) was measured in 144 current and former smokers by ultrasound. Concentrations of circulating IgG autoantibodies against full-length GRP78, determined by ELISA, were greater among subjects with abnormally increased cIMT (p < 0.01). Plasma levels of autoantibodies against a singular GRP78 peptide segment, amino acids 246–260 (anti-GRP78aa 246–260), were even more highly correlated with cIMT, especially among males with greater than or equal to moderate COPD (rs = 0.62, p = 0.001). Anti-GRP78aa 246–260 concentrations were independent of CRP, IL-6, and TNF-α levels. GRP78 autoantigen expression was upregulated among human aortic endothelial cells (HAECs) stressed by incubation with tunicamycin (an unfolded protein response inducer) or exposure to culture media flow disturbances. Autoantibodies against GRP78aa 246–260, isolated from patient plasma by immunoprecipitation, induced HAEC production of proatherosclerotic mediators, including IL-8. In conclusion, anti-GRP78 autoantibodies are highly associated with carotid atherosclerosis in COPD patients and exert atherogenic effects on HAECs. These data implicate Ag-specific autoimmunity in the pathogenesis of atherosclerosis among COPD patients and raise possibilities that directed autoantibody reduction might ameliorate vascular disease in this high-risk population.

Background Ankylosing spondylitis (AS) is the second most common cause of inflammatory arthritis worldwide affecting the axial skeleton. Single nucleotide polymorphisms (SNPs) of matrix metalloproteinase‐3 (MMP3) in the development of AS has few been investigated in Chinese population. Methods A total of 362 patients with AS and 362 healthy controls were enrolled in the study. Five SNPs in MMP3 genotypes were identified by Agena MassARRAY. Chi‐squared tests and genetic model were used to evaluate associations. Results rs522616 had a significant risk of AS development compared to those with the TT genotype (p = 0.008). By multiple logistic regression models analysis, in codominant model, rs522616 CT genotypes also had a 1.44‐fold risk (95% CI = 1.06–1.96, p = 0.008) for AS development compared to those with TT genotypes. In recessive model, the CC genotypes was a significantly reduced AS risk for individuals with TT/CT genotype (OR = 0.64; 95% CI = 0.41–0.99, p = 0.040). Conclusion The present study suggests that MMP3 rs522616 polymorphism is associated with AS susceptibility and MMP3 might be a potential diagnostic biomarker for AS. Further independent studies with larger cohorts are warranted to validate our findings in different populations.

Background Lumbar disc herniation (LDH) is a common musculoskeletal disorder affliction and associated with several genes polymorphism. Storkhead box 1 (STOX1) gene is a transcriptional factor related with several signaling pathways including inflammatory pathway. However, little is known about single‐nucleotide polymorphisms (SNPs) of STOX1 associated with LDH risk. Methods We conducted a case–control study among 508 LDH cases and well‐matched 508 controls, and six candidate SNPs in STOX1 were genotyped by Agena MassARRAY. Chi‐squared test, genetic model, and haploview analysis were used to evaluate associations. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression. Results In the allelic model analysis, we found the minor allele “T” of rs7903209 and “A” of rs4472827 were associated with an increased risk of LDH (p = .029, p = .016). Furthermore, in the genotype model analysis, rs7903209 polymorphism was associated with the increased susceptibility of LDH based on dominant (p = .033) and additive model (p = .024); and rs4472827 variant was found to play a harmful role in the LDH risk based on genotype (p = .014), dominant (p = .012), and additive model (p = .015). In the haplotype analysis, the haplotype “GT” in block (rs10998461 and rs10998468) decreased LDH risk (OR = 0.7, 95% CI = 0.52–0.93, p = .016). Functional assessment indicated that rs7903209 and rs4472827 polymorphisms may influence the expression of STOX1. Conclusion Our results provide evidence for polymorphisms of rs7903209 and rs4472827 in STOX1 associated with LDH risk in Chinese Han population., We aimed to explore the association between STOX1 polymorphisms and LDH risk, and we found that STOX1 might be a functional factor for the occurrence and development of LDH.

We hypothesized B cells are involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a progressive, restrictive lung disease that is refractory to glucocorticoids and other nonspecific therapies, and almost invariably lethal. Accordingly, we sought to identify clinically associated B cell–related abnormalities in these patients. Phenotypes of circulating B cells were characterized by flow cytometry. Intrapulmonary processes were evaluated by immunohistochemistry. Plasma B lymphocyte stimulating factor (BLyS) was assayed by ELISA. Circulating B cells of IPF subjects were more Ag differentiated, with greater plasmablast proportions (3.1 ± 0.8%) than in normal controls (1.3 ± 0.3%) (p < 0.03), and the extent of this differentiation correlated with IPF patient lung volumes (r = 0.44, p < 0.03). CD20+ B cell aggregates, diffuse parenchymal and perivascular immune complexes, and complement depositions were all prevalent in IPF lungs, but much less prominent or absent in normal lungs. Plasma concentrations of BLyS, an obligate factor for B cell survival and differentiation, were significantly greater (p < 0.0001) in 110 IPF (2.05 ± 0.05 ng/ml) than among 53 normal (1.40 ± 0.04 ng/ml) and 90 chronic obstructive pulmonary disease subjects (1.59 ± 0.05 ng/ml). BLyS levels were uniquely correlated among IPF patients with pulmonary artery pressures (r = 0.58, p < 0.0001). The 25% of IPF subjects with the greatest BLyS values also had diminished 1-y survival (46 ± 11%), compared with those with lesser BLyS concentrations (81 ± 5%) (hazard ratio = 4.0, 95% confidence interval = 1.8–8.7, p = 0.0002). Abnormalities of B cells and BLyS are common in IPF patients, and highly associated with disease manifestations and patient outcomes. These findings have implications regarding IPF pathogenesis and illuminate the potential for novel treatment regimens that specifically target B cells in patients with this lung disease.

Obliterative bronchiolitis is a frequent, morbid, and usually refractory complication of lung transplantation. Mechanistic study of obliterative bronchiolitis would be aided by development of a relevant model that uses human immune effector cells and airway targets. Our objective was to develop a murine chimera model that mimics obliterative bronchiolitis of lung allograft recipients in human airways in vivo. Human peripheral blood mononuclear cells were adoptively transferred to immunodeficient mice lacking activity of T, B, and NK cells, with and without concurrent transplantations of human small airways dissected from allogeneic cadaveric lungs. Chimerism with human T cells occurred in the majority of recipient animals. The chimeric T cells became highly activated, rapidly infiltrated into the small human airway grafts, and caused obliterative bronchiolitis. In contrast, airways implanted into control mice that did not also receive human peripheral blood mononuclear cell transfers remained intact. In vitro proliferation assays indicated that the chimeric T cells had enhanced specific proliferative responses to donor airway alloantigens. This model confirms the critical role of T cells in development of obliterative bronchiolitis among human lung allograft recipients and provides a novel and easily implemented mechanism for detailed, reductionist in vivo studies of human T-cell responses to allogeneic human small airways.

Background: Malignant blue nevi arise within cellular blue nevi and contain atypical mitoses, necrosis, nuclear pleomorphism and prominent nucleoli. Malignant blue nevus has been described as a distinct identity, a rare form of malignant melanoma, and a misdiagnosed melanoma. Methods: We present a patient with metastatic malignant blue nevus and studies on the histopathologic, immunohistochemical, and molecular features of the neoplasm. Results: Histology showed a malignant blue nevus arising in a combined intradermal and cellular blue nevus. CD117 (c-kit) staining showed diffuse cytoplasmic expression within the cellular blue nevus, decreased staining in the malignant component, and variable positivity within the lymph node metastases. Molecular loss of heterozygosity analysis showed different allelic patterns at the hOGG-1 locus between the melanoma and control skin specimens with a varying heterozygous allelic pattern in both the benign and malignant blue nevus. Conclusions: Our case of malignant blue nevus with lymph node metastasis involved mutation of the hOGG-1 DNA repair gene. CD117 showed decreased staining of the primary malignant blue nevus with marked upregulation in the metastatic lesion, unlike most metastatic melanomas. Further study is needed to determine if hOGG-1 mutation or c-kit upregulation play a role in the pathogenesis of dendritic melanocytic lesions (either benign or malignant).

Severe acute exacerbations (AE) of idiopathic pulmonary fibrosis (IPF) are medically untreatable and often fatal within days. Recent evidence suggests autoantibodies may be involved in IPF progression. Autoantibody-mediated lung diseases are typically refractory to glucocorticoids and nonspecific medications, but frequently respond to focused autoantibody reduction treatments. We conducted a pilot trial to test the hypothesis that autoantibody-targeted therapies may also benefit AE-IPF patients.Eleven (11) critically-ill AE-IPF patients with no evidence of conventional autoimmune diseases were treated with therapeutic plasma exchanges (TPE) and rituximab, supplemented in later cases with intravenous immunoglobulin (IVIG). Plasma anti-epithelial (HEp-2) autoantibodies and matrix metalloproteinase-7 (MMP7) were evaluated by indirect immunofluorescence and ELISA, respectively. Outcomes among the trial subjects were compared to those of 20 historical control AE-IPF patients treated with conventional glucocorticoid therapy prior to this experimental trial.Nine (9) trial subjects (82%) had improvements of pulmonary gas exchange after treatment, compared to one (5%) historical control. Two of the three trial subjects who relapsed after only five TPE responded again with additional TPE. The three latest subjects who responded to an augmented regimen of nine TPE plus rituximab plus IVIG have had sustained responses without relapses after 96-to-237 days. Anti-HEp-2 autoantibodies were present in trial subjects prior to therapy, and were reduced by TPE among those who responded to treatment. Conversely, plasma MMP7 levels were not systematically affected by therapy nor correlated with clinical responses. One-year survival of trial subjects was 46+15% vs. 0% among historical controls. No serious adverse events were attributable to the experimental medications.This pilot trial indicates specific treatments that reduce autoantibodies might benefit some severely-ill AE-IPF patients. These findings have potential implications regarding mechanisms of IPF progression, and justify considerations for incremental trials of autoantibody-targeted therapies in AE-IPF patients.ClinicalTrials.gov NCT01266317.

Background Severe acute exacerbations (AE) of idiopathic pulmonary fibrosis (IPF) are medically untreatable and often fatal within days. Recent evidence suggests autoantibodies may be involved in IPF progression. Autoantibody-mediated lung diseases are typically refractory to glucocorticoids and nonspecific medications, but frequently respond to focused autoantibody reduction treatments. We conducted a pilot trial to test the hypothesis that autoantibody-targeted therapies may also benefit AE-IPF patients. Methods Eleven (11) critically-ill AE-IPF patients with no evidence of conventional autoimmune diseases were treated with therapeutic plasma exchanges (TPE) and rituximab, supplemented in later cases with intravenous immunoglobulin (IVIG). Plasma anti-epithelial (HEp-2) autoantibodies and matrix metalloproteinase-7 (MMP7) were evaluated by indirect immunofluorescence and ELISA, respectively. Outcomes among the trial subjects were compared to those of 20 historical control AE-IPF patients treated with conventional glucocorticoid therapy prior to this experimental trial. Results Nine (9) trial subjects (82%) had improvements of pulmonary gas exchange after treatment, compared to one (5%) historical control. Two of the three trial subjects who relapsed after only five TPE responded again with additional TPE. The three latest subjects who responded to an augmented regimen of nine TPE plus rituximab plus IVIG have had sustained responses without relapses after 96-to-237 days. Anti-HEp-2 autoantibodies were present in trial subjects prior to therapy, and were reduced by TPE among those who responded to treatment. Conversely, plasma MMP7 levels were not systematically affected by therapy nor correlated with clinical responses. One-year survival of trial subjects was 46+15% vs. 0% among historical controls. No serious adverse events were attributable to the experimental medications. Conclusion This pilot trial indicates specific treatments that reduce autoantibodies might benefit some severely-ill AE-IPF patients. These findings have potential implications regarding mechanisms of IPF progression, and justify considerations for incremental trials of autoantibody-targeted therapies in AE-IPF patients. Trial Registration ClinicalTrials.gov NCT01266317

Rationale: C-X-C motif chemokine 13 (CXCL13) mediates B-cell trafficking and is increased, proportionately to disease activity, in many antibody-mediated syndromes. Dysregulated B cells have recently been implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis. Objectives: To determine if CXCL13 is associated with IPF progression. Methods: CXCL13 was measured in lungs by DNA microarray and immunohistochemistry, and in plasma by ELISA. Measurements and Main Results: CXCL13 mRNA was threefold and eightfold greater in IPF lungs (n = 92) compared with chronic obstructive pulmonary disease (COPD) (n = 191) and normal (n = 108) specimens, respectively (P < 0.0001). IPF lungs also showed increased CXCL13 staining. Plasma CXCL13 concentrations (pg/ml) were greater in 95 patients with IPF (94 ± 8) than in 128 subjects with COPD (53 ± 9) and 57 normal subjects (35 ± 3) (P < 0.0001). Circulating CXCL13 levels were highest in patients with IPF with pulmonary artery hypertension (P = 0.01) or acute exacerbations (P = 0.002). Six-month survival of patients with IPF in the highest quartile of plasma CXCL13 was 65 ± 10% versus 93 ± 10% in the others (hazard ratio, 5.5; 95% confidence interval, 1.8–16.9; P = 0.0008). CXCL13 increases by more than 50% in IPF serial assays, irrespective of initial values, also presaged respiratory failure (hazard ratio, 7.2; 95% confidence interval, 1.3–40.0; P = 0.008). In contrast, CXCL13 clinical associations in subjects with COPD were limited to modest correlations with FEV1 (P = 0.05) and progression of radiographic emphysema (P = 0.05). Conclusions: CXCL13 is increased and is a prognostic biomarker in patients with IPF, and more so than in patients with COPD. This contrast indicates CXCL13 overexpressions are intrinsic to IPF, rather than an epiphenomenon of lung injury. The present data implicate CXCL13 and B cells in IPF pathogenesis, and support considerations for trials of specific B-cell–targeted therapies in patients with this intractable disease.

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.