Autoantibody Profiles in Collagen Disease Patients with Interstitial Lung Disease (ILD): Antibodies to Major Histocompatibility Complex Class I-Related Chain A (MICA) as Markers of ILD.
ABSTRACT: Interstitial lung disease (ILD) is frequently associated with collagen disease. It is then designated as collagen vascular disease-associated ILD (CVD-ILD), and influences patients' prognosis. The prognosis of acute-onset diffuse ILD (AoDILD) occurring in patients with collagen disease is quite poor. Here, we report our investigation of auto-antibody (Ab) profiles to determine whether they may be useful in diagnosing CVD-ILD or AoDILD in collagen disease. Auto-Ab profiles were analyzed using the Lambda Array Beads Multi-Analyte System, granulocyte immunofluorescence test, Proto-Array Human Protein Microarray, AlphaScreen assay, and glutathione S-transferase capture enzyme-linked immunosorbent assay in 34 patients with rheumatoid arthritis (RA) with or without CVD-ILD and in 15 patients with collagen disease with AoDILD. The average anti-major histocompatibility complex class I-related chain A (MICA) Ab levels were higher in RA patients with CVD-ILD than in those without (P = 0.0013). The ratio of the average anti-MICA Ab level to the average anti-human leukocyte antigen class I Ab level (ie, MICA/Class I) was significantly higher in RA patients with CVD-ILD compared with those without (P = 4.47 × 10(-5)). To the best of our knowledge, this is the first report of auto-Ab profiles in CVD-ILD. The MICA/Class I ratio could be a better marker for diagnosing CVD-ILD than KL-6 (Krebs von den lungen-6).
Project description:Auto-antibody (Ab) profiles between acute-onset diffuse ILD (AoDILD) and stable states of 25 collagen disease patients were compared to screen biomarkers or pathogenic auto-Abs. Overall design: Auto-Ab levels in pooled sera were compared between the AoDILD and stable states with ProtoArray.
Project description:Interstitial lung disease (ILD) is a chronic, progressive fibrotic lung disease with a dismal prognosis. ILD of unknown etiology is referred to as idiopathic interstitial pneumonia (IIP), which is sporadic in the majority of cases. ILD is frequently accompanied by rheumatoid arthritis (RA), systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM), and other autoimmune diseases, and is referred to as collagen vascular disease-associated ILD (CVD-ILD). Susceptibility to ILD is influenced by genetic and environmental factors. Recent advances in radiographic imaging techniques such as high-resolution computed tomography (CT) scanning as well as high-throughput genomic analyses have provided insights into the genetics of ILD. These studies have repeatedly revealed an association between IIP (sporadic and familial) and a single nucleotide polymorphism (SNP) in the promoter region of the mucin 5B (MUC5B). HLA-DRB1*11 alleles have been reported to correlate with ILD in European patients with SSc, whereas in Japanese patients with RA, the HLA-DR2 serological group was identified. The aim of this review is to describe the genetic background of sporadic IIP, CVD-ILD, drug-induced-ILD (DI-ILD), pneumoconiosis, and hypersensitivity pneumonitis. The genetics of ILD is still in progress. However, this information will enhance the understanding of the pathogenesis of ILD and aid the identification of novel therapeutic targets for personalized medicine in future.
Project description:A population-based cohort showed an association between cigarette smoking and subclinical parenchymal lung disease defined as regions of increased computed tomography (CT) lung densitometry. This technique has not been applied to the rheumatoid arthritis (RA) population where associated ILD is highly prevalent. The association between cumulative cigarette smoking and volume of areas of high attenuation (HAA: >-600 and <-250 Hounsfield Units) on full inspiratory CT was compared in 172 RA participants and 3,969 controls in a general population sample. Multivariable regression models were used to adjust for demography, anthropometrics, percent emphysema, and CT parameters. The mean cumulative cigarette smoking exposure was 25 (IQR 10-42) and 15(IQR 5-31) pack-years for the RA and non-RA cohorts, respectively. Mean HAA was 153(±57) cm3 and 129(±50) cm3 in the RA and non-RA cohorts, respectively. Each 10 cigarette pack-year increment was associated with a higher HAA by 0.03% (95% CI, 0.007-0.05%) in RA patients and by 0.008% (95% CI, 0.003-0.01%) in those without RA (interaction p = 0.001). Cigarette smoking was associated with higher lung attenuation; with a magnitude of association more pronounced in those with RA than in the general population. These data suggest that cigarette smoking may be a more potent ILD risk factor for RA patients than in the general population.
Project description:OBJECTIVE:To compare serum anti-malondialdehyde-acetaldehyde (anti-MAA) antibody levels and MAA expression in lung tissue from patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) to those found in controls. METHODS:Anti-MAA antibody (IgA, IgM, IgG) concentrations were measured in patients with RA-ILD and compared to those of RA patients with chronic obstructive pulmonary disease (COPD) and RA patients without lung disease. Associations between anti-MAA antibody with RA-ILD were assessed using multivariable logistic regression. Lung tissue from patients with RA-ILD, other ILD, or emphysema, and from controls (n = 3 per group) were stained for MAA, citrulline, macrophages (CD68), T cells (CD3), B cells (CD19/CD27), and extracellular matrix proteins (type II collagen, fibronectin, vimentin). Tissue expression and colocalization with MAA were quantified and compared. RESULTS:Among 1,823 RA patients, 90 had prevalent RA-ILD. Serum IgA and IgM anti-MAA antibody concentrations were higher in RA-ILD than in RA with COPD or RA alone (P = 0.005). After adjustment for covariates, the highest quartiles of IgA anti-MAA antibody concentration (odds ratio 2.09 [95% confidence interval 1.11-3.90]) and IgM (odds ratio 2.23 [95% confidence interval 1.19-4.15]) were significantly associated with the presence of RA-ILD. MAA expression in RA-ILD lung tissue was greater than in tissue from all other groups (P < 0.001), and it colocalized with citrulline (r = 0.79), CD19+ B cells (r = 0.78), and extracellular matrix proteins (type II collagen [r = 0.72] and vimentin [r = 0.77]) to the greatest degree in RA-ILD. CONCLUSION:Serum IgA and IgM anti-MAA antibody is associated with ILD among RA patients. MAA is highly expressed in RA-ILD lung tissue, where it colocalizes with other RA autoantigens, autoreactive B cells, and extracellular matrix proteins, highlighting its potential role in the pathogenesis of RA-ILD.
Project description:This study compared the effect of collagen vascular disease-associated interstitial lung disease (CVD-ILD) with that of idiopathic interstitial pneumonias (IIPs) on the outcomes of lung cancer surgery.This study retrospectively reviewed the medical records of patients who underwent surgery for non-small cell lung cancer (NSCLC) and compared the data of 16 patients with CVD-ILD with those of 70 patients with IIPs. The patterns of interstitial lung disease (ILD) on chest computed tomography were classified into usual interstitial pneumonia (UIP) and non-specific interstitial pneumonia (NSIP) patterns.The numbers of UIP and NSIP patterns were 10 (62.5%) and 6 (37.5%) patients in CVD-ILD group, and 62 (88.6%) and 8 (11.4%) patients in IIPs group, respectively. A postoperative acute exacerbation (AE) appeared in 1 patient (6.3%) in the CVD-ILD group and 6 patients (8.6%) in the IIPs group. No significant differences in the incidence of postoperative AE and mortalities were observed between the two groups. The five-year overall survival rates of the CVD-ILD and IIPs groups were 37.5 and 49.2%, respectively.Surgery for NSCLC in CVD-ILD patients appear to cause no increase in postoperative AE and mortality in comparison to that seen in IIPs patients. Similar to IIPs, CVD-ILD might therefore affect the prognosis of resected NSCLC.
Project description:Interstitial lung disease (ILD) can be a severe extra-articular disease manifestation in Rheumatoid Arthritis (RA). A potential role of fibrocytes in RA associated ILD (RA-ILD) has not previously been described. We present a modified faster method for measuring circulating fibrocytes, without intracellular staining. The results are compared to the traditional culture method, where the number of monocytes that differentiate into mature fibrocytes in vitro are counted. The results are following compared to disease activity in patients with severe asthma, ILD, RA (without diagnosed ILD) and RA with verified ILD (RA-ILD).CD45+ CD34+ CD11b+ (7-AAD- CD3- CD19- CD294-) cells were isolated by cell sorting and stained for pro-collagen type 1. Thirty-nine patients (10 RA, 9 ILD and 10 with severe asthma, 10 with RA-ILD) and 10 healthy controls (HC) were included. Current medication, disease activity, pulmonary function test and radiographic data were collected. Circulating fibrocytes were quantified by flow cytometry. Peripheral blood mononuclear cells were isolated and cultured for 5 days and the numbers of mature fibrocytes were counted.90.2% (mean, SD = 1.5%) of the sorted cells were pro-collagen type 1 positive and thereby fulfilled the criteria for being circulating fibrocytes. The ILD and RA-ILD groups had increased levels of circulating fibrocytes compared to HC (p < 0.05). Levels of circulating fibrocytes correlated overall to number of monocytes that subsequently in vitro differentiated to mature fibrocytes (r = 0.81, p < 0.001). RA patients with pathologically reduced diffusion capacity for carbon monoxide adjusted for hemoglobin (DLCOc) in both the RA and in the combined RA + RA-ILD group, had significantly higher levels of both circulating and number of cultured mature fibrocytes (both p < 0.05). In both groups, the level of circulating fibrocytes and number of mature fibrocytes in culture also correlated to a reduction in DLCOc (r = -0.61 an r = -0.58 both p < 0.05).We presented a fast and valid method for measuring circulating fibrocytes using flow cytometry on lysed peripheral blood. Further, we showed for the first time, that the level of circulating fibrocytes correlated with the number of peripheral blood mononuclear cells, that differentiated into mature fibrocytes in vitro. Reduced DLCOc was correlated with high levels of circulating and mature fibrocytes in RA, which have not been reported previously. In such, this study suggests that fibrocytes may exhibit an important role in the pathogenesis of RA-ILD, which requires further clarification in future studies.ClinicalTrials.gov : NCT02711657 , registered 13/3-2016, retrospectively registered.
Project description:Rheumatoid arthritis (RA)-associated interstitial lung disease (ILD), a primary cause of mortality in patients with RA, has limited treatment options. A previously established RA model in D1CC transgenic mice aberrantly expressed major histocompatibility complex class II genes in joints, developing collagen II-induced polyarthritis and anti-cyclic citrullinated peptide antibodies and interstitial pneumonitis, similar to those in humans. Molecular hydrogen (H2 ) is an efficient antioxidant that permeates cell membranes and alleviates the reactive oxygen species-induced injury implicated in RA pathogenesis. We used D1CC mice to analyse chronic lung fibrosis development and evaluate H2 treatment effects. We injected D1CC mice with type II collagen and supplied them with H2 -rich or control water until analysis. Increased serum surfactant protein D values and lung densities images were observed 10 months after injection. Inflammation was patchy within the perilymphatic stromal area, with increased 8-hydroxy-2'-deoxyguanosine-positive cell numbers and tumour necrosis factor-α, BAX, transforming growth factor-β, interleukin-6 and soluble collagen levels in the lungs. Inflammatory and fibrotic changes developed diffusely within the perilymphatic stromal area, as observed in humans. H2 treatment decreased these effects in the lungs. Thus, this model is valuable for studying the effects of H2 treatment and chronic interstitial pneumonia pathophysiology in humans. H2 appears to protect against RA-ILD by alleviating oxidative stress.
Project description:Assess the impact of chronic lung diseases (CLD) on survival in rheumatoid arthritis (RA). Among participants in the Veterans Affairs Rheumatoid Arthritis (VARA) Registry, a prospective cohort of U.S. Veterans with RA, we identified CLD and cardiovascular disease (CVD) using administrative and registry data. Demographics, smoking status, RA characteristics including Disease Activity Score in 28 joints (DAS28), and disease-modifying anti-rheumatic drug (DMARD) use were obtained from registry data, which were linked to the National Death Index to obtain vital status. We evaluated associations of CLD with survival using the multivariable Cox regression models. Among a large (n?=?2053), male-predominant (91%) RA cohort, 554 (27%) had CLD at enrollment. Mortality risk was increased 1.51-fold (95% CI 1.26-1.81) in RA patients with CLD after multivariable adjustment, a risk that was similar to that observed with CVD (HR CLD alone 1.46 [1.03-2.06]; CVD alone 1.62 [1.35-1.94]). Survival was significantly reduced in those with interstitial lung disease (ILD) as well as other forms of CLD. Mortality risk with methotrexate and biologic use was not different in those with CLD compared to those without (p interaction ??0.15) using multiple exposure definitions and propensity score adjustment. Mortality risk is significantly increased in RA patients with CLD. This risk is attributable not only to ILD but also to other chronic lung conditions and does not appear to be substantially greater in those receiving methotrexate or biologic therapies. Comorbid lung disease should be targeted as a means of improving long-term outcomes in RA.
Project description:The pathogenesis of Rheumatoid Arthritis (RA) is not fully understood, probably influenced by genetic and environmental factors. Interstitial Lung Disease (ILD) is an extra-articular manifestation of RA, which contributes significantly to morbidity and mortality. The identification of anti-HLA antibodies has been useful in the transplantation field; however, its contribution to autoimmune diseases as RA has not been fully studied. We aimed to determine the presence of anti-HLA antibodies in RA patients with and without ILD and its possible association with clinical and biochemical markers. One-hundred and forty-seven RA patients, of which 65 had ILD (RA-ILD group), were included. Sera samples for Anti-HLA Class II LABScreen panel-reactive antibodies (PRA) were analyzed. In both groups, women predominated, and lung function was worse in patients with ILD. The anti-CCP+ (UI/mL) was higher in the RA group in comparison to RA-ILD (p < 0.001). Expositional risk factors (tobacco smoking and biomass-burning smoke) were higher in RA-ILD patients. PRA+ was identified in ~25% RA-ILD patients, while ~29% in the RA group. The CRP levels have a positive correlation with the percentage of reactivity (%PRA, p = 0.02, r2 = 0.60) in the RA-ILD group. In conclusion, anti-HLA antibodies correlate with C-reactive protein levels in RA patients with ILD.