The most critical forms of coronavirus disease 2019 (COVID-19) are associated with excessive activation of the inflammasome. Despite the COVID-19 impact on public health, we still do not fully ...understand the mechanisms by which the inflammatory response influences disease prognosis. Accordingly, we aimed to elucidate the role of polymorphisms in the key genes of the formation and signaling of the inflammasome as biomarkers of COVID-19 severity. For this purpose, a large and well-defined cohort of 377 COVID-19 patients with mild (n = 72), moderate (n = 84), severe (n = 100), and critical (n = 121) infections were included. A total of 24 polymorphisms located in inflammasome-related genes (
,
,
,
,
,
,
,
,
, and
) were genotyped in all of the patients and in the 192 healthy controls (HCs) (who were without COVID-19 at the time of and before the study) by RT-qPCR. Our results showed that patients with mild, moderate, severe, and critical COVID-19 presented similar allelic and genotypic distribution in all the variants studied. No statistically significant differences in the haplotypic distribution of
,
,
,
,
,
, and
were observed between COVID-19 patients, who were stratified by disease severity. Each stratified group of patients presented a similar genetic distribution to the HCs. In conclusion, our results suggest that the inflammasome polymorphisms studied are not associated with the worsening of COVID-19.
Interstitial lung disease (ILD) constitutes the most critical comorbidity in autoimmune diseases (ADs) and its early diagnosis remains a challenge for clinicians. Accordingly, we evaluated whether ...E-selectin, ICAM-1, and ET-1, key molecules in endothelial damage, could be useful biomarkers for the detection of AD-ILD
. We recruited patients with rheumatoid arthritis (RA)-ILD
(
= 21) and systemic sclerosis (SSc)-ILD
(
= 21). We included comparison groups of patients: RA-ILD
(
= 25), SSc-ILD
(
= 20), and idiopathic pulmonary fibrosis (IPF) (
= 21). Serum levels of these proteins were determined by ELISA. E-selectin, ICAM-1, and ET-1 serum levels were increased in RA-ILD
and IPF patients in comparison to RA-ILD
patients. Additionally, SSc-ILD
and IPF patients exhibited higher ICAM-1 levels than those with SSc-ILD
. The ability of E-selectin, ICAM-1, and ET-1 to discriminate RA-ILD
from RA-ILD
patients, and ICAM-1 to distinguish SSc-ILD
from SSc-ILD
patients was confirmed using ROC curve analysis. Furthermore, elevated levels of ET-1 and E-selectin correlated with lung function decline in RA-ILD
and SSc-ILD
patients, respectively. In conclusion, our findings support the relevant role of E-selectin, ICAM-1, and ET-1 in RA-ILD
patients as well as of ICAM-1 in SSc-ILD
patients, constituting potential screening blood biomarkers of ILD in AD. Moreover, this study suggests ET-1 and E-selectin as possible indicators of worsening lung function in RA-ILD
and SSc-ILD
patients, respectively.
Abstract
BAFF, APRIL and BAFF-R are key proteins involved in the development of B-lymphocytes and autoimmunity. Additionally,
BAFF, APRIL
and
BAFFR
polymorphisms were associated with immune-mediated ...conditions, being
BAFF
GCTGT>A a shared insertion-deletion genetic variant for several autoimmune diseases. Accordingly, we assessed whether
BAFF, APRIL
and
BAFFR
represent novel genetic risk factors for Immunoglobulin-A vasculitis (IgAV), a predominantly B-lymphocyte inflammatory condition.
BAFF
rs374039502, which colocalizes with
BAFF
GCTGT>A, and two tag variants within
APRIL
(rs11552708 and rs6608) and
BAFFR
(rs7290134 and rs77874543) were genotyped in 386 Caucasian IgAV patients and 806 matched healthy controls. No genotypes or alleles differences were observed between IgAV patients and controls when
BAFF, APRIL
and
BAFFR
variants were analysed independently. Likewise, no statistically significant differences were found in the genotype and allele frequencies of
BAFF, APRIL
or
BAFFR
when IgAV patients were stratified according to the age at disease onset or to the presence/absence of gastrointestinal (GI) or renal manifestations. Similar results were disclosed when
APRIL
and
BAFFR
haplotypes were compared between IgAV patients and controls and between IgAV patients stratified according to the clinical characteristics mentioned above. Our results suggest that
BAFF, APRIL
and
BAFFR
do not contribute to the genetic network underlying IgAV.
Interstitial lung disease (ILD) increases morbidity and mortality in patients with rheumatoid arthritis (RA). Although the pathogenesis of ILD associated with RA (RA-ILD
) remains poorly defined, ...vascular tissue is crucial in lung physiology. In this context, endothelial progenitor cells (EPC) are involved in endothelial tissue repair. However, little is known about their implication in RA-ILD
. Accordingly, we aimed to investigate the potential role of EPC related to endothelial damage in RA-ILD
. EPC quantification in peripheral blood from 80 individuals (20 RA-ILD
patients, 25 RA-ILD
patients, 21 idiopathic pulmonary fibrosis (IPF) patients, and 14 healthy controls) was performed by flow cytometry. EPC were considered as CD34
, CD45
, CD309
and CD133
. A significant increase in EPC frequency in RA-ILD
patients, as well as in RA-ILD
and IPF patients, was found when compared with controls (
< 0.001,
= 0.02 and
< 0.001, respectively). RA-ILD
patients exhibited a higher EPC frequency than the RA-ILD
ones (
= 0.003), but lower than IPF patients (
< 0.001). Our results suggest that EPC increase may represent a reparative compensatory mechanism in patients with RA-ILD
. The degree of EPC frequency may help to identify the presence of ILD in RA patients and to discriminate RA-ILD
from IPF.
Endothelial progenitor cells (EPC), which are key effectors in the physiologic vascular network, have been described as relevant players in autoimmune diseases. We previously showed that EPC ...frequency may help to identify the presence of interstitial lung disease (ILD) in rheumatoid arthritis patients. Given that ILD constitutes the main cause of mortality in systemic sclerosis (SSc) patients, we aimed to determine the EPC contribution to the pathogenic processes of vasculopathy and lung fibrosis in SSc-ILD+. EPC quantification was performed by flow cytometry on blood from 83 individuals: 21 SSc-ILD+ patients and subjects from comparative groups (20 SSc-ILD− and 21 idiopathic pulmonary fibrosis (IPF) patients and 21 healthy controls (HC)). EPC were considered as CD34+, CD45low, CD309+, and CD133+. A significant increase in EPC frequency was found in SSc-ILD+ patients when compared to HC (p < 0.001). SSc-ILD+ patients exhibited a higher EPC frequency than SSc-ILD− patients (p = 0.012), whereas it was markedly reduced compared to IPF patients (p < 0.001). EPC frequency was higher in males (p = 0.04) and negatively correlated to SSc duration (p = 0.04) in SSc-ILD+ patients. Our results indicate a role of EPC in the processes of vasculopathy and lung fibrosis in SSc-ILD+. EPC frequency may be considered as a biomarker of ILD in SSc patients.
(1) Background: We explored, for the first time, the contribution of angiogenic T cells (TAng) in interstitial lung disease associated to autoimmune disease (AD-ILD
) as potential biomarkers of the ...disease, evaluating their role in the underlying vasculopathy and lung fibrosis. Additionally, the relationship of TAng with clinical manifestations and cellular and molecular endothelial dysfunction-related biomarkers was assessed. (2) Methods: We included 57 AD-ILD
patients (21 with rheumatoid arthritis (RA)-ILD
, 21 with systemic sclerosis (SSc)-ILD
and 15 with other AD-ILD
) and three comparative groups: 45 AD-ILD
patients (25 RA-ILD
and 20 SSc-ILD
); 21 idiopathic pulmonary fibrosis (IPF) patients; 21 healthy controls (HC). TAng were considered as CD3
CD184
CD31
by flow cytometry. (3) Results: A similar TAng frequency was found between AD-ILD
and IPF, being in both cases lower than that observed in AD-ILD
and HC. A lower TAng frequency was associated with negative Scl-70 status and lower FEV1/FVC ratio in SSc-ILD
, as well as with men in RA-ILD
and non-specific interstitial pneumonia radiological pattern in other AD-ILD
. No relationship between TAng and endothelial progenitor cells, endothelial cells and vascular endothelial growth factor gene expression and protein levels was disclosed. (4) Conclusions: Our findings suggest TAng as potential biomarkers for the early diagnosis of ILD in AD.
The search for biomarkers that can help to establish an early diagnosis and prognosis of interstitial lung disease (ILD) is of potential interest.
polymorphisms have been implicated in the ...development of several lung disorders. Consequently, we assessed, for the first time, the role of
polymorphisms in the susceptibility and severity of ILD. A total of 436 Caucasian ILD patients (244 with idiopathic interstitial pneumonias (IIPs) and 192 with non-IIP) and 536 ethnically-matched healthy controls were genotyped for
rs833061, rs1570360, rs2010963, rs3025020, and rs3025039 polymorphisms by TaqMan assays. Pulmonary function tests were collected from all the patients. VEGF serum levels were determined by ELISA in a subgroup of patients. No
genotype, allele, carrier, or haplotype differences were found between ILD patients and controls as well as between IIP and non-IIP patients. However, an association of rs1570360 with IIP in women and also with lung function in IIP patients was found. None of the
polymorphisms were associated with VEGF levels. In conclusion, our results suggest that
does not seem to play a relevant role in ILD, although rs1570360 may influence the severity of ILD in women and a worse outcome in IIP patients.
Early diagnosis of interstitial lung disease (ILD) associated with rheumatoid arthritis (RA) constitutes a challenge for the clinicians. Pulmonary vasculopathy is relevant in the development of ...interstitial lung disease. Accordingly, we aimed to explore the role of vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and asymmetric dimethylarginine (ADMA), key molecules in the vasculopathy, as potential biomarkers of pulmonary fibrosis in RA-ILD
.
We included 21 RA-ILD
patients and two comparative groups: 25 RA-ILD
patients and 21 idiopathic pulmonary fibrosis (IPF) patients. Serum levels of the molecules were determined by ELISA, and mRNA expression was quantified by qPCR.
VCAM-1, MCP-1 and ADMA serum levels were increased in RA-ILD
patients in relation to RA-ILD
and IPF patients. Additionally, RA-ILD
patients exhibited increased
(gene encoding MCP-1) and decreased
(gene related to ADMA synthesis) mRNA expression in relation to RA-ILD
patients. A lower expression of
,
, and
was observed in RA-ILD
patients when compared with those with IPF. Furthermore, MCP-1 serum levels and
mRNA expression were positively correlated with RA duration, and ADMA serum levels were positively associated with C-reactive protein in RA-ILD
patients.
Our study suggests that VCAM-1, MCP-1 and ADMA could be considered as useful biomarkers to identify ILD in RA patients, as well as to discriminate RA-ILD
from IPF, contributing to the early diagnosis of RA-ILD
.
Objective
To investigate the genetic background influencing the development of cardiovascular (CV) disease in patients with rheumatoid arthritis (RA).
Methods
We performed a genome‐wide association ...study (GWAS) in which, after quality control and imputation, a total of 6,308,944 polymorphisms across the whole genome were analyzed in 2,989 RA patients of European origin. Data on subclinical atherosclerosis, obtained through assessment of carotid intima‐media thickness (CIMT) and presence/absence of carotid plaques by carotid ultrasonography, were available for 1,355 individuals.
Results
A genetic variant of the RARB gene (rs116199914) was associated with CIMT values at the genome‐wide level of significance (minor allele G β coefficient 0.142, P = 1.86 × 10−8). Interestingly, rs116199914 overlapped with regulatory elements in tissues related to CV pathophysiology and immune cells. In addition, biologic pathway enrichment and predictive protein–protein relationship analyses, including suggestive GWAS signals of potential relevance, revealed a functional enrichment of the collagen biosynthesis network related to the presence/absence of carotid plaques (Gene Ontology no. 0032964; false discovery rate–adjusted P = 4.01 × 10−3). Furthermore, our data suggest potential influences of the previously described candidate CV risk loci NFKB1, MSRA, and ZC3HC1 (P = 8.12 × 10−4, P = 5.94 × 10−4, and P = 2.46 × 10−4, respectively).
Conclusion
The present findings strongly suggest that genetic variation within RARB contributes to the development of subclinical atherosclerosis in patients with RA.
MUC5B rs35705950 (G/T) is strongly associated with idiopathic pulmonary fibrosis (IPF) and also contributes to the risk of interstitial lung disease (ILD) in rheumatoid arthritis (RA-ILD) and chronic ...hypersensitivity pneumonitis (CHP). Due to this, we evaluated the implication of MUC5B rs35705950 in antisynthetase syndrome (ASSD), a pathology characterised by a high ILD incidence. 160 patients with ASSD (142 with ILD associated with ASSD ASSD-ILD+), 232 with ILD unrelated to ASSD (comprising 161 IPF, 27 RA-ILD and 44 CHP) and 534 healthy controls were genotyped. MUC5B rs35705950 frequency did not significantly differ between ASSD-ILD+ patients and healthy controls nor when ASSD patients were stratified according to the presence/absence of anti Jo-1 antibodies or ILD. No significant differences in MUC5B rs35705950 were also observed in ASSD-ILD+ patients with a usual interstitial pneumonia (UIP) pattern when compared to those with a non-UIP pattern. However, a statistically significant decrease of MUC5B rs35705950 GT, TT and T frequencies in ASSD-ILD+ patients compared to patients with ILD unrelated to ASSD was observed. In summary, our study does not support a role of MUC5B rs35705950 in ASSD. It also indicates that there are genetic differences between ILD associated with and that unrelated to ASSD.
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