Ethnicity-specific epigenetic variation in naïve CD4+ T cells and the susceptibility to autoimmunity

Abstract Background Genetic and epigenetic variability contributes to the susceptibility and pathogenesis of autoimmune diseases. T cells play an important role in several autoimmune conditions, including lupus, which is more common and more severe in people of African descent. To investigate inherent epigenetic differences in T cells between ethnicities, we characterized genome-wide DNA methylation patterns in naïve CD4+ T cells in healthy African-Americans and European-Americans, and then confirmed our findings in lupus patients. Results Impressive ethnicity-specific clustering of DNA methylation profiling in naïve CD4+ T cells was revealed. Hypomethylated loci in healthy African-Americans were significantly enriched in pro-apoptotic and pro-inflammatory genes. We also found hypomethylated genes in African-Americans to be disproportionately related to autoimmune diseases including lupus. We then confirmed that these genes, such as IL32, CD226, CDKN1A, and PTPRN2 were similarly hypomethylated in lupus patients of African-American compared to European-American descent. Using patch DNA methylation and luciferase reporter constructs, we showed that methylation of the IL32 promoter region reduces gene expression in vitro. Importantly, bisulfite DNA sequencing demonstrated that cis-acting genetic variants within and directly disrupting CpG sites account for some ethnicity-specific variability in DNA methylation. Conclusion Ethnicity-specific inherited epigenetic susceptibility loci in CD4+ T cells provide clues to explain differences in the susceptibility to autoimmunity and possibly other T cell-related diseases between populations.http://deepblue.lib.umich.edu/bitstream/2027.42/116042/1/13072_2015_Article_37.pd

Surface translocation of ACE2 and TMPRSS2 upon TLR4/7/8 activation is required for SARS-CoV-2 infection in circulating monocytes

Infection of human peripheral blood cells by SARS-CoV-2 has been debated because immune cells lack mRNA expression of both angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease type 2 (TMPRSS2). Herein we demonstrate that resting primary monocytes harbor abundant cytoplasmic ACE2 and TMPRSS2 protein and that circulating exosomes contain significant ACE2 protein. Upon ex vivo TLR4/7/8 stimulation, cytoplasmic ACE2 was quickly translocated to the monocyte cell surface independently of ACE2 transcription, while TMPRSS2 surface translocation occurred in conjunction with elevated mRNA expression. The rapid translocation of ACE2 to the monocyte cell surface was blocked by the endosomal trafficking inhibitor endosidin 2, suggesting that endosomal ACE2 could be derived from circulating ACE2-containing exosomes. TLR-stimulated monocytes concurrently expressing ACE2 and TMPRSS2 on the cell surface were efficiently infected by SARS-CoV-2, which was significantly mitigated by remdesivir, TMPRSS2 inhibitor camostat, and anti-ACE2 antibody. Mass cytometry showed that ACE2 surface translocation in peripheral myeloid cells from patients with severe COVID-19 correlated with its hyperactivation and PD-L1 expression. Collectively, TLR4/7/8-induced ACE2 translocation with TMPRSS2 expression makes circulating monocytes permissive to SARS-CoV-2 infection

Analysis of the common genetic component of large-vessel vasculitides through a meta- Immunochip strategy

Giant cell arteritis (GCA) and Takayasu's arteritis (TAK) are major forms of large-vessel vasculitis (LVV) that share clinical features. To evaluate their genetic similarities, we analysed Immunochip genotyping data from 1,434 LVV patients and 3,814 unaffected controls. Genetic pleiotropy was also estimated. The HLA region harboured the main disease-specific associations. GCA was mostly associated with class II genes (HLA-DRB1/HLA-DQA1) whereas TAK was mostly associated with class I genes (HLA-B/MICA). Both the statistical significance and effect size of the HLA signals were considerably reduced in the cross-disease meta-analysis in comparison with the analysis of GCA and TAK separately. Consequently, no significant genetic correlation between these two diseases was observed when HLA variants were tested. Outside the HLA region, only one polymorphism located nearby the IL12B gene surpassed the study-wide significance threshold in the meta-analysis of the discovery datasets (rs755374, P?=?7.54E-07; ORGCA?=?1.19, ORTAK?=?1.50). This marker was confirmed as novel GCA risk factor using four additional cohorts (PGCA?=?5.52E-04, ORGCA?=?1.16). Taken together, our results provide evidence of strong genetic differences between GCA and TAK in the HLA. Outside this region, common susceptibility factors were suggested, especially within the IL12B locus

A genome-wide association study identifies risk alleles in plasminogen and P4HA2 associated with giant cell arteritis

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analysed in 2,134 cases and 9,125 unaffected controls from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, P = 1.94E-54, per-allele OR = 1.79; and rs9275592, P = 1.14E-40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, P = 1.23E-10, OR = 1.28; and rs128738, P = 4.60E-09, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis

Subclinical CMV viremia is associated with increased nosocomial infections and prolonged hospitalization in patients with systemic autoimmune diseases

Background: Subclinical cytomegalovirus (CMV) viremia is associated with adverse outcomes in select immunosuppressed populations, including other infections, prolonged hospitalization, and mortality. We examined the incidence and impact of subclinical CMV viremia in hospitalized patients with systemic autoimmune diseases (AD) [systemic lupus erythematosus (SLE) or anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV)] using the new Abbott RealTime CMV assay (RT assay). Methods: Prospectively collected blood samples were obtained from AD hospitalized patients at study entry and 1 week later or at discharge from the hospital. All samples were tested in batch using the RT assay, with a LLOD (LLOQ) at 21 IU/mL (32 IU/mL). Results: Twenty-three inpatients (10 SLE, 8 AAV, 5 controls), and 31 outpatient controls were recruited. Detectable CMV viremia was found in 61% (11/18) of inpatient AD subjects, 3% (1/31) of outpatient AD subjects, and no inpatient controls (p<0.001). Average CMV viremia for AD patients at entry was 51.8 IU/mL (33.1 copies/mL) and at 7 days was 175.3 IU/mL (112.4 copies/mL). CMV viremia was associated with increased ICU stay (25 vs. 5 days, p=0.033), hospital stay (35 vs. 10 days, p=0.014) and nosocomial infections (7 vs. 1, p=0.007). CMV viremia was not associated with overall severity of illness at entry nor disease activity or damage. Conclusions/Public Health Relevance: Over half of hospitalized AD patients in our cohort had detectable CMV viremia, which was associated with increased length of hospital stay and nosocomial infections. These data suggest that subclinical CMV viremia may wield significant adverse effects in hospitalized patients with SLE and AAV, and be a potentially modifiable risk factor to improve outcomes in this population

Autoimmune disease and vaccination: impact on infectious disease prevention and a look at future applications

Vaccines hold promise both for the prevention of infections and as potential immunologic therapy for patients with autoimmune disease (AD). These patients are at high risk for both common and opportunistic infections, but this risk can be significantly reduced and even obviated with the use of recommended available vaccines. Unfortunately, patients with ADs are not routinely offered or provided indicated vaccinations and have higher rates of complications from vaccine-preventable illnesses than patients without ADs. In addition, vaccine therapy is currently under study for the treatment of autoimmune disorders, with early studies demonstrating immunomodulatory effects that may counter undesired immune activation and alleviate disease activity

From a myth to a menace: Increased disease severity and poor outcomes in an urban cohort of african-american patients with ANCA-associated vasculitis

Background/Purpose: Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is a systemic inflammatory disorder frequently associated with significant disability and morbidity, which may lead to end-stage renal disease (ESRD) or death. The purpose of our study was to examine disease characteristics and outcomes in an urban African-American (AA) cohort with AAV and compare them with a matched Caucasian (CA) cohort with AAV. Methods: A detailed electronic chart review of patients with positive anti-neutrophil cytoplasmic antibody testing was performed to identify patients with AAV using the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Patients with isolated renal disease were included if they demonstrated biopsy evidence of necrotizing pauci-immune glomerulonephritis with P-ANCA/MPO or C-ANCA/PR-3 positivity at the time of diagnosis. African-American AAV patients were matched 1:2 to CA patients with AAV by gender and age within 5 years. Results: 21 AA patients with AAV were identified, of which fourteen (66.7%) were female, with a mean age at diagnosis of 61 years. Microscopic polyangiitis occurred more commonly in AA patients than CA patients (38% vs. 14%), while granulomatosis with polyangiitis was more common in CA patients (76% vs. 47%). AA patients had more severe disease at the time of diagnosis, with increased need on admission for ICU care (50% vs. 23%, p=0.04), mechanical ventilation (40% vs. 10%, p=0.007), hemodialysis (52% vs. 19% p=0.007), with lower hemoglobin (mean 7.0 vs. 10.0, p=0.001), and higher serum creatinine (mean 6.1 vs. 2.7, p=0.001). Although the likelihood of receiving high dose pulse steroid therapy at diagnosis was not significantly different between groups, the mean dose of prednisone initiated at disease diagnosis in AA patients was significantly lower (143 mg vs. 455 mg, p=0.004), while the concomitant use of steroid-sparing immunosuppressive agents for induction therapy did not differ significantly between groups. There was a significant increase in the incidence of ESRD in AA patients when compared to CA patients (62% vs. 19%, p=0.001) without significant differences in the prevalence or severity of hypertension and diabetes at the time of diagnosis between groups. Death occurred in 33% of the AA patients and 21% of CA patients during follow up. Conclusion: In an urban cohort, AA patients with AAV were more likely to present with severe disease requiring ICU care, mechanical ventilation, and hemodialysis compared to Caucasian patients with AAV. Despite similar rates and severity of diabetes and hypertension in these populations, African-American patients were significantly more likely to develop ESRD. There are many factors that could influence these outcomes, including other comorbid conditions, genetics, differences in treatment and response to immunosuppressive therapies, environmental factors, and limited access to care because of socioeconomic factors. Further study is needed to better understand factors that influence AAV severity and course in this population in order to improve long-term outcomes and survival

Subclinical CMV viremia is associated with increased nosocomial infections and prolonged hospitalization in patients with systemic autoimmune diseases

OBJECTIVE: Subclinical cytomegalovirus (CMV) viremia has been associated with other infections, prolonged hospitalization, and mortality in select immunosuppressed populations. We examined the incidence and outcomes of subclinical CMV viremia in hospitalized patients with systemic autoimmune diseases (AD) [systemic lupus erythematosus (SLE) or anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV)] using a highly sensitive CMV assay. METHODS: Prospectively collected samples were obtained from AD hospitalized patients at study entry with a second sample collected 1 week later or at hospital discharge. Controls included age- and gender- matched inpatients without AD and outpatients with AD. All samples were tested in batch using the Abbott RealTime CMV for investigational use assay (RT assay), with a LLOD (LLOQ) at 21 IU/mL (32 IU/mL). RESULTS: Twenty-three inpatients (10 SLE, 8 AAV, 5 controls), and 31 outpatient controls were recruited. Subclinical CMV viremia was found in 61% (11/18) of inpatient AD subjects, 3% (1/31) of outpatient AD subjects, and in none of the five inpatient controls (p \u3c 0.001). CMV viremia was associated with increased median length of ICU stay (13 vs. 4 days, p = 0.033), hospital stay (17 vs. 9 days, p = 0.014) and increased nosocomial infections (7 vs. 1, p = 0.007). CMV viremia was not associated with overall severity of illness nor with disease-specific activity or damage. CONCLUSION: Over one-half of hospitalized AD patients in our cohort had detectable CMV viremia, which was associated with increased length of hospital stay and nosocomial infections. These data suggest that further study of the immunomodulatory effects of subclinical CMV viremia in AD is warranted

Age-associated DNA methylation changes in naive CD4+ T cells suggest an evolving autoimmune epigenotype in aging T cells

AIM: We sought to define age-associated DNA methylation changes in naive CD4+ T cells. MATERIALS & METHODS: Naive CD4+ T cells were collected from 74 healthy individuals (age 19-66 years), and age-related DNA methylation changes were characterized. RESULTS: We identified 11,431 age-associated CpG sites, 57% of which were hypermethylated with age. Hypermethylated sites were enriched in CpG islands and repressive transcription factor binding sites, while hypomethylated sites showed T cell specific enrichment in active enhancers marked by H3K27ac and H3K4me1. Our data emphasize cancer-related DNA methylation changes with age, and also reveal age-associated hypomethylation in immune-related pathways, such as T cell receptor signaling, FCγR-mediated phagocytosis, apoptosis and the mammalian target of rapamycin signaling pathway. The MAPK signaling pathway was hypermethylated with age, consistent with a defective MAPK signaling in aging T cells. CONCLUSION: Age-associated DNA methylation changes may alter regulatory mechanisms and signaling pathways that predispose to autoimmunity