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Characterization of Regulatory Receptors on Plasmacytoid Dendritic Cells in Lupus [Meeting Abstract]

Jensen, M; Nln, I; Iwamoto, T; Dorschner, J; Vsetecka, D; Paredes, J; Ruiz, R F; Muskardin, T W; Niewold, T
Background/Purpose: To characterize regulatory surface receptors on blood plasmacytoid dendritic cells (PDCs) of lupus patients and controls to determine if receptor expression and function associates with disease activity or clinical characteristics in SLE.
Method(s): Quantitative multicolor flow cytometry was used to measure immunoglobulin like transcript 7 (ILT7), bone marrow derived antigen 2 (BDCA2), ILT3, Fc epsilon receptor I (FcRI), leukocyte-associated immunoglobulin-receptor 1 (LAIR1), natural killer cell P44-related protein (NKp44), bone marrow stromal cell antigen 2 (BST2), dendritic cell (DC) immunoreceptor (DCIR), and Fc gamma receptor IIa (FcgammaRII) on PDCs of peripheral blood mononuclear cells (PBMC) from 65 SLE patients and 15 controls. For functional studies, PBMC from 9 SLE and 9 controls were treated with ILT7 and BDCA2 crosslinking antibodies followed by TLR9 agonists.
Result(s): Significant associations were found between multiple receptors, IFN levels, SLEDAI scores, and autoreactive antibody titers. ILT7 expression correlated inversely with SLEDAI, and ANA titers. High IFN SLE patients had increased levels of the ILT7 ligand BST2 and at the same time reduced ILT7 expression. BDCA2 levels were 5-fold higher than ILT7 levels, and were also inversely correlated with SLEDAI. Crosslinking ILT7 only weakly inhibited IFN secretion. Crosslinking BDCA2 significantly reduced IFN production in SLE patient cells, but this was much greater in patients with low SLEDAI scores than those with high SLEDAI scores.
Conclusion(s): We identify associations between PDC regulatory receptors and clinical disease in lupus patients, and dominant inhibitory function of BDCA2 over ILT7 in pDC type I IFN secretion with dependency upon disease activity
EMBASE:639966024
ISSN: 2326-5205
CID: 5513062

Interferon pathway lupus risk alleles modulate risk of death from acute COVID-19

Nln, Ilona; Fernandez-Ruiz, Ruth; Muskardin, Theresa L Wampler; Paredes, Jacqueline L; Blazer, Ashira D; Tuminello, Stephanie; Attur, Mukundan; Iturrate, Eduardo; Petrilli, Christopher M; Abramson, Steven B; Chakravarti, Aravinda; Niewold, Timothy B
Type I interferon (IFN) is critical in our defense against viral infections. Increased type I IFN pathway activation is a genetic risk factor for systemic lupus erythematosus (SLE), and a number of common risk alleles contribute to the high IFN trait. We hypothesized that these common gain-of-function IFN pathway alleles may be associated with protection from mortality in acute COVID-19. We studied patients admitted with acute COVID-19 (756 European-American and 398 African-American ancestry). Ancestral backgrounds were analyzed separately, and mortality after acute COVID-19 was the primary outcome. In European-American ancestry, we found that a haplotype of interferon regulatory factor 5 (IRF5) and alleles of protein kinase cGMP-dependent 1 (PRKG1) were associated with mortality from COVID-19. Interestingly, these were much stronger risk factors in younger patients (OR=29.2 for PRKG1 in ages 45-54). Variants in the IRF7 and IRF8 genes were associated with mortality from COVID-19 in African-American subjects, and these genetic effects were more pronounced in older subjects. Combining genetic information with blood biomarker data such as C-reactive protein, troponin, and D-dimer resulted in significantly improved predictive capacity, and in both ancestral backgrounds the risk genotypes were most relevant in those with positive biomarkers (OR for death between 14 and 111 in high risk genetic/biomarker groups). This study confirms the critical role of the IFN pathway in defense against COVID-19 and viral infections, and supports the idea that some common SLE risk alleles exert protective effects in anti-viral immunity. BACKGROUND: We find that a number of IFN pathway lupus risk alleles significantly impact mortality following COVID-19 infection. These data support the idea that type I IFN pathway risk alleles for autoimmune disease may persist in high frequency in modern human populations due to a benefit in our defense against viral infections. TRANSLATIONAL SIGNIFICANCE: We develop multivariate prediction models which combine genetics and known biomarkers of severity to result in greatly improved prediction of mortality in acute COVID-19. The specific associated alleles provide some clues about key points in our defense against COVID-19.
PMID: 35114420
ISSN: 1878-1810
CID: 5153812

Axonal dysfunction is associated with interferon-γ levels in childhood-onset systemic lupus erythematosus: a multivoxel magnetic resonance spectroscopy study

Frittoli, Renan Bazuco; Pereira, Danilo Rodrigues; Lapa, Aline Tamires; Postal, Mariana; Sinicato, Nailu Angelica; Fernandes, Paula Teixeira; Cendes, Fernando; Castellano, Gabriela; Rittner, Leticia; Marini, Roberto; Niewold, Timothy B; Appenzeller, Simone
OBJECTIVE:Axonal/neuronal damage has been shown to be a pathological finding that precedes neuropsychiatric manifestations in systemic lupus erythematosus (SLE). Therefore, the objective of this study was to determine the presence of axonal dysfunction in childhood-onset SLE patients (cSLE) and to determine clinical, immunological, and treatment features associated with its occurrence. METHODS:We included 86 consecutive cSLE patients [median age 17 years (range 5-28)] and 71 controls [median age 18 years (5-28)]. We performed Proton Magnetic Resonance Spectroscopic Imaging (1H-MRSI) using point resolved spectroscopy sequence (PRESS) over the superior-posterior region of the corpus callosum and signals from N-acetylaspartate compounds (NAA), choline-based compounds (CHO); creatine containing compounds (Cr), myo-inositol (mI), lactate (Lac), glutamate (Glu), glutamine (Gln) and lactate (Lac) were measured and metabolites/Cr ratios were determined. Complete clinical, laboratory and neurological evaluations were performed in all subjects. Sera IL-4, IL-5, IL-6, IL-10, IL-12, IL-17, TNF- α, INF- γ cytokines levels, antiribosomal P protein antibodies (anti-P) and S100β were measured by enzyme-linked immunosorbent assay (ELISA) using commercial kits. Data were compared by non-parametric tests. RESULTS:NAA/Cr ratios (p= 0.035) and Lac/Cr ratios (p= 0.019) levels were significantly decreased in cSLE patients when compared with controls. In multivariate analysis, interferon (IFN) gamma (γ) levels (OR = 4.1; 95% 2.01-7.9) and depressive symptoms (OR = 1.9; 95%CI = 1.1-3.2) were associated with NAA/Cr ratio. Increased Cho/Cr was associated with the presence of cognitive impairment (OR = 3.4; p< 0.001; 95%CI = 2.034-5.078). mI/Cr ratio correlated with cumulative glucocorticoids dosage (r = 0.361; p= 0.014). CONCLUSION/CONCLUSIONS:NAA and CHO ratios may be useful as biomarkers in neuropsychiatric cSLE. Longitudinal studies are necessary to determine whether they predict structural damage.
PMID: 34282445
ISSN: 1462-0332
CID: 4948072

High Systemic Type I Interferon Activity is Associated with Active Class III/IV Lupus Nephritis

Iwamoto, Taro; Dorschner, Jessica M; Selvaraj, Shanmugapriya; Mezzano, Valeria; Jensen, Mark A; Vsetecka, Danielle; Amin, Shreyasee; Makol, Ashima; Osborn, Thomas; Moder, Kevin; Chowdhary, Vaidehi R; Izmirly, Peter; Belmont, H Michael; Clancy, Robert M; Buyon, Jill P; Wu, Ming; Loomis, Cynthia A; Niewold, Timothy B
OBJECTIVE:Previous studies suggest a link between high serum type I interferon (IFN) and lupus nephritis (LN). We determined whether serum IFN activity is associated with subtypes of LN and studied renal tissues and cells to understand the impact of IFN in LN. METHODS:). Podocyte cell line gene expression was measured by real-time PCR. RESULTS:expression was not closely co-localized with pDCs. IFN directly activated podocyte cell lines to induce chemokines and proapoptotic molecules. CONCLUSION/CONCLUSIONS:Systemic high IFN is involved in the pathogenesis of severe LN. We do not find co-localization of pDCs with IFN signature in renal tissue, and instead observe the greatest intensity of IFN signature in glomerular areas, which could suggest a blood source of IFN.
PMID: 34782453
ISSN: 0315-162x
CID: 5049012

Type I Interferons in Autoimmunity

Fernandez-Ruiz, Ruth; Niewold, Timothy B
Dysregulated IFN-1 responses play crucial roles in the development of multiple forms of autoimmunity. Many patients with lupus, systemic sclerosis, Sjogren's syndrome, and dermatomyositis demonstrate enhanced IFN-1 signaling. IFN-1 excess is associated with disease severity and autoantibodies and could potentially predict response to newer therapies targeting IFN-1 pathways. In this review, we provide an overview of the signaling pathway and immune functions of IFN-1s in health and disease. We also review the systemic autoimmune diseases classically associated with IFN-1 upregulation and current therapeutic strategies targeting the IFN-1 system.
PMID: 35016780
ISSN: 1523-1747
CID: 5118612

Artificial intelligence and deep learning to map immune cell types in inflamed human tissue

Van Buren, Kayla; Li, Yi; Zhong, Fanghao; Ding, Yuan; Puranik, Amrutesh; Loomis, Cynthia A; Razavian, Narges; Niewold, Timothy B
Biopsies of inflammatory tissue contain a complex network of interacting cells, orchestrating the immune or autoimmune response. While standard histological examination can identify relationships, it is clear that a great amount of data on each slide is not quantitated or categorized in standard microscopic examinations. To deal with the huge amount of data present in biopsy tissue in an unbiased and comprehensive way, we have developed a deep learning algorithm to identify immune cells in biopsies of inflammatory lesions. We focused on T follicular helper (Tfh) cell subsets and B cells in dermatomyositis biopsy images. We achieved strong performance on detection and classification of cells, including the rare Tfh cell subsets present in the tissue. This algorithm could be used to perform distance mapping between cell types in tissue, and could be easily adapted to other disease states.
PMID: 35131237
ISSN: 1872-7905
CID: 5175982

APOL1 variant-expressing endothelial cells exhibit autophagic dysfunction and mitochondrial stress

Blazer, Ashira; Qian, Yingzhi; Schlegel, Martin Paul; Algasas, Huda; Buyon, Jill P; Cadwell, Ken; Cammer, Michael; Heffron, Sean P; Liang, Feng-Xia; Mehta-Lee, Shilpi; Niewold, Timothy; Rasmussen, Sara E; Clancy, Robert M
Polymorphisms in the Apolipoprotein L1 (APOL1) gene are common in ancestrally African populations, and associate with kidney injury and cardiovascular disease. These risk variants (RV) provide an advantage in resisting Trypanosoma brucei, the causal agent of African trypanosomiasis, and are largely absent from non-African genomes. Clinical associations between the APOL1 high risk genotype (HRG) and disease are stronger in those with comorbid infectious or immune disease. To understand the interaction between cytokine exposure and APOL1 cytotoxicity, we established human umbilical vein endothelial cell (HUVEC) cultures representing each APOL1 genotype. Untreated HUVECs were compared to IFNÉ£-exposed; and APOL1 expression, mitochondrial function, lysosome integrity, and autophagic flux were measured. IFNÉ£ increased median APOL1 expression across all genotypes 22.1 (8.3 to 29.8) fold (p=0.02). Compared to zero risk variant-carrying HUVECs (0RV), HUVECs carrying 2 risk variant copies (2RV) showed both depressed baseline and maximum mitochondrial oxygen consumption (p<0.01), and impaired mitochondrial networking on MitoTracker assays. These cells also demonstrated a contracted lysosomal compartment, and an accumulation of autophagosomes suggesting a defect in autophagic flux. Upon blocking autophagy with non-selective lysosome inhibitor, hydroxychloroquine, autophagosome accumulation between 0RV HUVECs and untreated 2RV HUVECs was similar, implicating lysosomal dysfunction in the HRG-associated autophagy defect. Compared to 0RV and 2RV HUVECs, HUVECs carrying 1 risk variant copy (1RV) demonstrated intermediate mitochondrial respiration and autophagic flux phenotypes, which were exacerbated with IFNÉ£ exposure. Taken together, our data reveal that IFNÉ£ induces APOL1 expression, and that each additional RV associates with mitochondrial dysfunction and autophagy inhibition. IFNÉ£ amplifies this phenotype even in 1RV HUVECs, representing the first description of APOL1 pathobiology in variant heterozygous cell cultures.
PMCID:9551299
PMID: 36238153
ISSN: 1664-8021
CID: 5361182

Single-cell expression quantitative trait loci (eQTL) analysis of SLE-risk loci in lupus patient monocytes

Ghodke-Puranik, Yogita; Jin, Zhongbo; Zimmerman, Kip D; Ainsworth, Hannah C; Fan, Wei; Jensen, Mark A; Dorschner, Jessica M; Vsetecka, Danielle M; Amin, Shreyasee; Makol, Ashima; Ernste, Floranne; Osborn, Thomas; Moder, Kevin; Chowdhary, Vaidehi; Langefeld, Carl D; Niewold, Timothy B
BACKGROUND:We performed expression quantitative trait locus (eQTL) analysis in single classical (CL) and non-classical (NCL) monocytes from patients with systemic lupus erythematosus (SLE) to quantify the impact of well-established genetic risk alleles on transcription at single-cell resolution. METHODS:NCL) from SLE patients. Novel analysis methods were used to control for the within-person correlations observed, and eQTLs were compared between cell types and risk alleles. RESULTS:The SLE-risk alleles demonstrated significantly more eQTLs in NCLs as compared to CLs (p = 0.0004). There were 18 eQTLs exclusive to NCL cells, 5 eQTLs exclusive to CL cells, and only one shared eQTL, supporting large differences in the impact of the risk alleles between these monocyte subsets. The SPP1 and TNFAIP3 loci were associated with the greatest number of transcripts. Patterns of shared influence in which different SNPs impacted the same transcript also differed between monocyte subsets, with greater evidence for synergy in NCL cells. IRF1 expression demonstrated an on/off pattern, in which expression was zero in all of the monocytes studied from some individuals, and this pattern was associated with a number of SLE risk alleles. We observed corroborating evidence of this IRF1 expression pattern in public data sets. CONCLUSIONS:We document multiple SLE-risk allele eQTLs in single monocytes which differ greatly between CL and NCL subsets. These data support the importance of the SPP1 and TNFAIP3 risk variants and the IRF1 transcript in SLE patient monocyte function.
PMID: 34847931
ISSN: 1478-6362
CID: 5065602

Interferon pathway lupus risk alleles modulate risk of death from acute COVID-19

Nln, Ilona; Fernandez-Ruiz, Ruth; Wampler Muskardin, Theresa L; Paredes, Jacqueline L; Blazer, Ashira D; Tuminello, Stephanie; Attur, Mukundan; Iturrate, Eduardo; Petrilli, Christopher M; Abramson, Steven B; Chakravarti, Aravinda; Niewold, Timothy B
Type I interferon (IFN) is critical in our defense against viral infections. Increased type I IFN pathway activation is a genetic risk factor for systemic lupus erythematosus (SLE), and a number of common risk alleles contribute to the high IFN trait. We hypothesized that these common gain-of-function IFN pathway alleles may be associated with protection from mortality in acute COVID-19. We studied patients admitted with acute COVID-19 (756 European-American and 398 African-American ancestry). Ancestral backgrounds were analyzed separately, and mortality after acute COVID-19 was the primary outcome. In European-American ancestry, we found that a haplotype of interferon regulatory factor 5 (IRF5) and alleles of protein kinase cGMP-dependent 1 (PRKG1) were associated with mortality from COVID-19. Interestingly, these were much stronger risk factors in younger patients (OR=29.2 for PRKG1 in ages 45-54). Variants in the IRF7 and IRF8 genes were associated with mortality from COVID-19 in African-American subjects, and these genetic effects were more pronounced in older subjects. Combining genetic information with blood biomarker data such as C-reactive protein, troponin, and D-dimer resulted in significantly improved predictive capacity, and in both ancestral backgrounds the risk genotypes were most relevant in those with positive biomarkers (OR for death between 14 and 111 in high risk genetic/biomarker groups). This study confirms the critical role of the IFN pathway in defense against COVID-19 and viral infections, and supports the idea that some common SLE risk alleles exert protective effects in anti-viral immunity.
PMID: 34751274
ISSN: n/a
CID: 5362212

Risk of Toxicity After Initiating Immune Checkpoint Inhibitor Treatment in Patients With Rheumatoid Arthritis

Efuni, Elizaveta; Cytryn, Samuel; Boland, Patrick; Niewold, Timothy B; Pavlick, Anna; Weber, Jeffrey; Sandigursky, Sabina
INTRODUCTION/BACKGROUND:Immune checkpoint inhibitors (ICIs) are increasingly used to treat advanced cancer. Rheumatoid arthritis (RA) is associated with an increased risk of malignancies; however, patients with RA have been excluded from ICI trials. In this study, we evaluated risk of toxicity after initiation of ICI treatment in RA patients. METHODS:We conducted a single-institution, medical records review analysis to assess the incidence of immune-related adverse events (irAEs) and autoimmune disease (AID) flares among patients with AIDs treated with ICIs from 2011 to 2018. A subgroup analysis for RA patients was performed with frequencies of irAEs and AID flares reported. RESULTS:Twenty-two patients with RA who were treated with ICI for malignancy were identified. At the time of ICI initiation, 86% had inactive RA disease activity. Immune-related adverse events occurred in 7 (32%) of patients, with 2 (9%) developing grade 3 (i.e., severe) irAEs. Immune checkpoint inhibitors were temporarily discontinued because of irAEs in 5 patients (23%), and permanently in 1 patient. Rheumatoid arthritis flares occurred in 12 patients (55%). Of those, 10 (83%) received oral corticosteroids with an adequate treatment response. CONCLUSIONS:Our analysis suggests that irAEs following ICI treatment are not increased among RA patients compared with other cancer patients. Heightened RA disease activity during ICI treatment is common, but most adverse events are manageable with oral corticosteroids, and few require permanent ICI discontinuation. A close collaboration between the oncologist and rheumatologist is advisable when considering ICIs in patients with RA.
PMID: 31977647
ISSN: 1536-7355
CID: 4273562