Publications by authors named "Quan-Zhen Li"

156 Publications

Molecular signatures of long-term hepatocellular carcinoma risk in nonalcoholic fatty liver disease.

Sci Transl Med 2022 Jun 22;14(650):eabo4474. Epub 2022 Jun 22.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Prediction of hepatocellular carcinoma (HCC) risk is an urgent unmet need in patients with nonalcoholic fatty liver disease (NAFLD). In cohorts of 409 patients with NAFLD from multiple global regions, we defined and validated hepatic transcriptome and serum secretome signatures predictive of long-term HCC risk in patients with NAFLD. A 133-gene signature, prognostic liver signature (PLS)-NAFLD, predicted incident HCC over up to 15 years of longitudinal observation. High-risk PLS-NAFLD was associated with IDO1 dendritic cells and dysfunctional CD8 T cells in fibrotic portal tracts along with impaired metabolic regulators. PLS-NAFLD was validated in independent cohorts of patients with NAFLD who were HCC naïve (HCC incidence rates at 15 years were 22.7 and 0% in high- and low-risk patients, respectively) or HCC experienced (de novo HCC recurrence rates at 5 years were 71.8 and 42.9% in high- and low-risk patients, respectively). PLS-NAFLD was bioinformatically translated into a four-protein secretome signature, PLSec-NAFLD, which was validated in an independent cohort of HCC-naïve patients with NAFLD and cirrhosis (HCC incidence rates at 15 years were 37.6 and 0% in high- and low-risk patients, respectively). Combination of PLSec-NAFLD with our previously defined etiology-agnostic PLSec-AFP yielded improved HCC risk stratification. PLS-NAFLD was modified by bariatric surgery, lipophilic statin, and IDO1 inhibitor, suggesting that the signature can be used for drug discovery and as a surrogate end point in HCC chemoprevention clinical trials. Collectively, PLS/PLSec-NAFLD may enable NAFLD-specific HCC risk prediction and facilitate clinical translation of NAFLD-directed HCC chemoprevention.
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http://dx.doi.org/10.1126/scitranslmed.abo4474DOI Listing
June 2022

CXCR4+ Treg cells control serum IgM levels and natural IgM autoantibody production by B-1 cells in the bone marrow.

J Exp Med 2022 Jul 7;219(7). Epub 2022 Jun 7.

Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY.

Regulatory T (Treg) cells represent a specialized lineage of suppressive CD4+ T cells whose functionality is critically dependent on their ability to migrate to and dwell in the proximity of cells they control. Here we show that continuous expression of the chemokine receptor CXCR4 in Treg cells is required for their ability to accumulate in the bone marrow (BM). Induced CXCR4 ablation in Treg cells led to their rapid depletion and consequent increase in mature B cells, foremost the B-1 subset, observed exclusively in the BM without detectable changes in plasma cells or hematopoietic stem cells or any signs of systemic or local immune activation elsewhere. Dysregulation of BM B-1 B cells was associated with a highly specific increase in IgM autoantibodies and total serum IgM levels. Thus, Treg cells control autoreactive B-1 B cells in a CXCR4-dependent manner. These findings have significant implications for understanding the regulation of B cell autoreactivity and malignancies.
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http://dx.doi.org/10.1084/jem.20220047DOI Listing
July 2022

Comprehensive microRNA-seq transcriptomic profiling across 11 organs, 4 ages, and 2 sexes of Fischer 344 rats.

Sci Data 2022 05 12;9(1):201. Epub 2022 May 12.

State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences and Shanghai Cancer Center, Fudan University, Shanghai, 200438, China.

Rat is one of the most widely-used models in chemical safety evaluation and biomedical research. However, the knowledge about its microRNA (miRNA) expression patterns across multiple organs and various developmental stages is still limited. Here, we constructed a comprehensive rat miRNA expression BodyMap using a diverse collection of 320 RNA samples from 11 organs of both sexes of juvenile, adolescent, adult and aged Fischer 344 rats with four biological replicates per group. Following the Illumina TruSeq Small RNA protocol, an average of 5.1 million 50 bp single-end reads was generated per sample, yielding a total of 1.6 billion reads. The quality of the resulting miRNA-seq data was deemed to be high from raw sequences, mapped sequences, and biological reproducibility. Importantly, aliquots of the same RNA samples have previously been used to construct the mRNA BodyMap. The currently presented miRNA-seq dataset along with the existing mRNA-seq dataset from the same RNA samples provides a unique resource for studying the expression characteristics of existing and novel miRNAs, and for integrative analysis of miRNA-mRNA interactions, thereby facilitating better utilization of rats for biomarker discovery.
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http://dx.doi.org/10.1038/s41597-022-01285-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9098487PMC
May 2022

Hem-1 regulates protective humoral immunity and limits autoantibody production in a B cell-specific manner.

JCI Insight 2022 May 9;7(9). Epub 2022 May 9.

The Department of Comparative Medicine, University of Washington, Seattle, Washington, USA.

Hematopoietic protein-1 (Hem-1) is a member of the actin-regulatory WASp family verprolin homolog (WAVE) complex. Loss-of-function variants in the NCKAP1L gene encoding Hem-1 were recently discovered to result in primary immunodeficiency disease (PID) in children, characterized by poor specific Ab responses, increased autoantibodies, and high mortality. However, the mechanisms of how Hem-1 deficiency results in PID are unclear. In this study, we utilized constitutive and B cell-specific Nckap1l-KO mice to dissect the importance of Hem-1 in B cell development and functions. B cell-specific disruption of Hem-1 resulted in reduced numbers of recirculating follicular (FO), marginal zone (MZ), and B1 B cells. B cell migration in response to CXCL12 and -13 were reduced. T-independent Ab responses were nearly abolished, resulting in failed protective immunity to Streptococcus pneumoniae challenge. In contrast, T-dependent IgM and IgG2c, memory B cell, and plasma cell responses were more robust relative to WT control mice. B cell-specific Hem-1-deficient mice had increased autoantibodies against multiple autoantigens, and this correlated with hyperresponsive BCR signaling and increased representation of CD11c+T-bet+ age-associated B cell (ABC cells) - alterations associated with autoimmune diseases. These results suggest that dysfunctional B cells may be part of a mechanism explaining why loss-of-function Hem-1 variants result in recurring infections and autoimmunity.
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http://dx.doi.org/10.1172/jci.insight.153597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9090261PMC
May 2022

Non-Muscle Myosin II Is Essential for the Negative Regulation of B-Cell Receptor Signaling and B-Cell Activation.

Front Immunol 2022 14;13:842605. Epub 2022 Apr 14.

Department of Cell Biology & Molecular Genetics, University of Maryland, College Park, MD, United States.

Antigen (Ag)-triggered B-cell receptor (BCR) signaling initiates antibody responses. However, prolonged or uncontrolled BCR signaling is associated with the development of self-reactive B-cells and autoimmune diseases. We previously showed that actin-mediated B-cell contraction on Ag-presenting surfaces negatively regulates BCR signaling. Non-muscle myosin II (NMII), an actin motor, is involved in B-cell development and antibody responses by mediating B-cell migration, cytokinesis, and Ag extraction from Ag-presenting cells. However, whether and how NMII regulates humoral responses through BCR signaling remains elusive. Utilizing a B-cell-specific, partial NMIIA knockout (cIIAKO) mouse model and NMII inhibitors, this study examined the role of NMII in BCR signaling. Upon BCR binding to antibody-coated planar lipid bilayers (PLB), NMIIA was recruited to the B-cell contact membrane and formed a ring-like structure during B-cell contraction. NMII recruitment depended on phosphatidylinositol 5-phosphatase (SHIP1), an inhibitory signaling molecule. NMII inhibition by cIIAKO did not affect B-cell spreading on PLB but delayed B-cell contraction and altered BCR clustering. Surface BCR "cap" formation induced by soluble stimulation was enhanced in cIIAKO B-cells. Notably, NMII inhibition by cIIAKO and inhibitors up-regulated BCR signaling in response to both surface-associated and soluble stimulation, increasing phosphorylated tyrosine, CD79a, BLNK, and Erk and decreasing phosphorylated SHIP1. While cIIAKO did not affect B-cell development, the number of germinal center B-cells was significantly increased in unimmunized cIIAKO mice, compared to control mice. While cIIAKO mice mounted similar antibody responses when compared to control mice upon immunization, the percentages of high-affinity antibodies, Ag-specific germinal center B-cells and isotype switched B-cells were significantly lower in cIIAKO mice than in control mice. Furthermore, autoantibody levels were elevated in cIIAKO mice, compared to control mice. Collectively, our results reveal that NMII exerts a B-cell-intrinsic inhibition on BCR signaling by regulating B-cell membrane contraction and surface BCR clustering, which curtails the activation of non-specific and self-reactive B-cells.
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http://dx.doi.org/10.3389/fimmu.2022.842605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9047714PMC
May 2022

Advancing NGS quality control to enable measurement of actionable mutations in circulating tumor DNA.

Cell Rep Methods 2021 Nov 3;1(7):100106. Epub 2021 Nov 3.

Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA.

The primary objective of the FDA-led Sequencing and Quality Control Phase 2 (SEQC2) project is to develop standard analysis protocols and quality control metrics for use in DNA testing to enhance scientific research and precision medicine. This study reports a targeted next-generation sequencing (NGS) method that will enable more accurate detection of actionable mutations in circulating tumor DNA (ctDNA) clinical specimens. To accomplish this, a synthetic internal standard spike-in was designed for each actionable mutation target, suitable for use in NGS following hybrid capture enrichment and unique molecular index (UMI) or non-UMI library preparation. When mixed with contrived ctDNA reference samples, internal standards enabled calculation of technical error rate, limit of blank, and limit of detection for each variant at each nucleotide position in each sample. True-positive mutations with variant allele fraction too low for detection by current practice were detected with this method, thereby increasing sensitivity.
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http://dx.doi.org/10.1016/j.crmeth.2021.100106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9017191PMC
November 2021

Peripheral Blood Mononuclear Cell Gene Expression in Chronic Obstructive Pulmonary Disease: miRNA and mRNA Regulation.

J Inflamm Res 2022 1;15:2167-2180. Epub 2022 Apr 1.

Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.

Introduction: The mechanisms underlying chronic obstructive pulmonary disease (COPD) remain unclear. Genetic and genomic changes may play a significant role in the pathogenesis of COPD. Identification of differentially expressed genes and miRNAs and their regulatory mechanisms at the whole-genome level will provide a comprehensive understanding of the development of COPD.

Methods: Peripheral blood mononuclear cells (PBMCs) from 12 patients with COPD and 12 normal controls were examined at the miRNA and mRNA expression levels using Affymetrix GeneChip. Microarray data were analyzed with Affymetrix Transcriptome Analysis Console 2.0 and GeneSpring software. Gene interaction pathways of the differentially expressed genes and miRNA-mRNA regulation were analyzed using the Ingenuity Pathway Analysis software. Four differentially expressed genes and one miRNA were further confirmed using RT-qPCR.

Results: One hundred and thirty-three upregulated and 973 downregulated genes were identified in PBMCs of patients with COPD. Pathway analysis on the differentially expressed genes in COPD revealed significant enrichment in IL-8 signaling and iCOS-iCOSL signaling in T helper cells. Seventy-seven upregulated miRNAs and 43 downregulated miRNAs were differentially expressed between PBMCs from patients with COPD and normal controls. Among these 120 differentially expressed miRNAs, 42 miRNAs targeting 28 upregulated genes and 69 miRNAs targeting 498 downregulated genes were identified. The expression of CXCR1, HBEGF, TREM-1, and hsa-miR-148a-3p was more elevated in patients with COPD than in normal controls, whereas NFAT5 was decreased.

Conclusion: miRNAs and mRNAs are differentially expressed in PBMCs of patients with COPD, compared with normal controls. miRNAs regulate the expression of mRNAs, and thus play a role in the pathogenesis of COPD. Investigating these relationships may provide further insight into the mechanisms of COPD.
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http://dx.doi.org/10.2147/JIR.S337894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8983057PMC
April 2022

Autoimmunity is a hallmark of post-COVID syndrome.

J Transl Med 2022 03 16;20(1):129. Epub 2022 Mar 16.

Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 # 63c 69, 110010, Bogota, Colombia.

Autoimmunity has emerged as a characteristic of the post-COVID syndrome (PCS), which may be related to sex. In order to further investigate the relationship between SARS-CoV-2 and autoimmunity in PCS, a clinical and serological assessment on 100 patients was done. Serum antibody profiles against self-antigens and infectious agents were evaluated by an antigen array chip for 116 IgG and 104 IgM antibodies. Thirty pre-pandemic healthy individuals were included as a control group. The median age of patients was 49 years (IQR: 37.8 to 55.3). There were 47 males. The median post-COVID time was 219 (IQR: 143 to 258) days. Latent autoimmunity and polyautoimmunity were found in 83% and 62% of patients, respectively. Three patients developed an overt autoimmune disease. IgG antibodies against IL-2, CD8B, and thyroglobulin were found in more than 10% of the patients. Other IgG autoantibodies, such as anti-interferons, were positive in 5-10% of patients. Anti-SARS-CoV-2 IgG antibodies were found in > 85% of patients and were positively correlated with autoantibodies, age, and body mass index (BMI). Few autoantibodies were influenced by age and BMI. There was no effect of gender on the over- or under-expression of autoantibodies. IgG anti-IFN-λ antibodies were associated with the persistence of respiratory symptoms. In summary, autoimmunity is characteristic of PCS, and latent autoimmunity correlates with humoral response to SARS-CoV-2.
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http://dx.doi.org/10.1186/s12967-022-03328-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8924736PMC
March 2022

Association between Antibiotic Exposure and Systemic Immune Parameters in Cancer Patients Receiving Checkpoint Inhibitor Therapy.

Cancers (Basel) 2022 Mar 4;14(5). Epub 2022 Mar 4.

Department of Internal Medicine, Division of Hematology-Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Antibiotic administration is associated with worse clinical outcomes and changes to the gut microbiome in cancer patients receiving immune checkpoint inhibitors (ICI). However, the effects of antibiotics on systemic immune function are unknown. We, therefore, evaluated antibiotic exposure, therapeutic responses, and multiplex panels of 40 serum cytokines and 124 antibodies at baseline and six weeks after ICI initiation, with < 0.05 and false discovery rate (FDR) < 0.2 considered significant. A total of 251 patients were included, of whom the 135 (54%) who received antibiotics had lower response rates and shorter survival. Patients who received antibiotics prior to ICI initiation had modestly but significantly lower baseline levels of nucleolin, MDA5, c-reactive protein, and liver cytosol antigen type 1 (LC1) antibodies, as well as higher levels of heparin sulfate and Matrigel antibodies. After ICI initiation, antibiotic-treated patients had significantly lower levels of MDA5, CENP.B, and nucleolin antibodies. Although there were no clear differences in cytokines in the overall cohort, in the lung cancer subset (53% of the study population), we observed differences in IFN-γ, IL-8, and macrophage inflammatory proteins. In ICI-treated patients, antibiotic exposure is associated with changes in certain antibodies and cytokines. Understanding the relationship between these factors may improve the clinical management of patients receiving ICI.
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http://dx.doi.org/10.3390/cancers14051327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8909108PMC
March 2022

Induction of broadly reactive influenza antibodies increases susceptibility to autoimmunity.

Cell Rep 2022 03;38(10):110482

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address:

Infection and vaccination repeatedly expose individuals to antigens that are conserved between influenza virus subtypes. Nevertheless, antibodies recognizing variable influenza epitopes greatly outnumber antibodies reactive against conserved epitopes. Elucidating factors contributing to the paucity of broadly reactive influenza antibodies remains a major obstacle for developing a universal influenza vaccine. Here, we report that inducing broadly reactive influenza antibodies increases autoreactive antibodies in humans and mice and exacerbates disease in four distinct models of autoimmune disease. Importantly, transferring broadly reactive influenza antibodies augments disease in the presence of inflammation or autoimmune susceptibility. Further, broadly reactive influenza antibodies spontaneously arise in mice with defects in B cell tolerance. Together, these data suggest that self-tolerance mechanisms limit the prevalence of broadly reactive influenza antibodies, which can exacerbate disease in the context of additional risk factors.
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http://dx.doi.org/10.1016/j.celrep.2022.110482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9036619PMC
March 2022

Autoantibodies are present in the bronchoalveolar lavage but not circulation in patients with fibrotic interstitial lung disease.

ERJ Open Res 2022 Jan 14;8(1). Epub 2022 Feb 14.

National Heart and Lung Institute, Imperial College London, London, UK.

Background: Fibrotic interstitial lung disease (fILD) has previously been associated with the presence of autoantibody. While studies have focused on systemic autoimmunity, the role of local autoantibodies in the airways remains unknown. We therefore extensively characterised the airway and peripheral autoantibody profiles in patients with fILD, and assessed association with disease severity and outcome.

Methods: Bronchoalveolar lavage (BAL) fluid was collected from a cohort of fILD patients and total BAL antibody concentrations were quantified. An autoantigen microarray was used to measure IgG and IgA autoantibodies against 122 autoantigens in BAL from 40 idiopathic pulmonary fibrosis (IPF), 20 chronic hypersensitivity pneumonitis (CHP), 20 connective tissue disease-associated ILD (CTD-ILD) patients and 20 controls.

Results: A subset of patients with fILD but not healthy controls had a local autoimmune signature in their BAL that was not present systemically, regardless of disease. The proportion of patients with IPF with a local autoantibody signature was comparable to that of CTD-ILD, which has a known autoimmune pathology, identifying a potentially novel subset of patients. The presence of an airway autoimmune signature was not associated with reduced survival probability or changes in lung function in the cohort as a whole. Patients with IPF had increased BAL total IgA and IgG while subjects with CHP had increased BAL IgA, IgG and IgG. In patients with CHP, increased BAL total IgA was associated with reduced survival probability.

Conclusion: Airway autoantibodies that are not present systemically identify a group of patients with fILD and the mechanisms by which these autoantibodies contribute to disease requires further investigation.
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http://dx.doi.org/10.1183/23120541.00481-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8841989PMC
January 2022

Lower baseline autoantibody levels are associated with immune-related adverse events from immune checkpoint inhibition.

J Immunother Cancer 2022 01;10(1)

Hospital for Special Surgery/Weill Cornell Medical College, Department of Medicine, Division of Rheumatology, New York, NY, USA.

Introduction: Immune checkpoint inhibitors (ICI) are a novel cancer therapeutic that have been successful in treating advanced malignancies; however, they also cause immune-related adverse events (irAE). Given that some irAE are clinically similar to traditional autoimmune diseases, autoantibodies have been suggested as possible biomarkers of irAE. However, there are very little data on autoantibody investigation prior to ICI. Our aim was to determine if specific baseline autoantibodies were associated with irAE and see if changes in autoantibody concentration corresponded with irAE development.

Methods: This study used data from an oncologic clinical trial of adaptive dosing combination ICI therapy in patients with advanced melanoma. Plasma was collected at baseline and 6 weeks after ICI initiation and tested in a microarray of 120 autoantigens commonly associated with autoimmune disease, as well as antinuclear antibody (ANA), rheumatoid factor (RF), and anti-cyclic citrullinated peptide antibody (anti-CCP). Autoantibody concentrations were compared between patients experiencing an organ-specific event versus not. Heatmaps, volcano plots and hierarchical clustering were used to determine autoantibody concentration differences among irAE patient clusters as defined by signal intensity of autoantibodies. Kaplan-Meier curves were created and a log-rank test was performed to assess differences in survival.

Results: The microarray analysis demonstrated that patients who experienced specific irAE had fewer differentially expressed autoantibodies at baseline than those that did not have those specific irAE, and a greater fold change (FC) in antibody concentration from baseline to 6 weeks corresponded with specific irAE development. However, no autoantibodies were identified as being predictive of specific events. Time to first irAE was less than 6 weeks in 69% of patients, and these patients had less autoantibodies at baseline. Considering ANA, RF and CCP autoantibodies, there were no significant differences between the seropositive and seronegative patients in irAE development, severity, timing or survival.

Conclusion: Patients with low autoantibody concentrations at baseline as well as a greater FC in autoantibody concentration over 6 weeks developed more distinct organ-specific irAE. This may suggest differences in the balance of cellular immunity and humoral pathways that are relevant in the pathogenesis of irAE, though further investigation is needed.
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http://dx.doi.org/10.1136/jitc-2021-004008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8804686PMC
January 2022

Autoantigen microarrays reveal myelin basic protein autoantibodies in morphea.

J Transl Med 2022 01 24;20(1):41. Epub 2022 Jan 24.

Department of Dermatology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390-9069, USA.

Background: Morphea is an autoimmune, sclerosing skin disorder. Despite the recent emphasis on immune dysregulation in morphea, the role of autoantibodies in morphea pathogenesis or utility as biomarkers are poorly defined.

Methods: Autoantigen microarray was used to profile autoantibodies from the serum of participants from the Morphea in Adults and Children (MAC) cohort. Clinical and demographic features of morphea patients with myelin basic protein (MBP) autoantibodies were compared to those without. MBP immunohistochemistry staining was subsequently performed in morphea skin to assess for perineural inflammation in areas of staining. Immunofluorescence staining on mouse brain tissue was also performed using patient sera and mouse anti-myelin basic protein antibody to confirm the presence of MBP antibodies in patient sera.

Results: Myelin basic protein autoantibodies were found in greater frequency in morphea (n = 50, 71.4%) compared to systemic sclerosis (n = 2, 6.7%) and healthy controls (n = 7, 20%). Patients with MBP antibodies reported pain at higher frequencies. Morphea skin biopsies, highlighted by immunohistochemistry, demonstrated increased perineural inflammation in areas of MBP expression. Immunofluorescence staining revealed an increased fluorescence signal in myelinated areas of mouse brain tissue (i.e. axons) when incubated with sera from MBP antibody-positive morphea patients compared to sera from MBP antibody-negative morphea patients. Epitope mapping revealed target epitopes for MBP autoantibodies in morphea are distinct from those reported in MS, and included fragments 11-30, 41-60, 51-70, and 91-110.

Conclusions: A molecular classification of morphea based on distinct autoantibody biosignatures may be used to differentially classify morphea. We have identified anti-MBP as a potential antibody associated with morphea due to its increased expression in morphea compared to healthy controls and systemic sclerosis patients.
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http://dx.doi.org/10.1186/s12967-022-03246-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8785566PMC
January 2022

Elevated Cerebrospinal Fluid Anti-CD4 Autoantibody Levels in HIV Associate with Neuroinflammation.

Microbiol Spectr 2022 02 5;10(1):e0197521. Epub 2022 Jan 5.

Department of Microbiology and Immunology, Medical University of South Carolinagrid.259828.c, Charleston, South Carolina, USA.

The mechanisms of persistent central nervous system (CNS) inflammation in people with HIV (PWH) despite effective antiretroviral therapy (ART) are not fully understood. We have recently shown that plasma anti-CD4 IgGs contribute to poor CD4 T cell recovery during suppressive ART via antibody-mediated cytotoxicity (ADCC) against CD4 T cells, and that plasma anti-CD4 IgG levels are associated with worse cognitive performance and specific brain area atrophy. However, the role of anti-CD4 IgGs in neuroinflammation remains unclear. In the current study, plasma and cerebrospinal fluid (CSF) samples from 31 ART-naive and 26 treated, virologically suppressed PWH, along with 16 HIV-seronegative controls, were evaluated for CSF levels of anti-CD4 IgG, white blood cell (WBC) counts, soluble biomarkers of neuroinflammation, and neurofilament light chain (NfL). We found that 37% of the PWH exhibited elevated CSF anti-CD4 IgG levels, but few or none of the PWH were observed with elevated CSF anti-CD4 IgM, anti-CD8 IgG, or anti-double-strand DNA IgG. CSF anti-CD4 IgG levels in PWH were directly correlated with neuroinflammation (WBC counts, neopterin, and markers of myeloid cell activation), but not with CSF NfL levels. Using cells from one immune nonresponder to ART, we generated a pathogenic anti-CD4 monoclonal IgG (JF19) presenting with ADCC activity; JF19 induced the production of soluble CD14 (sCD14) and interleukin-8 (IL-8) in human primary monocyte-derived macrophages via CD4 binding . This study demonstrates for the first time that elevated CSF anti-CD4 IgG levels present in a subgroup of PWH which may play a role in neuroinflammation in HIV. This study reports that an autoantibody presents in the CNS of HIV patients and that its levels in the CSF correlate with some markers of neuroinflammation.
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http://dx.doi.org/10.1128/spectrum.01975-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8729763PMC
February 2022

DOCK8-expressing T follicular helper cells newly generated beyond self-organized criticality cause systemic lupus erythematosus.

iScience 2022 Jan 2;25(1):103537. Epub 2021 Dec 2.

Department of Medicine, Rheumatology and Orthopedic Surgery, Matsubara Mayflower Hospital, 944-25 Fujita, Katoshi 673-1462, Japan.

Pathogens including autoantigens all failed to induce systemic lupus erythematosus (SLE). We, instead, studied the integrity of host's immune response that recognized pathogen. By stimulating TCR with an antigen repeatedly to levels that surpass host's steady-state response, self-organized criticality, SLE was induced in mice normally not prone to autoimmunity, wherein T follicular helper (Tfh) cells expressing the guanine nucleotide exchange factor DOCK8 on the cell surface were newly generated. DOCK8Tfh cells passed through TCR re-revision and induced varieties of autoantibody and lupus lesions. They existed in splenic red pulp and peripheral blood of active lupus patients, which subsequently declined after therapy. Autoantibodies and disease were healed by anti-DOCK8 antibody in the mice including SLE-model (NZBxNZW) F1 mice. Thus, DOCK8Tfh cells generated after repeated TCR stimulation by immunogenic form of pathogen, either exogenous or endogenous, in combination with HLA to levels that surpass system's self-organized criticality, cause SLE.
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http://dx.doi.org/10.1016/j.isci.2021.103537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8689056PMC
January 2022

Molecular Signature Predictive of Long-Term Liver Fibrosis Progression to Inform Antifibrotic Drug Development.

Gastroenterology 2022 04 22;162(4):1210-1225. Epub 2021 Dec 22.

Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

Background & Aims: There is a major unmet need to assess the prognostic impact of antifibrotics in clinical trials because of the slow rate of liver fibrosis progression. We aimed to develop a surrogate biomarker to predict future fibrosis progression.

Methods: A fibrosis progression signature (FPS) was defined to predict fibrosis progression within 5 years in patients with hepatitis C virus and nonalcoholic fatty liver disease (NAFLD) with no to minimal fibrosis at baseline (n = 421) and was validated in an independent NAFLD cohort (n = 78). The FPS was used to assess response to 13 candidate antifibrotics in organotypic ex vivo cultures of clinical fibrotic liver tissues (n = 78) and cenicriviroc in patients with nonalcoholic steatohepatitis enrolled in a clinical trial (n = 19, NCT02217475). A serum protein-based surrogate FPS was developed and tested in a cohort of compensated cirrhosis patients (n = 122).

Results: A 20-gene FPS was defined and validated in an independent NAFLD cohort (adjusted odds ratio, 10.93; area under the receiver operating characteristic curve, 0.86). Among computationally inferred fibrosis-driving FPS genes, BCL2 was confirmed as a potential pharmacologic target using clinical liver tissues. Systematic ex vivo evaluation of 13 candidate antifibrotics identified rational combination therapies based on epigallocatechin gallate, which were validated for enhanced antifibrotic effect in ex vivo culture of clinical liver tissues. In patients with nonalcoholic steatohepatitis treated with cenicriviroc, FPS modulation was associated with 1-year fibrosis improvement accompanied by suppression of the E2F pathway. Induction of the PPARα pathway was absent in patients without fibrosis improvement, suggesting a benefit of combining PPARα agonism to improve the antifibrotic efficacy of cenicriviroc. A 7-protein serum protein-based surrogate FPS was associated with the development of decompensation in cirrhosis patients.

Conclusion: The FPS predicts long-term fibrosis progression in an etiology-agnostic manner, which can inform antifibrotic drug development.
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http://dx.doi.org/10.1053/j.gastro.2021.12.250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8934284PMC
April 2022

New insights into the taxonomy of autoimmune diseases based on polyautoimmunity.

J Autoimmun 2022 01 16;126:102780. Epub 2021 Dec 16.

Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia; Clinica del Occidente, Bogota, Colombia. Electronic address:

Objective: The clinical coexistence of two or more autoimmune diseases (ADs) fulfilling classification criteria is termed "overt polyautoimmunity" (PolyA), whereas the presence of autoantibodies unrelated to an index AD, without clinical criteria fulfillment, is known as "latent PolyA". We aimed to explore a new taxonomy of ADs based on PolyA.

Methods: In a cross-sectional study of 292 subjects, we evaluated the presence of PolyA in 146, 45, 29, 17, and 17 patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), autoimmune thyroid disease (AITD) and systemic sclerosis (SSc), respectively, and 38 healthy controls. Clinical assessment, autoantibody profile (by autoantigen array chip), lymphocytes immunophenotype and cytokine profile (by flow cytometry) were evaluated simultaneously. A mixed cluster methodology was used to classify ADs.

Results: Latent PolyA was more frequent than overt PolyA, ranging from 69.9% in RA to 100% in SSc. Nevertheless, both latent and overt PolyA clustered together. Over-expressed IgG autoantibodies were found to be hallmarks for the identification of index ADs. The combination of autoantibodies allowed high accuracy in the classification of ADs. Three well-defined clusters based on PolyA were observed with distinctive clinical and immunological phenotypes.

Conclusions: This proof-of-concept study indicates that ADs can be classified according to PolyA. PolyA should be considered in all studies dealing with ADs, including epidemiological, genetic, and clinical trials.
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http://dx.doi.org/10.1016/j.jaut.2021.102780DOI Listing
January 2022

Humoral and cellular correlates of a novel immune-related adverse event and its treatment.

J Immunother Cancer 2021 12;9(12)

Department of Internal Medicine (Division of Hematology and Oncology), University of Texas Southwestern Medical Center, Dallas, Texas, USA

Immune-related adverse events (irAE) may affect almost any organ system and occur at any point during treatment with immune checkpoint inhibitors (ICI). We present a patient with advanced lung cancer receiving antiprogrammed death 1 checkpoint inhibitor who developed a delayed-onset visual irAE treated with corticosteroids. Through assessment of longitudinal biospecimens, we analyzed serial autoantibodies, cytokines, and cellular populations. Months after ICI initiation and preceding clinical toxicity, the patient developed broad increases in cytokines (most notably interleukin-6 (IL-6), interferon-γ (IFNγ), C-X-C motif chemokine ligand 2 (CXCL2), and C-C motif chemokine ligand 17 (CCL17)), autoantibodies (including anti-angiotensin receptor, α-actin, and amyloid), CD8 T cells, and plasmablasts. Such changes were not observed in healthy controls and ICI-treated patients without irAE. Administration of corticosteroids resulted in immediate and profound decreases in cytokines, autoantibodies, and inflammatory cells. This case highlights the potential for late-onset changes in humoral and cellular immunity in patients receiving ICI. It also demonstrates the biologic effects of corticosteroids on these parameters. Application of humoral and cellular immune biomarkers across ICI populations may inform toxicity monitoring and management.
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http://dx.doi.org/10.1136/jitc-2021-003585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8655605PMC
December 2021

CSF-Derived CD4 T-Cell Diversity Is Reduced in Patients With Alzheimer Clinical Syndrome.

Neurol Neuroimmunol Neuroinflamm 2022 01 30;9(1). Epub 2021 Nov 30.

From the Department of Neurology (C.J., S.I., J.R., W.Z., D.S., R.L., D.L.-W., R.R., M.C., B.H., B.G., R.Z., B.K., N.M.), Department of Neuroscience (K.S.), Department of Population and Data Sciences, (S.C., L.C.), Department of Psychiatry (M.C.), Department of Immunology (Q-Z.L, N.M.) and Department of Surgery (R.H.), UT Southwestern Medical Center UNT Health Science Center (R.B.), Department of Pharmacology and Neuroscience, Department of Neurology (A.S.), University of Kentucky, Lexington, KY.

Background And Objectives: Patients with Alzheimer dementia display evidence of amyloid-related neurodegeneration. Our focus was to determine whether such patients also display evidence of a disease-targeting adaptive immune response mediated by CD4 T cells. To test this hypothesis, we evaluated the CSF immune profiles of patients with Alzheimer clinical syndrome (ACS), who display clinically defined dementia.

Methods: Innate and adaptive immune profiles of patients with ACS were measured using multicolor flow cytometry. CSF-derived CD4 and CD8 T-cell receptor repertoire genetics were measured using next-generation sequencing. Brain-specific autoantibody signatures of CSF-derived antibody pools were measured using array technology or ELISA. CSF from similar-age healthy controls (HCs) was used as a comparator cohort.

Results: Innate cells were expanded in the CSF of patients with ACS in comparison to HCs, and innate cell expansion increased with age in the patients with ACS, but not HCs. Despite innate cell expansion in the CSF, the frequency of total CD4 T cells reduced with age in the patients with ACS. T-cell receptor repertoire genetics indicated that T-cell clonal expansion is enhanced, and diversity is reduced in the patients with ACS compared with similar-age HCs.

Discussion: Examination of CSF indicates that CD4 T cell-mediated adaptive immune responses are altered in patients with ACS. Understanding the underlying mechanisms affecting adaptive immunity will help move us toward the goal of slowing cognitive decline.
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http://dx.doi.org/10.1212/NXI.0000000000001106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8631792PMC
January 2022

Autoantibodies Present in Hidradenitis Suppurativa Correlate with Disease Severity and Promote the Release of Proinflammatory Cytokines in Macrophages.

J Invest Dermatol 2022 03 1;142(3 Pt B):924-935. Epub 2021 Oct 1.

Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Dermatology, Howard University College of Medicine, Washington, District of Columbia, USA. Electronic address:

Hidradenitis suppurativa (HS), also known as acne inversa, is a debilitating inflammatory skin disorder that is characterized by nodules that lead to the development of connected tunnels and scars as it progresses from Hurley stages I to III. HS has been associated with several autoimmune diseases, including inflammatory bowel disease and spondyloarthritis. We previously reported dysregulation of humoral immune responses in HS, characterized by elevated serum total IgG, B-cell activation, and antibodies recognizing citrullinated proteins. In this study, we characterized IgG autoreactivity in HS sera and lesional skin compared with those in normal healthy controls using an array-based high-throughput autoantibody screening. The Cy3-labeled anti-human assay showed the presence of autoantibodies against nuclear antigens, cytokines, cytoplasmic proteins, extracellular matrix proteins, neutrophil proteins, and citrullinated antigens. Most of these autoantibodies were significantly elevated in stages II‒III in HS sera and stage III in HS skin lesions compared with those of healthy controls. Furthermore, immune complexes containing both native and citrullinated versions of antigens can activate M1 and M2 macrophages to release proinflammatory cytokines such as TNF-α, IL-8, IL-6, and IL-12. Taken together, the identification of specific IgG autoantibodies that recognize circulating and tissue antigens in HS suggests an autoimmune mechanism and uncovers putative therapeutic targets.
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http://dx.doi.org/10.1016/j.jid.2021.07.187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8860851PMC
March 2022

Cutting Edge: A Threshold of B Cell Costimulatory Signals Is Required for Spontaneous Germinal Center Formation in Autoimmunity.

J Immunol 2021 11 29;207(9):2217-2222. Epub 2021 Sep 29.

Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA;

Cognate interactions between autoreactive B and T cells promote systemic lupus erythematosus pathogenesis by inter alia facilitating spontaneous germinal center (GC) formation. Whereas both myeloid and B cell APCs express B7 ligands (CD80 and CD86), the prevailing model holds that dendritic cell costimulation is sufficient for CD28-dependent T cell activation. In this study, we report that B cell-intrinsic CD80/CD86 deletion unexpectedly abrogates GCs in murine lupus. Interestingly, absent GCs differentially impacted serum autoantibodies. In keeping with distinct extrafollicular and GC activation pathways driving lupus autoantibodies, lack of GCs correlated with loss of RNA-associated autoantibodies but preserved anti-dsDNA and connective tissue autoantibody titers. Strikingly, even heterozygous B cell CD80/CD86 deletion was sufficient to prevent autoimmune GCs and RNA-associated autoantibodies. Together, these findings identify a key mechanism whereby B cells promote lupus pathogenesis by providing a threshold of costimulatory signals required for autoreactive T cell activation.
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http://dx.doi.org/10.4049/jimmunol.2100548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530958PMC
November 2021

Chronic inflammation and extracellular matrix-specific autoimmunity following inadvertent periarticular influenza vaccination.

J Autoimmun 2021 11 14;124:102714. Epub 2021 Aug 14.

Translational Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland; Interdisciplinary Center for Immunology, Departments of Dermatology, Internal Medicine, and Rheumatology, University Hospital Basel, Basel, Switzerland. Electronic address:

Background: Viral infections may trigger autoimmunity in genetically predisposed individuals. Immunizations mimic viral infections immunologically, but only in rare instances vaccinations coincide with the onset of autoimmunity. Inadvertent vaccine injection into periarticular shoulder tissue can cause inflammatory tissue damage ('shoulder injury related to vaccine administration, SIRVA). Thus, this accident provides a model to study if vaccine-induced pathogen-specific immunity accompanied by a robust inflammatory insult may trigger autoimmunity in specific genetic backgrounds.

Methods: We studied 16 otherwise healthy adults with suspected SIRVA occurring following a single work-related influenza immunization campaign in 2017. We performed ultrasound, immunophenotypic analyses, HLA typing, and influenza- and self-reactivity functional immunoassays. Vaccine-related bone toxicity and T cell/osteoclast interactions were assessed in vitro.

Findings: Twelve of the 16 subjects had evidence of inflammatory tissue damage on imaging, including bone erosions in six. Tissue damage was associated with a robust peripheral blood T and B cell activation signature and extracellular matrix-reactive autoantibodies. All subjects with erosions were HLA-DRB1*04 positive and showed extracellular matrix-reactive HLA-DRB1*04 restricted T cell responses targeting heparan sulfate proteoglycan (HSPG). Antigen-specific T cells potently activated osteoclasts via RANK/RANK-L, and the osteoclast activation marker Trap5b was high in sera of patients with an erosive shoulder injury. In vitro, the vaccine component alpha-tocopheryl succinate recapitulated bone toxicity and stimulated osteoclasts. Auto-reactivity was transient, with no evidence of progression to rheumatoid arthritis or overt autoimmune disease.

Conclusion: Vaccine misapplication, potentially a genetic predisposition, and vaccine components contribute to SIRVA. The association with autoimmunity risk allele HLA-DRB1*04 needs to be further investigated. Despite transient autoimmunity, SIRVA was not associated with progression to autoimmune disease during two years of follow-up.
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http://dx.doi.org/10.1016/j.jaut.2021.102714DOI Listing
November 2021

Immune-Intrinsic Myd88 Directs the Production of Antibodies With Specificity for Extracellular Matrix Components in Primary Sjögren's Syndrome.

Front Immunol 2021 26;12:692216. Epub 2021 Jul 26.

Department of Oral Biology, School of Dental Medicine, The University at Buffalo, State University of New York, Buffalo, NY, United States.

Primary Sjögren's syndrome is an autoimmune disease that is predominantly seen in women. The disease is characterized by exocrine gland dysfunction in combination with serious systemic manifestations. At present, the causes of pSS are poorly understood. Pulmonary and renal inflammation are observed in pSS mice, reminiscent of a subset of pSS patients. A growing body of evidence indicates that inflammation mediated by Damage-Associated Molecular Patterns (DAMPs) contributes to autoimmunity, although this is not well-studied in pSS. Degraded extracellular matrix (ECM) constituents can serve as DAMPs by binding pattern-recognition receptors and activating Myd88-dependent signaling cascades, thereby exacerbating and perpetuating inflammatory cascades. The ECM components biglycan (Bgn) and decorin (Dcn) mediate sterile inflammation and both are implicated in autoimmunity. The objective of this study was to determine whether these ECM components and anti-ECM antibodies are altered in a pSS mouse model, and whether this is dependent on Myd88 activation in immune cells. Circulating levels of Bgn and Dcn were similar among pSS mice and controls and tissue expression studies revealed pSS mice had robust expression of both Bgn and Dcn in the salivary tissue, saliva, lung and kidney. Sera from pSS mice displayed increased levels of autoantibodies directed against ECM components when compared to healthy controls. Further studies using sera derived from conditional knockout pSS mice demonstrated that generation of these autoantibodies relies, at least in part, on Myd88 expression in the hematopoietic compartment. Thus, this study demonstrates that ECM degradation may represent a novel source of chronic B cell activation in the context of pSS.
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http://dx.doi.org/10.3389/fimmu.2021.692216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350326PMC
October 2021

A blood-based prognostic liver secretome signature and long-term hepatocellular carcinoma risk in advanced liver fibrosis.

Med (N Y) 2021 07 21;2(7):836-850.e10. Epub 2021 Apr 21.

Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, U.S.

Background: Accurate non-invasive prediction of long-term hepatocellular carcinoma (HCC) risk in advanced liver fibrosis is urgently needed for cost-effective HCC screening; however, this currently remains an unmet need.

Methods: A serum-protein-based prognostic liver secretome signature (PLSec) was bioinformatically derived from previously validated hepatic transcriptome signatures and optimized in 79 patients with advanced liver fibrosis. We independently validated PLSec for HCC risk in 331 cirrhosis patients with mixed etiologies (validation set 1 [V1]) and thereafter developed a score with clinical prognostic variables. The score was then validated in two independent cohorts: validation set 2 (V2): 164 patients with advanced liver fibrosis due to hepatitis C virus (HCV) infection cured after direct-acting antiviral therapy; validation set 3 (V3): 146 patients with advanced liver fibrosis with successfully-treated HCC and cured HCV infection.

Findings: An 8-protein blood-based PLSec recapitulated transcriptome-based hepatic HCC risk status. In V1, PLSec was significantly associated with incident HCC risk (adjusted hazard ratio [aHR], 2.35; 95% confidence interval [CI], 1.30-4.23). A composite score with serum alpha-fetoprotein (PLSec-AFP) was defined in V1, and validated in V2 (adjusted odds ratio, 3.80 [95%CI, 1.66-8.66]) and V3 (aHR, 3.08 [95%CI, 1.78-5.31]; c-index, 0.74). PLSec-AFP outperformed AFP alone (Brier score, 0.165 vs. 0.186 in V2; 0.196 vs. 0.206 in V3, respectively).

Conclusions: The blood-based PLSec-AFP can accurately stratify patients with advanced liver fibrosis for long-term HCC risk and thereby guide risk-based tailored HCC screening.
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http://dx.doi.org/10.1016/j.medj.2021.03.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312635PMC
July 2021

TACI haploinsufficiency protects against BAFF-driven humoral autoimmunity in mice.

Eur J Immunol 2021 09 27;51(9):2225-2236. Epub 2021 Jun 27.

Seattle Children's Research Institute, Seattle, WA, USA.

Polymorphisms in TACI, a BAFF family cytokine receptor, are linked to diverse human immune disorders including common variable immunodeficiency (CVID) and systemic lupus erythematosus (SLE). Functional studies of individual variants show modest impacts on surface TACI expression and/or downstream signal transduction, indicating that relatively subtle variation in TACI activity can impact human B-cell biology. However, significant complexity underlies TACI biology, including both positive and negative regulation of physiologic and pathogenic B-cell responses. To model these contradictory events, we compared the functional impact of TACI deletion on separate models of murine SLE driven by T cell-independent and -dependent breaks in B-cell tolerance. First, we studied whether reduced surface TACI expression was sufficient to protect against progressive BAFF-mediated systemic autoimmunity. Strikingly, despite a relatively modest impact on surface TACI levels, TACI haploinsufficiency markedly reduced pathogenic RNA-associated autoantibody titers and conferred long-term protection from BAFF-driven lupus nephritis. In contrast, B cell-intrinsic TACI deletion exerted a limited impact of autoantibody generation in murine lupus characterized by spontaneous germinal center formation and T cell-dependent humoral autoimmunity. Together, these combined data provide new insights into TACI biology and highlight how TACI signals must be tightly regulated during protective and pathogenic B-cell responses.
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http://dx.doi.org/10.1002/eji.202149244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410679PMC
September 2021

Association between body mass index, dosing strategy, and efficacy of immune checkpoint inhibitors.

J Immunother Cancer 2021 06;9(6)

Department of Internal Medicine (Division of Hematology-Oncology), The University of Texas Southwestern Medical Center, Dallas, Texas, USA

Background: Increased body mass index (BMI) has been associated with improved response to immune checkpoint inhibitors (ICIs) in multiple cancer types. We evaluated associations between BMI, ICI dosing strategy, and clinical outcomes.

Methods: We abstracted clinical data on patients with cancer treated with ICI, including age, sex, cancer type, BMI, ICI type, dosing strategy (weight-based or fixed), radiographic response, overall survival (OS), and progression-free survival (PFS). We compared clinical outcomes between low-BMI and high-BMI populations using Kaplan-Meier curves, Cox regressions, and Pearson product-moment correlation coefficients.

Results: A total of 297 patients were enrolled, of whom 40% were women and 59% were overweight (BMI≥25). Of these, 204 (69%) received fixed and 93 (31%) received weight-based ICI dosing. In the overall cohort, overweight BMI was associated with improved PFS (HR 0.69; 95% CI 0.51 to 0.94; p=0.02) and had a trend toward improved OS (HR 0.77; 95% CI 0.57 to 1.04; p=0.08). For both endpoints, improved outcomes in the overweight population were limited to patients who received weight-based ICI dosing (PFS HR 0.53; p=0.04 for weight-based; vs HR 0.79; p=0.2 for fixed dosing) (OS HR 0.56; p=0.03 for weight-based; vs HR 0.89; p=0.54 for fixed dosing). In multivariable analysis, BMI was not associated with PFS or OS. However, the interaction of BMI≥25 and weight-based dosing had a trend toward association with PFS (HR 0.53; 95% CI 0.26 to 1.10; p=0.09) and was associated with OS (HR 0.50; 95% CI 0.25 to 0.99; p=0.05). Patients with BMI<25 tended to have better outcomes with fixed-dose compared with weight-based ICI, while patients with BMI≥25 tended to have better outcomes with weight-based ICI, although these differences did not achieve statistical significance. There was no association between radiographic response and BMI with fixed-dose ICI (p=0.97), but a near-significant trend with weight-based ICI (p=0.1). In subset analyses, the association between BMI, ICI dosing strategy, and clinical outcomes appeared limited to men.

Conclusions: The clinical benefit of ICI in high-BMI populations appears limited to individuals receiving weight-based ICI dosing. Further research into optimal ICI dosing strategies may be warranted.
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http://dx.doi.org/10.1136/jitc-2021-002349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237749PMC
June 2021

Differential expression of sputum and serum autoantibodies in patients with chronic obstructive pulmonary disease.

Am J Physiol Lung Cell Mol Physiol 2021 06 28;320(6):L1169-L1182. Epub 2021 Apr 28.

Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.

Chronic obstructive pulmonary disease (COPD) is a complex and progressive respiratory disease. Autoimmune processes have been hypothesized to contribute to disease progression; however, the presence of autoantibodies in the serum has been variable. Given that COPD is a lung disease, we sought to investigate whether autoantibodies in sputum supernatant would better define pulmonary autoimmune processes. Matched sputum and serum samples were obtained from the Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study and at the Guangzhou Institute of Respiratory Health (GIRH). Samples were collected from patients with varying severity of COPD, asymptomatic smokers, and healthy control subjects. IgG and IgM autoantibodies were detected in sputum and serum of all subjects in both cohorts using a broad-spectrum autoantigen array. No differences were observed in sputum autoantibodies between COPD and asymptomatic smokers in either cohort. In contrast, 16% of detectable sputum IgG autoantibodies were decreased in subjects with COPD compared to healthy controls in the ADEPT cohort. Compared to asymptomatic smokers, approximately 13% of detectable serum IgG and 40% of detectable serum IgM autoantibodies were differentially expressed in GIRH COPD subjects. Of the differentially expressed specificities, anti-nuclear autoantibodies were predominately decreased. A weak correlation between increased serum IgM anti-tissue autoantibodies and a measure of airspace enlargement was observed. The differential expression of specificities varied between the cohorts. In closing, using a comprehensive autoantibody array, we demonstrate that autoantibodies are present in subjects with COPD, asymptomatic smokers, and healthy controls. Cohorts displayed high levels of heterogeneity, precluding the utilization of autoantibodies for diagnostic purposes.
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http://dx.doi.org/10.1152/ajplung.00518.2020DOI Listing
June 2021

Omega-3 Polyunsaturated Fatty Acid Intervention Against Established Autoimmunity in a Murine Model of Toxicant-Triggered Lupus.

Front Immunol 2021 7;12:653464. Epub 2021 Apr 7.

Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, United States.

Workplace exposure to respirable crystalline silica dust (cSiO) has been etiologically linked to the development of lupus and other human autoimmune diseases. Lupus triggering can be recapitulated in female NZBWF1 mice by four weekly intranasal instillations with 1 mg cSiO This elicits inflammatory/autoimmune gene expression and ectopic lymphoid structure (ELS) development in the lung within 1 week, ultimately driving early onset of systemic autoimmunity and glomerulonephritis. Intriguingly, dietary supplementation with docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid (PUFA) found in fish oil, beginning 2 week prior to cSiO challenge, prevented inflammation and autoimmune flaring in this novel model. However, it is not yet known how ω-3 PUFA intervention influences established autoimmunity in this murine model of toxicant-triggered lupus. Here we tested the hypothesis that DHA intervention after cSiO-initiated intrapulmonary autoimmunity will suppress lupus progression in the NZBWF1 mouse. Six-week old NZWBF1 female mice were fed purified isocaloric diet for 2 weeks and then intranasally instilled with 1 mg cSiO or saline vehicle weekly for 4 consecutive weeks. One week after the final instillation, which marks onset of ELS formation, mice were fed diets supplemented with 0, 4, or 10 g/kg DHA. One cohort of mice ( = 8/group) was terminated 13 weeks after the last cSiO instillation and assessed for autoimmune hallmarks. A second cohort of mice ( = 8/group) remained on experimental diets and was monitored for proteinuria and moribund criteria to ascertain progression of glomerulonephritis and survival, respectively. DHA consumption dose-dependently increased ω-3 PUFA content in the plasma, lung, and kidney at the expense of the ω-6 PUFA arachidonic acid. Dietary intervention with high but not low DHA after cSiO treatment suppressed or delayed: (i) recruitment of T cells and B cells to the lung, (ii) development of pulmonary ELS, (iii) elevation of a wide spectrum of plasma autoantibodies associated with lupus and other autoimmune diseases, (iv) initiation and progression of glomerulonephritis, and (v) onset of the moribund state. Taken together, these preclinical findings suggest that DHA supplementation at a human caloric equivalent of 5 g/d was an effective therapeutic regimen for slowing progression of established autoimmunity triggered by the environmental toxicant cSiO.
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http://dx.doi.org/10.3389/fimmu.2021.653464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058219PMC
September 2021

A verified genomic reference sample for assessing performance of cancer panels detecting small variants of low allele frequency.

Genome Biol 2021 04 16;22(1):111. Epub 2021 Apr 16.

Marketing, Integrated DNA Technologies, Inc., 1710 Commercial Park, Coralville, IA, 52241, USA.

Background: Oncopanel genomic testing, which identifies important somatic variants, is increasingly common in medical practice and especially in clinical trials. Currently, there is a paucity of reliable genomic reference samples having a suitably large number of pre-identified variants for properly assessing oncopanel assay analytical quality and performance. The FDA-led Sequencing and Quality Control Phase 2 (SEQC2) consortium analyze ten diverse cancer cell lines individually and their pool, termed Sample A, to develop a reference sample with suitably large numbers of coding positions with known (variant) positives and negatives for properly evaluating oncopanel analytical performance.

Results: In reference Sample A, we identify more than 40,000 variants down to 1% allele frequency with more than 25,000 variants having less than 20% allele frequency with 1653 variants in COSMIC-related genes. This is 5-100× more than existing commercially available samples. We also identify an unprecedented number of negative positions in coding regions, allowing statistical rigor in assessing limit-of-detection, sensitivity, and precision. Over 300 loci are randomly selected and independently verified via droplet digital PCR with 100% concordance. Agilent normal reference Sample B can be admixed with Sample A to create new samples with a similar number of known variants at much lower allele frequency than what exists in Sample A natively, including known variants having allele frequency of 0.02%, a range suitable for assessing liquid biopsy panels.

Conclusion: These new reference samples and their admixtures provide superior capability for performing oncopanel quality control, analytical accuracy, and validation for small to large oncopanels and liquid biopsy assays.
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http://dx.doi.org/10.1186/s13059-021-02316-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051128PMC
April 2021
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