Autoimmunity

Cellular aging over 13 years associated with incident antinuclear antibody positivity in the Baltimore Longitudinal Study of Aging Publication date: Available online 11 July 2019 Source: Journal of Autoimmunity Author(s): Helen C.S. Meier, Christine G. Parks, Hans B. Liu, Dale P. Sandler, Eleanor M. Simonsick, Kevin Deane, Nan-ping Weng Abstract Age-associated increases in antinuclear antibodies (ANA) in the general population are commonly noted but the mechanisms underlying this observation are unclear. This study aims to evaluate whether shorter peripheral blood mononuclear cell (PBMC) telomere length, a marker of more advanced biological age, is associated with ANA positivity prevalence and incidence in middle and older aged autoimmune disease-free individuals from the Baltimore Longitudinal Study of Aging (BLSA). Telomere length was measured by Southern Blot and categorized into tertiles. ANA was measured in a 1:80 and a 1:160 dilution of sera by immunofluorescence using HEp-2 cells (seropositive = 3 or 4). Multiple logistic regression was used to estimate the odds ratios and 95% confidence intervals of ANA positivity comparing the shorter tertiles of telomere length to the longest tertile for two cross-sectional points in time and then longitudinally to assess the association between shorter telomere length and incident ANA positivity. Cross-sectional analyses were adjusted for sex, race and BMI (N = 368 baseline, N = 370 follow-up) and longitudinal analyses were adjusted for sex, race, BMI and time between baseline and follow-up (N = 246). No statistically significant cross-sectional associations were observed at baseline or follow-up. Among those where ANA negative at baseline, individuals with shorter telomeres were more likely to be ANA positive at follow-up, an average 13 years later. Individuals with short telomeres at both time periods were more likely to be ANA positive. Findings suggest that ANA positivity in the general population may be indicative of immune dysfunction resulting from advanced cellular aging processes.

DNGR1-mediated deletion of A20/Tnfaip3 in dendritic cells alters T and B-cell homeostasis and promotes autoimmune liver pathology Publication date: Available online 9 July 2019 Source: Journal of Autoimmunity Author(s): Tridib Das, Ingrid M. Bergen, Thomas Koudstaal, Jennifer A.C. van Hulst, Geert van Loo, André Boonstra, Thomas Vanwolleghem, Patrick S.C. Leung, M. Eric Gershwin, Rudi W. Hendriks, Mirjam Kool Abstract Dendritic cells (DCs) are central regulators of tolerance versus immunity. The outcome depends amongst others on DC subset and activation status. Whereas CD11b+ type 2 conventional DCs (cDC2s) initiate proinflammatory helper T (Th)-cell responses, CD103+ cDC1s are crucial for regulatory T-cell (Treg) induction and CD8+ T-cell activation. DC activation is controlled by the transcription factor NF-κB. Ablation of A20/Tnfaip3, a critical regulator of NF-κB activation, in DCs leads to constitutive DC activation and development of systemic autoimmunity. We hypothesized that the activation status of cDCs controls the development of autoimmunity. To target cDCs, DNGR1(Clec9a)-cre-mediated excision of A20/Tnfaip3 was used through generation of Tnfaip3fl/flxClec9a+/cre (Tnfaip3DNGR1−KO) mice. Immune cell activation was evaluated at 31-weeks of age. We found that DNGR1-cre-mediated deletion of A20/Tnfaip3 resulted in liver pathology characterized by inflammatory infiltrates adjacent to the portal triads. Both cDC subsets as well as monocyte-derived DCs (moDCs) in Tnfaip3DNGR1−KO livers harbored an activated phenotype. Specifically, the costimulatory molecule CD40 in liver cDCs and moDCs was regulated by A20/Tnfaip3 expression. Livers from Tnfaip3DNGR1−KO mice had augmented proportions of Th1, Th17, Treg, and follicular Th (Tfh)-cells compared to control mice, accompanied by an increase in IgA-producing plasma cells. Serum IgA from Tnfaip3DNGR1−KO mice recognized self-proteins, specifically cytoplasmic proteins in liver periportal regions. These data show that enhanced activation of cDCs and moDCs, due to A20/Tnfaip3 ablation, promotes the development of organ-specific autoimmunity but not systemic autoimmunity. This model could be useful to examine the pathobiological processes contributing to autoimmune liver diseases.

Selective deletion of Eos (Ikzf4) in T-regulatory cells leads to loss of suppressive function and development of systemic autoimmunity Publication date: Available online 8 July 2019 Source: Journal of Autoimmunity Author(s): Ameya S. Gokhale, Arunakumar Gangaplara, Maria Lopez-Occasio, Angela M. Thornton, Ethan M. Shevach Abstract Eos (lkzf4) is a member of the Ikaros family of transcription factors and is preferentially expressed in T-regulatory (Treg) cells. However, the role of Eos in Treg function is controversial. One study using siRNA knock down of Eos demonstrated that it was critical for Treg suppressor function. In contrast, Treg from mice with a global deficiency of Eos had normal Treg function in vitro and in vivo. To further dissect the function of Eos in Tregs, we generated mice with a conditional knock out of Eos in Treg cells (lkzf4fl/fl X Foxp3YFP−cre, Eos cKO). Deletion of Eos in Treg resulted in activation of CD4+Foxp3- and CD8+ T cells at the age of 3 months, cellular infiltration in non-lymphoid tissues, hyperglobulinemia, and anti-nuclear antibodies. While Tregs from Eos cKO mice displayed normal suppressive function in vitro, Eos cKO mice developed severe Experimental Autoimmune Encephalomyletis (EAE) following immunization with myelin oligodendrocyte glycoprotein (MOG) and Eos cKO Treg were unable to suppress Inflammatory Bowel Disease (IBD). Eos cKO mice had decreased growth of the transplantable murine adenocarcinoma MC38 tumor accompanied by enhanced IFN-γ/TNF-α production by CD8+ T cells in tumor draining lymph nodes. Mice with a global deficiency of Eos or a deficiency of Eos only in T cells developed autoimmunity at a much older age (12 months or 7–8 months, respectively). Taken together, Eos appears to play an essential role in multiple aspects of Treg suppressor function, but also plays an as yet unknown role in the function of CD4+Foxp3- and CD8+ T cells and potentially in non-T cells.

Predicting drug-free remission in rheumatoid arthritis: A prospective interventional cohort study Publication date: Available online 4 July 2019 Source: Journal of Autoimmunity Author(s): Kenneth F. Baker, Andrew J. Skelton, Dennis W. Lendrem, Adam Scadeng, Ben Thompson, Arthur G. Pratt, John D. Isaacs Abstract Background Many patients with rheumatoid arthritis (RA) achieve disease remission with modern treatment strategies. However, having achieved this state, there are no tests that predict when withdrawal of therapy will result in drug-free remission rather than flare. We aimed to identify predictors of drug-free remission in RA. Methods The Biomarkers of Remission in Rheumatoid Arthritis (BioRRA) Study was a unique, prospective, interventional cohort study of complete and abrupt cessation of conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs). Patients with RA of at least 12 months duration and in clinical and ultrasound remission discontinued DMARDs and were monitored for six months. The primary outcome was time-to-flare, defined as disease activity score in 28 joints with C-reactive protein (DAS28-CRP) ≥ 2.4. Baseline clinical and ultrasound measures, circulating inflammatory biomarkers, and peripheral CD4+ T cell gene expression were assessed for their ability to predict time-to-flare and flare/remission status by Cox regression and receiver-operating characteristic (ROC) analysis respectively. Results 23/44 (52%) eligible patients experienced an arthritis flare after a median (IQR) of 48 (31.5–86.5) days following DMARD cessation. A composite score incorporating five baseline variables (three transcripts [FAM102B, ENSG00000228010, ENSG00000227070], one cytokine [interleukin-27], one clinical [Boolean remission]) differentiated future flare from drug-free remission with an area under the ROC curve of 0.96 (95% CI 0.91–1.00), sensitivity 0.91 (0.78–1.00) and specificity 0.95 (0.84–1.00). Conclusion We provide proof-of-concept evidence for predictors of drug-free remission in RA. If validated, these biomarkers could help to personalize immunosuppressant withdrawal: a therapy paradigm shift with ensuing patient and economic benefits.

PD-1 aborts the activation trajectory of autoreactive CD8+ T cells to prohibit their acquisition of effector functions Publication date: Available online 2 July 2019 Source: Journal of Autoimmunity Author(s): Hikari Okamura, Il-mi Okazaki, Kenji Shimizu, Takumi Maruhashi, Daisuke Sugiura, Reina Mizuno, Taku Okazaki Abstract Anti-PD-1 therapy can induce eradication of tumors and immune-related adverse events (irAEs) in humans and model animals. However, how anti-PD-1 therapy modifies cellular phenotypes of CD8+ T cells to destroy tumors and damage self-tissues remains to be clarified. Here we performed single cell mRNA expression profiling of autoreactive CD8+ T cells under or beyond PD-1 suppression in target tissues and reconstructed their activation trajectory. Autoreactive CD8+ T cells went through four activation phases and PD-1 strongly attenuated the transition from the second- to the third-phase, where effector functions were acquired. Shifts in cluster composition of autoreactive CD8+T cells markedly reflected the severity of autoimmunity. In addition, genes up-regulated along the activation-trajectory in autoimmunity were highly expressed in responders of melanoma patients in anti-PD-1 therapy, suggesting that tumor-specific T cells need to be activated in a similar trajectory to destroy tumors in human patients upon PD-1 blockade. These findings reveal that PD-1 blockade facilitates the activation trajectory of CD8+ T cells to boost their effector functions. Targeted manipulation of the trajectory could lead to new therapeutic opportunities.

Extracellular traps and PAD4 released by macrophages induce citrullination and auto-antibody production in autoimmune arthritis Publication date: Available online 2 July 2019 Source: Journal of Autoimmunity Author(s): Mohey Eldin M. El Shikh, Riham El Sayed, Alessandra Nerviani, Katriona Goldmann, Christopher Robert John, Rebecca Hands, Liliane Fossati-Jimack, Myles J. Lewis, Costantino Pitzalis Abstract The mechanisms underlying the transition of rheumatoid arthritis (RA) systemic autoimmunity to the joints remain largely unknown. Here, we demonstrate that macrophages in the secondary lymphoid organs (SLOs) and synovial ectopic lymphoid-like structures (ELSs) express peptidylarginine deiminase 4 (PAD4) in murine collagen induced arthritis (CIA) and synovial biopsies from RA patients. Moreover, peptidyl citrulline colocalized with macrophages in SLOs and ELSs, and depletion of macrophages in CIA decreased lymphoid tissue citrullination and serum anti-citrullinated protein/peptide antibody (ACPA) levels. Furthermore, PAD was released from activated murine and RA synovial tissue and fluid (SF) macrophages which functionally deiminated extracellular proteins/peptides in vitro. Additionally, activated murine and SF macrophages displayed macrophage extracellular trap formation (METosis) and release of intracellular citrullinated histones. Moreover, presentation of citrullinated proteins induced ACPA production in vitro. Thus, lymphoid tissue macrophages contribute to self-antigen citrullination and ACPA production, indicating that their selective targeting would potentially ameliorate citrullination-dependent autoimmune disorders.

The identification of CCL18 as biomarker of disease activity in localized scleroderma Publication date: July 2019 Source: Journal of Autoimmunity, Volume 101 Author(s): J.S. Mertens, E.M.G.J. de Jong, L.L. van den Hoogen, J. Wienke, R.M. Thurlings, M.M.B. Seyger, E.P.A.H. Hoppenreijs, C.A. Wijngaarde, I.M.J.J. van Vlijmen-Willems, E. van den Bogaard, B. Giovannone, F. van Wijk, A. van Royen-Kerkhof, W. Marut, T.R.D. Radstake Abstract Background Localized Scleroderma (LoS) encompasses a group of idiopathic skin conditions characterized by (sub)cutaneous inflammation and subsequent development of fibrosis. Currently, lack of accurate tools enabling disease activity assessment leads to suboptimal treatment approaches. Objective To investigate serum concentrations of cytokines and chemokines implicated in inflammation and angiogenesis in LoS and explore their potential to be utilized as biomarker of disease activity. Additionally, to investigate the implication of potential biomarkers in disease pathogenesis. Methods A 39-plex Luminex immuno-assay was performed in serum samples of 74 LoS and 22 Healthy Controls. The relation between a validated clinical measure of disease activity (mLoSSI) and serum analytes was investigated. Additionally, gene and protein expression were investigated in circulating cells and skin biopsies. Results From the total of 39, 10 analytes (CCL18, CXCL9, CXCL10, CXCL13, TNFRII, Galectin-9, TIE-1, sVCAM, IL-18, CCL19) were elevated in LoS serum. Cluster analysis of serum samples revealed CCL18 as most important analyte to discriminate between active and inactive disease. At individual patient level, CCL18 serum levels correlated strongest with mLoSSI-scores (rs = 0.4604, P < 0.0001) and in longitudinal measures CCL18 concentrations normalised with declining disease activity upon treatment initiation. Additionally, CCL18 was elevated in LoS serum, and not in (juvenile) dermatomyositis or spinal muscular atrophy. Importantly, CCL18 gene and protein expression was increased at the inflammatory border of cutaneous LoS lesions, with normal expression in unaffected skin and circulating immune cells. Conclusion CCL18 is specific for disease activity in LoS thereby providing relevance as a biomarker for this debilitating disease.

CD30L/CD30 protects against psoriasiform skin inflammation by suppressing Th17-related cytokine production by Vγ4+ γδ T cells Publication date: July 2019 Source: Journal of Autoimmunity, Volume 101 Author(s): Dan Yue, Yong You, Xiaoqing Zhang, Biao Wang, Xiao Wang, Ruiqun Qi, Fan Yang, Xin Meng, Yasunobu Yoshikai, Yuanyuan Wang, Xun Sun Abstract Psoriasis is a common, autoimmune, chronic inflammatory skin disease. It has been demonstrated that cutaneous T17 cells play an important pro-inflammatory role in the pathogenesis of psoriasis, through the production of various Th17-related cytokines. Our previous studies have demonstrated that CD30L/CD30 signal plays a pivotal role in the differentiation of CD4+ Th17 cells and Vγ6+γδ T17 cells in the gut-associated lymphoid tissues of mouse. However, its effect on the pathogenesis of psoriasis is unknown. Here, we fully prove that CD30L/CD30 signaling plays a novel protective role in the development of psoriasis in mice, through selective inhibition of CCR6 expression and Th17-related cytokine synthesis in the Vγ4+γδ T17 cell subset. Meanwhile, treatment with agonistic anti-CD30 mAb had a significant therapeutic effect on our psoriasis mouse model. Therefore, the CD30L/CD30 signaling pathway is an ideal target for antibody therapy, which may become a new approach for the immunobiological treatment of psoriasis.

Sex-specific Tau methylation patterns and synaptic transcriptional alterations are associated with neural vulnerability during chronic neuroinflammation Publication date: July 2019 Source: Journal of Autoimmunity, Volume 101 Author(s): Alessandro Didonna, Ester Cantó, Hengameh Shams, Noriko Isobe, Chao Zhao, Stacy J. Caillier, Carlo Condello, Hana Yamate-Morgan, Seema K. Tiwari-Woodruff, Mohammad R.K. Mofrad, Stephen L. Hauser, Jorge R. Oksenberg Abstract The molecular events underlying the transition from initial inflammatory flares to the progressive phase of multiple sclerosis (MS) remain poorly understood. Here, we report that the microtubule-associated protein (MAP) Tau exerts a gender-specific protective function on disease progression in the MS model experimental autoimmune encephalomyelitis (EAE). A detailed investigation of the autoimmune response in Tau-deficient mice excluded a strong immunoregulatory role for Tau, suggesting that its beneficial effects are presumably exerted within the central nervous system (CNS). Spinal cord transcriptomic data show increased synaptic dysfunctions and alterations in the NF-kB activation pathway upon EAE in Tau-deficient mice as compared to wildtype animals. We also performed the first comprehensive characterization of Tau post-translational modifications (PTMs) in the nervous system upon EAE. We report that the methylation levels of the conserved lysine residue K306 are significantly decreased in the chronic phase of the disease. By combining biochemical assays and molecular dynamics (MD) simulations, we demonstrate that methylation at K306 decreases the affinity of Tau for the microtubule network. Thus, the down-regulation of this PTM might represent a homeostatic response to enhance axonal stability against an autoimmune CNS insult. The results, altogether, position Tau as key mediator between the inflammatory processes and neurodegeneration that seems to unify many CNS diseases.

Frequency, mutual exclusivity and clinical associations of myositis autoantibodies in a combined European cohort of idiopathic inflammatory myopathy patients Publication date: July 2019 Source: Journal of Autoimmunity, Volume 101 Author(s): Z. Betteridge, S. Tansley, G. Shaddick, H. Chinoy, R.G. Cooper, R.P. New, J.B. Lilleker, J. Vencovsky, L. Chazarain, K. Danko, M. Nagy-Vincze, L. Bodoki, M. Dastmalchi, L. Ekholm, I.E. Lundberg, N. McHugh, UKMyonet contributors Abstract Objectives To determine prevalence and co-existence of myositis specific autoantibodies (MSAs) and myositis associated autoantibodies (MAAs) and associated clinical characteristics in a large cohort of idiopathic inflammatory myopathy (IIM) patients. Methods Adult patients with confirmed IIM recruited to the EuroMyositis registry (n = 1637) from four centres were investigated for the presence of MSAs/MAAs by radiolabelled-immunoprecipitation, with confirmation of anti-MDA5 and anti-NXP2 by ELISA. Clinical associations for each autoantibody were calculated for 1483 patients with a single or no known autoantibody by global linear regression modelling. Results MSAs/MAAs were found in 61.5% of patients, with 84.7% of autoantibody positive patients having a sole specificity, and only three cases (0.2%) having more than one MSA. The most frequently detected autoantibody was anti-Jo-1 (18.7%), with a further 21 specificities each found in 0.2–7.9% of patients. Autoantibodies to Mi-2, SAE, TIF1, NXP2, MDA5, PMScl and the non-Jo-1 tRNA-synthetases were strongly associated (p < 0.001) with cutaneous involvement. Anti-TIF1 and anti-Mi-2 positive patients had an increased risk of malignancy (OR 4.67 and 2.50 respectively), and anti-SRP patients had a greater likelihood of cardiac involvement (OR 4.15). Interstitial lung disease was strongly associated with the anti-tRNA synthetases, anti-MDA5, and anti-U1RNP/Sm. Overlap disease was strongly associated with anti-PMScl, anti-Ku, anti-U1RNP/Sm and anti-Ro60. Absence of MSA/MAA was negatively associated with extra-muscular manifestations. Conclusions Myositis autoantibodies are present in the majority of patients with IIM and identify distinct clinical subsets. Furthermore, MSAs are nearly always mutually exclusive endorsing their credentials as valuable disease biomarkers.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
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alsfakia@gmail.com