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A Systemic Inflammatory Signature Reflecting Cross Talk Between 2434 Diabetes Volume 67, November 2018 A Systemic Inflammatory Signature Reflecting Cross Talk Between Innate and Adaptive Immunity Is Associated With Incident Polyneuropathy: KORA F4/FF4 Study Christian Herder,1,2,3 Julia M. Kannenberg,1,2 Maren Carstensen-Kirberg,1,2 Alexander Strom,1,2 Gidon J. Bönhof,1 Wolfgang Rathmann,2,4 Cornelia Huth,2,5 Wolfgang Koenig,6,7,8 Margit Heier,5 Jan Krumsiek,2,9,10 Annette Peters,2,5 Christa Meisinger,2,5,11 Michael Roden,1,2,3 Barbara Thorand,2,5 and Dan Ziegler1,2,3 Diabetes 2018;67:2434–2442 | https://doi.org/10.2337/db18-0060 Prospective analyses of biomarkers of inflammation and that multiple cell types from innate and adaptive immunity distal sensorimotor polyneuropathy (DSPN) are scarce are involved in the development of DSPN. We thus iden- and limited to innate immunity. We therefore aimed to tified novel associations between biomarkers of inflam- assess associations between biomarkers reflecting mul- mation and incident DSPN pointing to a complex cross tiple aspects of immune activation and DSPN. The study talk between innate and adaptive immunity in the patho- was based on 127 case subjects with incident DSPN and genesis of the disease. 386 noncase subjects from the population-based Co- operative Health Research in the Region of Augsburg (KORA) F4/FF4 cohort (follow-up 6.5 years). Proximity Several lines of evidence have linked inflammatory pro- extension assay technology was used to measure serum cesses to the development of distal sensorimotor poly- levels of biomarkers of inflammation. Of 71 biomarkers COMPLICATIONS neuropathy (DSPN). An activation of the immune system assessed, 26 were associated with incident DSPN. After fl adjustment for multiple testing, higher levels of six bio- contributes to diabetic neuropathy, and inhibiting in am- markers remained related to incident DSPN. Three of matory pathways ameliorates the condition in different – fi these proteins (MCP-3/CCL7, MIG/CXCL9, IP-10/CXCL10) rodent models (1 5). Preclinical ndings relating to an were chemokines, and the other three (DNER, CD40, activation of the innate immunity are corroborated by TNFRSF9) were soluble forms of transmembrane recep- cross-sectional studies in humans that have reported tors. The chemokines had neurotoxic effects on neuro- higher systemic levels of acute-phase proteins, proinflam- blastoma cells in vitro. Addition of all six biomarkers matory cytokines, and soluble adhesion molecules in indi- improved the C statistic of a clinical risk model from viduals with DSPN or neuropathic symptoms and deficits 0.748 to 0.783 (P = 0.011). Pathway analyses indicated compared with individuals without DSPN (6–14). 1Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for 10Department of Physiology and Biophysics, Institute for Computational Biomed- Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany icine, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, 2German Center for Diabetes Research (DZD), München-Neuherberg, Germany NY 3Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine 11Chair of Epidemiology, Ludwig-Maximilians-Universität München am UNIKA-T University Düsseldorf, Düsseldorf, Germany Augsburg, Augsburg, Germany 4 Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center Corresponding author: Christian Herder, [email protected]. for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany Received 15 January 2018 and accepted 6 August 2018. 5Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany This article contains Supplementary Data online at http://diabetes 6Deutsches Herzzentrum München, Technische Universität München, Munich, .diabetesjournals.org/lookup/suppl/doi:10.2337/db18-0060/-/DC1. Germany B.T. and D.Z. contributed equally to this work. 7German Center for Cardiovascular Research (DZHK), Partner site Munich Heart © 2018 by the American Diabetes Association. Readers may use this article as Alliance, Munich, Germany long as the work is properly cited, the use is educational and not for profit, and the 8Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, work is not altered. More information is available at http://www.diabetesjournals Ulm, Germany .org/content/license. 9Institute of Computational Biology, Helmholtz Zentrum München, German Re- search Center for Environmental Health, Neuherberg, Germany diabetes.diabetesjournals.org Herder and Associates 2435 However, to characterize biomarkers of subclinical in- Chamber of Physicians Ethics Board (Munich, Germany) flammation as risk factors of DSPN, prospective studies approved the study. are required due to the potential of reverse causality (i.e., Supplementary Fig. 1 describes the study sample for the DSPN affecting inflammatory processes rather than vice current study. From 1,161 KORA F4 study participants versa), as recently highlighted for cardiovascular epidemi- aged 62–81 years, 1,048 individuals represented the base- ological research (15). The Cooperative Health Research in line sample, which was used for correlation analysis be- the Region of Augsburg (KORA) F4/FF4 cohort is the only tween biomarkers of inflammation. Exclusions for the cohort in which the relationship between biomarkers of prospective study resulted in an analysis sample of 513 indi- inflammation and incident DSPN has been assessed so far viduals without DSPN at baseline, including 127 incident (16). These analyses were based on eight biomarkers show- case subjects and 386 noncase subjects. The mean follow- ing that cross-sectional and prospective associations be- up time (6SD) was 6.46 6 0.23 years. A drop-out analysis tween biomarkers of inflammation and DSPN overlap only comparing participants and nonparticipants in KORA FF4 partially (10,16,17). Importantly, we identified the proin- was published before (16). flammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-a as novel biomarkers for incident DSPN and Assessment of DSPN suggested that both cytokines may also improve the pre- The assessment of DSPN using the Michigan Neuropathy diction of DSPN beyond established risk factors (16). Screening Instrument (MNSI) has also been described A crucial limitation of the aforementioned human before (16). The examination part of the MNSI included studies—in addition to the mostly cross-sectional design— items for the appearance of feet, foot ulceration, ankle is the selection of biomarkers such as IL-6 and TNF-a reflexes, and vibration perception threshold at the great reflecting only the activation state of innate immunity. toes. Age-dependent limits of normal vibration perception Sural nerve biopsy specimens demonstrated a higher threshold were considered (28). The neuropathy assess- content of T cells in patients with peripheral neuropathy ment was extended by a bilateral examination of sensory compared with healthy control subjects and thus suggested perception using a 10-g monofilament (Neuropen) (16). an involvement of the adaptive immunity (18,19). Sup- This resulted in a total MNSI score ranging from 0 (all porting data from larger epidemiological studies are not aspects normal) to a maximum of 10 points. Incident available but would be relevant before inflammation can DSPN was defined using a cutoff at .3 points for the be addressed as a potential therapeutic target for DSPN follow-up assessment in KORA FF4 in accordance with our (5,20,21). previous study (16), thus satisfying the diagnostic criteria Therefore, the aims of this study were 1) to use a novel for possible DSPN according to the Toronto Diabetic protein-based multimarker approach (22–25) for a detailed Neuropathy Expert Group (29). Other potential causes assessment of different aspects of immune activation in of peripheral neuropathy, such as HIV infection and heavy peripheral blood and to characterize inflammatory signa- alcohol consumption, were excluded, whereas data on tures that are associated with incident DSPN in a large hypothyroidism, vitamin deficiencies, and chronic inflam- sample of the general older population, 2) to investigate matory demyelinating polyneuropathy were not available. the neurotoxic potential of biomarkers related to incident DSPN in an in vitro assay using human neuroblastoma Measurement of Biomarkers of Subclinical fl cells, 3) to assess their predictive value for incident DSPN, In ammation fl and 4) to identify pathways and upstream regulators of Biomarkers of subclinical in ammation were measured in fl differentially regulated biomarkers to gain insight into the fasting serum using the OLINK In ammation multiplex mechanisms underlying DSPN. immunoassay (OLINK Proteomics, Uppsala, Sweden). The OLINK Inflammation panel covers 92 protein biomarkers, including pro- and anti-inflammatory cytokines, chemo- RESEARCH DESIGN AND METHODS kines, growth factors, and factors involved in acute in- Study Design and Participants flammatory and immune responses, angiogenesis, fibrosis, The study design has been described before (16,26,27). and endothelial activation (Supplementary Table 1). Briefly, this study is based on the KORA F4 (2006–2008) This immunoassay is based on the proximity extension and the KORA FF4 studies (2013–2014), both follow-up assay (PEA) technology, which combines a detection step examinations of the population-based KORA S4 study using oligonucleotide-labeled antibodies, a proximity- (1999–2001)
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