Potential of Point-of-Care and At-Home Assessment of Immune Status via Rapid Cytokine Detection and Questionnaire-Based Anamnesis.

Monitoring the immune system's status has emerged as an urgent demand in critical health conditions. The circulating cytokine levels in the blood reflect a thorough insight into the immune system status. Indeed, measuring one cytokine may deliver more information equivalent to detecting multiple diseases at a time. However, if the reported cytokine levels are interpreted with considering lifestyle and any comorbid health conditions for the individual, this will promote a more precise assessment of the immune status. Therefore, this study addresses the most recent advanced assays that deliver rapid, accurate measuring of the cytokine levels in human blood, focusing on add-on potentials for point-of-care (PoC) or personal at-home usage, and investigates existing health questionnaires as supportive assessment tools that collect all necessary information for the concrete analysis of the measured cytokine levels. We introduced a ten-dimensional featuring of cytokine measurement assays. We found 15 rapid cytokine assays with assay time less than 1 h; some could operate on unprocessed blood samples, while others are mature commercial products available in the market. In addition, we retrieved several health questionnaires that addressed various health conditions such as chronic diseases and psychological issues. Then, we present a machine learning-based solution to determine what makes the immune system fit. To this end, we discuss how to employ topic modeling for deriving the definition of immune fitness automatically from literature. Finally, we propose a prototype model to assess the fitness of the immune system through leveraging the derived definition of the immune fitness, the cytokine measurements delivered by a rapid PoC immunoassay, and the complementary information collected by the health questionnaire about other health factors. In conclusion, we discovered various advanced rapid cytokine detection technologies that are promising candidates for point-of-care or at-home usage; if paired with a health status questionnaire, the assessment of the immune system status becomes solid and we demonstrated potentials for promoting the assessment tool with data mining techniques.

Unique autoantibody prevalence in long-term recovered SARS-CoV-2-infected individuals.

The variability in resolution of SARS-CoV-2-infections between individuals neither is comprehended, nor are the long-term immunological consequences. To assess the long-term impact of a SARS-CoV-2-infection on the immune system, we conducted a prospective study of 80 acute and former SARS-CoV-2 infected individuals and 39 unexposed donors to evaluate autoantibody responses and immune composition. Autoantibody levels against cyclic citrullinated peptide (CCP), a specific predictor for rheumatoid arthritis (RA), were significantly (p = 0.035) elevated in convalescents only, whereas both acute COVID-19 patients and long-term convalescents showed critically increased levels of anti-tissue transglutaminase (TG), a specific predictor of celiac disease (CD) (p = 0.002). Both, anti-CCP and anti-TG antibody levels were still detectable after 4-8 months post infection. Anti-TG antibodies occurred predominantly in aged patients in a context of a post-SARS-CoV-2-specific immune composition (R2 = 0.31; p = 0.044). This study shows that increased anti-CCP and anti-TG autoantibody levels can remain long-term after recovering even from mildly experienced COVID-19. The inter-relationship of the lung as viral entry side and RA- and CD-associated autoimmunity indicates that a SARS-CoV-2-infection could be a relevant environmental factor in their pathogenesis.

Response to IL-6 trans- and IL-6 classic signalling is determined by the ratio of the IL-6 receptor α to gp130 expression: fusing experimental insights and dynamic modelling.

BACKGROUND: Interleukin-6 is a pleiotropic cytokine with high clinical relevance and an important mediator of cellular communication, orchestrating both pro- and anti-inflammatory processes. Interleukin-6-induced signalling is initiated by binding of IL-6 to the IL-6 receptor α and subsequent binding to the signal transducing receptor subunit gp130. This active receptor complex initiates signalling through the Janus kinase/signal transducer and activator of transcription pathway. Of note, IL-6 receptor α exists in a soluble and a transmembrane form. Binding of IL-6 to membrane-bound IL-6 receptor α induces anti-inflammatory classic signalling, whereas binding of IL-6 to soluble IL-6 receptor α induces pro-inflammatory trans-signalling. Trans-signalling has been described to be markedly stronger than classic signalling. Understanding the molecular mechanisms that drive differences between trans- and classic signalling is important for the design of trans-signalling-specific therapies. These differences will be addressed here using a combination of dynamic mathematical modelling and molecular biology. METHODS: We apply an iterative systems biology approach using set-based modelling and validation approaches combined with quantitative biochemical and cell biological analyses. RESULTS: The combination of experimental analyses and dynamic modelling allows to relate the observed differences between IL-6-induced trans- and classic signalling to cell-type specific differences in the expression and ratios of the individual subunits of the IL-6 receptor complex. Canonical intracellular Jak/STAT signalling is indifferent in IL-6-induced trans- and classic signalling. CONCLUSION: This study contributes to the understanding of molecular mechanisms of IL-6 signal transduction and underlines the power of combined dynamical modelling, model-based validation and biological experiments. The opposing pro- and anti-inflammatory responses initiated by IL-6 trans- and classic signalling depend solely on the expression ratios of the subunits of the entire receptor complex. By pointing out the importance of the receptor expression ratio for the strength of IL-6 signalling this study lays a foundation for future precision medicine approaches that aim to selectively block pro-inflammatory trans-signalling. Furthermore, the derived models can be used for future therapy design.

Robustness and Information Transfer within IL-6-induced JAK/STAT Signalling.

Cellular communication via intracellular signalling pathways is crucial. Expression and activation of signalling proteins is heterogenous between isogenic cells of the same cell-type. However, mechanisms evolved to enable sufficient communication and to ensure cellular functions. We use information theory to clarify mechanisms facilitating IL-6-induced JAK/STAT signalling despite cell-to-cell variability. We show that different mechanisms enabling robustness against variability complement each other. Early STAT3 activation is robust as long as cytokine concentrations are low. Robustness at high cytokine concentrations is ensured by high STAT3 expression or serine phosphorylation. Later the feedback-inhibitor SOCS3 increases robustness. Channel Capacity of JAK/STAT signalling is limited by cell-to-cell variability in STAT3 expression and is affected by the same mechanisms governing robustness. Increasing STAT3 amount increases Channel Capacity and robustness, whereas increasing STAT3 tyrosine phosphorylation reduces robustness but increases Channel Capacity. In summary, we elucidate mechanisms preventing dysregulated signalling by enabling reliable JAK/STAT signalling despite cell-to-cell heterogeneity.