Inflammatory protein biomarkers of human diseases

As inflammation is a centrally important process across a diverse range of pathologies, the study of cytokines, chemokines, their respective receptors and many other types of proteins involved in inflammatory and immune response processes has been pivotal in our understanding and treatment of human disease. Olink® panels focused on inflammation-related proteins have been used extensively in such studies and below we present examples taken from just four of the many disease areas where this has been applied.

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Cytokine release syndrome in severe COVID-19

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Neurological diseases and neuroinflammation

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Inflammatory Bowel Disease (IBD)

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Dermatological diseases

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Inflammatory proteins drive severe COVID-19

In the unprecedented global research effort that resulted from the SARS-CoV-2 pandemic, inflammatory proteins soon took center stage after it became clear that extreme immune system reactions to viral infection were centrally involved in the most severe cases of the disease.

To date, more than 80 peer-reviewed articles based on COVID-19 studies citing the use of Olink panels have been published. Early in the pandemic, Olink collaborated with leading research teams to investigate COVID-19, the results of which provided a better understanding of the biology involved in disease progression, prognostic outcomes and responses to COVID vaccines. Olink assays for cytokines and other inflammation-related proteins were pivotal to these studies, defining the inflammatory/immune responses in mild and severe disease.

The powerful impact of Olink protein biomarker panels in COVID-19 research

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Suhre et al. Identification of Robust Protein Associations With COVID-19 Disease Based on Five Clinical Studies (2022) Frontiers in Immunology, DOI: 10.3389/fimmu.2021.781100

This study compared protein data from Olink inflammation and CVD panels from two population cohorts with three other independent COVID-19 clinical studies using Olink panels to identify which proteins were implicated in the disease. Overall, 68 of 253 overlapping proteins showed consistent expression patterns across all five studies. Importantly, 14 proteins were found to be up- or down-regulated to the same extent in COVID-19 patients compared to controls, regardless of patient nationality, blood matrix, COVID-19 inactivation process, or study design. These proteins were primarily linked to inflammatory/immunological processes such as cytokine-cytokine interaction, IL-18 signaling, fluid shear stress and rheumatoid arthritis (CCL16, CCL7, CXCL10, CCL8, LGALS9, CXCL11, IL1RN, CCL2, CD274, IL6, IL18, MERTK, IFNγ, and IL18R1).

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Using advance protein biomarker approaches to better understand rare disease and COVID-19

In this webinar, Dr. Frank Schmidt discusses two clinical studies run by the Weill Cornell Medicine Proteomics core using Olink protein assays to understand COVID-19. These two studies were then included in an inter-study comparison to find commonalities in the findings of important protein biomarkers in the disease.

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The results speak to Olink’s robust technology, as results were similar despite significant variations in study design, patient demographics, sample origin and sample handling protocols.

 

A storm we can’t weather… yet.

The five-clinical study comparison by Suhre and his colleagues has demonstrated the central role of cytokine release syndrome in severe COVID-19. This complex process involves a plethora of immune system cell-type and effector molecules, which is illustrated in a poster that you can download.

Human Immunity to Sars-Co-V2 – webinar

Prabhu Arunachalam and colleagues from Bali Pulendran’s group at Stanford University undertook a comprehensive multiomics study of immune responses in 76 COVID-19 patients and 69 healthy individuals. Their study combined single-cell transcriptomics, plasma proteomics and mass cytometry to assess cellular and molecular immune system responses at both a local and a systemic level. Results revealed a spatial dichotomy in the innate immune response, with suppression of peripheral innate immunity in the face of a pro-inflammatory response in the lung, which develops into a systemic pro-inflammatory response. Using a multiplexed Olink panel to assess 92 inflammation biomarkers in circulation, this work identified EN-RAGE, OSM and TNFSF14 as potential protein biomarkers associated with disease severity.

Webinar

Human Immunity to Sars-Co-V2

In this webinar, Dr. Prahbu Arunachalam reviews a protein biomarker study that revealed how the immune system goes awry leading to severe disease during SARS-CoV-2 infections, as well as identified potential prognostic biomarkers that may serve as therapeutic targets for the disease.

COVID-19-induced cytokine storm demonstrates the devastating effects of immune dysregulation

COVID-19-induced cytokine storm demonstrates the devastating effects of immune dysregulation

Read more about the interaction between the triggered driver cells (both adaptive T-cells and antigen-presenting cells) and the important cytokine players involved (including IL-18, TNF, IL-1b, IFN-gamma, IL-6 and IL-17).

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Inflammation plays a central role in neurological diseases

Some neurological diseases have long been recognised as primarily neuroinflammatory in nature, such as multiple sclerosis where there is an autoimmune response against myelin proteins. While other types of conditions were originally classified as degenerative, traumatic, psychiatric etc., it is now clear that inflammation plays important roles in these diseases as well.

Inflammation across a wide range of neurological conditions

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The central nervous system (CNS) has extensive links with the immune system, mediated by inflammatory proteins that may originate from both neuronal (e.g. brain microglia) or non-neuronal cells. Inflammatory proteins have now been associated with a very broad range of diseases and conditions that are connected to both the central and peripheral nervous systems, covering the entire span of pathogenesis from classical neuroinflammatory disease through to psychiatric/psychological disorders.

Inflammatory proteins associated diseases and conditions

  • Multiple sclerosis
  • Alzheimer’s disease
  • Parkinson’s disease
  • Traumatic brain injury
  • Neuropathic pain
  • Bipolar disorder and anxiety

Technologies such as Olink that can accurately measure multiple cytokines, chemokines, and other inflammatory mediators in small sample volumes from within (cerebrospinal fluid, brain microdialysis fluid etc.) and outside (plasma, serum) the CNS are greatly facilitating this urgently needed research which is needed to develop novel effective therapies.

Olink protein panels reveal key inflammatory biomarkers in neuroinflammation research

Douglas Galasko, MD

CSF neuroinflammatory biomarkers for Alzheimer’s disease & HIV

HIV and Alzheimer’s disease are associated with cognitive changes characterized by neuroinflammation or neurodegeneration, respectively. Dr. Galasko describes how Olink® PEA technology was employed to profile proteins related to mild cognitive impairment in HIV and Alzheimer’s patients compared to controls using cerebrospinal fluid (CSF).

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Predictive protein biomarkers for mortality in traumatic brain injury

This exploratory study investigated the use of prognostic protein biomarkers to predict mortality in patients with severe traumatic brain injury (sTBI). The study identified 3 plasma proteins that predicted with 100% accuracy ICU mortality in their sTBI patient cohort, outperforming current mortality prediction biomarker tests. Read the post on our Olink to Science blog to learn more.

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Understanding Inflammatory bowel disease with protein biomarkers

Inflammatory bowel disease (IBD) affects more than 10 million people globally. It comprises several autoimmune inflammatory conditions that can affect any part of the gastrointestinal tract, primarily Crohn’s disease (CD) and ulcerative colitis (UC).

Biology and treatment – current knowledge and challenges in IBD

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IBD is highly debilitating, and there is currently no cure available. The root causes of IBD remain elusive, although influencing factors are likely to include genetics, the environment, and the gut microbiome. IBD pathogenesis is complex and is characterized by an impaired function of the gut epithelial barrier that allows microbes and microbial products to penetrate and activate the immune system. This leads to the production of inflammatory cytokines, immune cell activation and ultimately to a chronic state of inflammation.

Key dysfunctions involved in IBD

  • Impaired epithelial barrier function
  • Translocation of microbial products
  • Immune cell activation
  • Proinflammatory cytokines
  • Chronic inflammation
  • Tissue destruction and complications

Effective therapies targeting some of the key inflammatory mediators involved (principally TNFα as well as others such as IL12/IL23) have been developed to manage and control symptoms, enabling stable remission in many patients. Despite these advances, several challenges remain.

  • Diagnosis and discrimination of CD and UC can be difficult and require invasive biopsies
  • A significant proportion of patients develop complications such as fistulas or fibrosis – this may require specific therapy approaches but cannot be easily predicted
  • Not all patients respond to current therapies and a proportion of those that do respond initially become resistant to treatment over time

All these challenges could benefit enormously from non-invasive blood biomarkers for diagnosis, prognosis and treatment response prediction in IBD.

Predicting drug responders in juvenile IBD – webinar

The Crohn’s & Colitis Foundation recently ran a major study to find prognostic markers that can determine if children with Crohn’s disease will develop serious complications such as fibrosis and/or fistulas, and markers that predict whether they are likely to respond to anti-TNF therapy. The first phase of the project used RNAseq data from mucosal biopsy samples to identify gene expression signatures linked to development of complications and anti-TNF response, before employing Olink panels to look for less invasive blood-based markers. Machine learning algorithms identified both a 14-protein prognostic signature that predicts fibrosis/fistula developmet with an accuracy of 84%, as well as a signature of just 3 proteins that predicts responders to anti-TNFα therapy with an accuracy of 90%.

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Dr. Hurtado-Lorenzo, VP of Translational Research for the Crohn’s

Colitis Foundation has presented this impressive work in a recent webinar. You can listen to snippet from the webinar  or access the full presentation.

Selected publication highlights in IBD research

Read the publications

  • Bourgonje AR, Hu S, Spekhorst LM, et al. The Effect of Phenotype and Genotype on the Plasma Proteome in Patients with Inflammatory Bowel Disease. (2021) Journal of Crohns and Colitis, DOI: 10.1093/ecco-jcc/jjab157


  • Bergemalm D, Andersson E, Hultdin J, et al.  Systemic Inflammation in Preclinical Ulcerative Colitis. (2021) Gastroenterology, DOI: 10.1053/j.gastro.2021.07.026


  • Ungaro R, Hu L, Ji J, et al. Machine learning identifies novel blood protein predictors of penetrating and stricturing complications in newly diagnosed paediatric Crohn’s disease. (2020) limentary Pharmacology & Therapy, DOI: 10.1111/apt.16136

  • Kalla R, Adams A, Bergemalm D, et al. Serum proteomic profiling at diagnosis predicts clinical course, and need for intensification of treatment in inflammatory bowel disease. (2020) Journal of Crohn’s and Colitis, DOI: 10.1093/ecco-jcc/jjaa230
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Olink inflammatory biomarkers transform dermatological disease research

Dermatological diseases such as atopic dermatitis (AD), psoriasis and Hidradenitis Suppurativa (HS) are relatively common inflammatory disorders. In addition to causing discomfort and distress to patients, they can also be associated with serious comorbidities such as cardiovascular problems. Molecular profiling of disease lesions by techniques such as RNAseq is providing better insights into disease biology and potential therapeutic approaches, but this frequently requires biopsy sampling associated with patient discomfort and increased infection risk.

Recent studies, however, suggest that in some cases, disease site biology as measured by gene expression can be mirrored systemically at the protein level as blood biomarkers. This offers a minimally invasive method to study the inflammatory proteins involved in disease pathophysiology and treatment responses, as well as the potential to identify new diagnostic, prognostic, and predictive risk markers.

Getting under the skin of dermatological diseases using protein biomarkers – webinar

For Professor Emma Guttman and Professor James G. Kruege, the analysis of protein biomarkers have helped them to understand the underlying biological mechanisms and pathways involved in Atopic Dermatitis (AD) and Psoriasis. They utilized Olink to understand the complex interplay of inflammatory and immunological processes in AD and psoriasis, and how they link to other diseases and how this may enable new therapeutic opportunities.

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Getting under the skin of dermatological diseases using protein biomarkers

Leading experts, Dr. Emma Guttman and Dr. James Krueger, talk about the challenges of research into dermatological diseases and how proteomics is helping to move this field forward.

Selected publications

Inflammatory protein responses to anti-IL17RA therapy in hidradentis suppurativa

Navrazhina K, Frew JW, Grand D, et al. IL-17RA blockade by brodalumab decreases inflammatory pathways in hidradenitis suppurativa skin and serum.  (2022) British Journal of Dermatology, DOI: 10.1111/bjd.21060

This longitudinal study examined a small subset of patients enrolled in a trial for the anti-IL17RA drug brodalumab, using RNAseq and immunohistochemistry to look at local effects (lesional and perilesional skin), and proteomics using the Olink platform to look at systemic responses in serum. Protein data identified circulating IL-17A as a good baseline predictor of drug response and showed that some cytokines such as IL8 and TNF that were readily detectable at baseline were significantly reduced after 12 weeks of drug treatment

This research identifies lipocalin-2 in skin and IL-17A in serum as potential predictive biomarkers for treatment response. This may be useful in guiding physicians in choosing the appropriate therapy for patients with moderate-to-severe HS

Proteomic monitoring of drug responses in atopic dermatitis from tape-strip samples

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He H, Olesen C, Pavel A, et al. Tape-Strip Proteomic Profiling of Atopic Dermatitis on Dupilumab Identifies Minimally Invasive Biomarkers (2021) Frontiers in Immunology, DOI: 10.3389/fimmu.2020.01768

In this exploratory study, the authors sought to characterize the proteomic signature of tape-strips from atopic dermatitis (AD) patients before and after treatment with the drug dupilumab. Analysis of samples from lesional and non-lesional skin using Olink panels showed that levels of >130 markers changed after drug treatment, with significant decreases in proteins associated with general inflammation, Th2 & Th17/Th22 responses, and innate immunity. These results demonstrate the feasibility of minimally invasive tape-strips for proteomic monitoring of therapeutic responses in AD patients.

These data emphasize the potential utility of tape-strip proteomic profiling for tracking biomarkers of therapeutic response in real-life settings as well as clinical trials and longitudinal studies of AD and beyond

Investigating drug mode of action in atopic dermatitis with proteomics

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Bissonnette R, Maai C, Forman S, Bhatia N, Lee M, Fowler J, Tyring S, Pariser D, Sofen H, Dhawan S, Zook M, Zammit D, Usansky H, Denis L, Rao N, Song T, Pavel A and Guttman-Yassky E. (2019) The oral Janus kinase/spleen tyrosine kinase inhibitor ASN002 demonstrates efficacy and improves associated systemic inflammation in patients with moderate‐to‐severe atopic dermatitis: results from a randomized double‐blind placebo‐controlled study. British Journal of Dermatology, Doi: 10.1111/bjd.17932

In a clinical trial of dual kinase inhibitor therapy for atopic dermatitis, samples were taken longitudinally over the course of treatment and protein levels compared to those from placebo subjects. Drug treatment resulted in a significant reduction in serum levels of individual markers of general inflammation, T-cell/B-cell markers, T-cell activation, innate immunity, and T helper cell regulation.  Pathway enrichment analysis indicated that cytokine–cytokine-receptor interaction, cytokine, Th1–Th2, inflammatory, chemokine-receptor binding, chemokine signaling, JAK-STAT signaling and IL-23 signaling were the primary pathways affected.

Based on serum biomarker analyses, our study showed that ASN002 provided greater and more significant modulation of many key AD circulatory biomarkers compared with placebo, particularly at high dosages.

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