Measure biomarkers of inflammation with ProcartaPlex multiplex immunoassay panels. Simultaneously quantitate up to 65 soluble immune biomarkers from a single sample. Use preconfigured chemokine and cytokine panels or select from single targets to create your own custom panel to detect and quantitate the inflammatory response.
Inflammation and hyper-inflammation
As part of the immune response, inflammation plays an important role in defending the body against pathogens, such as viruses, bacteria, fungi, and other parasites. However, the inappropriate activation of inflammatory processes is an underlying contributor to many common pathological conditions. For example, autoimmune conditions arise when our immune system mistakes our cells or tissues for pathogens and attacks them. In addition, studies show that tumor proliferation and metastasis may occur when inflammatory cytokines create a microenvironment conducive to cancer progression.
Acute versus chronic inflammation
Acute inflammation is a short-lived response that is characterized by extravasation of leukocytes, erythrocytes, and plasma components into the injured tissue. If left unchecked, the acute inflammatory process can lead to chronic inflammation. Unlike acute inflammation, chronic inflammation is characterized primarily by tissue infiltration by lymphocytes and macrophages. Chronic inflammation is closely associated with allergy, atherosclerosis, cancer, arthritis, and Alzheimer’s disease, as well as autoimmune diseases. The process of acute inflammation is well defined, but the causes of chronic inflammation and its associated molecular and cellular pathways are still not well understood.
The critical balance between pro- and anti-inflammatory mediators
The overall effect of an inflammatory response is dictated by the balance between pro- and anti-inflammatory mediators. Pro-inflammatory cytokines such as IL-1 beta, IL-6, and TNF alpha are responsible for early responses and amplify inflammatory reactions, whereas anti-inflammatory cytokines, which include IL-4, IL-10, and IL-13, have the opposite effect in that they limit the inflammatory reactions. The increasing complexity of pro- and anti-inflammatory cytokine and chemokine networks has made it crucial to examine them in relevant functional groups rather than individually.
Hyper-Inflammation and the Cytokine Storm
A typical immune response involves production of cytokines that orchestrate the differentiation of lymphocytes based on the type of pathogen being cleared. Ultimately the immune system self-regulates and shuts down once the infection is resolved. In some cases, however, the immune response does not shut down, and there is an overproduction of inflammatory cytokines that causes systemic damage to host cells.
The so-called cytokine storm or cytokine release syndrome (CRS) is characterized by an aggressive pro-inflammatory response in combination with an insufficient an anti-inflammatory response, which results in the loss of homeostasis of the immune response. The key factors identified in the pathology of a cytokine storm are TNF alpha, Interferons, IL-1 beta, MCP-1 (CCL2), and most importantly IL-61.
Activation of mainly T cells or lysis of immune cells induces a release of IFN gamma or TNF alpha. This leads to the activation of macrophages, dendritic cells, other immune cells, and endothelial cells. After activation, these cells further release proinflammatory cytokines. Large amounts of Interleukin 6 (IL-6) are produced by macrophages and endothelial cells, activating T cells and other immune cells and creating a positive feedback-loop that results in a cytokine storm, inducing the release of many more cytokines and chemokines but also upregulating acute phase proteins. The resulting cytokine storm syndromes are heterogeneous but have the described immune dysregulation in common, leading to hyperinflammation, fever, cytopenia, splenomegaly, hepatitis, coagulopathy, and may result in fatal multisystem organ dysfunction.
Infectious diseases associated with a hyperreactive immune system may be caused by different pathogens, such as bacteria (e.g. toxic shock syndrome (TSS)) and viruses (e.g. Influenza, Epstein-Barr Virus, SARS and SARS COV-2)). In addition, the cytokine storm has been described in therapeutic environments such as immunotherapy and CAR-T cell therapy in cancer. Treatment of patients with therapeutic monoclonal antibodies may stimulate a massive cytokine release syndrome leading to life threatening side effects of immunotherapy2. Recently described by Cheng et al., exposure to organic pollutants could elicit a hyper reactive immune response. Exposure to polycyclic aromatic hydrocarbons was linked to increased serum levels of cytokines associated with a cytokine storm3.
Protein biomarkers for Cytokine Storm or Cytokine Release Syndrome in the ProcartaPlex Multiplex Cytokine Assay
|Target||Type||Role associated with cytokine release syndrome (CRS)|
|G-CSF (CSF-3)||Cytokine (Colony-Stimulating Factors)||CRS, cytokine profile associated with sHLH and severe COVID-19|
|GM-CSF||Cytokine (Colony-Stimulating Factors)||Inflammatory cytokine released during CRS4, stimulates IL-65|
|IFN alpha||Cytokine (Interferon), pro-inflammatory||Key player in CRS, innate immunity to viruses|
|IFN gamma||Cytokine (Interferon), pro-inflammatory||Key mediator of CRS, described in SARS patients6, potential marker to predict COVID-19 outcome, potential therapeutic target7|
|IL-1 beta||Cytokine, pro-inflammatory||Plays a central role in CRS, is considered a potential target for COVID-197|
|IL-2||Cytokine, pro-inflammatory||Released during CRS4, stimulates IL-65|
|IL-4||Cytokine, anti-inflammatory||Important for homeostasis in the immune response, stimulates IL-65|
|IL-5||Cytokine||Main biomarker for sepsis, involved in CRS and has a role in influenza infection induced CRS8|
|IL-6||Cytokine, pro-inflammatory||Key mediator of CRS, potential therapeutic target, blocking IL-6 potentially beneficial for patients with severe inflammation in the lungs due to CRS, increased plasma levels in ICU vs. non-ICU patients for COVID199|
|IL-8 (CXCL8)||Chemokine (CXC type), pro-inflammatory||CRS in SARS patients6, chemoattractant for various immune cells|
|IL-10||Cytokine, anti-inflammatory||Important for homeostasis in the immune response, stimulates IL-65|
|IL-12p70||Cytokine, pro-inflammatory||Plays a role in CRS|
|IL-13||Cytokine, immunoregulatory||Secreted by NK cells, plays a role in MAS10|
|IL-17A (CTLA-8)||Cytokine, pro-inflammatory||Plays a role in CRS provoked by TSS11, increased level in PAH exposure associated cytokine storm3|
|IL-18||Cytokine, pro-inflammatory||Involved in CRS in SARS patients6|
|IP-10 (CXCL10)||Chemokine (CXC type)||CRS associated with sHLH, and severity of COVID-1912, increased plasma levels in ICU vs. non-ICU patients9|
|MCP-1 (CCL2)||Chemokine (CC type)||Central role in CRS, associated with sHLH; CRS in SARS patients9 and severity of COVID-1912, increased plasma levels in ICU vs. non-ICU patients9|
|MIP-1 alpha (CCL3)||Chemokine (CC type)||Cytokine profile associated with sHLH and severity of COVID-1912; increased plasma levels in ICU vs. non-ICU patients9, potential marker to predict COVID-19 disease severity/outcome|
|MIP-1 beta (CCL4)||Chemokine (CC type)||Biomarker for sepsis and CRS in general|
|TNF alpha||Tumor necrosis factor||Central role in CRS, blocking TNF alpha potentially beneficial for patients with severe inflammation in the lung due to CRS, increased plasma levels in ICU vs. non-ICU patients9|
|TNF beta||Tumor necrosis factor||CRS in SARS patients6, plays a role in the TNF-dominated response to superantigens leading to STSS13|
|Abbreviations–COVID-19: Coronavirus disease 2019, ICU: Intensive care unit, MAS: Macrophage activation syndrome, PAH: Polycyclic aromatic hydrocarbons, sHLH: Secondary haemophagocytic lymphohistiocytosis, SARS: Severe acute respiratory syndrome, STSS: Streptococcal toxic shock syndrome|
Study other immune biomarkers with Procartaplex Preconfigured Panels
Since many different causes and pathologic conditions for the induction of a cytokine storm do exist, and not all syndromes involving cytokine release result in the same pathogenic cytokine profile, it is of great interest to analyze the level of a broader panel of immunomodulatory markers to get the whole picture of a patient’s immune status. For studying a broader set of biomarkers, we recommend the following ProcartaPlex Preconfigured Panels:
|Panel Name||Cat. No.||Analytes|
|Human Cytokine Assays|
|Immune Monitoring 65-Plex Human ProcartaPlex Panel||EPX650-10065-901||APRIL, BAFF, BLC (CXCL13), CD30, CD40L, ENA-78 (CXCL5), Eotaxin (CCL11), Eotaxin-2 (CCL24), Eotaxin-3 (CCL26), FGF-2, Fractalkine (CX3CL1), G-CSF (CSF-3), GM-CSF, GRO alpha (CXCL1), HGF, IFN alpha, IFN gamma, IL-10, IL-12p70, IL-13, IL-15, IL-16, IL-17A (CTLA-8), IL-18, IL-1 alpha, IL-1 beta, IL-2, IL-20, IL-21, IL-22, IL-23, IL-27, IL-2R, IL-3, IL-31, IL-4, IL-5, IL-6, IL-7, IL-8 (CXCL8), IL-9, IP-10 (CXCL10), I-TAC (CXCL11), LIF, MCP-1 (CCL2), MCP-2 (CCL8), MCP-3 (CCL7), M-CSF, MDC, MIF, MIG (CXCL9), MIP-1 alpha (CCL3), MIP-1 beta (CCL4), MIP-3 alpha (CCL20), MMP-1,NGF beta, SCF, SDF-1 alpha, TNF beta, TNF alpha, TNF-RII, TRAIL, TSLP, TWEAK, VEGF-A|
|Cytokine/Chemokine/Growth Factor Convenience 45-Plex Human ProcartaPlex Panel 1||EPXR450-12171-901||BDNF, EGF, Eotaxin (CCL11), FGF-2, GM-CSF, GRO alpha (CXCL1), HGF, IFN gamma, IFN alpha, IL-1RA, IL-1 beta, IL-1 alpha, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8 (CXCL8), IL-9, IL-10, IL-12p70, IL-13, IL-15, IL-17A (CTLA-8), IL-18, IL-21, IL-22, IL-23, IL-27, IL-31, IP-10 (CXCL10), LIF, MCP-1 (CCL2), MIP-1 alpha (CCL3), MIP-1 beta (CCL4), NGF beta, PDGF-BB, PlGF-1, RANTES (CCL5), SCF, SDF-1 alpha, TNF alpha, TNF beta, VEGF-A, VEGF-D|
|Cytokine & Chemokine Convenience 34-Plex Human ProcartaPlex Panel 1A||EPXR340-12167-901||Eotaxin (CCL11), GM-CSF, GRO alpha (CXCL1), IFN alpha, IFN gamma, IL-1 beta, IL-1 alpha, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8 (CXCL8), IL-9, IL-10, IL-12p70, IL-13, IL-15, IL-17A (CTLA-8), IL-18, IL-21, IL-22, IL-23, IL-27, IL-31, IP-10 (CXCL10), MCP-1 (CCL2), MIP-1 alpha (CCL3), MIP-1 beta (CCL4), RANTES (CCL5), SDF-1 alpha, TNF alpha, TNF beta|
|Inflammation 20-Plex Human ProcartaPlex Panel||EPX200-12185-901||E-selectin (CD62E), GM-CSF, ICAM-1, IFN alpha, IFN gamma, IL-1 alpha, IL-1 beta, IL-4, IL-6, IL-8 (CXCL8), IL-10, IL-12p70, IL-13, IL-17A (CTLA-8), IP-10 (CXCL10), MCP-1 (CCL2), MIP-1 alpha (CCL3), MIP-1 beta (CCL4), P-Selectin, TNF alpha|
|Mouse Cytokine Assays|
|Immune Monitoring 48-Plex Mouse ProcartaPlex Panel||EPX480-20834-901||BAFF, BTC, ENA-78, Eotaxin (CCL11), G-CSF, GM-CSF, GRO alpha (CXCL1), IFN alpha, IFN gamma, IL-10, IL-12p70, IL-13, IL-15, IL-17A, IL-18, IL-19, IL-1 alpha, IL-1 beta, IL-2, IL-22, IL-23, IL-25 (IL-17E), IL-27, IL-28, IL-2Ra, IL-3, IL-31, IL-33, IL-33R, IL-4, IL-5, IL-6, IL-7, IL-7Ra, IL-9, IP-10 (CXCL10), Leptin, LIF, MCP-1 (CCL2), MCP-3 (CCL7), M-CSF, MIP-1 alpha (CCL3), MIP-1 beta (CCL4), MIP-2 alpha (CXCL2), RANKL, RANTES, TNF alpha, VEGF-A|
|Cytokine & Chemokine Convenience 36-Plex Mouse ProcartaPlex Panel 1A||EPXR360-26092-901||BAFF, BTC, ENA-78, Eotaxin (CCL11), G-CSF, GM-CSF, GRO alpha (CXCL1), IFN alpha, IFN gamma, IL-10, IL-12p70, IL-13, IL-15, IL-17A, IL-18, IL-19, IL-1 alpha, IL-1 beta, IL-2, IL-22, IL-23, IL-25 (IL-17E), IL-27, IL-28, IL-2Ra, IL-3, IL-31, IL-33, IL-33R, IL-4, IL-5, IL-6, IL-7, IL-7Ra, IL-9, IP-10 (CXCL10), Leptin, LIF, MCP-1 (CCL2), MCP-3 (CCL7), M-CSF, MIP-1 alpha (CCL3), MIP-1 beta (CCL4), MIP-2 alpha (CXCL2), RANKL, RANTES, TNF alpha, VEGF-A|
Recommended reading and references
- Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. 2012. Into the Eye of the Cytokine Storm. Microbiol Mol Biol Rev. 76(1):16-32.
- Shimabukuro-Vornhagen A, Gödel P, Subklewe M, Stemmler HJ, Schlößer HA, Schlaak M, Kochanek M, Böll B, von Bergwelt-Baildon MS. 2018. Cytokine release syndrome. J Immunother Cancer. 6(1):56.
- Cheng Z, Huo X, Dai Y, Lu X, Hylkema MN, Xu X. 2020. Elevated expression of AhR and NLRP3 link polycyclic aromatic hydrocarbon exposure to cytokine storm in preschool children. Environ Int. 139:105720.
- Eastwood D, Bird C, Dilger P, Hockley J, Findlay L, Poole S, Thorpe SJ, Wadhwa M, Thorpe R, Stebbings R. 2013. Severity of the TGN1412 trial disaster cytokine storm correlated with IL-2 release. Br J Clin Pharmacol. 76(2):299-315.
- Yiu HH, Graham AL, Stengel RF. 2012. Dynamics of a cytokine storm. PLoS One. 7(10):e45027.
- Huang KJ, Su IJ, Theron M, Wu YC, Lai SK, Liu CC, Lei HY. 2005. An Interferon-g-Related Cytokine Storm in SARS patients. J Med Virol. 75(2):185-94.
- Shi Y, Wang Y, Shao C, Huang J, Gan J, Huang X, Bucci E, Piacentini M, Ippolito G, Melino G. 2020. COVID-19 infection: the perspectives on immune responses. Cell Death Differ. 27(5):1451-1454.
- Guo XJ, Thomas PG. 2017. New fronts emerge in the influenza cytokine storm. Semin Immunopathol. 39(5):541-550.
- Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. 2020. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 395(10223):497-506.
- Vandenhaute J, Wouters CH, Matthys P. 2020. Natural Killer Cells in Systemic Autoinflammatory Diseases: A Focus on Systemic Juvenile Idiopathic Arthritis and Macrophage Activation Syndrome. Front Immunol. 10:3089.
- Szabo PA, Goswami A, Mazzuca DM, Kim K, O'Gorman DB, Hess DA, Welch ID, Young HA, Singh B, McCormick JK, Haeryfar SM. 2017. Rapid and Rigorous IL-17A Production by a Distinct Subpopulation of Effector Memory T Lymphocytes Constitutes a Novel Mechanism of Toxic Shock Syndrome. Immunopathology. J Immunol. 198(7):2805-2818.
- Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. 2020. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 395(10229):1033-1034.
- Emgård J, Bergsten H, McCormick JK, Barrantes I, Skrede S, Sandberg JK, Norrby-Teglund A. 2019. MAIT Cells Are Major Contributors to the Cytokine Response in Group A Streptococcal Toxic Shock Syndrome. Proc Natl Acad Sci. 116(51):25923-25931.
- Liu Q, Zhou YH, Yang ZQ. 2016. The cytokine storm of severe influenza and development of immunomodulatory therapy. Cell Mol Immunol. 13(1):3-10.
- Weaver LK, Behrens EM. 2017. Weathering the storm: Improving therapeutic interventions for cytokine storm syndromes by targeting disease pathogenesis. Curr Treatm Opt Rheumatol. 3(1):33-48.
- Francois B, Jeannet R, Daix T, Walton AH, Shotwell MS, Unsinger J, Monneret G, Rimmelé T, Blood T, Morre M, Gregoire A, Mayo GA, Blood J, Durum SK, Sherwood ER, Hotchkiss RS. 2018. Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial. JCI Insight. 3(5).
- Thevarajan I, Nguyen THO, Koutsakos M, Druce J, Caly L, van de Sandt CE, Jia X, Nicholson S, Catton M, Cowie B, Tong SYC, Lewin SR, Kedzierska K. 2020. Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19. Nat Med. 26(4):453-455.
- Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. 2020. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 395(10229):1054-1062.
- Moore JB, June CH. 2020. Cytokine release syndrome in severe COVID-19. Science. 368(6490):473-474.
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