Results Interpretations

Cytokine/Chemokine/Growth Factor Panel Interpretation Guide

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Cytokine groupings were determined using unsupervised clustering analyses on >130 plasma-EDTA specimens provided to us for diagnostic testing from patients with a variety of inflammatory, autoimmune, and neoplastic conditions, using the methodology detailed in Eve Technologies’ publication:

Polley DJ et al. Identification of novel clusters of co-expressing cytokines in a diagnostic cytokine multiplex test. Frontiers in Immunology. 2023-July-31 2023;14 doi:10.3389/fimmu.2023.1223817.

The designations of physiological/pathological significance assigned to each grouping are speculative, based on an analysis of the immune signatures in our database of clinical specimens and on the functional/pathological roles of the analytes in each grouping established in the scientific literature.

 

Relevant Dx Tests

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FGF-2, IFNα2, IL-1α, IL-1β, IL-1RA, IL-2, IL-17A

High results across the analytes in this group are often observed in autoimmune and autoinflammatory conditions, and in severe systemic inflammation.

Autoimmunity

  • IL-17A (major effector cytokine of Th17 cells) is known to be a key factor in autoimmune diseases1
  • FGF-2 and IL-17A expression are higher in RA patients than healthy, synergistically enhance autoimmune inflammation in mouse model of arthritis2
  • FGF-2 is involved in autoimmune diseases RA and MS3.
  • IFNα2 contributes to SLE and Sjogrens pathogenesis4
  • IFNα2 can exacerbate Th17-mediated inflammation in autoimmune diseases5,6
  • IFNα2 and IL-17A (with BAFF – group B) form a pathological signaling axis in SLE7
  • IL-2 has context-specific dual roles in either promoting or suppressing autoimmunity8
  • IL-1 blockade is an effective treatment for some autoimmune disorders (psoriatic arthritis, ankylosing spondylitis, RA), but not others (SLE, Sjögren syndrome)3
  • Pathogenic IFN-γ/GM-CSF (group B1)-producing Th17.1 cells result from prolonged IL-1β and IL-23 (group D) signaling6

Innate immunity

  • IL-1α+ß are major pro-inflammatory alarmins that activate innate immune response9
  • IFNα2 (Type I IFNs) are induced by PAMPs and DAMPs and contributes to innate immune response against viral exposure4
  • Type I IFNs regulate IL-1 expression following exposure to TB as protective measure to prevent excessive neutrophil-induced tissue damage6
  • Inflammatory cytokines including IL-1β can stimulate FGF-2 production in endothelial cells10

Autoinflammation

  • IL-1α+ß are known to be major contributors to autoinflammatory conditions, such as CAPS, FMF9,11
  • Overproduction of type I IFNs is a common feature in autoinflammatory skin conditions12

Type 1/Type 3 immune responses

  • IL-17A is one of the key effector cytokines released by Th17 cells1
  • IL-1 drives differentiation/maturation of Th17 cells when present with IL-23 (group D1)9
  • IFNα2 is an innate IFN that promotes Th1 differentiation13, but also has immunomodulatory function that may be protective in Th1-mediated inflammation5
  • IL-2 is a key factor in Th1, Th2, and Treg proliferation and clonal expansion (but inhibitory of Th17 development)14
References:
  1. Kuwabara T, Ishikawa F, Kondo M, Kakiuchi T. The Role of IL-17 and Related Cytokines in Inflammatory Autoimmune Diseases. Mediators Inflamm. 2017;2017:3908061. doi:10.1155/2017/3908061
  2. Shao X, Chen S, Yang D, et al. FGF2 cooperates with IL-17 to promote autoimmune inflammation. Sci Rep. 08 01 2017;7(1):7024. doi:10.1038/s41598-017-07597-8
  3. Xie Y, Su N, Yang J, et al. FGF/FGFR signaling in health and disease. Signal Transduct Target Ther. 09 2020;5(1):181. doi:10.1038/s41392-020-00222-7
  4. Paul F, Pellegrini S, Uzé G. IFNA2: The prototypic human alpha interferon. Gene. Aug 2015;567(2):132-7. doi:10.1016/j.gene.2015.04.087
  5. Axtell RC, Raman C, Steinman L. Type I interferons: beneficial in Th1 and detrimental in Th17 autoimmunity. Clin Rev Allergy Immunol. Apr 2013;44(2):114-20. doi:10.1007/s12016-011-8296-5
  6. Mourik BC, Lubberts E, de Steenwinkel JEM, Ottenhoff THM, Leenen PJM. Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases. Front Immunol. 2017;8:294. doi:10.3389/fimmu.2017.00294
  7. López P, Rodríguez-Carrio J, Caminal-Montero L, Mozo L, Suárez A. A pathogenic IFNα, BLyS and IL-17 axis in Systemic Lupus Erythematosus patients. Sci Rep. Feb 05 2016;6:20651. doi:10.1038/srep20651
  8. Sharma R, Fu SM, Ju ST. IL-2: a two-faced master regulator of autoimmunity. J Autoimmun. Mar 2011;36(2):91-7. doi:10.1016/j.jaut.2011.01.001
  9. Deng C, Peng N, Tang Y, et al. Roles of IL-25 in Type 2 Inflammation and Autoimmune Pathogenesis. Front Immunol. 2021;12:691559. doi:10.3389/fimmu.2021.691559
  10. Yang YL, Li XF, Song B, et al. The Role of CCL3 in the Pathogenesis of Rheumatoid Arthritis. Rheumatol Ther. Aug 2023;10(4):793-808. doi:10.1007/s40744-023-00554-0
  11. Kaneko N, Kurata M, Yamamoto T, Morikawa S, Masumoto J. The role of interleukin-1 in general pathology. Inflamm Regen. 2019;39:12. doi:10.1186/s41232-019-0101-5
  12. Broderick L, Hoffman HM. IL-1 and autoinflammatory disease: biology, pathogenesis and therapeutic targeting. Nat Rev Rheumatol. Aug 2022;18(8):448-463. doi:10.1038/s41584-022-00797-1
  13. Turnier JL, Kahlenberg JM. The Role of Cutaneous Type I IFNs in Autoimmune and Autoinflammatory Diseases. J Immunol. Dec 01 2020;205(11):2941-2950. doi:10.4049/jimmunol.2000596
  14. Jarry A, Malard F, Bou-Hanna C, et al. Interferon-Alpha Promotes Th1 Response and Epithelial Apoptosis via Inflammasome Activation in Human Intestinal Mucosa. Cell Mol Gastroenterol Hepatol. Jan 2017;3(1):72-81. doi:10.1016/j.jcmgh.2016.09.007
  15. Arenas-Ramirez N, Woytschak J, Boyman O. Interleukin-2: Biology, Design and Application. Trends Immunol. Dec 2015;36(12):763-777. doi:10.1016/j.it.2015.10.003

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Fractalkine, IFNγ, IL-4, IL-5, IL-9, IL-12p40, IL-12p70, IL-13, IL-17F, IL-22, MCP-3, MIP-1α, TGFα, TNFα, TNFβ

This group of analytes includes pro-inflammatory cytokines involved in initiating innate inflammation and adaptive immune responses.

Pro-inflammatory

  • Fractalkine is induced by IFNγ, TNFα, IL-11, TNFα and IFNγ synergistically induce fractalkine in RA osteoblasts2
  • Circulating fractalkine and TNFα are both released from the cell membrane by ADAM17 under inflammatory conditions3
  • TNFα can prime cells (e.g., fibroblast-like synoviocytes (FLS) in RA) to be more responsive to interferons and release more interferon-inducible factors (e.g., MIG, IP-10 in group B3)4
  • IFNγ drives TNFα expression in macrophages, as well as IL-12 and IL-235
  • IFN drives expression of chemokines MIG, MIP-1α, MIP-1ß, IP-10, I-TAC, RANTES, MCP-15

Innate immunity

  • IFNγ, TNFα contribute to cytokine storm6
  • IFNγ is released from innate lymphoid cells upon PRR activation or IL-12/IL-18 signaling7
  • TNFα can be induced following PRR activation8

Type 1 (Th1-type) immunity

  • IFNγ is the major effector cytokine released by Th1 cells7
  • IL-12p70 is the main driver of Th1 cell differentiation and synergizes with IL-18 (group B) to potentiate IFNγ release9
  • IL-12p70 expression is increased by IFNγ signaling in macrophages (positive feedback loop)
  • IL-12p70 promotes proliferation of NK cells (a major cellular effector of type 1 immunity)9
  • TNFα is released by Th1 cells and contributes to type 1 immunity10
  • TNFα acts as a co-stimulatory molecule for naïve CD4+ T cells that potentiates differentiation, activation and clonal expansion11
  • Fractalkine drives the recruitment of Th1 cells, CD8+ T cells, NK cells, monocytes, macrophages (type 1 effector cells)12
  • TNFβ is released by Th1, CD8+ T cells and NK cells and is essential in the differentiation, recruitment and activation of NK cells13
  • IL-12p40 is a subunit of the IL-12p70 heterodimer14
  • MCP-3 can drive Th1 recruitment via CCR215

Type 2 (Th2-type) immunity

  • IL-4, IL-5, IL-13 are the signature cytokines released by Th2 cells that mediate type 2 immune responses16.
  • IL-9 can be released by Th2 and ILC2s and is a contributor to type 2 immune responses17,18.
  • MCP-3 can drive Th2 recruitment via CCR3 (CCR3 is preferentially expressed on Th2 cells)15.
  • IL-9 is highly expressed by Th9 cells, which can contribute to type 2 immunity, allergic diseases and autoinflammatory/autoimmune diseases17,18.

Type 3 (Th17-type) immunity

  • IL-17F is released by and is a main effector cytokine of Th17 cells19.
  • IL-22 can be released by Th17 cells and ILC3s. IL-22 contributes to epithelial homeostasis and defense, and to type 3 immune responses20.
  • IL-12p40 is a subunit of the IL-23 heterodimer14.
  • Th22 cells are thought to be the major source of IL-22 in the peripheral circulation20.
  • Th22 cells can also secrete IL-1321

T helper cell plasticity22

  • Th0 – Th1/Th2 cells: Co-express IFNγ, IL4, IL-5, IL-13 (Th2 cells that acquire ability to secrete IFNy– caused by IL-12 or IFN-induced T-bet co-expression with GATA3)
  • Th17.1 – Th17/Th1 cells: IL-17A, IL-17F, IL-21, IFNγ (with GM-CSF23) –pathogenic (Th17 cells that acquire ability to secrete IFNy – caused by IL-12-induced T-bet co-expression with RORγt)
  • Th17/Th2 – IL-17A, IL-17F, IL-4 (Th17 cells that acquire ability to secrete IL-4 – caused by IL-4-induced GATA3 co-expression with RORγt)
  • Th1 and Th17 cells can produce IL-1324
References:
  1. Jones BA, Beamer M, Ahmed S. Fractalkine/CX3CL1: a potential new target for inflammatory diseases. Mol Interv. Oct 2010;10(5):263-70. doi:10.1124/mi.10.5.3
  2. Isozaki T, Kasama T, Takahashi R, et al. Synergistic induction of CX3CL1 by TNF alpha and IFN gamma in osteoblasts from rheumatoid arthritis: involvement of NF-kappa B and STAT-1 signaling pathways. J Inflamm Res. 2008;1:19-28. doi:10.2147/jir.s4019
  3. Zunke F, Rose-John S. The shedding protease ADAM17: Physiology and pathophysiology. Biochim Biophys Acta Mol Cell Res. Nov 2017;1864(11 Pt B):2059-2070. doi:10.1016/j.bbamcr.2017.07.001
  4. Kalliolias GD, Ivashkiv LB. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol. Jan 2016;12(1):49-62. doi:10.1038/nrrheum.2015.169
  5. Kak G, Raza M, Tiwari BK. Interferon-gamma (IFN-γ): Exploring its implications in infectious diseases. Biomol Concepts. May 30 2018;9(1):64-79. doi:10.1515/bmc-2018-0007
  6. Fajgenbaum DC, June CH. Cytokine Storm. N Engl J Med. 12 03 2020;383(23):2255-2273. doi:10.1056/NEJMra2026131
  7. Ivashkiv LB. IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy. Nat Rev Immunol. 09 2018;18(9):545-558. doi:10.1038/s41577-018-0029-z
  8. Thompson MR, Kaminski JJ, Kurt-Jones EA, Fitzgerald KA. Pattern recognition receptors and the innate immune response to viral infection. Viruses. Jun 2011;3(6):920-40. doi:10.3390/v3060920
  9. Ullrich KA, Schulze LL, Paap EM, Müller TM, Neurath MF, Zundler S. Immunology of IL-12: An update on functional activities and implications for disease. EXCLI J. 2020;19:1563-1589. doi:10.17179/excli2020-3104
  10. Annunziato F, Romagnani C, Romagnani S. The 3 major types of innate and adaptive cell-mediated effector immunity. J Allergy Clin Immunol. Mar 2015;135(3):626-35. doi:10.1016/j.jaci.2014.11.001
  11. Mehta AK, Gracias DT, Croft M. TNF activity and T cells. Cytokine. Jan 2018;101:14-18. doi:10.1016/j.cyto.2016.08.003
  12. Lee M, Lee Y, Song J, Lee J, Chang SY. Tissue-specific Role of CX. Immune Netw. Feb 2018;18(1):e5. doi:10.4110/in.2018.18.e5
  13. Calmon-Hamaty F, Combe B, Hahne M, Morel J. Lymphotoxin α revisited: general features and implications in rheumatoid arthritis. Arthritis Res Ther. Jul 2011;13(4):232. doi:10.1186/ar3376
  14. Cooper AM, Khader SA. IL-12p40: an inherently agonistic cytokine. Trends Immunol. Jan 2007;28(1):33-8. doi:10.1016/j.it.2006.11.002
  15. Sokol CL, Luster AD. The chemokine system in innate immunity. Cold Spring Harb Perspect Biol. Jan 29 2015;7(5)doi:10.1101/cshperspect.a016303
  16. Raphael I, Nalawade S, Eagar TN, Forsthuber TG. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine. Jul 2015;74(1):5-17. doi:10.1016/j.cyto.2014.09.011
  17. Do-Thi VA, Lee JO, Lee H, Kim YS. Crosstalk between the Producers and Immune Targets of IL-9. Immune Netw. Dec 2020;20(6):e45. doi:10.4110/in.2020.20.e45
  18. Chakraborty S, Kubatzky KF, Mitra DK. An Update on Interleukin-9: From Its Cellular Source and Signal Transduction to Its Role in Immunopathogenesis. Int J Mol Sci. Apr 2019;20(9)doi:10.3390/ijms20092113
  19. Wacleche VS, Landay A, Routy JP, Ancuta P. The Th17 Lineage: From Barrier Surfaces Homeostasis to Autoimmunity, Cancer, and HIV-1 Pathogenesis. Viruses. Oct 19 2017;9(10)doi:10.3390/v9100303
  20. Dudakov JA, Hanash AM, van den Brink MR. Interleukin-22: immunobiology and pathology. Annu Rev Immunol. 2015;33:747-85. doi:10.1146/annurev-immunol-032414-112123
  21. Jiang Q, Yang G, Xiao F, et al. Role of Th22 Cells in the Pathogenesis of Autoimmune Diseases. Front Immunol. 2021;12:688066. doi:10.3389/fimmu.2021.688066
  22. Cosmi L, Maggi L, Santarlasci V, Liotta F, Annunziato F. T helper cells plasticity in inflammation. Cytometry A. Jan 2014;85(1):36-42. doi:10.1002/cyto.a.22348
  23. Mourik BC, Lubberts E, de Steenwinkel JEM, Ottenhoff THM, Leenen PJM. Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases. Front Immunol. 2017;8:294. doi:10.3389/fimmu.2017.00294
  24. Gallo E, Katzman S, Villarino AV. IL-13-producing Th1 and Th17 cells characterize adaptive responses to both self and foreign antigens. Eur J Immunol. Sep 2012;42(9):2322-8. doi:10.1002/eji.201142227

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GM-CSF, G-CSF, IL-3, IL-7

The analytes in this group are hematopoietic growth factors and could indicate the expansion and activation of lymphocytes (IL-7) and/or leukocytes (GM-CSF, G-CSF, IL-3).

Lymphocyte development

  • IL-7 is an essential factor in the proliferation, survival, and development of T- and B-lymphocytes1.

Leukocyte development

  • GM-CSF drives M1 macrophage polarization, and the growth and development of monocytes, neutrophils, eosinophils, DCs, microglia2,3
  • G-CSF is an important driver of neutrophil development and proliferation4
  • IL-3 drives the differentiation of bone marrow precursors to a wide variety of leukocytes including monocytes, macrophages, neutrophils, eosinophils, basophils, and mast cells, and stimulates proliferation in hematopoietic stem cells5
References:
  1. Mackall CL, Fry TJ, Gress RE. Harnessing the biology of IL-7 for therapeutic application. Nat Rev Immunol. May 2011;11(5):330-42. doi:10.1038/nri2970
  2. Hamilton JA. Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol. Jul 2008;8(7):533-44. doi:10.1038/nri2356
  3. Lee KMC, Achuthan AA, Hamilton JA. GM-CSF: A Promising Target in Inflammation and Autoimmunity. Immunotargets Ther. 2020;9:225-240. doi:10.2147/ITT.S262566
  4. Bendall LJ, Bradstock KF. G-CSF: From granulopoietic stimulant to bone marrow stem cell mobilizing agent. Cytokine Growth Factor Rev. Aug 2014;25(4):355-67. doi:10.1016/j.cytogfr.2014.07.011
  5. Dougan M, Dranoff G, Dougan SK. GM-CSF, IL-3, and IL-5 Family of Cytokines: Regulators of Inflammation. Immunity. 04 2019;50(4):796-811. doi:10.1016/j.immuni.2019.03.022

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BAFF, FLT-3L, IL-27, IL-6, IL-8, IP-10, I-TAC, IL-10, IL-15, IL-18, MCP-1, MCP-2, M-CSF, MIG, MIP-1β, MIP-3α, MIP-3β

High levels of the analytes in this group may be associated with innate immune responses. High results across this group may indicate severe systemic inflammatory responses such as ‘cytokine storm’ (cytokine release syndrome; CRS) – similar profiles are frequently observed in conditions associated with CRS, such as macrophage activation syndrome (MAS), adult-onset Still’s disease (AOSD), and systemic arthritis, as well as lymphoproliferative disorders such as hemophagocytic lymphohistiocytosis (HLH) and lymphocytic leukemia.

Innate immunity

  • IL-6 plays a central role in innate immunity as a key factor driving acute phase protein release1,2
  • IL-18 is a pro-inflammatory alarmin released following inflammasome activation3
  • Flt-3L is an important factor in ILC and dendritic cell development4

Cytokine storm5

  • IL-6, IL-10, IL-18, IL-8, MIG, IP-10, MIP-1ß, MCP-1, BCA-1 found to be soluble mediators of cytokine storm
  • IL-10 is upregulated in cytokine storm, likely representing an insufficient regulatory response
    • Also IL-1, IL-2, IL-17A, (Group A1); IFNγ, TNFα, GM-CSF, IL-12, IL-9, MIP-1α (Group A2), IL-33 (Group D2).

Adaptive immunity

  • IL-18 synergizes with IL-12 to induce antigen-independent IFNγ release from Th1 cells3
  • MIG and IP-10 are chemokines induced by IFNγ and are major factors in Th1 differentiation and recruitment to sites of inflammation6,7
  • IL-27 promotes Th1 polarization and expansion at onset of type 1 immune response, also inhibits IL-2 and induces IL-10 expression which attenuates Th1 activity, so IL-27 may be implicated in both initiation and resolution of type 1 immune response8
  • BAFF, BCA-1 and Flt-3L are important factors in B cell differentiation/trafficking and establishment of tertiary lymphoid organs at mucosal sites (BCA-1 also drives Tfh differentiation/recruitment)

Inflammation resolution

  • IL-27 inhibits IL-2 and induces IL-10 expression which attenuates Th1 activity, so IL-27 may be implicated in both initiation and resolution of type 1 immune response8
  • IL-10 promotes Treg development and is released by Tregs and is a potent anti-inflammatory factor9
  • I-309 drives recruitment of Th2, ILC210, and Treg11 cells to sites of inflammation, which are anti-inflammatory in Th1-mediated immune responses
  • M-CSF is thought to favour M2 macrophage polarization, which is immunomodulatory in type 1 immune responses12

Angiogenesis13

  • IL-8 and MCP-1 are pro-angiogenic chemokines
  • IP-10, I-TAC and MIG are anti-angiogenic chemokines
References:
  1. Kany S, Vollrath JT, Relja B. Cytokines in Inflammatory Disease. Int J Mol Sci. Nov 2019;20(23)doi:10.3390/ijms20236008
  2. Narazaki M, Kishimoto T. The Two-Faced Cytokine IL-6 in Host Defense and Diseases. Int J Mol Sci. Nov 09 2018;19(11)doi:10.3390/ijms19113528
  3. Kaneko N, Kurata M, Yamamoto T, Morikawa S, Masumoto J. The role of interleukin-1 in general pathology. Inflamm Regen. 2019;39:12. doi:10.1186/s41232-019-0101-5
  4. Watowich SS, Liu YJ. Mechanisms regulating dendritic cell specification and development. Immunol Rev. Nov 2010;238(1):76-92. doi:10.1111/j.1600-065X.2010.00949.x
  5. Fajgenbaum DC, June CH. Cytokine Storm. N Engl J Med. 12 03 2020;383(23):2255-2273. doi:10.1056/NEJMra2026131
  6. Liu M, Guo S, Hibbert JM, et al. CXCL10/IP-10 in infectious diseases pathogenesis and potential therapeutic implications. Cytokine Growth Factor Rev. Jun 2011;22(3):121-30. doi:10.1016/j.cytogfr.2011.06.001
  7. Metzemaekers M, Vanheule V, Janssens R, Struyf S, Proost P. Overview of the Mechanisms that May Contribute to the Non-Redundant Activities of Interferon-Inducible CXC Chemokine Receptor 3 Ligands. Front Immunol. 2017;8:1970. doi:10.3389/fimmu.2017.01970
  8. Iwasaki Y, Fujio K, Okamura T, Yamamoto K. Interleukin-27 in T cell immunity. Int J Mol Sci. Jan 27 2015;16(2):2851-63. doi:10.3390/ijms16022851
  9. Saraiva M, Vieira P, O’Garra A. Biology and therapeutic potential of interleukin-10. J Exp Med. 01 2020;217(1)doi:10.1084/jem.20190418
  10. Knipfer L, Schulz-Kuhnt A, Kindermann M, et al. A CCL1/CCR8-dependent feed-forward mechanism drives ILC2 functions in type 2-mediated inflammation. J Exp Med. 12 2019;216(12):2763-2777. doi:10.1084/jem.20182111
  11. Ohue Y, Nishikawa H. Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target? Cancer Sci. Jul 2019;110(7):2080-2089. doi:10.1111/cas.14069
  12. Hamilton JA. Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol. Jul 2008;8(7):533-44. doi:10.1038/nri2356
  13. Mehrad B, Keane MP, Strieter RM. Chemokines as mediators of angiogenesis. Thromb Haemost. May 2007;97(5):755-62.

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Perforin, sFas, TRAIL

The analytes in this group influence cell death through facilitating (perforin) or directly regulating apoptosis (sFas, TRAIL).

Perforin1 – Cell death-inducing glycoprotein released mainly by NK cells and CD8+ T cells which forms pores in the membranes of target cells. Perforin deficiency has been associated with hemophagocytic lymphohistiocytosis (HLH), leukemias and lymphomas, infectious diseases, and autoimmune diseases.

sFas (Soluble Fas)2,3 – Soluble form of the apoptosis-inducing receptor Fas. May protect Fas-expressing cells from FasL-induced apoptosis. High circulating levels of sFas have been observed in SLE patients and may contribute to autoimmunity.

TRAIL (TNF-related apoptosis-inducing ligand)4  – Apoptosis-inducing member of the TNF superfamily. TRAIL is an important factor in NK-mediated apoptosis and has potent anti-tumour activity by preferentially inducing apoptosis in cancer cells but not in normal cells. TRAIL has also been shown to promote the resolution of inflammation by accelerating apoptosis of neutrophils and has anti-inflammatory effects on T cell function by inhibiting the proliferation of Th1 cells, promoting Treg proliferation, and inducing apoptosis in autoreactive T cells and B cells.

References:
  1. Osińska I, Popko K, Demkow U. Perforin: an important player in immune response. Cent Eur J Immunol. 2014;39(1):109-15. doi:10.5114/ceji.2014.42135
  2. Nagata S. Fas-induced apoptosis, and diseases caused by its abnormality. Genes Cells. Oct 1996;1(10):873-9. doi:10.1046/j.1365-2443.1996.d01-214.x
  3. Cheng J, Zhou T, Liu C, et al. Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. Science. Mar 25 1994;263(5154):1759-62. doi:10.1126/science.7510905
  4. Beyer K, Baukloh AK, Stoyanova A, Kamphues C, Sattler A, Kotsch K. Interactions of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) with the Immune System: Implications for Inflammation and Cancer. Cancers (Basel). Aug 13 2019;11(8)doi:10.3390/cancers11081161

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BCA-1, CCL28, Granzyme, A, Granzyme, B, I-309, IL-16, IL-23, IL-35, Lymphotactin, sCD137, sFasL, TPO

Elevated levels of the analytes in this group could indicate the recruitment and regulation of NK cells, T cells, and B cells.

Lymphocyte recruitment/regulation

  • BCA-1 drives the recruitment and promotes the differentiation of B cells and TFH cells via CXCR5, playing a key role in the generation of lymphoid follicles1
  • CCL28 drives the trafficking of T and B cells via CCR102
  • I-309 drives the recruitment of T cells, Tregs and ILC2s via CCR83
  • IL-16 acts as a chemoattractant and activating factor for CD4+ T cells via CD44
  • Lymphotactin is a key factor in the activation and function of cytotoxic T cells5
  • IL-23 promotes Th17 development and has context-specific regulatory effects on NK and CD8+ T cell function6
  • IL-35 is a potent anti-inflammatory cytokine secreted by Tregs and Bregs that suppresses T cell proliferation and induces IL-35-secreting Treg cells (iTr35)7

Lymphocyte activity

  • Granzyme A and granzyme B are cytotoxic mediators released by NK cells and CD8+ T cells8
  • sCD137 is an indicator of NK and T cell activity9,10
  • sFasL is a regulator of cell death and apoptosis, and is shed by NK cells and CD8+ T cells11
References:
  1. Kazanietz MG, Durando M, Cooke M. CXCL13 and Its Receptor CXCR5 in Cancer: Inflammation, Immune Response, and Beyond. Front Endocrinol (Lausanne). 2019;10:471. doi:10.3389/fendo.2019.00471
  2. Mohan T, Deng L, Wang BZ. CCL28 chemokine: An anchoring point bridging innate and adaptive immunity. Int Immunopharmacol. Oct 2017;51:165-170. doi:10.1016/j.intimp.2017.08.012
  3. Knipfer L, Schulz-Kuhnt A, Kindermann M, et al. A CCL1/CCR8-dependent feed-forward mechanism drives ILC2 functions in type 2-mediated inflammation. J Exp Med. 12 2019;216(12):2763-2777. doi:10.1084/jem.20182111
  4. Cruikshank WW, Kornfeld H, Center DM. Interleukin-16. J Leukoc Biol. Jun 2000;67(6):757-66. doi:10.1002/jlb.67.6.757
  5. Matsuo K, Yoshie O, Kitahata K, Kamei M, Hara Y, Nakayama T. Recent Progress in Dendritic Cell-Based Cancer Immunotherapy. Cancers (Basel). May 20 2021;13(10)doi:10.3390/cancers13102495
  6. Mirlekar B, Pylayeva-Gupta Y. IL-12 Family Cytokines in Cancer and Immunotherapy. Cancers (Basel). Jan 06 2021;13(2)doi:10.3390/cancers13020167
  7. Ye C, Yano H, Workman CJ, Vignali DAA. Interleukin-35: Structure, Function and Its Impact on Immune-Related Diseases. J Interferon Cytokine Res. Nov 2021;41(11):391-406. doi:10.1089/jir.2021.0147
  8. Chowdhury D, Lieberman J. Death by a thousand cuts: granzyme pathways of programmed cell death. Annu Rev Immunol. 2008;26:389-420. doi:10.1146/annurev.immunol.26.021607.090404
  9. Dharmadhikari B, Wu M, Abdullah NS, et al. CD137 and CD137L signals are main drivers of type 1, cell-mediated immune responses. Oncoimmunology. Apr 2016;5(4):e1113367. doi:10.1080/2162402X.2015.1113367
  10. Luu K, Shao Z, Schwarz H. The relevance of soluble CD137 in the regulation of immune responses and for immunotherapeutic intervention. J Leukoc Biol. May 2020;107(5):731-738. doi:10.1002/JLB.2MR1119-224R
  11. Nagata S. Fas-induced apoptosis, and diseases caused by its abnormality. Genes Cells. Oct 1996;1(10):873-9. doi:10.1046/j.1365-2443.1996.d01-214.x

description

Eotaxin-3, HMGB1, IFNβ, IFNω, IL-11, IL-17E/IL-25, IL-20, IL-21, IL-24, IL-28A, IL-29, IL-31, IL-33, IL-34, LIF, TSLP

Elevated levels of the analytes in this group could indicate a state of tissue injury and mucosal inflammation.

Mucosal immune response/tissue damage

  • IL-17E/IL-251, TSLP2 and IL-333 are epithelial alarmins that may play a key role in sensing and initiating type 2 inflammatory/repair responses to tissue damage4
  • Eotaxin-3 is a plasma biomarker of mucosal eosinophil infiltration (IL-33 and TSLP also elevated with eosinophil infiltration)4
  • IFNβ and IFNω are type 1 interferons and IL-28A and IL-29 are type 3 intererons, which are associated with innate anti-viral responses and mucosal immunity5
  • HMGB1 is an alarmin released by damaged cells and can drive interferon expression6
  • IL-34 plays a role in maintaining mucosal resident macrophages7
  • IL-118, IL-209, and IL-2110 are important factors in epithelial defence and tissue repair.
References:
  1. Brevi A, Cogrossi LL, Grazia G, et al. Much More Than IL-17A: Cytokines of the IL-17 Family Between Microbiota and Cancer. Front Immunol. 2020;11:565470. doi:10.3389/fimmu.2020.565470
  2. Tsilingiri K, Fornasa G, Rescigno M. Thymic Stromal Lymphopoietin: To Cut a Long Story Short. Cell Mol Gastroenterol Hepatol. Mar 2017;3(2):174-182. doi:10.1016/j.jcmgh.2017.01.005
  3. Molofsky AB, Savage AK, Locksley RM. Interleukin-33 in Tissue Homeostasis, Injury, and Inflammation. Immunity. Jun 2015;42(6):1005-19. doi:10.1016/j.immuni.2015.06.006
  4. Lloyd CM, Snelgrove RJ. Type 2 immunity: Expanding our view. Sci Immunol. Jul 06 2018;3(25)doi:10.1126/sciimmunol.aat1604
  5. Mangan NE, Fung KY. Type I interferons in regulation of mucosal immunity. Immunol Cell Biol. May 2012;90(5):510-9. doi:10.1038/icb.2012.13
  6. Kang R, Chen R, Zhang Q, et al. HMGB1 in health and disease. Mol Aspects Med. Dec 2014;40:1-116. doi:10.1016/j.mam.2014.05.001
  7. Lelios I, Cansever D, Utz SG, Mildenberger W, Stifter SA, Greter M. Emerging roles of IL-34 in health and disease. J Exp Med. Mar 02 2020;217(3)doi:10.1084/jem.20190290
  8. Fung KY, Louis C, Metcalfe RD, et al. Emerging roles for IL-11 in inflammatory diseases. Cytokine. Jan 2022;149:155750. doi:10.1016/j.cyto.2021.155750
  9. Rutz S, Wang X, Ouyang W. The IL-20 subfamily of cytokines–from host defence to tissue homeostasis. Nat Rev Immunol. Dec 2014;14(12):783-95. doi:10.1038/nri3766
  10. Yi JS, Cox MA, Zajac AJ. Interleukin-21: a multifunctional regulator of immunity to infections. Microbes Infect. Dec 2010;12(14-15):1111-9. doi:10.1016/j.micinf.2010.08.008

description

6CKine, CTACK, CXCL16, Eotaxin, Eotaxin-2, MDC, MIP-1δ, MPIF-1, RANTES, SCF, SDF-1

The analytes in this group drive the recruitment, homing and activation of leukocytes and lymphocytes.

Immune cell trafficking/activation

  • 6Ckine (CCL21) drives the recruitment and trafficking of T cells via CCR7. Plays a key role in homing of lymphocytes to lymph nodes and Peyer’s patches1
  • CTACK (CCL27) drives the recruitment and homeostatic trafficking of CCR10-expressing T cells to the skin2
  • Eotaxin-1 (CCL11) and eotaxin-2 (CCL24) drive the recruitment of eosinophils, basophils, mast cells, and activated Th2 cells to sites of inflammation via CCR33
  • MDC (CCL22) drives the recruitment of CCR4-expressing immune cells, most notably Th2 cells, to sites of inflammation4
  • MIP-1δ (CCL15) drives the recruitment of various immune cells, particularly eosinophils and basophils, via CCR1 and CCR35
  • MPIF-1 (CCL23) drives the recruitment of dendritic cells, resting T cells, and monocytes via CCR16
  • RANTES (CCL5) drives the recruitment of T cells (both Th1 and Th2), dendritic cells, eosinophils, NK cells, mast cells and basophils via CCR1, CCR3 and CCR57
  • SCF drives the maturation, degranulation, and homing of mast cells8
  • SDF-1 contributes to the homing and maintenance of hematopoietic stem cells and the production of immune cells, including B cells, pDCs, and NK cells9
References:
  1. Förster R, Davalos-Misslitz AC, Rot A. CCR7 and its ligands: balancing immunity and tolerance. Nat Rev Immunol. May 2008;8(5):362-71. doi:10.1038/nri2297
  2. Xiong N, Fu Y, Hu S, Xia M, Yang J. CCR10 and its ligands in regulation of epithelial immunity and diseases. Protein Cell. Aug 2012;3(8):571-80. doi:10.1007/s13238-012-2927-3
  3. Zajkowska M, Mroczko B. From Allergy to Cancer-Clinical Usefulness of Eotaxins. Cancers (Basel). Jan 2021;13(1)doi:10.3390/cancers13010128
  4. Solari R, Pease JE. Targeting chemokine receptors in disease–a case study of CCR4. Eur J Pharmacol. Sep 2015;763(Pt B):169-77. doi:10.1016/j.ejphar.2015.05.018
  5. Shimizu Y, Dobashi K. CC-chemokine CCL15 expression and possible implications for the pathogenesis of IgE-related severe asthma. Mediators Inflamm. 2012;2012:475253. doi:10.1155/2012/475253
  6. Korbecki J, Kojder K, Simińska D, et al. CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of the Ligands of Receptors CCR1, CCR2, CCR3, and CCR4. Int J Mol Sci. Nov 09 2020;21(21)doi:10.3390/ijms21218412
  7. Marques RE, Guabiraba R, Russo RC, Teixeira MM. Targeting CCL5 in inflammation. Expert Opin Ther Targets. Dec 2013;17(12):1439-60. doi:10.1517/14728222.2013.837886
  8. Lennartsson J, Rönnstrand L. Stem cell factor receptor/c-Kit: from basic science to clinical implications. Physiol Rev. Oct 2012;92(4):1619-49. doi:10.1152/physrev.00046.2011
  9. Nagasawa T. CXCL12/SDF-1 and CXCR4. Front Immunol. 2015;6:301. doi:10.3389/fimmu.2015.00301

 

description

APRIL, EGF, ENA-78, GCP-2, GROα, MCP-4, PDGF-AA, PDGF-AB/BB, sCD40L, TARC, VEGF-A

High levels of most or all of the analytes in this group could indicate a platelet activation/wound healing response, as all of these factors are stored in and released by platelets and/or take part in angiogenic, tissue remodeling or inflammatory processes during wound healing1. We often observe high results in this group in conditions typically associated with vascular injury, angiogenesis and/or thrombocytosis, such as AOSD 2, Kawasaki disease 3, juvenile arthritis4, familial Mediterranean fever (FMF)5,  COVID-196, and Crohn’s disease7, whereas conditions that are generally associated with thrombocytopenia, such as HLH8, lymphocytic leukemia9, and hematopoietic stem cell transplantation10 tend to have lower values.

References:

1. von Hundelshausen P, Weber C. Platelets as immune cells: bridging inflammation and cardiovascular disease. Circ Res. Jan 05 2007;100(1):27-40. doi:10.1161/01.RES.0000252802.25497.b7

2. Olvera-Acevedo A, Hurtado-Díaz J, Espinoza-Sánchez ML. Still’s disease: a rare condition, in a patient of unusual age. Rev Med Inst Mex Seguro Soc. 2020;58(4):517-521. doi:10.24875/RMIMSS.M20000078

3. Arora K, Guleria S, Jindal AK, Rawat A, Singh S. Platelets in Kawasaki disease: Is this only a numbers game or something beyond? Genes Dis. Mar 2020;7(1):62-66. doi:10.1016/j.gendis.2019.09.003

4. Spiegel LR, Schneider R, Lang BA, et al. Early predictors of poor functional outcome in systemic-onset juvenile rheumatoid arthritis: a multicenter cohort study. Arthritis Rheum. Nov 2000;43(11):2402-9. doi:10.1002/1529-0131(200011)43:11<2402::AID-ANR5>3.0.CO;2-C

5. Coban E, Adanir H. Platelet activation in patients with Familial Mediterranean Fever. Platelets. Sep 2008;19(6):405-8. doi:10.1080/09537100802187121

6. Rohlfing AK, Rath D, Geisler T, Gawaz M. Platelets and COVID-19. Hamostaseologie. Oct 2021;41(5):379-385. doi:10.1055/a-1581-4355

7. Yan SL, Russell J, Harris NR, Senchenkova EY, Yildirim A, Granger DN. Platelet abnormalities during colonic inflammation. Inflamm Bowel Dis. May 2013;19(6):1245-53. doi:10.1097/MIB.0b013e318281f3df

8. Sadaat M, Jang S. Hemophagocytic lymphohistiocytosis with immunotherapy: brief review and case report. J Immunother Cancer. Jun 05 2018;6(1):49. doi:10.1186/s40425-018-0365-3

9. Shahrabi S, Behzad MM, Jaseb K, Saki N. Thrombocytopenia in leukemia: Pathogenesis and prognosis. Histol Histopathol. Sep 2018;33(9):895-908. doi:10.14670/HH-11-976

10. Mahat U, Rotz SJ, Hanna R. Use of Thrombopoietin Receptor Agonists in Prolonged Thrombocytopenia after Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. Mar 2020;26(3):e65-e73. doi:10.1016/j.bbmt.2019.12.003

 

description

An in-depth analysis of the inflammatory microenvironment is provided based on the qualitative results of groups of analytes representing different characteristics of inflammatory responses.

Relevant Dx Tests

description

Type 1 (cell-mediated) immunity targets intracellular pathogens and cancer cells by inducing cell death. Important cellular contributors to type 1 immunity are Th1 cells, type 1 innate lymphoid cells (ILC1s), natural killer (NK) cells, CD8+ cytotoxic T cells, and M1-polarized macrophages. Dysregulation of type 1 immunity can result in autoimmunity.

Type 1 Immunity Initiation/Propagation Markers

IL-2 – Plays an essential role in the activation and proliferation of Th1 cells1

IL-12p70 –Released mainly by DCs, monocytes, and macrophages upon bacterial- or viral-specific pattern recognition receptor activation, IL-12p70 is the main driver of Th1 cell differentiation and induces IFNγ release from Th1 cells2

IL-18 – Produced mainly by macrophages and DCs upon the recognition of intracellular pathogens, IL-18 is a key factor in type 1 immunity. IL-18 acts synergistically with IL-12p70 to stimulate the expression of IFNγ in Th1 cells and ILC1s, sustains Th1 and cytotoxic T cell activation, and is a key component regulating ILC1 and NK cell function3

IL-27 – Contributes to Th1 cell differentiation and expansion at the onset of a type 1 immune response, but also inhibits the release of IL-2 and induces the release of IL-10 which suppresses the Th1 response, so IL-27 may contribute to both the initiation and resolution of type 1 inflammatory responses4

Type 1 Immunity Effector Cytokines

IFNγ – The major signature cytokine secreted by Th1 cells, as well as NKs, ILC1s, and antigen-presenting cells like DCs and macrophages, IFNγ signaling is the key factor that orchestrates type 1 immune responses5

TNFα – A pro-inflammatory cytokine involved in systemic inflammation and a member of a group of cytokines that stimulate the acute phase reaction. It is secreted by macrophages, NK cells, and Th1 cells6

TNFβ (Lymphotoxin-α) – Type 1 cytokine released by Th1 cells, CD8+ T cells, NK cells, and macrophages7

Type 1 Immunity Cytotoxic Markers

Granzyme A, Granzyme B – Cell death-inducing serine proteases stored in the granules of NK cells and cytotoxic T cells that contribute to cell killing in type 1 immune responses8

Perforin – Cell death-inducing glycoprotein released mainly by NK cells and CD8+ T cells which forms pores in the membranes of target cells and contributes to cell killing in  type 1 immune responses9

Type 1 Immunity Chemokines

MIG (CXCL9), IP-10 (CXCL10), I-TAC (CXCL11) – CXCR3 ligands induced by IFNγ that drive the recruitment of macrophages, dendritic cells, NK cells, and Th1 cells to sites of inflammation10,11

References:
  1. Liao W, Lin JX, Leonard WJ. IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation. Curr Opin Immunol. Oct 2011;23(5):598-604. doi:10.1016/j.coi.2011.08.003
  2. Ullrich KA, Schulze LL, Paap EM, Müller TM, Neurath MF, Zundler S. Immunology of IL-12: An update on functional activities and implications for disease. EXCLI J. 2020;19:1563-1589. doi:10.17179/excli2020-3104
  3. Kaneko N, Kurata M, Yamamoto T, Morikawa S, Masumoto J. The role of interleukin-1 in general pathology. Inflamm Regen. 2019;39:12. doi:10.1186/s41232-019-0101-5
  4. Iwasaki Y, Fujio K, Okamura T, Yamamoto K. Interleukin-27 in T cell immunity. Int J Mol Sci. Jan 27 2015;16(2):2851-63. doi:10.3390/ijms16022851
  5. Ivashkiv LB. IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy. Nat Rev Immunol. 09 2018;18(9):545-558. doi:10.1038/s41577-018-0029-z
  6. Parameswaran N, Patial S. Tumor necrosis factor-α signaling in macrophages. Crit Rev Eukaryot Gene Expr. 2010;20(2):87-103. doi:10.1615/critreveukargeneexpr.v20.i2.10
  7. Calmon-Hamaty F, Combe B, Hahne M, Morel J. Lymphotoxin α revisited: general features and implications in rheumatoid arthritis. Arthritis Res Ther. Jul 2011;13(4):232. doi:10.1186/ar3376
  8. Chowdhury D, Lieberman J. Death by a thousand cuts: granzyme pathways of programmed cell death. Annu Rev Immunol. 2008;26:389-420. doi:10.1146/annurev.immunol.26.021607.090404
  9. Osińska I, Popko K, Demkow U. Perforin: an important player in immune response. Cent Eur J Immunol. 2014;39(1):109-15. doi:10.5114/ceji.2014.42135
  10. Liu M, Guo S, Hibbert JM, et al. CXCL10/IP-10 in infectious diseases pathogenesis and potential therapeutic implications. Cytokine Growth Factor Rev. Jun 2011;22(3):121-30. doi:10.1016/j.cytogfr.2011.06.001
  11. Metzemaekers M, Vanheule V, Janssens R, Struyf S, Proost P. Overview of the Mechanisms that May Contribute to the Non-Redundant Activities of Interferon-Inducible CXC Chemokine Receptor 3 Ligands. Front Immunol. 2017;8:1970. doi:10.3389/fimmu.2017.01970

description

Type 2 (humoral) immunity targets multicellular helminth parasites. Important cellular contributors to type 2 immunity are Th2 cells, type 2 innate lymphoid cells (ILC2s), Th9 cells, eosinophils, basophils, mast cells, and M2-polarized macrophages. Dysregulation of type 2 immunity can result in allergy and allergic diseases.

Type 2 Immunity Initiation/Propagation Markers

IL-4 – Promotes the differentiation, proliferation and survival of Th2 cells and is also a major effector cytokine released by activated Th2 cells that drives type 2 responses. IL-4 induces Ig isotype switching to IgG1 and IgE in B cells and drives the maturation and activation of DCs1

IL-17E/IL-25 – An epithelial alarmin released in response to danger signals, IL-17E/IL-25 amplifies type 2 immune responses by promoting the production of IL-4, IL-5, and IL-13 by Th2 cells and ILC2s2

IL-33 – A key cytokine in type 2 immunity, IL-33 induces type 2 cytokine release (IL-4, IL-5, IL-13) in Th2 cells, ILC2s, basophils, mast cells, and macrophages. Also, DCs activated by IL-33 promote Th2 polarization upon antigen presentation to naïve T helper cells3,4

TSLP (Thymic stromal lymphopoietin) – Produced mainly by epithelial tissues in response to inflammatory stimuli, TSLP primes DCs to induce Th2 polarization, plays a role in the development of ILC2s, and drives the expression of type 2 cytokines (IL-4, IL-5, IL-13)5

Type 2 Immunity Effector Cytokines

IL-5 – Stimulates antibody production in B cells and is an essential factor in eosinophilic inflammation by promoting the development, survival and activation of mature eosinophils. As a key factor in Th2-mediated responses, IL-5 contributes to diseases of allergic inflammation such as asthma1

IL-13 – Contributes to the type 2 immune response by serving as a co-stimulator that drives B cell maturation, activation and antibody release. IL-13 has been shown to inhibit the production of pro-inflammatory cytokines (IL-1β, TNFα, IL-12) by monocytes and may have a protective effect in type 1 inflammation, although both Th1 and Th17 cells have been shown to co-express IL-13 with their signature cytokines in some contexts6. IL-13 contributes to allergic inflammatory responses and is thought to drive the effector, rather than the initiation, phase of allergic diseases such as asthma1

IL-9 – A pleiotropic cytokine that is highly expressed by Th9 cells, mast cells and type 2 ILCs, and contributes to type 2 immune responses by promoting the growth and differentiation of mast cells, and stimulating the proliferation of T and B cells7,8

IL-31 – A pro-inflammatory cytokine released mainly by Th2 cells, macrophages, dendritic cells, and a sub-population of T helper cells that migrate selectively to the skin. IL-31 has been identified as a major contributor to non-histamine-mediated skin itch, and is prominently implicated in the pathogenesis of atopic dermatitis. IL-31 may also contribute to the pathogenesis of other allergic diseases such as asthma9

Type 2 Immunity Chemokines

Eotaxin-1 (CCL11), -2 (CCL24), -3 (CCL26))10 – Recruitment of eosinophils, basophils, mast cells, and activatedTh2 cells, to sites of inflammation via CCR3.

TARC (Thymus and activation regulated chemokine; CCL17)11 – Drives the recruitment of CCR4-expressing immune cells, most notably Th2 cells, to sites of inflammation.

References:
  1. Raphael I, Nalawade S, Eagar TN, Forsthuber TG. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine. Jul 2015;74(1):5-17. doi:10.1016/j.cyto.2014.09.011
  2. Brevi A, Cogrossi LL, Grazia G, et al. Much More Than IL-17A: Cytokines of the IL-17 Family Between Microbiota and Cancer. Front Immunol. 2020;11:565470. doi:10.3389/fimmu.2020.565470
  3. Molofsky AB, Savage AK, Locksley RM. Interleukin-33 in Tissue Homeostasis, Injury, and Inflammation. Immunity. Jun 2015;42(6):1005-19. doi:10.1016/j.immuni.2015.06.006
  4. Mantovani A, Dinarello CA, Molgora M, Garlanda C. Interleukin-1 and Related Cytokines in the Regulation of Inflammation and Immunity. Immunity. Apr 16 2019;50(4):778-795. doi:10.1016/j.immuni.2019.03.012
  5. Tsilingiri K, Fornasa G, Rescigno M. Thymic Stromal Lymphopoietin: To Cut a Long Story Short. Cell Mol Gastroenterol Hepatol. Mar 2017;3(2):174-182. doi:10.1016/j.jcmgh.2017.01.005
  6. Gallo E, Katzman S, Villarino AV. IL-13-producing Th1 and Th17 cells characterize adaptive responses to both self and foreign antigens. Eur J Immunol. Sep 2012;42(9):2322-8. doi:10.1002/eji.201142227
  7. Do-Thi VA, Lee JO, Lee H, Kim YS. Crosstalk between the Producers and Immune Targets of IL-9. Immune Netw. Dec 2020;20(6):e45. doi:10.4110/in.2020.20.e45
  8. Chakraborty S, Kubatzky KF, Mitra DK. An Update on Interleukin-9: From Its Cellular Source and Signal Transduction to Its Role in Immunopathogenesis. Int J Mol Sci. Apr 2019;20(9)doi:10.3390/ijms20092113
  9. Borgia F, Custurone P, Li Pomi F, Cordiano R, Alessandrello C, Gangemi S. IL-31: State of the Art for an Inflammation-Oriented Interleukin. Int J Mol Sci. Jun 10 2022;23(12)doi:10.3390/ijms23126507
  10. Zajkowska M, Mroczko B. From Allergy to Cancer-Clinical Usefulness of Eotaxins. Cancers (Basel). Jan 2021;13(1)doi:10.3390/cancers13010128
  11. Solari R, Pease JE. Targeting chemokine receptors in disease–a case study of CCR4. Eur J Pharmacol. Sep 2015;763(Pt B):169-77. doi:10.1016/j.ejphar.2015.05.018

description

Type 3 (mucosal) immunity is an important contributor to epithelial integrity, and targets extracellular unicellular pathogens (bacteria, fungi, viruses). Important cellular contributors to type 3 immunity are Th17 cells, type 3 innate lymphoid cells (ILC3s), Th22 cells, and neutrophils. Dysregulation of type 3 immunity can result in autoimmunity.

Type 3 Immunity Initiation/Propagation Markers

IL-23 – Drives the differentiation of Th17 cells (when present with IL-1) and induces IL-17 release. Prolonged exposure to elevated levels of IL-23 and IL-1β induces the ability of Th17 cells to secrete IFN-γ/GM-CSF (the highly inflammatory and pathogenic Th17.1 phenotype)1. IL-23 blocking agents have been approved or are being investigated for the treatment of psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn’s disease, and ankylosing spondylitis, and inflammatory bowel disease. IBD patients that do not respond to TNF blockers (indicative of a refractory phenotype) tend to respond well to anti-IL-23 antibody therapy2,3

IL-1α, IL-1β – IL-1 is an important factor in the differentiation, proliferation and function of Th17 cells, acting synergistically with IL-23 to induce the release of IL-17A. IL-1β also supports the production of type 3 cytokines IL-17A and IL-22 in ILC3s4

IL-6 – A key factor in inducing the differentiation of Th17 cells when co-signaling with TGFß5,6

Type 3 Effector Cytokines

IL-17A –Contributes to host defense and pathogen clearance of extracellular bacteria and fungi, as well as regulation of the gut microbiota. IL-17A blocking agents have been approved or are being investigated for the treatment of psoriasis, rheumatoid arthritis, ankylosing spondylitis, and multiple sclerosis7

IL-17F –IL-17F forms homodimers or heterodimers with IL-17A to promote host defense at mucosal barriers. Unlike IL-17A, IL-17F can also be produced by activated monocytes and epithelial cells8

IL-21 – Pleiotropic cytokine with broad effects in regulating both innate and adaptive immune responses, IL-21 is an important factor in promoting sustained immunity to chronic infections. IL-21 also drives differentiation of naïve CD4+ T cells to Th17 cells (with TGF-β) and to Tfh cells (in the absence of TGF-β)9

IL-22 – A cytokine released primarily by lymphoid cells, including Th22 cells (thought to be the major source of IL-22 in the peripheral circulation), as well as Th17 cells, type 3 innate lymphoid cells (ILC3s), and NKs. Depending on the tissue and pathological context, IL-22 can either reduce inflammation and drive epithelial repair and regeneration, or it can induce pro-inflammatory mediators and promote type 3 inflammation10

Pathogenic Th17 Activity Markers

IFNγ, GM-CSF – Highly pathogenic Th17.1 cells (Th17 cells that acquire ability to secrete IFNy – caused by IL-12-induced T-bet co-expression with RORγt) may contribute to disease severity in several autoimmune and inflammatory diseases1,11

References:
  1. Mourik BC, Lubberts E, de Steenwinkel JEM, Ottenhoff THM, Leenen PJM. Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases. Front Immunol. 2017;8:294. doi:10.3389/fimmu.2017.00294
  2. Duvallet E, Semerano L, Assier E, Falgarone G, Boissier MC. Interleukin-23: a key cytokine in inflammatory diseases. Ann Med. Nov 2011;43(7):503-11. doi:10.3109/07853890.2011.577093
  3. Atreya R, Neurath MF. IL-23 Blockade in Anti-TNF Refractory IBD: From Mechanisms to Clinical Reality. J Crohns Colitis. May 11 2022;16(Supplement_2):ii54-ii63. doi:10.1093/ecco-jcc/jjac007
  4. Kaneko N, Kurata M, Yamamoto T, Morikawa S, Masumoto J. The role of interleukin-1 in general pathology. Inflamm Regen. 2019;39:12. doi:10.1186/s41232-019-0101-5
  5. Kany S, Vollrath JT, Relja B. Cytokines in Inflammatory Disease. Int J Mol Sci. Nov 2019;20(23)doi:10.3390/ijms20236008
  6. Narazaki M, Kishimoto T. The Two-Faced Cytokine IL-6 in Host Defense and Diseases. Int J Mol Sci. Nov 09 2018;19(11)doi:10.3390/ijms19113528
  7. Chen K, Kolls JK. Interluekin-17A (IL17A). Gene. May 2017;614:8-14. doi:10.1016/j.gene.2017.01.016
  8. Brevi A, Cogrossi LL, Grazia G, et al. Much More Than IL-17A: Cytokines of the IL-17 Family Between Microbiota and Cancer. Front Immunol. 2020;11:565470. doi:10.3389/fimmu.2020.565470
  9. Yi JS, Cox MA, Zajac AJ. Interleukin-21: a multifunctional regulator of immunity to infections. Microbes Infect. Dec 2010;12(14-15):1111-9. doi:10.1016/j.micinf.2010.08.008
  10. Dudakov JA, Hanash AM, van den Brink MR. Interleukin-22: immunobiology and pathology. Annu Rev Immunol. 2015;33:747-85. doi:10.1146/annurev-immunol-032414-112123
  11. Cosmi L, Maggi L, Santarlasci V, Liotta F, Annunziato F. T helper cells plasticity in inflammation. Cytometry A. Jan 2014;85(1):36-42. doi:10.1002/cyto.a.22348

description

Active Immunosuppressive Factors

IL-10 – A potent anti-inflammatory factor. IL-10 promotes immunomodulatory Treg development, decreases inflammatory cytokine production and prevents the development of T cell-mediated immune responses1

IL-35 – A potent anti-inflammatory cytokine secreted by Tregs and Bregs that suppresses T cell proliferation and induces IL-35-secreting Treg cells (iTr35)2

TRAIL – Promotes the resolution of inflammation by accelerating apoptosis of neutrophils and has anti-inflammatory effects on T cell function by inhibiting the proliferation of Th1 cells, promoting Treg proliferation, and inducing apoptosis in autoreactive T cells and B cells3

Cytokine Receptor Antagonist

IL-1RA (IL-1 receptor antagonist) – Antagonist of the IL-1 receptor, IL-1RA blocks the effects of IL-1α and IL-1β. Thought to be an acute phase factor that balances the physiologic effects of IL-14

References:
  1. Saraiva M, Vieira P, O’Garra A. Biology and therapeutic potential of interleukin-10. J Exp Med. 01 2020;217(1)doi:10.1084/jem.20190418
  2. Ye C, Yano H, Workman CJ, Vignali DAA. Interleukin-35: Structure, Function and Its Impact on Immune-Related Diseases. J Interferon Cytokine Res. Nov 2021;41(11):391-406. doi:10.1089/jir.2021.0147
  3. Beyer K, Baukloh AK, Stoyanova A, Kamphues C, Sattler A, Kotsch K. Interactions of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) with the Immune System: Implications for Inflammation and Cancer. Cancers (Basel). Aug 13 2019;11(8)doi:10.3390/cancers11081161
  4. Kaneko N, Kurata M, Yamamoto T, Morikawa S, Masumoto J. The role of interleukin-1 in general pathology. Inflamm Regen. 2019;39:12. doi:10.1186/s41232-019-0101-5

description

The potential activation or expansion of different cell types can be inferred by the presence of factors known to drive the differentiation, proliferation, and activation of each cell type.

Inference of Immune Cell Activation/Expansion Based on Cytokine Signatures

B cells1-5 – IL-7, sCD40L, IL-4, IL-6, BCA-1, BAFF, APRIL, IL-21
T cells6 – IL-2, IL-7, IL-15
Cytotoxic T cells7-10 – IFNγ, IL-2, IL-12p70, IL-21, TNFα, Lymphotactin
NK cells11,12 – IL-2, IL-12p70, IL-15, IL-18, TNFβ
Neutrophils13,14 – G-CSF, IL-8, GM-CSF, IL-6
Basophils15,16 – IL-3, GM-CSF, IL-33, TSLP
Macrophages17,18 – GM-CSF, M-CSF, IL-34
Dendritic cells19,20 – IL-3, FLT-3L, GM-CSF
Mast cells19,21 – SCF, IL-9, IL-33, IL-4
Eosinophils19 – IL-3, IL-5, GM-CSF

References:

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