Biomarkers and immune cells in allergen-specific immunotherapy Toward objective evaluation
Main Article Content
Keywords
biological markers, immune cell subsets, immune tolerance, specific immunotherapy, treatment monitoring
Abstract
Background: Allergen-specific immunotherapy (AIT) is the only intervention capable of modifying the natural course of allergic diseases by inducing long-term immune tolerance. Its clinical efficacy depends on complex regulations of humoral and cellular immunity, yet objective assessment remains hindered by the absence of standardized biomarkers.
Summary: This review summarizes recent advances in the immunological mechanisms of AIT and highlights emerging biomarkers—including allergen-specific immunoglobulin G4, regulatory T and B cells, and innate lymphoid cells—that may provide objective measures of efficacy and support individualized treatment strategies.
Key messages: (1) AIT uniquely modifies the natural history of allergic diseases; (2) current evaluation relies on subjective measures, highlighting the urgent need for standardized and clinically applicable biomarkers; (3) molecular markers and immune cell subsets offer promising tools for bridging mechanistic insights with clinical endpoints, supporting real-time monitoring and precision-guided optimization of AIT.
References
1. Sousa L, Martín-Sierra C, Pereira C, Loureiro G, Tavares B, Pedreiro S, et al. Subcutaneous immunotherapy induces alterations in monocytes and dendritic cells homeostasis in allergic rhinitis patients. Allergy Asthma Clin Immunol. 2018 Nov 15;14:45. https://doi.org/10.1186/s13223-018-0271-8
2. Akdis CA, Akdis M. Mechanisms of allergen-specific immunotherapy and immune tolerance to allergens. World Allergy Organ J. 2015 May 14;8(1):17. https://doi.org/10.1186/s40413-015-0063-2
3. Pitsios C. Allergen immunotherapy: Biomarkers and clinical outcome measures. J Asthma Allergy. 2021 Feb 18;14:141-14–8. https://doi.org/10.2147/JAA.S267522
4. Incorvaia C, Ridolo E, Bagnasco D, Scurati S, Canonica GW. Personalized medicine and allergen immunotherapy: The beginning of a new era? Clin Mol Allergy. 2021 Jul 7;19(1):10. https://doi.org/10.1186/s12948-021-00150-z
5. Tan TJ, Delgado-Dolset MI, Escribese MM, Barber D, Layhadi JA, Shamji MH. Biomarkers of AIT: Models of prediction of efficacy. Allergol Select. 2022 Nov 21;6:267-2–75. https://doi.org/10.5414/ALX02333E
6. Taylor A, Verhagen J, Blaser K, Akdis M, Akdis CA. Mechanisms of immune suppression by interleukin-10 and transforming growth factor-beta: The role of T regulatory cells. Immunology. 2006 Apr;117(4):433-–42. https://doi.org/10.1111/j.1365-2567.2006.02321.x
7. James LK, Till SJ. Potential mechanisms for IgG4 inhibition of immediate hypersensitivity reactions. Curr Allergy Asthma Rep. 2016 Mar;16(3):23. https://doi.org/10.1007/s11882-016-0600-2
8. van der Neut Kolfschoten M, Schuurman J, Losen M, Bleeker WK, Martínez-Martínez P, Vermeulen E, et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science. 2007 Sep 14;317(5844):1554-–7. https://doi.org/10.1126/science.1144603
9. Davies AM, Sutton BJ. Human IgG4: aA structural perspective. Immunol Rev. 2015 Nov;268(1):139-–59. https://doi.org/10.1111/imr.12349
10. Orengo JM, Radin AR, Kamat V, Badithe A, Ben LH, Bennett BLOrengo, J.M., Radin, A.R., Kamat, V,. et al.[CEd.4.1][SCW4.2] Treating cat allergy with monoclonal IgG antibodies that bind allergen and prevent IgE engagement. Nat Commun. 2018;9:, 1421 (2018). https://doi.org/10.1038/s41467-018-03636-8
11. Heeringa JJ, McKenzie CI, Varese N, Hew M, Bakx ATCM, Aui PM, et al. Induction of IgG2 and IgG4 B-cell memory following sublingual immunotherapy for ryegrass pollen allergy. Allergy. 2020 May;75(5):1121-–1132. https://doi.org/10.1111/all.14073
12. Gao P, Morita N, Shinkura R. Role of mucosal IgA antibodies as novel therapies to enhance mucosal barriers. Semin Immunopathol. 2024 Nov 20;47(1):1. https://doi.org/10.1007/s00281-024-01027-4
13. Boonpiyathad T, Pradubpongsa P, Mitthamsiri W, Satitsuksanoa P, Jacquet A, Sangasapaviliya A. Allergen-specific immunotherapy boosts allergen-specific IgD production in house dust mite-sensitized asthmatic patients. Allergy. 2020 Jun;75(6):1457-–1460. https://doi.org/10.1111/all.14133
14. Satitsuksanoa P, van de Veen W, Tan G, Lopez JF, Wirz O, Jansen K, Sokolowska M, Mirer D, et al. Allergen-specific B cell responses in oral immunotherapy-induced desensitization, remission, and natural outgrowth in cow's milk allergy. Allergy. 2025 Jan;80(1):161-–180. https://doi.org/10.1111/all.16220
15. Selb R, Eckl-Dorna J, Neunkirchner A, Schmetterer K, Marth K, Gamper J, J et al. CD23 surface density on B cells is associated with IgE levels and determines IgE-facilitated allergen uptake, as well as activation of allergen-specific T cells. J Allergy Clin Immunol. 2017 Jan;139(1):290-–299.e4. https://doi.org/10.1016/j.jaci.2016.03.042
16. Asaumi T, Sato S, Yanagida N, Matsuhara H, Kobayashi S, Fukano C, et al. Formation of IgE-Allergen-CD23 complex changes in children treated with subcutaneous immunotherapy for Japanese cedar pollinosis. Int Arch Allergy Immunol. 2021;182(3):190-–194. https://doi.org/10.1159/000510640
17. Catalán D, Mansilla MA, Ferrier A, Soto L, Oleinika K, Aguillón JC, et al. Immunosuppressive mechanisms of regulatory B Ccells. Front Immunol. 2021 Apr 29;12:611795. https://doi.org/10.3389/fimmu.2021.611795
18. Jansen K, Cevhertas L, Ma S, Satitsuksanoa P, Akdis M, van de Veen W. Regulatory B cells, A to Z. Allergy. 2021 Sep;76(9):2699-–2715. https://doi.org/10.1111/all.14763
19. van de Veen W, Stanic B, Yaman G, Wawrzyniak M, Söllner S, Akdis DG, et al. IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responses. J Allergy Clin Immunol. 2013 Apr;131(4):1204-–12. https://doi.org/10.1016/j.jaci.2013.01.014
20. Zhang Y, Lan F, Zhang L. Advances and highlights in allergic rhinitis. Allergy. 2021 Nov;76(11):3383-–3389. https://doi.org/10.1111/all.15044
21. Boonpiyathad T, van de Veen W, Wirz O, Sokolowska M, Rückert B, Tan G, et al. Role of Der p 1-specific B cells in immune tolerance during 2 years of house dust mite-specific immunotherapy. J Allergy Clin Immunol. 2019 Mar;143(3):1077-–1086.e10. https://doi.org/10.1016/j.jaci.2018.10.061
22. Shi LL, Xiong P, Yang M, Ardicli O, Schneider SR, Funch AB, et al. Role of IgG4 antibodies in human health and disease. Cells. 2025 Apr 25;14(9):639. https://doi.org/10.3390/cells14090639
23. Shamji MH, Valenta R, Jardetzky T, Verhasselt V, Durham SR, Würtzen PA, et al. The role of allergen-specific IgE, IgG and IgA in allergic disease. Allergy. 2021 Dec;76(12):3627-–3641. https://doi.org/10.1111/all.14908
24. Shan M, Carrillo J, Yeste A, Gutzeit C, Segura-Garzón D, Walland AC, et al. Secreted IgD amplifies humoral T helper 2 cell responses by binding basophils via Galectin-9 and CD44. Immunity. 2018 Oct 16;49(4):709-–724.e8. https://doi.org/10.1016/j.immuni.2018.08.013
25. Shamji MH, Kappen J, Abubakar-Waziri H, Zhang J, Steveling E, Watchman S, et al. Nasal allergen-neutralizing IgG4 antibodies block IgE-mediated responses: Novel biomarker of subcutaneous grass pollen immunotherapy. J Allergy Clin Immunol. 2019 Mar;143(3):1067-–1076. https://doi.org/10.1016/j.jaci.2018.09.039
26. Conrad ML, Barrientos G, Cai X, Mukherjee S, Das M, Stephen‐Victor E, et al. Regulatory T cells and their role in allergic disease. Allergy. 2025 Jan;80(1):77–93. https://doi.org/10.1111/all.16326
27. Nedoszytko B, Lange M, Sokołowska-Wojdyło M, Renke J, Trzonkowski P, Sobjanek M, et al. The role of regulatory T cells and genes involved in their differentiation in pathogenesis of selected inflammatory and neoplastic skin diseases. Part I: Treg properties and functions. Postepy Dermatol Alergol. 2017 Aug;34(4):285-–294. https://doi.org/10.5114/ada.2017.69305
28. Matsuda M, Terada T, Kitatani K, Kawata R, Nabe T. Roles of type 1 regulatory T (Tr1) cells in allergen-specific immunotherapy. Front Allergy. 2022 Aug 3;3:981126. https://doi.org/10.3389/falgy.2022.981126
29. Schmidt A, Oberle N, Krammer PH. Molecular mechanisms of Treg-mediated T cell suppression. Front Immunol. 2012 Mar 21;3:51. https://doi.org/10.3389/fimmu.2012.00051
30. Głobińska A, Boonpiyathad T, Satitsuksanoa P, Kleuskens M, van de Veen W, Sokolowska M, et al. Mechanisms of allergen-specific immunotherapy: Diverse mechanisms of immune tolerance to allergens. Ann Allergy Asthma Immunol. 2018 Sep;121(3):306-–312. https://doi.org/10.1016/j.anai.2018.06.026
31. Allan, S. Bee-keepers hold clues for T-cell tolerance. Nat Rev Immunol. 2008;8:, 910 (2008). https://doi.org/10.1038/nri2466
32. Boonpiyathad T, Sokolowska M, Morita H, Rückert B, Kast JI, Wawrzyniak M, et al. Der p 1-specific regulatory T-cell response during house dust mite allergen immunotherapy. Allergy. 2019 May;74(5):976-–985. https://doi.org/10.1111/all.13684
33. Lopez-Pastrana J, Shao Y, Chernaya V, Wang H, Yang XF. Epigenetic enzymes are the therapeutic targets for CD4(+)CD25(+/high)Foxp3(+) regulatory T cells. Transl Res. 2015 Jan;165(1):221-–40. https://doi.org/10.1016/j.trsl.2014.08.001
34. Zhang X, Zhang Z, He Z, Ju M, Li J, Yuan J, et al. Interleukin 35 induced Th2 and Tregs bias under normal conditions in mice. Peer J. 2018 Sep 21;6:e5638. https://doi.org/10.7717/peerj.5638
35. Zhang X, Zhang X, Zhuang L, Xu C, Li T, Zhang G, et al. Decreased regulatory T-cell frequency and interleukin-35 levels in patients with rheumatoid arthritis. Exp Ther Med. 2018 Dec;16(6):5366-–5372. https://doi.org/10.3892/etm.2018.6885
36. Chen Q, Abdi AM, Luo W, Yuan X, Dent AL. T follicular regulatory cells in food allergy promote IgE via IL-4. JCI Insight. 2024 Oct 8;9(19):e171241. https://doi.org/10.1172/jci.insight.171241
37. He J, Tsai LM, Leong YA, Hu X, Ma CS, Chevalier N, et al. Circulating precursor CCR7(lo)PD-1(hi) CXCR5⁺ CD4⁺ T cells indicate Tfh cell activity and promote antibody responses upon antigen reexposure. Immunity. 2013 Oct 17;39(4):770-–81. https://doi.org/10.1016/j.immuni.2013.09.007
38. Shigehara K, Kamekura R, Ikegami I, Sakamoto H, Yanagi M, Kamiya S, et al. Circulating T follicular helper 2 cells, T follicular regulatory cells and regulatory B cells are effective biomarkers for predicting the response to house dust mite sublingual immunotherapy in patients with allergic respiratory diseases. Front Immunol. 2023 Nov 24;14:1284205. https://doi.org/10.3389/fimmu.2023.1284205
39. Wambre E. Effect of allergen-specific immunotherapy on CD4+ T cells. Curr Opin Allergy Clin Immunol. 2015 Dec;15(6):581-–7. https://doi.org/10.1097/ACI.0000000000000216
40. Lambrou P, Zervas E, Oikonomidou E, Papageorgiou N, Alchanatis M, Gaga M. Eosinophilic infiltration in the nasal mucosa of rhinitis patients: iIs it affected by the presence of asthma or the allergic status of the patients? Ann Allergy Asthma Immunol. 2007 Jun;98(6):567-–72. https://doi.org/10.1016/S1081-1206(10)60737-5
41. Otsuka K, Otsuka H, Matsune S, Okubo K. Allergen-specific subcutaneous immunotherapy for Japanese cedar pollinosis decreases the number of metachromatic cells and eosinophils in nasal swabs during the preseason and in season. Immun Inflamm Dis. 2020 Sep;8(3):258-–266. https://doi.org/10.1002/iid3.301
42. Xi Y, Deng YQ, Li HD, Jiao WE, Chen J, Chen JJ, et al. Diagnostic value of a novel eosinophil cationic protein-myeloperoxidase test paper before and after treatment for allergic rhinitis. J Asthma Allergy. 2022 Aug 4;15:1005-–1019. https://doi.org/10.2147/JAA.S375069
43. Vega-Rioja A, Chacón P, Fernández-Delgado L, Doukkali B, Del Valle Rodríguez A, Perkins JR, et al. Regulation and directed inhibition of ECP production by human neutrophils. Front Immunol. 2022 Nov 28;13:1015529. https://doi.org/10.3389/fimmu.2022.1015529
44. Galli SJ, Tsai M. IgE and mast cells in allergic disease. Nat Med. 2012 May 4;18(5):693-–704. https://doi.org/10.1038/nm.2755
45. Bruhns P, Iannascoli B, England P, Mancardi DA, Fernandez N, Jorieux S, et al. Specificity and affinity of human Fc gamma receptors and their polymorphic variants for human IgG subclasses. Blood. 2009 Apr 16;113(16):3716-–25. https://doi.org/10.1182/blood-2008-09-179754
46. Thangam EB, Jemima EA, Singh H, Baig MS, Khan M, Mathias CB, et al. The role of histamine and histamine receptors in mast cell-mediated allergy and inflammation: The hunt for new therapeutic targets. Front Immunol. 2018 Aug 13;9:1873. https://doi.org/10.3389/fimmu.2018.01873
47. Matsuyama T, Machida K, Mizuno K, Matsuyama H, Dotake Y, Shinmura M, et al. The functional role of group 2 innate lymphoid cells in asthma. Biomolecules. 2023 May 26;13(6):893. https://doi.org/10.3390/biom13060893
48. Doherty TA, Scott D, Walford HH, Khorram N, Lund S, Baum R, et al. Allergen challenge in allergic rhinitis rapidly induces increased peripheral blood type 2 innate lymphoid cells that express CD84. J Allergy Clin Immunol. 2014 Apr;133(4):1203-–5. https://doi.org/10.1016/j.jaci.2013.12.1086
49. Maazi H, Akbari O. Type two innate lymphoid cells: The Janus cells in health and disease. Immunol Rev. 2017 Jul;278(1):192-–206. https://doi.org/10.1111/imr.12554
50. Van Kaer L, Postoak JL, Song W, Wu L. Innate and innate-like effector lymphocytes in health and disease. J Immunol. 2022 Jul 15;209(2):199-–207. https://doi.org/10.4049/jimmunol.2200074
51. Bartemes KR, Kita H. Roles of innate lymphoid cells (ILCs) in allergic diseases: The 10-year anniversary for ILC2s. J Allergy Clin Immunol. 2021 May;147(5):1531-–1547. https://doi.org/10.1016/j.jaci.2021.03.015
52. Tynecka M, Radzikowska U, Eljaszewicz A. IL-10-producing innate lymphoid cells: Did we find a missing piece of the puzzle? Allergy. 2021 Dec;76(12):3849-–3851. https://doi.org/10.1111/all.14980
53. Emami Fard N, Xiao M, Sehmi R. Regulatory ILC2-Role of IL-10 Pproducing ILC2 in Aasthma. Cells. 2023 Oct 31;12(21):2556. https://doi.org/10.3390/cells12212556
54. Swiecki M, Colonna M. The multifaceted biology of plasmacytoid dendritic cells. Nat Rev Immunol. 2015 Aug;15(8):471-–85. https://doi.org/10.1038/nri3865
55. Bosteels C, Neyt K, Vanheerswynghels M, van Helden MJ, Sichien D, Debeuf N, et al. Inflammatory Ttype 2 cDCs acquire features of cDC1s and macrophages to orchestrate immunity to respiratory virus infection. Immunity. 2020 Jun 16;52(6):1039-–1056.e9. https://doi.org/10.1016/j.immuni.2020.04.005
56. Miyanaga N, Takagi H, Uto T, Fukaya T, Nasu J, Fukui T, et al. Essential role of submandibular lymph node dendritic cells in protective sublingual immunotherapy against murine allergy. Commun Biol. 2020 Dec 7;3(1):742. https://doi.org/10.1038/s42003-020-01466-3
57. Benito-Villalvilla C, Pérez-Diego M, Angelina A, Kisand K, Rebane A, Subiza JL, et al. Allergoid-Mannan conjugates reprogram monocytes into tolerogenic dendritic cells via epigenetic and metabolic rewiring. J Allergy Clin Immunol. 2022 Jan;149(1):212-–222.e9. https://doi.org/10.1016/j.jaci.2021.06.012
58. Chou PY, Lin SY, Wu YN, Shen CY, Sheu MT, Ho HO. Glycosylation of OVA antigen-loaded PLGA nanoparticles enhances DC-targeting for cancer vaccination. J Control Release. 2022 Nov;351:970-–988. https://doi.org/10.1016/j.jconrel.2022.10.002
59. Angelina A, Pérez-Diego M, López-Abente J, Rückert B, Nombela I, Akdis M, et al. Cannabinoids induce functional Tregs by promoting tolerogenic DCs via autophagy and metabolic reprograming. Mucosal Immunol. 2022 Jan;15(1):96-–108. https://doi.org/10.1038/s41385-021-00455-x
60. Jafarzadeh A, Nemati M, Jafarzadeh S, Chauhan P, Saha B. The immunomodulatory potentials of interleukin-27 in airway allergies. Scand J Immunol. 2021 Feb;93(2):e12959. https://doi.org/10.1111/sji.12959
61. Wei Y, Wang M, Ma Y, Que Z, Yao D. Classical dichotomy of macrophages and alternative activation models proposed with technological progress. Biomed Res Int. 2021 Oct 21;2021:9910596. https://doi.org/10.1155/2021/9910596
62. Saradna A, Do DC, Kumar S, Fu QL, Gao P. Macrophage polarization and allergic asthma. Transl Res. 2018 Jan;191:1-–14. https://doi.org/10.1016/j.trsl.2017.09.002
63. Wang LX, Zhang SX, Wu HJ, Rong XL, Guo J. M2b macrophage polarization and its roles in diseases. J Leukoc Biol. 2019 Aug;106(2):345-–358. https://doi.org/10.1002/JLB.3RU1018-378RR
64. Kapellos TS, Bonaguro L, Gemünd I, Reusch N, Saglam A, Hinkley ER, et al. Human monocyte subsets and phenotypes in major chronic inflammatory diseases. Front Immunol. 2019 Aug 30;10:2035. https://doi.org/10.3389/fimmu.2019.02035
65. Eljaszewicz A, Ruchti F, Radzikowska U, Globinska A, Boonpiyathad T, Gschwend A, et al. Trained immunity and tolerance in innate lymphoid cells, monocytes, and dendritic cells during allergen-specific immunotherapy. J Allergy Clin Immunol. 2021 May;147(5):1865-–1877. https://doi.org/10.1016/j.jaci.2020.08.042
66. Eljaszewicz A, Ruchti F, Radzikowska U, Globinska A, Boonpiyathad T, Gschwend A, et al. Trained immunity and tolerance in innate lymphoid cells, monocytes, and dendritic cells during allergen-specific immunotherapy. J Allergy Clin Immunol. 2021 May;147(5):1865-–1877.68. https://doi.org/10.1016/j.jaci.2020.08.042
67. Sousa L, Martín-Sierra C, Pereira C, Loureiro G, Tavares B, Pedreiro S, et al. Subcutaneous immunotherapy induces alterations in monocytes and dendritic cells homeostasis in allergic rhinitis patients. Allergy Asthma Clin Immunol. 2018 Nov 15;14:45. https://doi.org/10.1186/s13223-018-0271-8
68. Aktas E, Akdis M, Bilgic S, Disch R, Falk CS, Blaser K, et al. Different natural killer (NK) receptor expression and immunoglobulin E (IgE) regulation by NK1 and NK2 cells. Clin Exp Immunol. 2005 May;140(2):301-–9. https://doi.org/10.1111/j.1365-2249.2005.02777.x
69. Palomares O, Martín-Fontecha M, Lauener R, Traidl-Hoffmann C, Cavkaytar O, Akdis M, et al. Regulatory T cells and immune regulation of allergic diseases: rRoles of IL-10 and TGF-β. Genes Immun. 2014 Dec;15(8):511-–20. https://doi.org/10.1038/gene.2014.45
70. Akdis CA, Blaser K. Mechanisms of interleukin-10-mediated immune suppression. Immunology. 2001 Jun;103(2):131-–6. https://doi.org/10.1046/j.1365-2567.2001.01235.x
71. Amniai L, Ple C, Barrier M, de Nadai P, Marquillies P, Vorng H, et al. Natural killer cells from allergic donors are defective in their response to CCL18 Cchemokine. Int J Mol Sci. 2021 Apr 9;22(8):3879. https://doi.org/10.3390/ijms22083879
2. Akdis CA, Akdis M. Mechanisms of allergen-specific immunotherapy and immune tolerance to allergens. World Allergy Organ J. 2015 May 14;8(1):17. https://doi.org/10.1186/s40413-015-0063-2
3. Pitsios C. Allergen immunotherapy: Biomarkers and clinical outcome measures. J Asthma Allergy. 2021 Feb 18;14:141-14–8. https://doi.org/10.2147/JAA.S267522
4. Incorvaia C, Ridolo E, Bagnasco D, Scurati S, Canonica GW. Personalized medicine and allergen immunotherapy: The beginning of a new era? Clin Mol Allergy. 2021 Jul 7;19(1):10. https://doi.org/10.1186/s12948-021-00150-z
5. Tan TJ, Delgado-Dolset MI, Escribese MM, Barber D, Layhadi JA, Shamji MH. Biomarkers of AIT: Models of prediction of efficacy. Allergol Select. 2022 Nov 21;6:267-2–75. https://doi.org/10.5414/ALX02333E
6. Taylor A, Verhagen J, Blaser K, Akdis M, Akdis CA. Mechanisms of immune suppression by interleukin-10 and transforming growth factor-beta: The role of T regulatory cells. Immunology. 2006 Apr;117(4):433-–42. https://doi.org/10.1111/j.1365-2567.2006.02321.x
7. James LK, Till SJ. Potential mechanisms for IgG4 inhibition of immediate hypersensitivity reactions. Curr Allergy Asthma Rep. 2016 Mar;16(3):23. https://doi.org/10.1007/s11882-016-0600-2
8. van der Neut Kolfschoten M, Schuurman J, Losen M, Bleeker WK, Martínez-Martínez P, Vermeulen E, et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science. 2007 Sep 14;317(5844):1554-–7. https://doi.org/10.1126/science.1144603
9. Davies AM, Sutton BJ. Human IgG4: aA structural perspective. Immunol Rev. 2015 Nov;268(1):139-–59. https://doi.org/10.1111/imr.12349
10. Orengo JM, Radin AR, Kamat V, Badithe A, Ben LH, Bennett BLOrengo, J.M., Radin, A.R., Kamat, V,. et al.[CEd.4.1][SCW4.2] Treating cat allergy with monoclonal IgG antibodies that bind allergen and prevent IgE engagement. Nat Commun. 2018;9:, 1421 (2018). https://doi.org/10.1038/s41467-018-03636-8
11. Heeringa JJ, McKenzie CI, Varese N, Hew M, Bakx ATCM, Aui PM, et al. Induction of IgG2 and IgG4 B-cell memory following sublingual immunotherapy for ryegrass pollen allergy. Allergy. 2020 May;75(5):1121-–1132. https://doi.org/10.1111/all.14073
12. Gao P, Morita N, Shinkura R. Role of mucosal IgA antibodies as novel therapies to enhance mucosal barriers. Semin Immunopathol. 2024 Nov 20;47(1):1. https://doi.org/10.1007/s00281-024-01027-4
13. Boonpiyathad T, Pradubpongsa P, Mitthamsiri W, Satitsuksanoa P, Jacquet A, Sangasapaviliya A. Allergen-specific immunotherapy boosts allergen-specific IgD production in house dust mite-sensitized asthmatic patients. Allergy. 2020 Jun;75(6):1457-–1460. https://doi.org/10.1111/all.14133
14. Satitsuksanoa P, van de Veen W, Tan G, Lopez JF, Wirz O, Jansen K, Sokolowska M, Mirer D, et al. Allergen-specific B cell responses in oral immunotherapy-induced desensitization, remission, and natural outgrowth in cow's milk allergy. Allergy. 2025 Jan;80(1):161-–180. https://doi.org/10.1111/all.16220
15. Selb R, Eckl-Dorna J, Neunkirchner A, Schmetterer K, Marth K, Gamper J, J et al. CD23 surface density on B cells is associated with IgE levels and determines IgE-facilitated allergen uptake, as well as activation of allergen-specific T cells. J Allergy Clin Immunol. 2017 Jan;139(1):290-–299.e4. https://doi.org/10.1016/j.jaci.2016.03.042
16. Asaumi T, Sato S, Yanagida N, Matsuhara H, Kobayashi S, Fukano C, et al. Formation of IgE-Allergen-CD23 complex changes in children treated with subcutaneous immunotherapy for Japanese cedar pollinosis. Int Arch Allergy Immunol. 2021;182(3):190-–194. https://doi.org/10.1159/000510640
17. Catalán D, Mansilla MA, Ferrier A, Soto L, Oleinika K, Aguillón JC, et al. Immunosuppressive mechanisms of regulatory B Ccells. Front Immunol. 2021 Apr 29;12:611795. https://doi.org/10.3389/fimmu.2021.611795
18. Jansen K, Cevhertas L, Ma S, Satitsuksanoa P, Akdis M, van de Veen W. Regulatory B cells, A to Z. Allergy. 2021 Sep;76(9):2699-–2715. https://doi.org/10.1111/all.14763
19. van de Veen W, Stanic B, Yaman G, Wawrzyniak M, Söllner S, Akdis DG, et al. IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responses. J Allergy Clin Immunol. 2013 Apr;131(4):1204-–12. https://doi.org/10.1016/j.jaci.2013.01.014
20. Zhang Y, Lan F, Zhang L. Advances and highlights in allergic rhinitis. Allergy. 2021 Nov;76(11):3383-–3389. https://doi.org/10.1111/all.15044
21. Boonpiyathad T, van de Veen W, Wirz O, Sokolowska M, Rückert B, Tan G, et al. Role of Der p 1-specific B cells in immune tolerance during 2 years of house dust mite-specific immunotherapy. J Allergy Clin Immunol. 2019 Mar;143(3):1077-–1086.e10. https://doi.org/10.1016/j.jaci.2018.10.061
22. Shi LL, Xiong P, Yang M, Ardicli O, Schneider SR, Funch AB, et al. Role of IgG4 antibodies in human health and disease. Cells. 2025 Apr 25;14(9):639. https://doi.org/10.3390/cells14090639
23. Shamji MH, Valenta R, Jardetzky T, Verhasselt V, Durham SR, Würtzen PA, et al. The role of allergen-specific IgE, IgG and IgA in allergic disease. Allergy. 2021 Dec;76(12):3627-–3641. https://doi.org/10.1111/all.14908
24. Shan M, Carrillo J, Yeste A, Gutzeit C, Segura-Garzón D, Walland AC, et al. Secreted IgD amplifies humoral T helper 2 cell responses by binding basophils via Galectin-9 and CD44. Immunity. 2018 Oct 16;49(4):709-–724.e8. https://doi.org/10.1016/j.immuni.2018.08.013
25. Shamji MH, Kappen J, Abubakar-Waziri H, Zhang J, Steveling E, Watchman S, et al. Nasal allergen-neutralizing IgG4 antibodies block IgE-mediated responses: Novel biomarker of subcutaneous grass pollen immunotherapy. J Allergy Clin Immunol. 2019 Mar;143(3):1067-–1076. https://doi.org/10.1016/j.jaci.2018.09.039
26. Conrad ML, Barrientos G, Cai X, Mukherjee S, Das M, Stephen‐Victor E, et al. Regulatory T cells and their role in allergic disease. Allergy. 2025 Jan;80(1):77–93. https://doi.org/10.1111/all.16326
27. Nedoszytko B, Lange M, Sokołowska-Wojdyło M, Renke J, Trzonkowski P, Sobjanek M, et al. The role of regulatory T cells and genes involved in their differentiation in pathogenesis of selected inflammatory and neoplastic skin diseases. Part I: Treg properties and functions. Postepy Dermatol Alergol. 2017 Aug;34(4):285-–294. https://doi.org/10.5114/ada.2017.69305
28. Matsuda M, Terada T, Kitatani K, Kawata R, Nabe T. Roles of type 1 regulatory T (Tr1) cells in allergen-specific immunotherapy. Front Allergy. 2022 Aug 3;3:981126. https://doi.org/10.3389/falgy.2022.981126
29. Schmidt A, Oberle N, Krammer PH. Molecular mechanisms of Treg-mediated T cell suppression. Front Immunol. 2012 Mar 21;3:51. https://doi.org/10.3389/fimmu.2012.00051
30. Głobińska A, Boonpiyathad T, Satitsuksanoa P, Kleuskens M, van de Veen W, Sokolowska M, et al. Mechanisms of allergen-specific immunotherapy: Diverse mechanisms of immune tolerance to allergens. Ann Allergy Asthma Immunol. 2018 Sep;121(3):306-–312. https://doi.org/10.1016/j.anai.2018.06.026
31. Allan, S. Bee-keepers hold clues for T-cell tolerance. Nat Rev Immunol. 2008;8:, 910 (2008). https://doi.org/10.1038/nri2466
32. Boonpiyathad T, Sokolowska M, Morita H, Rückert B, Kast JI, Wawrzyniak M, et al. Der p 1-specific regulatory T-cell response during house dust mite allergen immunotherapy. Allergy. 2019 May;74(5):976-–985. https://doi.org/10.1111/all.13684
33. Lopez-Pastrana J, Shao Y, Chernaya V, Wang H, Yang XF. Epigenetic enzymes are the therapeutic targets for CD4(+)CD25(+/high)Foxp3(+) regulatory T cells. Transl Res. 2015 Jan;165(1):221-–40. https://doi.org/10.1016/j.trsl.2014.08.001
34. Zhang X, Zhang Z, He Z, Ju M, Li J, Yuan J, et al. Interleukin 35 induced Th2 and Tregs bias under normal conditions in mice. Peer J. 2018 Sep 21;6:e5638. https://doi.org/10.7717/peerj.5638
35. Zhang X, Zhang X, Zhuang L, Xu C, Li T, Zhang G, et al. Decreased regulatory T-cell frequency and interleukin-35 levels in patients with rheumatoid arthritis. Exp Ther Med. 2018 Dec;16(6):5366-–5372. https://doi.org/10.3892/etm.2018.6885
36. Chen Q, Abdi AM, Luo W, Yuan X, Dent AL. T follicular regulatory cells in food allergy promote IgE via IL-4. JCI Insight. 2024 Oct 8;9(19):e171241. https://doi.org/10.1172/jci.insight.171241
37. He J, Tsai LM, Leong YA, Hu X, Ma CS, Chevalier N, et al. Circulating precursor CCR7(lo)PD-1(hi) CXCR5⁺ CD4⁺ T cells indicate Tfh cell activity and promote antibody responses upon antigen reexposure. Immunity. 2013 Oct 17;39(4):770-–81. https://doi.org/10.1016/j.immuni.2013.09.007
38. Shigehara K, Kamekura R, Ikegami I, Sakamoto H, Yanagi M, Kamiya S, et al. Circulating T follicular helper 2 cells, T follicular regulatory cells and regulatory B cells are effective biomarkers for predicting the response to house dust mite sublingual immunotherapy in patients with allergic respiratory diseases. Front Immunol. 2023 Nov 24;14:1284205. https://doi.org/10.3389/fimmu.2023.1284205
39. Wambre E. Effect of allergen-specific immunotherapy on CD4+ T cells. Curr Opin Allergy Clin Immunol. 2015 Dec;15(6):581-–7. https://doi.org/10.1097/ACI.0000000000000216
40. Lambrou P, Zervas E, Oikonomidou E, Papageorgiou N, Alchanatis M, Gaga M. Eosinophilic infiltration in the nasal mucosa of rhinitis patients: iIs it affected by the presence of asthma or the allergic status of the patients? Ann Allergy Asthma Immunol. 2007 Jun;98(6):567-–72. https://doi.org/10.1016/S1081-1206(10)60737-5
41. Otsuka K, Otsuka H, Matsune S, Okubo K. Allergen-specific subcutaneous immunotherapy for Japanese cedar pollinosis decreases the number of metachromatic cells and eosinophils in nasal swabs during the preseason and in season. Immun Inflamm Dis. 2020 Sep;8(3):258-–266. https://doi.org/10.1002/iid3.301
42. Xi Y, Deng YQ, Li HD, Jiao WE, Chen J, Chen JJ, et al. Diagnostic value of a novel eosinophil cationic protein-myeloperoxidase test paper before and after treatment for allergic rhinitis. J Asthma Allergy. 2022 Aug 4;15:1005-–1019. https://doi.org/10.2147/JAA.S375069
43. Vega-Rioja A, Chacón P, Fernández-Delgado L, Doukkali B, Del Valle Rodríguez A, Perkins JR, et al. Regulation and directed inhibition of ECP production by human neutrophils. Front Immunol. 2022 Nov 28;13:1015529. https://doi.org/10.3389/fimmu.2022.1015529
44. Galli SJ, Tsai M. IgE and mast cells in allergic disease. Nat Med. 2012 May 4;18(5):693-–704. https://doi.org/10.1038/nm.2755
45. Bruhns P, Iannascoli B, England P, Mancardi DA, Fernandez N, Jorieux S, et al. Specificity and affinity of human Fc gamma receptors and their polymorphic variants for human IgG subclasses. Blood. 2009 Apr 16;113(16):3716-–25. https://doi.org/10.1182/blood-2008-09-179754
46. Thangam EB, Jemima EA, Singh H, Baig MS, Khan M, Mathias CB, et al. The role of histamine and histamine receptors in mast cell-mediated allergy and inflammation: The hunt for new therapeutic targets. Front Immunol. 2018 Aug 13;9:1873. https://doi.org/10.3389/fimmu.2018.01873
47. Matsuyama T, Machida K, Mizuno K, Matsuyama H, Dotake Y, Shinmura M, et al. The functional role of group 2 innate lymphoid cells in asthma. Biomolecules. 2023 May 26;13(6):893. https://doi.org/10.3390/biom13060893
48. Doherty TA, Scott D, Walford HH, Khorram N, Lund S, Baum R, et al. Allergen challenge in allergic rhinitis rapidly induces increased peripheral blood type 2 innate lymphoid cells that express CD84. J Allergy Clin Immunol. 2014 Apr;133(4):1203-–5. https://doi.org/10.1016/j.jaci.2013.12.1086
49. Maazi H, Akbari O. Type two innate lymphoid cells: The Janus cells in health and disease. Immunol Rev. 2017 Jul;278(1):192-–206. https://doi.org/10.1111/imr.12554
50. Van Kaer L, Postoak JL, Song W, Wu L. Innate and innate-like effector lymphocytes in health and disease. J Immunol. 2022 Jul 15;209(2):199-–207. https://doi.org/10.4049/jimmunol.2200074
51. Bartemes KR, Kita H. Roles of innate lymphoid cells (ILCs) in allergic diseases: The 10-year anniversary for ILC2s. J Allergy Clin Immunol. 2021 May;147(5):1531-–1547. https://doi.org/10.1016/j.jaci.2021.03.015
52. Tynecka M, Radzikowska U, Eljaszewicz A. IL-10-producing innate lymphoid cells: Did we find a missing piece of the puzzle? Allergy. 2021 Dec;76(12):3849-–3851. https://doi.org/10.1111/all.14980
53. Emami Fard N, Xiao M, Sehmi R. Regulatory ILC2-Role of IL-10 Pproducing ILC2 in Aasthma. Cells. 2023 Oct 31;12(21):2556. https://doi.org/10.3390/cells12212556
54. Swiecki M, Colonna M. The multifaceted biology of plasmacytoid dendritic cells. Nat Rev Immunol. 2015 Aug;15(8):471-–85. https://doi.org/10.1038/nri3865
55. Bosteels C, Neyt K, Vanheerswynghels M, van Helden MJ, Sichien D, Debeuf N, et al. Inflammatory Ttype 2 cDCs acquire features of cDC1s and macrophages to orchestrate immunity to respiratory virus infection. Immunity. 2020 Jun 16;52(6):1039-–1056.e9. https://doi.org/10.1016/j.immuni.2020.04.005
56. Miyanaga N, Takagi H, Uto T, Fukaya T, Nasu J, Fukui T, et al. Essential role of submandibular lymph node dendritic cells in protective sublingual immunotherapy against murine allergy. Commun Biol. 2020 Dec 7;3(1):742. https://doi.org/10.1038/s42003-020-01466-3
57. Benito-Villalvilla C, Pérez-Diego M, Angelina A, Kisand K, Rebane A, Subiza JL, et al. Allergoid-Mannan conjugates reprogram monocytes into tolerogenic dendritic cells via epigenetic and metabolic rewiring. J Allergy Clin Immunol. 2022 Jan;149(1):212-–222.e9. https://doi.org/10.1016/j.jaci.2021.06.012
58. Chou PY, Lin SY, Wu YN, Shen CY, Sheu MT, Ho HO. Glycosylation of OVA antigen-loaded PLGA nanoparticles enhances DC-targeting for cancer vaccination. J Control Release. 2022 Nov;351:970-–988. https://doi.org/10.1016/j.jconrel.2022.10.002
59. Angelina A, Pérez-Diego M, López-Abente J, Rückert B, Nombela I, Akdis M, et al. Cannabinoids induce functional Tregs by promoting tolerogenic DCs via autophagy and metabolic reprograming. Mucosal Immunol. 2022 Jan;15(1):96-–108. https://doi.org/10.1038/s41385-021-00455-x
60. Jafarzadeh A, Nemati M, Jafarzadeh S, Chauhan P, Saha B. The immunomodulatory potentials of interleukin-27 in airway allergies. Scand J Immunol. 2021 Feb;93(2):e12959. https://doi.org/10.1111/sji.12959
61. Wei Y, Wang M, Ma Y, Que Z, Yao D. Classical dichotomy of macrophages and alternative activation models proposed with technological progress. Biomed Res Int. 2021 Oct 21;2021:9910596. https://doi.org/10.1155/2021/9910596
62. Saradna A, Do DC, Kumar S, Fu QL, Gao P. Macrophage polarization and allergic asthma. Transl Res. 2018 Jan;191:1-–14. https://doi.org/10.1016/j.trsl.2017.09.002
63. Wang LX, Zhang SX, Wu HJ, Rong XL, Guo J. M2b macrophage polarization and its roles in diseases. J Leukoc Biol. 2019 Aug;106(2):345-–358. https://doi.org/10.1002/JLB.3RU1018-378RR
64. Kapellos TS, Bonaguro L, Gemünd I, Reusch N, Saglam A, Hinkley ER, et al. Human monocyte subsets and phenotypes in major chronic inflammatory diseases. Front Immunol. 2019 Aug 30;10:2035. https://doi.org/10.3389/fimmu.2019.02035
65. Eljaszewicz A, Ruchti F, Radzikowska U, Globinska A, Boonpiyathad T, Gschwend A, et al. Trained immunity and tolerance in innate lymphoid cells, monocytes, and dendritic cells during allergen-specific immunotherapy. J Allergy Clin Immunol. 2021 May;147(5):1865-–1877. https://doi.org/10.1016/j.jaci.2020.08.042
66. Eljaszewicz A, Ruchti F, Radzikowska U, Globinska A, Boonpiyathad T, Gschwend A, et al. Trained immunity and tolerance in innate lymphoid cells, monocytes, and dendritic cells during allergen-specific immunotherapy. J Allergy Clin Immunol. 2021 May;147(5):1865-–1877.68. https://doi.org/10.1016/j.jaci.2020.08.042
67. Sousa L, Martín-Sierra C, Pereira C, Loureiro G, Tavares B, Pedreiro S, et al. Subcutaneous immunotherapy induces alterations in monocytes and dendritic cells homeostasis in allergic rhinitis patients. Allergy Asthma Clin Immunol. 2018 Nov 15;14:45. https://doi.org/10.1186/s13223-018-0271-8
68. Aktas E, Akdis M, Bilgic S, Disch R, Falk CS, Blaser K, et al. Different natural killer (NK) receptor expression and immunoglobulin E (IgE) regulation by NK1 and NK2 cells. Clin Exp Immunol. 2005 May;140(2):301-–9. https://doi.org/10.1111/j.1365-2249.2005.02777.x
69. Palomares O, Martín-Fontecha M, Lauener R, Traidl-Hoffmann C, Cavkaytar O, Akdis M, et al. Regulatory T cells and immune regulation of allergic diseases: rRoles of IL-10 and TGF-β. Genes Immun. 2014 Dec;15(8):511-–20. https://doi.org/10.1038/gene.2014.45
70. Akdis CA, Blaser K. Mechanisms of interleukin-10-mediated immune suppression. Immunology. 2001 Jun;103(2):131-–6. https://doi.org/10.1046/j.1365-2567.2001.01235.x
71. Amniai L, Ple C, Barrier M, de Nadai P, Marquillies P, Vorng H, et al. Natural killer cells from allergic donors are defective in their response to CCL18 Cchemokine. Int J Mol Sci. 2021 Apr 9;22(8):3879. https://doi.org/10.3390/ijms22083879
Article Sidebar
Published
Mar 1, 2026
Article Details
How to Cite
Huang, C., & Tang, Z. . (2026). Biomarkers and immune cells in allergen-specific immunotherapy: Toward objective evaluation. Allergologia Et Immunopathologia, 54(2), 156–163. https://doi.org/10.15586/aei.v54i2.1533
Section
Review Article
How to Cite
Huang, C., & Tang, Z. . (2026). Biomarkers and immune cells in allergen-specific immunotherapy: Toward objective evaluation. Allergologia Et Immunopathologia, 54(2), 156–163. https://doi.org/10.15586/aei.v54i2.1533