T follicular helper cells mediate local production of allergen-specific IgE and IgG4

The prevalence of allergies such as allergic conjunctivitis, allergic rhinitis, rhinosinusitis, bronchial asthma, and food allergies has been increasing in recent years, and allergic conditions are known to affect more than a billion individuals worldwide. The nasal, bronchial, or intestinal mucosa serves as an important barrier that maintains tissue homeostasis and protects host tissues from allergens. Accumulating evidence suggests that local production of allergen-specific IgE antibodies in the mucosa may be associated with mucosal mast cell activation.1Cao P.P. Zhang Y.N. Liao B. Ma J. Wang B.F. Wang H. et al.Increased local IgE production induced by common aeroallergens and phenotypic alteration of mast cells in Chinese eosinophilic, but not non-eosinophilic, chronic rhinosinusitis with nasal polyps.Clin Exp Allergy. 2014; 44: 690-700Crossref PubMed Scopus (79) Google Scholar In contrast, local production of allergen-specific IgG4 antibodies protects host mucosal tissues against allergic inflammation by competing with IgE antibodies for allergen binding, which blocks IgE antibody–mediated allergic inflammation. In fact, IgG4 antibodies locally produced in nasal fluids showed a higher level of inhibitory activity in patients treated with grass pollen subcutaneous immunotherapy than in those with seasonal allergic rhinitis.2Shamji M.H. 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; 143: 1067-1076Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar Importantly, the level of inhibitory activity was significantly higher in nasal fluid IgG4 antibodies than in serum IgG4 antibodies.2Shamji M.H. 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; 143: 1067-1076Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar Furthermore, the magnitude of the inhibitory activity in nasal fluid IgG4 antibodies was correlated with improvements in allergic symptoms.2Shamji M.H. 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; 143: 1067-1076Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar Therefore, local production of allergen-specific IgE or IgG4 antibodies in mucosal tissues is an important determinant of aggravation or alleviation of allergic symptoms. Recent studies suggest that local production of allergen-specific IgE or IgG4 antibodies might be mediated by T follicular helper (TFH) cells, as discussed in this review. Class switching of Ig to IgE is usually known to occur in the germinal centers of secondary lymphoid organs. However, identification of tertiary lymphoid organs (TLOs) together with class switch recombination molecules in mucosal tissues in patients with allergies suggests that local production of allergen-specific IgE antibodies is mediated in the germinal centers of TLOs.3Gevaert P. Nouri-Aria K.T. Wu H. Harper C.E. Takhar P. Fear D.J. et al.Local receptor revision and class switching to IgE in chronic rhinosinusitis with nasal polyps.Allergy. 2013; 68: 55-63Crossref PubMed Scopus (115) Google Scholar TLOs develop in nonlymphoid organs at sites of chronic inflammation in patients with allergies; they consist of TFH cells, B cells, and follicular dendritic cells. Functionally, TLOs show germinal center activities and contribute to local adaptive immune responses observed at sites of chronic inflammation. The study of nasal tissues from patients with nasal polyps has demonstrated that TFH cells in TLOs play a key role in B-cell differentiation and Ig class switching.4Zhang Y.N. Song J. Wang H. Wang H. Zeng M. Zhai G.T. et al.Nasal IL-4(+)CXCR5(+)CD4(+) T follicular helper cell counts correlate with local IgE production in eosinophilic nasal polyps.J Allergy Clin Immunol. 2016; 137: 462-473Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Expression of CXCR5 and the transcription factor BCL6 distinguishes TFH cells from other TH cells. Recent studies have reported that TFH cells producing high levels of IL-21 typically show additional PD-1 and TIGIT expression.5Akiyama M. Suzuki K. Yoshimoto K. Yasuoka H. Kaneko Y. Takeuchi T. Peripheral TIGIT+ T follicular helper cells that produce high levels of interleukin-21 via OX40 represent disease activity in IgG4-related disease.Front Immunol. 2021; 12: 651357Crossref PubMed Scopus (13) Google Scholar Furthermore, TFH cells are a heterogeneous population and can be classified into the following subsets: TFH1 cells, TFH2 cells, and TFH17 cells, with distinct transcription factors, surface chemokine receptor expression, cytokine secretion, and B-cell–assisting ability in each subset (Fig 1, A). Among all TFH cells, the TFH2 subgroup has been shown to assist human naive B cells in differentiation into plasma cells and promote class switching to IgE or IgG4 (Fig 1, A).4Zhang Y.N. Song J. Wang H. Wang H. Zeng M. Zhai G.T. et al.Nasal IL-4(+)CXCR5(+)CD4(+) T follicular helper cell counts correlate with local IgE production in eosinophilic nasal polyps.J Allergy Clin Immunol. 2016; 137: 462-473Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar,6Akiyama M. Yasuoka H. Yamaoka K. Suzuki K. Kaneko Y. Kondo H. et al.Enhanced IgG4 production by follicular helper 2 T cells and the involvement of follicular helper 1 T cells in the pathogenesis of IgG4-related disease.Arthritis Res Ther. 2016; 18: 167Crossref PubMed Scopus (128) Google Scholar,7Eisenbarth S.C. Baumjohann D. Craft J. Fazilleau N. Ma C.S. Tangye S.G. et al.CD4+ T cells that help B cells - a proposal for uniform nomenclature..Trends Immunol. 2021; 42: 658-669Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar On the other hand, TFH1 and TFH17 cells are inefficient in inducing human naive B cells to differentiate into plasma cells in vitro (Fig 1, A).6Akiyama M. Yasuoka H. Yamaoka K. Suzuki K. Kaneko Y. Kondo H. et al.Enhanced IgG4 production by follicular helper 2 T cells and the involvement of follicular helper 1 T cells in the pathogenesis of IgG4-related disease.Arthritis Res Ther. 2016; 18: 167Crossref PubMed Scopus (128) Google Scholar,7Eisenbarth S.C. Baumjohann D. Craft J. Fazilleau N. Ma C.S. Tangye S.G. et al.CD4+ T cells that help B cells - a proposal for uniform nomenclature..Trends Immunol. 2021; 42: 658-669Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar However, TFH1 and TFH17 cells can help human memory B cells to induce IgG production (Fig 1, A).7Eisenbarth S.C. Baumjohann D. Craft J. Fazilleau N. Ma C.S. Tangye S.G. et al.CD4+ T cells that help B cells - a proposal for uniform nomenclature..Trends Immunol. 2021; 42: 658-669Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar In this review, we have focused on the contribution of TFH2 cells in allergy and IgG4-related disease (IgG4-RD). Studies have reported infiltration of TFH2 cells in TLOs of nasal tissues in allergic conditions.4Zhang Y.N. Song J. Wang H. Wang H. Zeng M. Zhai G.T. et al.Nasal IL-4(+)CXCR5(+)CD4(+) T follicular helper cell counts correlate with local IgE production in eosinophilic nasal polyps.J Allergy Clin Immunol. 2016; 137: 462-473Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Those nasal TFH2 cells proliferate in response to stimulation with Dermatophagoides pteronyssinus group 1.4Zhang Y.N. Song J. Wang H. Wang H. Zeng M. Zhai G.T. et al.Nasal IL-4(+)CXCR5(+)CD4(+) T follicular helper cell counts correlate with local IgE production in eosinophilic nasal polyps.J Allergy Clin Immunol. 2016; 137: 462-473Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Notably, nasal TFH2 cells and not CXCR5-negative TH cells have been shown to trigger IgE and IgG4 antibody production following coculture with naive B cells,4Zhang Y.N. Song J. Wang H. Wang H. Zeng M. Zhai G.T. et al.Nasal IL-4(+)CXCR5(+)CD4(+) T follicular helper cell counts correlate with local IgE production in eosinophilic nasal polyps.J Allergy Clin Immunol. 2016; 137: 462-473Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar suggesting that local TFH2 cells have potential to mediate local production of IgE and IgG4 antibodies. Recent studies have observed local production of allergen-specific IgG4 antibodies in nasal tissues and have also described a close correlation between these antibodies and clinical efficacy of subcutaneous grass pollen immunotherapy.2Shamji M.H. 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; 143: 1067-1076Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar Reportedly, successful allergen immunotherapy results in an increase in the allergen-specific TFH cells in peripheral blood, which highlights TFH cell–dependent production of IgG4 antibody in immune tolerance associated with allergen immunotherapy.8Ryan J.F. Hovde R. Glanville J. Lyu S.C. Ji X. Gupta S. et al.Successful immunotherapy induces previously unidentified allergen-specific CD4+ T-cell subsets.Proc Natl Acad Sci U S A. 2016; 113: E1286-E1295Crossref PubMed Scopus (102) Google Scholar IgG4-RD is a chronic fibroinflammatory disease characterized by elevated serum IgG4 levels and infiltration of IgG4 antibody–producing plasma cells in inflamed tissues. IgG4-RD is histologically characterized by excessive TLO formation in the inflamed tissues, with consequent enlargement of the affected organs.9Chen Y. Lin W. Yang H. Wang M. Zhang P. Feng R. et al.Aberrant expansion and function of follicular helper T cell subsets in IgG4-related disease.Arthritis Rheumatol. 2018; 70: 1853-1865Crossref PubMed Scopus (66) Google Scholar Several studies have confirmed that Ig class switching to IgG4 is locally triggered in the TLOs by TFH cells (specifically, TFH2 cells), in patients with IgG4-RD (Fig 1, B).9Chen Y. Lin W. Yang H. Wang M. Zhang P. Feng R. et al.Aberrant expansion and function of follicular helper T cell subsets in IgG4-related disease.Arthritis Rheumatol. 2018; 70: 1853-1865Crossref PubMed Scopus (66) Google Scholar A history of allergies or concomitant allergies, such as allergic conjunctivitis, allergic rhinitis, rhinosinusitis, or asthma, is frequently reported in patients with IgG4-RD, and serum IgE antibody levels are elevated in these patients.10Michailidou D. Schwartz D.M. Mustelin T. Hughes G.C. Allergic aspects of IgG4-related disease: implications for pathogenesis and therapy.Front Immunol. 2021; 12: 693192Crossref PubMed Scopus (14) Google Scholar Currently however, there is no evidence showing local production of allergen-specific IgE or IgG4 antibodies in IgG4-RD. We observed that the levels of allergen-specific IgE antibodies were increased in the affected site in a patient with IgG4-RD (Fig 2). We need to note that this observation was derived from the case and therefore further studies are required to confirm our observation in multiple cases of IgG4-RD and also to determine whether IgG4-RD is attributable to allergen exposure. Much research in this domain has confirmed the critical role of TFH cells in the local production of allergen-specific IgE and IgG4 antibodies. A more comprehensive understanding of the molecular mechanisms underlying aberrant activation of TFH cells in allergies and IgG4-RD may offer novel potential therapeutic targets. For example, ontogeny and polarization of TFH cells in TLOs remain unknown. The ontogeny and function of follicular dendritic cells, which serve as a key immune cell subset that orchestrates TLO formation and function, also remain unclear. Further investigations are warranted to gain deeper insight into these issues and to identify novel therapeutic targets in patients with allergies and IgG4-RD.