TY - JOUR
T1 - Distinct disease-specific Tfh cell populations in 2 different fibrotic diseases
T2 - IgG4-related disease and Kimura disease
AU - Munemura, Ryusuke
AU - Maehara, Takashi
AU - Murakami, Yuka
AU - Koga, Risako
AU - Aoyagi, Ryuichi
AU - Kaneko, Naoki
AU - Doi, Atsushi
AU - Perugino, Cory A.
AU - Della-Torre, Emanuel
AU - Saeki, Takako
AU - Sato, Yasuharu
AU - Yamamoto, Hidetaka
AU - Kiyoshima, Tamotsu
AU - Stone, John H.
AU - Pillai, Shiv
AU - Nakamura, Seiji
N1 - Funding Information:
This study was supported by Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (KAKENHI) (grants JP18KK0260 , 21K19607 , and JP19H03854 ), the Kanae Foundation for the Promotion of Medical Science , the R3QR program (Qdai-jump research program 01216), and the Takeda Science Foundation ) (all to T.M.) and by JSPS KAKENHI grant JP20H00553 (to S.N.). S.P. was supported by National Institutes of Health grant U19 AI110495 . C.A.P. was supported by a Rheumatology Research Foundation Scientist Development Award.
Publisher Copyright:
© 2022 American Academy of Allergy, Asthma & Immunology
PY - 2022
Y1 - 2022
N2 - Background: How T follicular (Tfh) cells contribute to many different B-cell class-switching events during T-cell–dependent immune responses has been unclear. Diseases with polarized isotype switching offer a unique opportunity for the exploration of Tfh subsets. Secondary and tertiary lymphoid organs in patients with elevated tissue expression levels of IgE (Kimura disease, KD) and those of IgG4 (IgG4-related disease, IgG4-RD) can provide important insights regarding cytokine expression by Tfh cells. Objective: We sought to identify disease-specific Tfh cell subsets in secondary and tertiary lymphoid organs expressing IL-10 or IL-13 and thus identify different cellular drivers of class switching in 2 distinct types of fibrotic disorders: allergic fibrosis (driven by type 2 immune cells) and inflammatory fibrosis (driven by cytotoxic T lymphocytes). Methods: Single-cell RNA sequencing, in situ sequencing, and multicolor immunofluorescence analysis were used to investigate B cells, Tfh cells, and infiltrating type 2 cells in lesion tissues from patients with KD or IgG4-RD. Results: Infiltrating Tfh cells in tertiary lymphoid organs from IgG4-RD were divided into 6 main clusters. We encountered abundant infiltrating IL-10–expressing LAG3+ Tfh cells in patients with IgG4-RD. Furthermore, we found that infiltrating AICDA+CD19+ B cells expressing IL-4, IL-10, and IL-21 receptors correlated with IgG4 expression. In contrast, we found that infiltrating IL-13–expressing Tfh cells were abundant in affected tissues from patients with KD. Moreover, we observed few infiltrating IL-13–expressing Tfh cells in tissues from patients with IgG4-RD, despite high serum levels of IgE (but low IgE in the disease lesions). Cytotoxic T cells were abundant in IgG4-RD; in contrast, type 2 immune cells were abundant in KD. Conclusions: Our analysis revealed a novel subset of IL-10+LAG3+ Tfh cells infiltrating the affected organs of IgG4-RD patients. In contrast, IL-13+ Tfh cells and type 2 immune cells infiltrated those of KD patients.
AB - Background: How T follicular (Tfh) cells contribute to many different B-cell class-switching events during T-cell–dependent immune responses has been unclear. Diseases with polarized isotype switching offer a unique opportunity for the exploration of Tfh subsets. Secondary and tertiary lymphoid organs in patients with elevated tissue expression levels of IgE (Kimura disease, KD) and those of IgG4 (IgG4-related disease, IgG4-RD) can provide important insights regarding cytokine expression by Tfh cells. Objective: We sought to identify disease-specific Tfh cell subsets in secondary and tertiary lymphoid organs expressing IL-10 or IL-13 and thus identify different cellular drivers of class switching in 2 distinct types of fibrotic disorders: allergic fibrosis (driven by type 2 immune cells) and inflammatory fibrosis (driven by cytotoxic T lymphocytes). Methods: Single-cell RNA sequencing, in situ sequencing, and multicolor immunofluorescence analysis were used to investigate B cells, Tfh cells, and infiltrating type 2 cells in lesion tissues from patients with KD or IgG4-RD. Results: Infiltrating Tfh cells in tertiary lymphoid organs from IgG4-RD were divided into 6 main clusters. We encountered abundant infiltrating IL-10–expressing LAG3+ Tfh cells in patients with IgG4-RD. Furthermore, we found that infiltrating AICDA+CD19+ B cells expressing IL-4, IL-10, and IL-21 receptors correlated with IgG4 expression. In contrast, we found that infiltrating IL-13–expressing Tfh cells were abundant in affected tissues from patients with KD. Moreover, we observed few infiltrating IL-13–expressing Tfh cells in tissues from patients with IgG4-RD, despite high serum levels of IgE (but low IgE in the disease lesions). Cytotoxic T cells were abundant in IgG4-RD; in contrast, type 2 immune cells were abundant in KD. Conclusions: Our analysis revealed a novel subset of IL-10+LAG3+ Tfh cells infiltrating the affected organs of IgG4-RD patients. In contrast, IL-13+ Tfh cells and type 2 immune cells infiltrated those of KD patients.
KW - B cell
KW - class switch
KW - fibrosis
KW - IgE
KW - IgG
KW - IgG-RD
KW - IgG-related disease
KW - interleukin-10
KW - Single-cell RNA sequencing
KW - Tfh cell
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U2 - 10.1016/j.jaci.2022.03.034
DO - 10.1016/j.jaci.2022.03.034
M3 - Article
C2 - 35568079
AN - SCOPUS:85132810929
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
SN - 0091-6749
ER -