https://orcid.org/0000-0001-5075-8977
Dear Editor, We read the article by Mancuso et al. [1] with great interest. They reported that the number of circulating follicular helper T (Tfh) cells from patients with IgG4-related disease (IgG4-RD) remained unchanged even after clinical improvement and B cell depletion by rituximab. They also suggested that persisting Tfh might be associated with future relapse of the disease. In line with their observations, we previously reported that the increased number of circulating Tfh cells was not corrected after clinical improvement by glucocorticoid in patients with IgG4-RD [2–4]. Furthermore, we found reactivation of Tfh cells at relapse of the disease [2]. These results suggest that glucocorticoid or B cell targeting therapy such as rituximab is insufficient to suppress the number of Tfh cells and/or their pathogenic function in IgG4-RD. Considering the frequent relapse of the disease and the toxic effects of glucocorticoids, new therapeutic targets are obviously desired in this disease.
We would like to provide our observation that follicular dendritic cells (FDCs) might be one of the culprit cell types that plays a role in the disease pathogenesis. In the affected tissues of IgG4-RD, it is well known that the ectopic germinal centres, so-called tertiary lymphoid organs, emerge and are involved in IgG4-producing plasma cell differentiation with the help of Tfh cells [5]. In general, FDC attracts CXCR5+ Tfh and B cells by secreting CXCL13 to initiate germinal centre formation [6]. Similar to the report by Mancuso et al. [1], we previously reported that serum CXCL13 levels were elevated in IgG4-RD by comprehensive proteomic analysis [7]. We found that CD21+ FDCs reside within the light zone of ectopic germinal centres of IgG4-RD (Fig. 1). Of note, a recent study has revealed that FDCs not only initiate germinal centre formation by attracting Tfh and B cells through CXCL13 secretion, but are also involved in the antigen-dependent selection process of Tfh and B cells through HLA-DR expression [6]. In fact, the shape of FDCs in the affected site of IgG4-RD is like ‘meshwork’, enabling their intimate contact with both Tfh and B cells (Fig. 1). In addition, FDCs directly activate Tfh cells in the germinal centres [6]. We note that T cells residing outside of the ectopic germinal centres are involved in inducing the fibrosis of IgG4-RD because those T cells, but not B cells, are infiltrating the fibrosis area of the affected site (Fig. 1). Of interest, in the other autoimmunity-associated fibrotic diseases, such as RA-associated interstitial lung disease, the ectopic germinal centre formation, so-called inducible bronchus-associated lymphoid tissue, is characteristically found in the lungs and consisting of FDCs, Tfh cells and B cells, surrounded by the fibrosis areas [8]. Thus FDC-mediated ectopic germinal centre formation might commonly play a crucial role in autoimmunity-associated chronic inflammation and fibrosis. FDCs might be the upstream immune cell type in the disease process of IgG4-RD as well as other autoimmunity-associated fibrotic diseases, making them a potential therapeutic target in the future.
FDCs reside within the ectopic germinal centres in the affected tissue of IgG4-RD
(A) Biopsy specimen of the affected lacrimal gland from IgG4-RD shows the ectopic germinal centre formations as well as fibrosis (pink) outside of the ectopic germinal centres. Elastica van Gieson (EVG) staining. (B) CD21+ FDCs reside within the ectopic germinal centres, shaped like ‘meshwork’ and contacting both T cells and B cells. (C) CD3+ T cells reside inside and outside of the ectopic germinal centres. CD3+ T cells are also infiltrating in the fibrosis areas. (D) CD20+ B cells mainly reside within the ectopic germinal centres and do not exist in the fibrosis areas.
Acknowledgements
This work was supported by a Japan Society for the Promotion of Science KAKENHI grant (21K16292) to M.A.
Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.
Disclosure statement: M.A. has received speaker fees from Pfizer Japan and Asahi Kasei Pharma. Y.K. has received grants or speaker fees from AbbVie, Astellas, Ayumi, Asahi Kasei Pharma, Bristol Myers Squibb, Chugai, Eisai, Eli Lilly, Hisamitsu, Jansen, Kissei, Pfizer, Sanofi, Takeda, Tanabe-Mitsubishi and UCB.
Data availability statement
The data underlying this article are available in the article.
Comments