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. 2022 Apr;72(4):252-260.
doi: 10.1111/pin.13212. Epub 2022 Feb 11.

Pathogenesis of follicular thymic hyperplasia associated with rheumatoid arthritis

Rintaro Ohe  1 , Suran Yang  1   2 , Daisuke Yamashita  3 , Chihiro Ichikawa  4 , Akihisa Saito  5 , Takanobu Kabasawa  1 , Aya Utsunomiya  1 , Naing Ye Aung  1 , Yuka Urano  1 , Takumi Kitaoka  1 , Kazushi Suzuki  1 , Daiichiro Takahara  1   2 , Akiko Sasaki  2 , Yuya Takakubo  2 , Michiaki Takagi  2 , Mitsunori Yamakawa  1 , Mitsuru Futakuchi  1
Affiliations

Pathogenesis of follicular thymic hyperplasia associated with rheumatoid arthritis

Rintaro Ohe et al. Pathol Int. 2022 Apr.

Abstract

Lymphoproliferative disorders may occur in patients with rheumatoid arthritis (RA) who are treated with methotrexate. However, follicular thymic hyperplasia (FTH) associated with RA (FTH-RA) is generally not considered a lymphoproliferative disorder. To investigate the pathogenesis of FTH-RA, we examined 12 cases of FTH involving thymic enlargement, four of FTH involving RA and eight of FTH involving myasthenia gravis (MG). Increased numbers and larger germinal center (GC) size were observed in FTH-RA group. The percentage of distorted GCs was 13.3% in FTH-RA group and 3.25% in FTH associated with MG (FTH-MG) group. A greater meshwork of follicular dendritic cells was observed in the GCs of FTH-RA group. Positive indices of CD27+ cells and PD-1+ cells per GC in FTH-RA group were significantly higher than those in FTH-MG group, though positive indices of CD68+ cells and CD163+ cells were similar. Myoid cell proliferation, as evaluated by α-SMA, tenascin-C, and l-caldesmon expression, was significantly increased in the FTH-RA group compared with the FTH-MG group. These results suggest that FTH should be considered in patients with RA treated with methotrexate. The pathogenesis of FTH-RA includes GC expansion and increased numbers of memory B cells, follicular helper T cells, and myoid cells, indicating humoral immunity activation.

Keywords: follicular helper T-cell; follicular thymic hyperplasia; germinal center; humoral immunity; memory B-cell; myasthenia gravis; myoid cell; rheumatoid arthritis.

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Conflict of interest statement

All authors declare that there are no conflict of interests.

Figures

Figure 1
Figure 1
Macroscopic findings of follicular thymic hyperplasia in patients with rheumatoid arthritis. (a–d) There were well‐defined white masses within thymuses (Patients 1‐4). (b–d) A mass is formed by the combination of many nodules (Patients 2–4). a, Patient 1; b, Patient 2; c, Patient 3; d, Patient 4. Bars, 1 mm
Figure 2
Figure 2
Histological findings of follicular thymic hyperplasia in rheumatoid arthritis (FTH‐RA) and in myasthenia gravis (FTH‐MG). (a) Gross image of an FTH‐RA sample shows numerous lymphocytic infiltrates. (b) The germinal center (GC) in the FTH‐RA sample is large and distorted in shape. (c) The GC of the FTH‐MG sample compared with that of the FTH‐RA sample. (d) The size of GCs in FTH‐RA group was significantly larger than that in FTH‐MG group (FTH‐RA vs. FTH‐MG; 0.33 ± 0.16 mm2 vs. 0.073 ± 0.079 mm2). (e) The number of GCs in FTH‐RA group was significantly larger than that in FTH‐MG group (FTH‐RA vs. FTH‐MG; 0.61 ± 0.22 pieces/mm2 vs. 0.080 ± 0.085 pieces/mm2). (f) The average percentage of distorted GCs was 13.3% in FTH‐RA group and 3.25% in FTH‐MG group
Figure 3
Figure 3
Immunohistochemical findings of follicular thymic hyperplasia in rheumatoid arthritis (FTH‐RA) and in myasthenia gravis (FTH‐MG). (a,b) The CD21+ follicular dendritic cell meshwork was thicker and denser in FTH‐RA GCs (a) than in FTH‐MG GCs (b). (c,d) CD27+ memory B cells were more abundant in FTH‐RA GCs (c) than in FTH‐MG GCs (D). (e,f) PD‐1+ follicular helper T cells were more abundant in FTH‐RA GCs (e) than in FTH‐MG GCs (f). (g,h) α‐SMA+ myoid cells/fibroblastic reticular cells were more abundant in FTH‐RA GCs (g) than in FTH‐MG GCs (h). Bars, 50 μm
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