Table 3.
Potential mechanisms that may promote TLS formation in lupus.
| Study | Patients/Model | Study design | Findings | Comment |
|---|---|---|---|---|
| Steinmetz, et al, 2008 (67) | 32 patients with LN | Lymphoid chemokine BCA-1 (CXCL13) and its receptor CXCR5 detected by IHC/real time PCR | In regions of B cell infiltration, increased BCA-1 expressed in cells of a dendritic-like morphology and most B cells expressed CXCR5 | BCA-1/CXCR5 may play role in B cell infiltration into the kidney. |
| He, et al, 2016 (70) | 89 LN and 25 non-LN SLE | Serum CXCL13 by ELISA, and renal biopsy staining for B cells. | LN patients with kidney TLS had more serum CXCL13 than those without. Serum CXCL13 levels correlated with the number of B cells in kidney biopsies | CXCL13 might be involved in renal TLS formation. |
| Kang, et al, 2017 (54) | AID-/-MRL/lpr passive transfer (anti-nucleosome IgG) model | BAFF-secreting cells enumerated by ELISpot in isolated kidney cells. Treating mice with BR3-Fc to reduce BAFF. | Increased BAFF production in the kidneys during LN development. Reducing BAFF in vivo prevented the formation of TLS and LN | BAFF induces TLS during LN |
| Dorraji, et al, 2018 (72) | NZB/NZW F1 mice kidneys, and human MSCs | IF staining of kidneys from mice, and in vitro culture of human MSC with T cells. | MSCs detected in TLS in NZB/NZW kidneys. Stimulated human MSCs increased the expression of CCL19, VCAM1, ICAM1, TNF-α, and IL-1β, and induced T cell proliferation | Tissue-specific or migratory MSCs could play roles as LTo cells in initiating kidney TLS. |
| Masum, et al, 2020 (63) | MRL-lpr and BXSB/MpJ-Yaa (Yaa) mice | Transcriptomic analysis of kidney tissue | Increased Cxcl13 and CXCR5, upregulated expression signatures associated with lymphoid tissue formation, leukocyte migration, HEV forming, and adhesion molecules | Identified molecules associated with TLS formation in kidneys |
| Wang, et al., 2021 (65) | TLR8-ko model of LN and Sjogren’s disease | Double TLR7/8-deficient C57BL/6 mice; histology and IF of salivary gland and lung tissues | TLS formation is abrogated in double TLR7/8-deficient mice | Suggests a role of TLR7 signaling in TLS formation |
| Li, et al, 2023 (73) | MRL-lpr mice | ILC detected in kidneys by microscopy and transcriptomics | Increased ILC3 in perivascular ELTs; ILC3 cells promoted differentiation of B cells into plasma cells | Potential role of ILC3 cells in TLS formation/function |
| Sato, et al, 2023 (71) | MRL-lpr, wild-type and Fli-1+/− | Serum and renal CXCL13, renal infiltrate, TLS, and LN | Reduced renal CXCL13+ immune cells in kidneys in Fli-1+/− MRL/lpr | Fli-1 may regulate TLS formation in LN kidneys via CXCL13 |
| Eriksson and Singh, 2008 (37) | MRL/lpr mice | Staining of skin and lymph node for DC | Skin-resident DCs do not migrate to the draining lymph nodes, accumulate as clusters in skin, and attract other immune cells, which mimics ELT | A possible role of impaired DC migration in TLS |
BR3-Fc, soluble BAFF receptor fused to the Fc portion of mouse IgG1; DC, dendritic cells; ELT, ectopic lymphoid tissue; Fli-1, Friend leukemia virus integration 1; IF, immunofluorescence; IHC, immunohistochemistry; ILC3, group 3 innate lymphoid cells; ko, knockout; LTo, lymphoid tissue organizer cells; MSC, mesenchymal stem-like cells; VALT, vasculature-associated lymphoid tissue.