Tertiary lymphoid structures as local perpetuators of organ-specific immune injury: implication for lupus nephritis

Abstract

In response to inflammatory stimuli in conditions such as autoimmune disorders, infections and cancers, immune cells organize in nonlymphoid tissues, which resemble secondary lymphoid organs. Such immune cell clusters are called tertiary lymphoid structures (TLS). Here, we describe the potential role of TLS in the pathogenesis of autoimmune disease, focusing on lupus nephritis, a condition that incurs major morbidity and mortality. In the kidneys of patients and animals with lupus nephritis, the presence of immune cell aggregates with similar cell composition, structure, and gene signature as lymph nodes and of lymphoid tissue-inducer and -organizer cells, along with evidence of communication between stromal and immune cells are indicative of the formation of TLS. TLS formation in kidneys affected by lupus may be instigated by local increases in lymphorganogenic chemokines such as CXCL13, and in molecules associated with leukocyte migration and vascularization. Importantly, the presence of TLS in kidneys is associated with severe tubulointerstitial inflammation, higher disease activity and chronicity indices, and poor response to treatment in patients with lupus nephritis. TLS may contribute to the pathogenesis of lupus nephritis by increasing local IFN-I production, facilitating the recruitment and supporting survival of autoreactive B cells, maintaining local production of systemic autoantibodies such as anti-dsDNA and anti-Sm/RNP autoantibodies, and initiating epitope spreading to local autoantigens. Resolution of TLS, along with improvement in lupus, by treating animals with soluble BAFF receptor, docosahexaenoic acid, complement inhibitor C4BP(β-), S1P1 receptor modulator Cenerimod, dexamethasone, and anti-CXCL13 further emphasizes a role of TLS in the pathogenesis of lupus. However, the mechanisms underlying TLS formation and their roles in the pathogenesis of lupus nephritis are not fully comprehended. Furthermore, the lack of non-invasive methods to visualize/quantify TLS in kidneys is also a major hurdle; however, recent success in visualizing TLS in lupus-prone mice by photon emission computed tomography provides hope for early detection and manipulation of TLS.

Keywords: autoimmune disease; ectopic lymphoid tissue; lupus nephritis; systemic lupus erythematosus; tertiary lymphoid structure.

Figure 1

The initiation, formation and function of TLS. Activated immune cells produce CXCL13 and IL-7, recruit LTi cells to the site of inflammation. LTi cells secrete lymphotoxin (LT) αβ, which binds to lymphotoxin β receptor (LTβR) expressed on local stromal cells, inducing the production of chemokines such as CXCL13, CXCL12, CCL21, and CCL19. These chemokines then trigger the recruitment of lymphocytes, which initiate the development of TLS. The interaction of LTβ and LTβR also leads to the secretion of VEGF, FGF and hepatocyte growth factor (HGF) by stromal cells, as well as the secretion of vascular cell adhesion molecule 1 (VCAM1) and ICAM1. VEGF, FGF, and HGF play a crucial role in promoting the development of high endothelial venules (HEVs), while ICAM and VCAM expressed on local stromal cells facilitate the recruitment of T and B cells from nearby HEVs and promote their eventual organization into TLS. Some local stromal cells differentiate into FDCs upon stimulation with LTα, and FDCs aid in the development and sustenance of TLS by producing chemokines and providing a cellular network that facilitates B cell migration. A subset of CD4+ T cells polarizes into T follicular helper (Tfh, CXCR5^hiPD-1^hiICOS^hi) cells that promote B cell activation and antibody production. TLS facilitate the process of affinity maturation and differentiation of naïve B cells into germinal center B cells and plasma cells that produce antibodies.