The roles of tertiary lymphoid structures in chronic diseases

Abstract

Tertiary lymphoid structures (TLSs) are ectopic lymphoid tissues that drive antigen-specific immune responses at sites of chronic inflammation. Unlike secondary lymphoid organs such as lymph nodes, TLSs lack capsules and have their own unique characteristics and functions. The presumed influence of TLSs on the disease course has led to widespread interest in obtaining a better understanding of their biology and function. Studies using single-cell analyses have suggested heterogeneity in TLS composition and phenotype, and consequently, functional correlates with disease progression are sometimes conflicting. The presence of TLSs correlates with a favourable disease course in cancer and infection. Conversely, in autoimmune diseases and chronic age-related inflammatory diseases including chronic kidney disease, the presence of TLSs is associated with a more severe disease course. However, the detailed mechanisms that underlie these clinical associations are not fully understood. To what extent the mechanisms of TLS development and maturation are shared across organs and diseases is also still obscure. Improved understanding of TLS development and function at the cellular and molecular levels may enable the exploitation of these structures to improve therapies for chronic diseases, including chronic kidney disease.• In autoimmunity, chronic inflammation and ageing, the presence of TLSs correlates with pathological conditions and a more severe disease course.• Functional characterization of TLSs in human diseases and the development of interventions to induce or reduce TLSs could lead to promising therapeutic avenues.Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author selfarchiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Stem-like CD4 + T cells in perivascular tertiary lymphoid structures sustain autoimmune vasculitis

“…All cases of GCA aortitis analyzed had adventitial TLSs, supporting the local renewal of disease stem cells, implicating TLS and local production of stem- like T cells in disease chronicity. These data have implications for the diagnosis and management of autoimmune vasculitis, but the principle of local distribution centers for disease-relevant effector cells may be equally important in other autoimmune conditions associated with TLS formation (14). As a minimum, our data suggest that therapies directed only at effector T cells are insufficient to arrest the in situ autoimmune responses and offer strategies for the elimination of disease stem cells.…”

“…Structurally, aortic wall TLSs are heterogeneous, with only some containing germinal center reactions, whereas 25% were occupied by mostly CD4 + T cells, challenging the concept that TLSs are B cell-oriented structures dedicated to autoantibody production (14,15). GCA patients typically lack autoantibodies; rather, macrophages and T cells are the dominant tissue-destructive cell populations (1,2).…”

“…1C) and Ki67 + proliferating cells (fig. S1B), indicating that the highly organized lymphoid architectures in the adventitia functioned as TLSs, inducible ectopic lymphoid tissues under chronic inflammatory conditions (14,15). Aortic TLSs were composed of three distinct zones: T cell zones, B cell zones, and T/B mixed zones.…”

The Evolving Landscape of Bladder Tertiary Lymphoid Structures

“…An increased immune activation in women with autoimmune conditions, such as thyroid disease and diabetes, could therefore be speculated as one of the predisposing factors leading to formation of CC lesions following a UTI. 1 The paradoxical association between TLSs and rUTI in this study is indicative of the exhausted nature of the immune cells, which is a potential factor underlying lack of resolution of CC lesions in women who were treated with vaginal estrogen. Since newer promising prophylactic oral vaccines, such as the polyvalent Uromune vaccine, are explored in women experiencing rUTI in some countries, 5 future studies should investigate whether the use of this vaccine augments resolution of CC or any prior CC lesions leads to lack of benefit due to a chronic state of immune exhaustion.…”

“…Mucosal immune responses to local, chronic antigenic stimuli of infectious or noninfectious nature are generally exhibited by formation of immune cell aggregates called “tertiary lymphoid structures” (TLSs) at the site of inflammation. 1 While research on TLSs is still in its infancy in the urogenital tract, the role of such unique mucosa-associated lymphoid tissue at anatomically distinct sites, including the respiratory and gastric mucosae, has been long known in chronic infectious diseases such as tuberculosis or following mucosal vaccinations. 2 From the evolutionary perspective, TLSs occupy the oldest known receptor-based immune responses given their resemblance to aggregates found in jawless and cartilaginous fish.…”