Clinical bottom line
Tertiary lymphoid structures (TLS) are ectopic lymphoid aggregates that form in chronically inflamed tissues and contribute to local immune responses in various autoimmune diseases. Emerging therapies targeting TLS formation, maintenance, or function represent a novel approach to modulate pathogenic autoimmunity by disrupting local antigen presentation and lymphocyte activation. Current evidence is largely preclinical and early-phase, suggesting potential efficacy in reducing tissue-specific inflammation and autoantibody production, but safety and long-term outcomes remain uncertain. Clinicians should view TLS-targeted therapies as promising but experimental, warranting further validation before routine clinical adoption.
What the evidence shows
TLS are increasingly recognized as key contributors to autoimmune pathogenesis by sustaining local immune activation and autoantibody generation within affected tissues (Dong et al., 2024). Their presence correlates with disease severity in conditions such as rheumatoid arthritis, Sjögren’s syndrome, and systemic lupus erythematosus (Wang et al., 2026). TLS comprise organized aggregates of B cells, T cells, dendritic cells, and stromal cells that resemble secondary lymphoid organs, facilitating local germinal center reactions.
Therapeutic strategies under investigation aim to disrupt TLS by targeting molecular pathways involved in their formation and maintenance, including lymphotoxin-β receptor signaling, chemokines such as CXCL13, and cytokines like IL-17 and IL-21 (Chatenoud et al., 2020). Preclinical models demonstrate that blockade of these pathways can reduce TLS development and ameliorate autoimmune tissue damage. For example, lymphotoxin-β receptor antagonists have shown efficacy in animal models of autoimmune arthritis by preventing TLS neogenesis and reducing joint inflammation (Dong et al., 2024).
Early-phase clinical trials are underway evaluating biologics and small molecules that interfere with TLS-associated pathways, although published human data remain limited (Wang et al., 2026). Mechanistic pharmacokinetic/pharmacodynamic modeling supports the rationale for targeting TLS components such as CD19+ B cells within TLS to modulate local autoimmunity (Chandra et al., 2026). These approaches may complement systemic immunosuppression by focusing on pathogenic immune niches.
Caveats and uncertainty
The clinical evidence for TLS-targeted therapies is preliminary, with most data derived from animal models or in vitro studies. Translating these findings to human autoimmune diseases is challenging due to heterogeneity in TLS composition, dynamics, and tissue localization (Dong et al., 2024). The precise role of TLS in disease progression versus protective immunity remains incompletely understood, raising concerns about potential adverse effects of disrupting TLS, such as impaired local immune surveillance.
Safety profiles of TLS-targeted agents are not yet established, and long-term immunologic consequences are unknown. Because TLS share features with secondary lymphoid organs, off-target effects on systemic immunity are possible. Additionally, biomarkers to identify patients who would benefit most from TLS-directed therapies are lacking, complicating patient selection and monitoring (Wang et al., 2026).
Current clinical trials are small and lack robust efficacy endpoints, limiting conclusions about therapeutic benefit. The heterogeneity of autoimmune diseases and TLS presence across patient populations further complicates interpretation. More comprehensive clinical studies with standardized TLS assessment and validated outcome measures are needed.
How this may change practice
If ongoing and future studies confirm safety and efficacy, TLS-targeted therapies could represent a paradigm shift by enabling localized immunomodulation within affected tissues, potentially reducing systemic immunosuppression and associated risks. This approach may be particularly valuable for patients with refractory disease characterized by prominent TLS formation.
Clinicians should remain informed about emerging TLS biomarkers and imaging techniques that may facilitate identification of TLS-positive patients. Integration of TLS assessment into clinical decision-making could personalize therapy selection. However, TLS-targeted treatments should currently be considered investigational and used within clinical trials or specialized centers.
Ultimately, TLS modulation may complement existing biologics and small molecules, expanding the therapeutic arsenal for autoimmune diseases. Multidisciplinary collaboration and longitudinal studies will be essential to define optimal use and long-term outcomes.