Tertiary Lymphoid Tissues: Their Impact on Chronic Diseases

Tertiary lymphoid tissues (TLTs) are structures that develop in response to chronic inflammation and persistent immune activation. Unlike primary and secondary lymphoid organs, these ectopic formations arise in non-lymphoid tissues where prolonged immune responses occur. Their presence has been linked to various chronic diseases, including autoimmune disorders, cancer, and inflammatory conditions.

Understanding TLTs is crucial as they can both contribute to disease progression and support protective immune functions. Researchers are actively investigating their role in pathology and potential therapeutic targeting.

Structural Components

TLTs exhibit a microarchitecture resembling secondary lymphoid organs while maintaining distinct adaptations suited to their ectopic formation. They consist of organized cellular aggregates, including B-cell follicles, T-cell zones, and specialized stromal networks. Unlike lymph nodes, which are encapsulated, TLTs lack a fibrous capsule, integrating directly into surrounding tissue. This absence allows dynamic interactions between immune cells and the local environment, influencing their persistence and function.

The stromal framework plays a foundational role, with fibroblastic reticular cells (FRCs) and lymphoid tissue organizer (LTo) cells providing structural support. These stromal elements produce chemokines such as CXCL13, CCL19, and CCL21, guiding immune cell compartmentalization. High endothelial venules (HEVs) further distinguish TLTs, facilitating lymphocyte recruitment through adhesion molecules like PNAd.

B-cell follicles often contain germinal center-like structures where B cells undergo somatic hypermutation and affinity maturation. Follicular dendritic cells (FDCs) present antigen-antibody complexes, promoting high-affinity B-cell selection. Meanwhile, T-cell zones, enriched with antigen-presenting cells, facilitate T-cell activation and differentiation. Though structurally similar to lymph nodes, TLTs form in response to chronic inflammation rather than embryonic development.

Differences From Secondary Lymphoid Organs

While TLTs and secondary lymphoid organs (SLOs) share structural similarities, their formation, persistence, and function differ. SLOs, including lymph nodes, spleen, and Peyer’s patches, arise during embryogenesis through regulated developmental programs. In contrast, TLTs emerge in response to chronic inflammation, forming in non-lymphoid tissues where prolonged immune activity reshapes the local environment.

A key distinction is structural constraints. SLOs are encapsulated by a fibrous outer layer, maintaining compartmentalization and controlled immune cell trafficking. TLTs lack this rigid boundary, integrating directly into affected tissues. This adaptability allows them to persist in diverse locations, including synovial membranes in rheumatoid arthritis and tumor microenvironments.

Vascular architecture also differs. While both contain HEVs, their development follows different regulatory pathways. In SLOs, HEVs form during organogenesis and remain stable. In TLTs, HEVs arise due to sustained inflammatory signaling and exhibit altered molecular profiles reflecting the local pathological state. Studies show HEVs in TLTs express higher levels of adhesion molecules like VCAM-1 and ICAM-1, facilitating immune cell infiltration in chronic diseases.

Cytokine and chemokine signaling further distinguishes these structures. SLOs rely on lymphoid tissue inducer (LTi) cells and stromal organizers producing lymphotoxin-α and -β, driving early lymphoid organogenesis. TLTs form in response to persistent inflammatory cytokines like IL-17, TNF-α, and IFN-γ, inducing stromal cells to adopt lymphoid-like characteristics. Unlike SLOs, which persist throughout life, TLTs can regress if inflammation resolves, highlighting their transient nature.

Key Cells Involved

TLTs contain a diverse array of immune and stromal cells. B cells play a central role, forming follicular-like aggregates that facilitate local antibody production. These clusters undergo affinity maturation and somatic hypermutation, processes typically restricted to germinal centers in secondary lymphoid organs. FDCs support antigen retention, ensuring high-affinity B-cell populations persist.

T cells are equally integral. CD4+ helper T cells sustain B-cell activity through cytokine signaling, while regulatory T cells (Tregs) modulate immune activation to prevent tissue damage. CD8+ cytotoxic T cells contribute to targeted immune responses, particularly in chronic disease settings requiring persistent immune surveillance.

Stromal cells maintain TLT integrity. FRCs create a supportive scaffold, producing extracellular matrix components and chemokines like CXCL13 and CCL21 to guide immune cell positioning. LTo cells, typically associated with embryonic lymphoid organ development, can be induced in inflamed tissues, promoting immune cell recruitment. HEVs sustain the TLT microenvironment by facilitating continuous lymphocyte influx.

Mechanisms Driving Formation

TLT development results from inflammatory signals, cellular interactions, and tissue remodeling. Chronic inflammation creates a cytokine- and chemokine-rich environment that recruits and retains immune cells. Persistent signaling induces stromal cells to adopt lymphoid-like properties, supporting lymphocyte aggregation. Unlike embryonic lymphoid organogenesis, TLT formation is reactive, shaped by local pathology.

Homeostatic chemokines like CXCL13, CCL19, and CCL21 guide immune cell recruitment. These signals originate from activated stromal and endothelial cells altered by prolonged immune activation. HEVs, typically restricted to secondary lymphoid organs, emerge in inflamed tissues, facilitating continuous lymphocyte influx. This vascular adaptation is reinforced by lymphotoxin-β receptor (LTβR) signaling, stabilizing HEVs and maintaining immune cell niches.

Association With Autoimmune Disorders

TLTs contribute to autoimmune disease pathology, correlating with disease severity and persistence. They frequently arise in affected tissues, such as the synovium in rheumatoid arthritis (RA), salivary glands in Sjögren’s syndrome, and thyroid in Hashimoto’s thyroiditis. These structures amplify local immune responses by fostering antigen presentation, lymphocyte activation, and autoantibody production, perpetuating tissue damage.

In RA, synovial TLTs support ectopic germinal center formation, where autoreactive B cells undergo affinity maturation and produce pathogenic autoantibodies like rheumatoid factor and anti-citrullinated protein antibodies (ACPAs). Similarly, in Sjögren’s syndrome, salivary gland TLTs expand autoreactive B and T cells, leading to glandular destruction and severe dry mouth and eye symptoms. Their persistence correlates with higher disease activity and resistance to conventional immunosuppressive therapies, making TLTs a potential therapeutic target.

Role In Cancer Pathology

TLTs, often called tertiary lymphoid structures (TLSs) in oncology, can either support antitumor immunity or contribute to tumor progression. Their presence in tumors has been associated with improved prognosis in cancers like melanoma, lung cancer, and colorectal cancer. TLSs enhance immune responses by fostering tumor-infiltrating lymphocyte activation, antigen presentation, and local antibody production. Well-developed TLSs correlate with better survival rates and increased responsiveness to immunotherapy.

However, in some malignancies, TLSs create an immunosuppressive niche that shields cancer cells. This occurs in certain breast and pancreatic cancers, where TLS-associated regulatory T cells and myeloid-derived suppressor cells dampen antitumor immunity. In lymphomas, B-cell-driven TLSs can support malignant B-cell expansion. Understanding TLS function is a growing research area, with efforts focused on enhancing their antitumor effects while mitigating tumor-supportive roles.

Relevance In Chronic Inflammatory Conditions

Beyond autoimmune diseases and cancer, TLTs play a role in chronic inflammatory disorders where persistent immune activation leads to tissue remodeling. In conditions like chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), TLTs emerge within affected lung tissues, sustaining local inflammation and immune cell recruitment. Their presence in chronic viral infections, such as hepatitis C and HIV, has also been documented, where they serve as reservoirs for immune activation and viral persistence.

In COPD, bronchial-associated TLTs correlate with disease severity, with studies linking their density to airflow obstruction and progressive lung damage. These structures recruit immune cells, including B and T lymphocytes, contributing to chronic inflammation. Similarly, in IPF, TLTs form in fibrotic lung regions, exacerbating tissue scarring by perpetuating immune-mediated fibroblast activation. Their persistence in chronic inflammatory conditions underscores their role in prolonged immune dysregulation, making them potential therapeutic targets.

Diagnostic Indicators

Identifying TLTs in clinical settings relies on histological, molecular, and imaging techniques. Immunohistochemistry (IHC) visualizes TLT organization, with markers like CD20 for B cells, CD3 for T cells, and PNAd for HEVs providing structural insights. Germinal center-like features can be confirmed by staining for BCL6 and CD21, marking follicular dendritic cells and germinal center B cells.

Molecular profiling has identified TLT-associated gene signatures as potential biomarkers for disease prognosis and treatment response. Transcriptomic studies link elevated CXCL13, CCL19, and lymphotoxin-related gene expression to TLT formation in autoimmune diseases and cancer. Non-invasive imaging techniques, including positron emission tomography (PET) and high-resolution ultrasound, are being explored for detecting TLT-related inflammation in organs like the lungs and salivary glands, aiding disease monitoring and targeted therapy development.