Tertiary Lymphoid Structures: Autoimmunity Goes Local

Abstract

Tertiary lymphoid structures (TLS) are frequently observed in target organs of autoimmune diseases. TLS present features of secondary lymphoid organs such as segregated T and B cell zones, presence of follicular dendritic cell networks, high endothelial venules and specialized lymphoid fibroblasts and display the mechanisms to support local adaptive immune responses toward locally displayed antigens. TLS detection in the tissue is often associated with poor prognosis of disease, auto-antibody production and malignancy development. This review focuses on the contribution of TLS toward the persistence of the inflammatory drive, the survival of autoreactive lymphocyte clones and post-translational modifications, responsible for the pathogenicity of locally formed autoantibodies, during autoimmune disease development.

Keywords: B-cells; autoantibodies; germinal center response; glycosylation; tertiary lymphoid structures (TLS).

Figure 1

(A) In TLS, naïve B cells (NB), enter the follicle to initiate a classical germinal center reaction. In the dark zone, centroblasts (CB) proliferate and acquire somatic hypermutations in their variable region. In the light zone, centrocytes (CC) are selected after their interaction with specific antigen found on the surface of follicular dendritic cells (FDCs). Lectin-BCR signaling can potentially result in enhanced selection of B cells. Failure to receive survival signals from either TF_H (T follicular helper cells) or FDCs leads to B cell apoptosis. Successful affinity maturation results in either mature B cell (MB) of plasma cells generation. GC microenvironment can control the outcome of the immune response by regulating the glycosylation profile of the antibodies. (B) TLS display a less organized anatomical structure and a predominant infiltration of MB and marginal zone B cells (MB). Aberrant production of survival and chemoattractant signals is observed at these sites.