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  • Review Article
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Ectopic lymphoid-like structures in infection, cancer and autoimmunity

Subjects

Key Points

  • Ectopic lymphoid-like structure neogenesis is a common clinical occurrence and contributes to the pathology that is associated with cancer, autoimmunity, infection and tissue rejection. In this Review, we discuss the mechanisms that drive the neogenesis of ectopic lymphoid-like structures and their involvement in disease processes.

  • By drawing information from animal studies and clinical observations, we consider why certain patients develop ectopic lymphoid-like structures in inflamed tissues, whereas others do not.

  • The current status of therapies that target ectopic lymphoid-like structures is discussed.

  • We consider clinical approaches that may help to support the diagnosis, treatment and clinical management of patients who have ectopic lymphoid-like structures as part of their disease.

Abstract

Ectopic lymphoid-like structures often develop at sites of inflammation where they influence the course of infection, autoimmune disease, cancer and transplant rejection. These lymphoid aggregates range from tight clusters of B cells and T cells to highly organized structures that comprise functional germinal centres. Although the mechanisms governing ectopic lymphoid neogenesis in human pathology remain poorly defined, the presence of ectopic lymphoid-like structures within inflamed tissues has been linked to both protective and deleterious outcomes in patients. In this Review, we discuss investigations in both experimental model systems and patient cohorts to provide a perspective on the formation and functions of ectopic lymphoid-like structures in human pathology, with particular reference to the clinical implications and the potential for therapeutic targeting.

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Figure 1: Mechanisms that control the induction and maintenance of ectopic lymphoneogenesis.
Figure 2: Cytokines and chemokine regulate ELS formation and function.

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Acknowledgements

G.W.J. is funded by Arthritis Research UK as a non-clinical Career Development Fellow.

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Glossary

Secondary lymphoid organs

(SLOs). In contrast to primary (central) lymphoid organs, where lymphocytes are generated from immature progenitor cells, SLOs — that is, the spleen, Peyer's patches and lymph nodes — maintain mature naive lymphocytes and are sites of lymphocyte activation by antigen.

Lymphoid neogenesis

The de novo development and cellular organization of lymphoid tissue into distinct anatomical and functional compartments.

Ectopic lymphoid-like structures

(ELSs). Highly organized lymphoid aggregates that form in tissue sites that are not typically associated with lymphoid neogenesis.

Encapsulated SLOs

Organized secondary lymphoid organs (SLOs) that are encased in a connective tissue capsule that contains blood vessels.

Lymphoid tissue inducer cells

(LTi cells). These cells are present in developing lymph nodes, Peyer's patches and nasopharynx-associated lymphoid tissue (NALT) and they are required for the development of these lymphoid organs. The inductive capacity of LTi cells for the generation of Peyer's patches and NALT has been shown by adoptive transfer and it is generally assumed that they have a similar function in the formation of lymph nodes.

T follicular helper cells

(TFH cells). Antigen-experienced CD4+ T cells that are present in B cell-rich regions of structurally organized lymphoid aggregates or organs.

Lymphoid tissue organizer cells

These cells are of mesenchymal origin that are activated by lymphoid cells through lymphotoxin-β receptor signalling to express adhesion molecules and chemokines that regulate lymphoid tissue development.

High endothelial venules

(HEVs). These are specialized venules that occur in secondary lymphoid organs, except the spleen. HEVs allow the continuous transmigration of lymphocytes as a consequence of the constitutive expression of adhesion molecules and chemokines at their luminal surface.

Innate lymphoid cell

(ILC). A type of innate immune cell that is lymphoid in morphology and developmental origin but that lacks properties of adaptive B cells and T cells, such as recombined antigen-specific receptors. These cells regulate immunity, tissue homeostasis and inflammation in response to cytokine stimulation.

Germinal centre

Located in peripheral lymphoid tissues (for example, the spleen or lymph nodes), these are sites in which B cells proliferate and clones that produce antigen-specific antibodies of higher affinity are selected.

Angiogenesis

The development of new blood vessels from existing blood vessels. It is frequently associated with tumour development and inflammation.

Activation-induced cytidine deaminase

(AID). An enzyme that is required for two crucial events in the germinal centre — somatic hypermutation and class-switch recombination.

Granuloma

A chronic inflammatory tissue response that occurs at the site of implantation of certain foreign bodies and, in particular, at sites of long-term microbial persistence. Granulomas are typically well-organized structures that are composed of T cells and macrophages, some of which fuse to form giant cells.

Severe combined immunodeficiency mice

(SCID mice). A strain of mice that possesses a genetic defect in DNA recombination that leads to severe immunodeficiency. SCID mice lack B cells and T cells, and they are incompetent at rejecting tissue grafts from allogeneic and xenogeneic sources.

Cryoglobulinaemia

An autoimmune, extra-hepatic manifestation that is associated with certain viral infections and chronic inflammatory conditions, whereby antigen–antibody complexes are deposited in capillaries and arterioles (and occasionally small arteries) causing vasculitis, renal disease, arthralgias or arthritis.

Non-obese diabetic mice

(NOD mice). These mice spontaneously develop diabetes as a result of autoreactive T cell-mediated destruction of pancreatic β-islet cells.

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Pitzalis, C., Jones, G., Bombardieri, M. et al. Ectopic lymphoid-like structures in infection, cancer and autoimmunity. Nat Rev Immunol 14, 447–462 (2014). https://doi.org/10.1038/nri3700

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