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  • Review Article
  • Published:

Lymphoid neogenesis in chronic inflammatory diseases

Nature Reviews Immunology volume 6, pages 205–217 (2006)Cite this article

Key Points

  • Lymphoid neogenesis that is induced during highly destructive, chronic inflammatory processes, such as autoimmunity and infection, leads to the formation of ectopic germinal centres (GCs) and T-cell areas. Tertiary lymphoid organs (TLOs) are embedded in the target tissue and lack afferent lymph vessels.

  • The direct access to antigen and the microarchitectural differences between secondary lymphoid organs (SLOs) and TLOs might determine whether the immune responses induced in TLOs are qualitatively different from those that are induced in canonical SLOs.

  • The molecular mechanisms that underlie the formation and maintenance of SLOs and TLOs are remarkably similar. In both processes, lymphotoxin-α1β2 (LTα1β2) and lymphoid chemokines, such as CC-chemokine ligand 19 (CCL19), CCL21, CXC-chemokine ligand 12 (CXCL12) and CXCL13, that regulate lymphocyte homing and compartmentalization have a key role.

  • In addition to the lymphotoxin-driven chemokine loop, antigenic stimulation is required to induce and maintain TLO formation.

  • There are marked differences in the degree of permissiveness of different tissues in supporting TLO formation, indicating that the host tissue actively contributes to this process.

  • In some autoimmune diseases, TLOs fulfil many of the criteria for having a pathological role in the disease process. These include: features of an active GC reaction, presence of plasma cells that produce autoantibodies and correlation with circulating antibody titres.

  • TLOs that form in infected tissues most probably have a protective role and function to contain local infection, but they might enhance the risk of autoimmunity.

  • Several tools are available that inhibit lymphoid tissue formation by interfering with adhesion molecules, LTα1β2 or lymphoid chemokines. Suppression of lymphoid neogenesis could be a useful strategy to block chronic inflammation, particularly in autoimmune diseases.

Abstract

The frequent observation of organized lymphoid structures that resemble secondary lymphoid organs in tissues that are targeted by chronic inflammatory processes, such as autoimmunity and infection, has indicated that lymphoid neogenesis might have a role in maintaining immune responses against persistent antigens. In this Review, we discuss recent progress in several aspects of lymphoid neogenesis, focusing on the similarities with lymphoid tissue development, the mechanisms of induction, functional competence and pathophysiological significance. As more information on these issues becomes available, a better understanding of the role of lymphoid neogenesis in promoting chronic inflammation might eventually lead to new strategies to target immunopathological processes.

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Figure 1: Basic structure of secondary and tertiary lymphoid organs.
Figure 2: Molecular and cellular interactions in lymphoid tissue development and homeostasis.
Figure 3: Schematic model of cellular and cytokine–chemokine networks in the initiation of inflammation and in the development of chronic inflammation and lymphoid neogenesis.

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Acknowledgements

We thank M. P. Armengol for critically reading the manuscript and for useful suggestions. The work in the laboratory of F.A. is supported by the Italian Ministry of Health and Program of Collaboration between Istituto Superiore di Sanità and National Institutes of Health, and Sixth Framework Programme of the European Union (NeuroproMiSe). The work of the laboratory of R.P.-B. is supported by the Spanish Ministry of Health, Instituto de Salud Carlos III, Ministry of Education and Science (Interministerial de Ciencia y Tecnología (CICYT) Plan Nacional), the Department of Universities and Information Society (DURSI) of the Generalitat de Catalunya, Fundació la Marató de TV3 (Barcelona) and Sixth Framework Programme of the European Community (EURO-THYMAIDE).

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Authors and Affiliations

  1. Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Rome, Italy

    Francesca Aloisi

  2. Laboratory of Immunology (LIRAD), Banc de Sang i Teixits,

    Ricardo Pujol-Borrell

  3. Institute for Research in Health Sciences, Germans Trias i Pujol, Badalona, Barcelona, 08916, Spain

    Ricardo Pujol-Borrell

  4. Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, 08193, Spain

    Ricardo Pujol-Borrell

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  1. Francesca Aloisi
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Correspondence to Francesca Aloisi.

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Glossary

Somatic hypermutation

An accumulation of point mutations in the variable-region genes of immunoglobulin heavy and light chains that gives rise to high-affinity antibodies specific for a given antigen in a process known as affinity maturation. B cells that express high-affinity immunoglobulins on their surface are selected by limited amounts of the antigen and competition for survival factors.

Immunoglobulin class switching

DNA rearrangement of the variable, diversity and junction (VDJ) regions from IgM to any of the IgG, IgA and IgE constant genes at the heavy-chain locus. Recombination occurs in repetitive sequences of DNA that are located upstream of each constant gene.

Receptor revision

A molecular process, also known as editing, that involves secondary variable-region gene rearrangements (either in the heavy- or light-chain loci) that generate a new B-cell receptor with altered specificity.

Canalicular system

A network of channels lined by fibroblastic reticular cells in the lymph-node cortex and paracortex. Conduits drain lymph (which consists mainly of water and low-molecular-weight molecules) from the subcapsular sinus to high endothelial venules (HEVs). Corridors are broad spaces around HEVs where emigrating lymphocytes are retained.

Germinal centre

A highly specialized and dynamic microenvironment that gives rise to secondary B-cell follicles during an immune response. It is the principal site of B-cell maturation, which leads to the generation of memory B cells and plasma cells that produce high-affinity antibodies.

High endothelial venule

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

Follicular dendritic cells

(FDCs). Specialized reticular fibroblasts located in the germinal centre that present antigen to B cells through antigen–antibody complexes and promote B-cell survival and proliferation.

Mucosa-associated lymphoid tissue

(MALT). Lymphoid tissue that enables antigen sampling from the mucosal surfaces and stimulation of cognate naive B and T cells. Its function is to ensure a rapid protective response to invading pathogens and the induction of tolerance to innocuous soluble antigens and commensal bacteria.

CD3−CD4+CD45+ haematopoietic inducer cells

A population of haematopoietic precursors that colonize lymphoid tissues early in development and can differentiate into dendritic cells and natural killer cells, but not B or T cells. They are essential components of lymphoid organogenesis, owing to their ability to express LTα1β2, interact with stromal cells and induce expression of adhesion molecules and chemokines that regulate lymphocyte migration and segregation in the lymphoid tissue.

Stromal organizer cells

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

Immune-privileged site

Areas in the body with a decreased immune response to foreign antigens, including tissue grafts. These sites include the brain, eye, testis and uterus.

Meninges

Fibroblastic layers that ensheath the brain and spinal cord and line the subarachnoid space where the cerebrospinal fluid circulates. The meninges contain a resident population of macrophages and dendritic cells and are a less immune-privileged central-nervous-system compartment compared with the neural parenchyma.

Anti-idiotypic network

A peripheral immunoregulatory mechanism by which anti-idiotypic T cells and antibodies recognize idiotypic determinants residing within the variable or hypervariable regions (CDR2 and CDR3) of T-cell receptors or antibodies. Such a regulatory network is thought to have an important role in the regulation of autoimmune responses.

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Aloisi, F., Pujol-Borrell, R. Lymphoid neogenesis in chronic inflammatory diseases. Nat Rev Immunol 6, 205–217 (2006). https://doi.org/10.1038/nri1786

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