Elsevier

Seminars in Immunology

Volume 20, Issue 1, February 2008, Pages 26-42
Seminars in Immunology

Review
Ectopic lymphoid tissues and local immunity

https://doi.org/10.1016/j.smim.2007.12.004Get rights and content

Abstract

Ectopic or tertiary lymphoid tissues develop at sites of inflammation or infection in peripheral, non-lymphoid organs. These tissues are architecturally similar to conventional secondary lymphoid organs, with separated B and T cell areas, specialized populations of dendritic cells, well-differentiated stromal cells and high endothelial venules. Ectopic lymphoid tissues are often associated with the local pathology that results from chronic infection or chronic inflammation. However, there are also examples in which ectopic lymphoid tissues appear to contribute to local protective immune responses. Here we review how ectopic lymphoid structures develop and function in the context of local immunity and pathology.

Introduction

Secondary lymphoid organs are an integral part of the immune system and are important sites of immune activation. Encapsulated lymph nodes (LNs) are found along lymphatic vessels that drain regional tissues, while mucosal lymphoid organs, including Peyer's patches and Nasal Associated Lymphoid Tissue (NALT) are not encapsulated and are found directly beneath the mucosal epithelium. Despite their structural differences, lymphoid organs are organized in a similar fashion, with B cell follicles, separated T cell areas, multiple populations of dendritic cells and specialized stromal cells. Each secondary lymphoid organ has the ability to recruit naïve lymphocytes from the blood as well as activated antigen-presenting cells from the surrounding tissues or mucosal surfaces. Moreover, the specific architecture of each secondary lymphoid organ has evolved to maximize encounters between antigen, antigen-presenting cells and lymphocytes in order to efficiently generate rapid and robust adaptive immune responses (reviewed in [1], [2], [3], [4], [5]).

The development of LNs as well as many of the mucosal lymphoid organs is pre-programmed and does not require pathogen-induced inflammation or any type of adaptive immune response (reviewed in [6], [7]). In contrast, tertiary lymphoid tissues, also known as ectopic lymphoid tissues, develop in adults in response to chronic inflammation, chronic infection or autoimmunity (previously reviewed in [8]). These tissues can develop in nearly every organ in the body and do not appear in predictable sites. Moreover, these tissues are not encapsulated like LNs, nor are they typically sub-mucosal tissues like Peyer's patches or NALT. Instead they are often embedded in non-lymphoid organs at sites of inflammation or infection.

Many of the cellular and molecular signals that control the development of secondary lymphoid organs have been identified, and not surprisingly, many of these signals are also involved in the development of ectopic lymphoid tissues (reviewed in [6], [8]). However, the development of ectopic follicles is not identical that of secondary lymphoid organs and it is not well understood what triggers their formation. Here we propose that secondary and tertiary lymphoid tissues are part of a spectrum of lymphoid tissues that ranges from highly organized encapsulated tissues, which develop at specific sites according to pre-programmed developmental pathways, to granulomas and ectopic follicles, which develop only after local inflammation or infection at a variety of sites in multiple tissues. All of these lymphoid tissues participate in immune responses to some degree and while ectopic follicles have been primarily associated with pathology and detrimental autoimmune responses, they are also likely to participate in protective immune responses to local infections.

Section snippets

Current model of secondary lymphoid organ development

The development of lymphoid organs has received considerable attention since the discovery that mice lacking molecules in the lymphotoxin (LT) signaling pathway do not develop LNs and Peyer's patches [9], [10], [11], [12], [13]. It is now generally accepted that lymphoid tissue inducer (LTi) cells are instrumental for the initiation of lymphoid organ development [14], [15]. LTi cells are derived from common lymphoid progenitors in fetal liver [16] and can be distinguished from other lymphocytes

Transgenic models of tertiary lymphoid organogenesis

Much of what we know about the formation of tertiary lymphoid tissues comes from transgenic mice in which various chemokines and cytokines are expressed at ectopic sites. For example, LTα expressed in the pancreas under the control of the rat insulin promoter leads to inflammatory lesions in the kidney and pancreas [40]. These areas are organized like secondary lymphoid tissues with separated T and B cell zones, specialized stromal cells and HEVs. These ectopic tissues also appear to be

The role of LTi cells in the formation of ectopic lymphoid tissues

Although the organogenesis of LNs and Peyer's patches clearly requires LTi cells [54], [55], [56], [57], it is less clear whether LTi cells are required for the formation of ectopic follicles. In transgenic mice that express CXCL13 in the pancreas, CD4+CD3− cells are the first hematopoietic cell types recruited to the islets very early after birth [46], suggesting that LTi cells may be involved in the development of the tertiary lymphoid tissues that will eventually develop in this location.

The role of local stromal cells in the formation of ectopic follicles

The counterparts to LTi cells in the development of secondary lymphoid organs are lymph node organizer cells. These cells are mesenchymal in origin and form the stromal cell matrix of the developing lymphoid organ [19], [22], [23], [75]. Just as there are multiple populations of LTi cells, there are also multiple types of LN organizer cells, with different expression patterns of adhesion molecules, cytokines and receptors [76]. In fact, different lymphoid tissue organizer cells are found at

Autoimmunity and the development of lymphoid follicles

Tertiary lymphoid organs often develop in autoimmune diseases and tend to appear in the organs that are under autoimmune attack, such the joints and lungs of rheumatoid arthritis patients [38], [81], [82], [83], [84], the salivary glands in Sjogren's syndrome [85], [86], [87], the thyroid in Hashimoto's thyroiditis or Grave's disease [51], [88], [89], the pancreas in diabetes [90], [91] and the central nervous system in multiple sclerosis [92], [93], [94], [95] (Table 1). In many cases, the

Infection often elicits the formation of ectopic lymphoid follicles

The development of ectopic lymphoid tissues probably evolved as a response to local infections, as numerous infectious agents trigger the development of tertiary lymphoid tissues in a variety of non-lymphoid organs (Table 2). For example, infection of the liver triggers the formation of ectopic lymphoid tissue in the portal area known as portal tract-associated lymphoid tissue or PALT [110], [111], [112]. Liver biopsies from patients with chronic hepatitis C infection exhibit PALT, with B cell

Some mucosal lymphoid tissues have properties of both conventional secondary lymphoid organs and tertiary lymphoid tissues

The studies cited above demonstrate that tertiary lymphoid tissues can form in numerous sites in a wide variety of non-lymphoid organs given the appropriate stimulation by pathogens or autoantigens. In contrast, LNs and Peyer's patches form at predetermined sites in the absence of stimulation via pathogens or antigens. However, there are other types of lymphoid tissues that are formed at predetermined locations, but require some level of microbial stimulation for their development. For example,

Relationship between the formation of tertiary lymphoid tissues and tumor progression and regression

Given the apparent immune function of ectopic lymphoid tissues in response to infectious disease, it seems that the development of functional tertiary lymphoid tissues surrounding tumors could be beneficial for tumor antigen recognition and tumor regression. In fact, tumor cell lines that are transfected with LTα promote the formation of tertiary lymphoid tissues, with B cell follicles, dendritic cells, HEVs and FDCs surrounding the tumors [154]. Interestingly, these LTα-expressing tumor lines

The role of Tregs in the formation of ectopic lymphoid follicles

Given that T regulatory cells (Tregs) are reduced in numbers or functionally impaired in many autoimmune diseases [171], [172], [173], [174], [175], it is not surprising that they might play a role in either the formation or maintenance of ectopic lymphoid tissues. However, it is difficult to distinguish the role of Tregs in the prevention of autoimmunity from their role in tertiary lymphoid organ development. For example, the impaired homing of Tregs to LNs is at least partly responsible for

Lymphocyte recirculation and the acquisition of antigen in ectopic follicles

CCR7 also plays a critical role in lymphocyte recirculation through secondary lymphoid organs [184] as well as tertiary lymphoid tissues. For example, PNAd-expressing HEVs that coexpress CCL21 are often observed in tertiary lymphoid tissues [49], [77], suggesting that CCR7 and L-selectin may be the primary means that lymphocytes use to gain entry to these tissues from the blood. In fact, CCL21 is shown to trigger integrin-dependent adhesion of T cells to venules and to promote extravasation in

Concluding remarks

The development of ectopic or tertiary lymphoid tissues at sites of inflammation or infection is an important part of local immune responses. Depending on the type of immune responses, the development of these tissues can lead to detrimental or pathological immune responses (autoimmunity) or may help resolve local infection. In this respect, one might view ectopic lymphoid tissues much like other local lymphoid tissues that serve to initiate and amplify immune responses. However, there are

Acknowledgements

This work was supported by the Trudeau Institute, NIH grants HL69409 and AI072689 and by the Sandler Program for Asthma Research.

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