Elsevier

Autoimmunity Reviews

Volume 7, Issue 3, January 2008, Pages 204-208
Autoimmunity Reviews

Toll-like receptors and autoimmunity

https://doi.org/10.1016/j.autrev.2007.11.006Get rights and content

Abstract

The understanding of autoimmune diseases experienced an impressive boost since the Toll-like receptors (TLRs) have been identified as possible key players in autoimmune pathophysiology. Although these receptors recognize a variety of structures derived from viruses, bacteria and fungi leading to subsequent initiation of the relevant immune responses recent data support the idea that TLRs are crucial in the induction and perpetuation of certain autoimmune diseases, especially the systemic lupus erythematosus (SLE). In this review we will summarize recent data on involvement of TLRs in the development of autoimmune diseases. This review will focus on TLRs 7, 8 and 9 which were originally identified as receptors specific for bacterial and viral RNA/DNA, but more recent in vitro and in vivo studies have linked these receptors to the detection of host RNA, DNA, and RNA- or DNA-associated proteins in the context of autoimmunity.

Introduction

Toll-like receptors are one of the most studied pattern recognition receptors and key components of the innate immune defense. As a response of the innate immune system TLRs play a key role in the innate immunity against various infectious agents. To date, at least 11 TLRs in humans and 13 in mice have been identified which are fundamental in recognition of pathogen associated molecular patterns (PAMPs).

Toll-like receptors are type I transmembrane proteins that are expressed in various immune cells such as B cells, DCs, macrophages and specific types of T-cells and are evolutionary conserved between insects and vertebrates [1]. Toll was first described in Drosophila as a transmembrane receptor for dorsal ventral patterning of the embryo [2]. After the identification of Toll in Drosophila, several homologous TLRs have been identified in mammals. The family of TLRs have the ability to recognize various PAMPs from different pathogenic origins such as bacteria, viruses, fungi or protozoan parasites. The TLR subfamily members including TLR 3, 7, 8 and 9, show intracellular localization in the endoplasmatic reticulum, (and) endosomes or lysosomes where these receptors recognize nucleic acid components that are normally found in bacteria or viruses [3].

Upon activation by pathogens, the TLR signalling pathway via interactions with 5 different adaptor proteins including MyD88 and Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) triggers a signalling cascade which results in the production several proinflammatory cytokines and immunomodulatory factors subsequently inducing an adaptive immune response [4].

Although the described TLR mediated activation can initiate rapid and effective control of infection it may also be involved in the induction of chronic inflammation and autoimmune reactions.

Section snippets

TLR 7, TLR 8, and TLR9

Endogenous ligands such as RNA and DNA can activate TLRs under certain conditions and induce a typical autoimmune reaction such as systemic lupus erythematosus (SLE) [5]. Nucleic acid components of certain pathogens have the ability not only to induce a powerful innate immune reaction but also an inflammatory response that is directed to “self” structures.

The TLR9 subfamily including TLR7, TLR8 and TLR9 participates in the discrimination of nuclein acid-like structures in microorganisms and is

TLR gene expression

Studies of human genome polymorphisms emphasize the idea that aberrant gene expression due to duplications and deletions may increase or decrease the amount of protein normally maintained at optimal levels in a healthy individual. In the field of autoimmunity, Fcγ RIII gene dosage is associated to the predisposition of immune complexes, leading to glomerulonephritis. Recently, a link between TLR gene dosage and autoimmunity has been found in the Y chromosome autoimmune accelerator (Yaa) mouse

Role of dendritic cells in TLR mediated autoimmunity

In vivo activation followed by cell migration into peripheral lymphoid tissues and sites of inflammation causes the 50–100-fold decrease in the number of pDCs circulation in the blood of patients with SLE [23]. It is known that plasmacytoid DCs produce large amounts of IFNα in response to viral infection. The stimulation through TLR7 and TLR9, which are expressed by human pDCs leads to a high level of IFNα with a important relevance to SLE. Sera from patients with SLE can induce pDCs to produce

Interaction of BCR and TLR

For the formation of immune complexes nuclear self-autoantigens and autoantibodies against DNA, histones, RNA or RNA-binding proteins are required. The autoantibodies recognizing nucleic acid and associated proteins, which are usually in patients with SLE, are produced from self-reactive B cells [25]. In this system, the B-cell receptor (BCR) first binds to the Fc-region of the autoantibody containing the IC and triggers the BCR-mediated endocytosis of the ICs into an internal compartment where

Conclusion

The role of TLRs in systemic autoimmunity becomes more important for the understanding and treatment of autoimmune diseases.

Most probably they are key molecules in the development and in the propagation of autoimmune reactions.

Concluding the herein presented observations, an important result is that the amount of functional Toll-like receptor caused by elevated gene dosage seems to have remarkable influence on the induction and maintenance of an autoimmune response (e.g. Yaa modifier). The

Take-home messages

  • Toll-like receptors have been identified as possible key players in autoimmune pathophysiology.

  • Endogenous ligands such as RNA and DNA can activate TLRs under certain conditions and induce autoimmune reactions.

  • Activation of autoreactive B-cells needs the dual engagement of TLR and BCR.

  • The amount of functional TLR seems to have remarkable influence on the induction and maintenance of an autoimmune response.

  • The resulting cytokine production after TLR activation could trigger and continue the

References (40)

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    Citation Excerpt :

    Moreover the DNA and RNA of the host have specific characteristics in order to prevent autoimmunity (rev. in [17]). More in detail, although also in vertebrates DNA is characterized by the methylation of CpG nucleotides, it shows a reduced frequency; furthermore there are specific sequences, identified also in the telomere [2], able to inhibit the signaling through TLR9 [2,58]. RNA of vertebrates differs from bacterial RNA for the presence of many modified nucleotides with a reduced ability to activate DCs in respect to the RNA of bacteria [59].

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