Elsevier

Clinical Immunology

Volume 147, Issue 3, June 2013, Pages 216-222
Clinical Immunology

Review
Innate immune processes in lupus erythematosus

https://doi.org/10.1016/j.clim.2012.11.012Get rights and content

Abstract

The innate immune system is involved in the pathogenesis of systemic autoimmune diseases such as systemic lupus erythematosus (SLE) or dermatomyositis. The important role of complement factors of the classical pathway and of Toll like receptors (TLRs) is well established, based on genetic and clinical evidence. Immune complexes activate tumor necrosis factor (TNF) in myeloid cells and interferon-α (IFNα) in plasmacytoid dendritic cells. The latter initiates a positive feedback loop that drives autoimmunity. More recently, mutations in genes encoding intracellular enzymes involved in RNA and DNA handling, which likewise lead to increased IFNα, have been found to cause familial chilblain lupus and to be associated with SLE. Within the immunological disease continuum, these disorders can be placed between autoinflammation and autoimmunity, and we would propose the term autoadjuvant for this group, since the activation of the innate immune system in these diseases appears to lower the threshold for (auto)immune reactions.

Highlights

► Mechanisms of innate immunity are intimately involved in SLE pathophysiology. ► Classical pathway complement component deficiences are highly associated with SLE. ► Toll like receptors 7 and 9, blocked by antimalarials, lead to IFNα, TNF production. ► Genes necessary for RNA/DNA handling are found mutated in lupus patients. ► IFNα, which appears to function as an adjuvant, probably links these findings.

Introduction

A focus on the role of the innate immune system in systemic autoimmunity may sound surprising at first sight. However, there is indeed increasing evidence that innate immune mechanisms, which mediate processes that have primed our view of autoinflammation, are also involved in pathogenic pathways underlying systemic autoimmune disease. This is particularly evident for SLE, a prototypical autoimmune disease characterized by the formation of a wide variety of auto-antibodies, some of which are clearly pathogenic. Moreover, recent clinical data suggest that targeting either IFNα or T or B cells may be of therapeutic benefit in patients with SLE [1], [2], [3], [4].

Although patients with periodic fever syndromes presenting with symptoms such as serositis, fever, joint symptoms and skin involvement [5], [6] may occasionally pose questions in the clinical setting as they appear to fulfill some American College of Rheumatology (ACR) criteria for SLE [7], the overall clinical picture and the pathomechanisms underlying periodic fever syndromes appear quite distinct from SLE [8], [9]. In particular, there are absolutely no auto-antibodies involved as far as we know. Likewise, crystal arthritis, which typically features activation of the innate immune system [10], is very much different from SLE both from a clinical and an immunological perspective. In contrast to these primary autoinflammatory disorders, in SLE there is almost no aspect within the immune system that is not affected in some way.

On a factual basis, there are at least three lines of evidence illustrating that the innate immune system is intimately involved in SLE pathogenesis.

Section snippets

Complement deficiencies in SLE

The oldest piece of evidence comes from studies on the beneficial and detrimental roles of the complement system. Vascular deposition of immune complexes containing antigens of microbial origin or released from dying cells leads to complement activation and triggers a chain of events resulting in inflammation and subsequent clearance of immune complexes. One important aspect in this context is the observation that apoptotic cells are not readily removed in many patients with SLE [11], [12], [13]

Toll like receptors in SLE

The second piece of evidence stems from the well-known clinical observation that hydroxychloroquine is one of the most beneficial drugs in SLE, recommended to almost all patients [4], [22]. While not sufficient for treating severe inflammatory SLE organ manifestations, hydroxychloroquine has been shown to prevent anything from disease flares affecting skin or internal organs to thrombotic events, and has also been linked to improved overall survival [23], [24]. Notably, this drug may interfere

Familial chilblain lupus and Aicardi–Goutières syndrome

The third piece of evidence illustrating the important role of the innate immune system in the pathogenesis of systemic autoimmunity comes from a rather interesting association between a rare subtype of chronic cutaneous lupus erythematosus, namely familial chilblain lupus, with mutations in the DNA exonuclease TREX1 (3′repair exonuclease) [46], [47], [48], [49] or the phosphohydrolase SAMHD1 (sterile alpha motif domain and HD domain containing protein 1) [50]. Familial chilblain lupus is

Interferon-α fosters autoimmune disease

IFNα fosters autoimmunity by several mechanisms. It promotes dendritic cell maturation [68], it turns tolerogenic antigen presenting cells into cells that no longer sustain suppression by regulatory T-cells [69], and it induces plasma cell differentiation [70]. In part, IFNα signals via Stat4 (signal transducer and activator of transcription 4), which is another gene strongly associated with SLE [71].

Overexpression of IFNα-induced genes in peripheral white blood cells, also referred to as

Between autoinflammation and autoimmunity

When the term autoinflammation was coined by Daniel Kastner in 1999, it was meant to describe a non-infectious inflammatory condition without auto-antibodies caused by defects of components of the innate immune system [84]. The pathogenic mechanisms that lead to the loss of immune tolerance and the formation of auto-antibodies in SLE are absolutely dependent on the adaptive immune system, and therefore this aspect of the disease does not meet this definition of autoinflammation. However, there

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgments

All three authors are supported by grants from the Deutsche Forschungsgemeinschaft (AR 757/1-1 to M.A., GU 1212/1-1 to C.G., LE 1074/4-1 to M.L.-K.).

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