Lupus erythematosus. Part I: epidemiology, genetics and immunology

Authors


  • Section Editor Prof. Dr. Jan C. Simon, Leipzig

  • Fundamentally, cutaneous lupus forms (CLE) and systemic LE (SLE) can be differentiated. However, this differentiation is not always consistently found in the literature.

  • On the basis of a revised LE classification in 2004, CLE is divided into four types: acute cutaneous LE (ACLE), subacute cutaneous LE (SCLE), chronic cutaneous LE (CCLE) and intermittent cutaneous LE (ICLE).

  • Based on the recommendations of the American College of Rheumatology (ACR), 4 of 11 criteria are required to make the diagnosis of SLE.

  • The incidence of CLE is around 4.0 per 100,000 population and year, based on a Swedish study of over 1,000 patients.

  • The incidence rate of SLE in Europe is 3.3–4.8 cases per 100,000 population and year and in the USA 2.0–7.6.

  • CCLE accounts for about two-thirds of cases.

  • Patients with 4 and more criteria had in 95% an elevated ANA titer, while in the group with less than 4 criteria the ANA titer was elevated only in 40%.

  • Even though estrogen levels are not increased in lupus patients, one does find elevated levels of estrogen metabolites such as 16-α-hydroxyestrone and estriol.

  • Smokers respond to antimalarials in the therapy of CLE worse than non-smokers. In SLE the relationship with environmental factors is not well-proven.

  • In the recently identified mutation in the TREX1 gene that codes for a DNA-degrading exonuclease a direct association between the mutation and the occurrence of familial chilblain LE (CHLE) could be found.

  • The strongest genetic association still exists between the HLA (human leukocyte antigen) or MHC (major histocompatibility) locus and SLE.

  • A recently published study identified in CLE associations with the genetic loci for the genes TYK2, IRF5, CTLA4 and ITGAM.

  • New SNP analyses demonstrate an association with TNFAIP3, that also appears to play a role in other autoimmune diseases such as psoriasis and rheumatoid arthritis.

  • The significance of epigenetic phenomena in SLE is underscored by the fact that the drugs hydralazine and procainamide inhibit epigenetic DNA methylation and simultaneously can induce SLE [3]. Further, in LE increased DNA hypomethylation in T cells has been reported.

  • These studies demonstrate for the first time what is termed the interferon signature, i.e. gene patterns that are particularly induced by type I interferons (interferon α/β).

  • Interestingly, in the second study a gene signature for genes of granulopoiesis was found.

  • Three basic mechanisms appear to underlie the immune or autoimmune processes: (1) an altered clearance of material containing nucleic acids (DNA/RNA) and immune complexes, (2) an excessive activation of the innate immune system with participation of Toll-like receptors (TLRs) and type I interferons, and (3) an abnormal B and T cell activation.

  • Intracellularly there is then an activation of the TLR7/9 effector MyD88 and subsequently an activation of NF-κB and the two interferon response factors IRF5 and IRF7.

  • Indications exist that both central as well as peripheral immunologic checkpoints for the elimination of autoreactive B cells do not function adequately in LE.

  • T cells of lupus patients demonstrate altered signal transduction. There is an increased activation of the T-cell receptor.

Correspondence to Prof. Dr. Manfred Kunz, Department of Dermatology, Venereology and Allergology, University of Leipzig, Philipp-Rosenthal-Strafle 23, 04103 Leipzig, Germany

E-mail: manfed.kunz@medizin.uni-leipzig.de

Summary

Lupus erythematosus (LE) is an important dermatologic autoimmune disease and in many aspects, including epidemiology, genetics, immunology, diagnostics and treatment, may be regarded as model for many other autoimmune diseases. Constant efforts in the past years have unraveled important new aspects of LE pathogenesis. Among these are the genetic associations with immunoregulatory signaling pathways such as TNF-, NF-κB-, IL23/IL17- and interferon pathway as well as new insights into the relevance of the innate immune system. Here Toll-like receptors and neutrophils play a central role. The knowledge about immune and autoimmune interactions in LE pathogenesis and the contributing cell types is steadily increasing and has led to new therapeutic approaches using antibodies directed against the B-cell activating factor BLyS. In the first part of this review article, the current knowledge about epidemiology, genetics and immunology is summarized. A second article will deal with diagnostics, clinical picture and different treatment modalities.

Introduction

Very different clinical presentations may hide behind the diagnosis lupus erythematosus (LE). Fundamentally, cutaneous lupus forms (CLE) and systemic LE (SLE) can be differentiated. However, this differentiation is not always consistently found in the literature. In fact, there are many overlaps between cutaneous and systemic manifestations. On the basis of a revised LE classification in 2004, CLE is divided into four types: acute cutaneous LE (ACLE), subacute cutaneous LE (SCLE), chronic cutaneous LE (CCLE) and intermittent cutaneous LE (ICLE) [1]. These four types differ with respect to their clinical, histopathological and immunoserological findings as well as in the prognosis. Besides the specific cutaneous lesions, LE (CLE and SLE) can also demonstrate unspecific skin lesions, such as periungual telangiectases, livedo racemosa, Raynaud syndrome, leukocytoclastic vasculitis and urticarial vasculitis. In addition, non-scarring alopecia, calcinosis cutis and papular mucinosis can exist [1].

Based on the recommendations of the American College of Rheumatology (ACR), 4 of 11 criteria are required to make the diagnosis of SLE [2]. These 11 criteria include butterfly erythema, discoid skin lesions, photosensitivity and oral ulcerations, arthritis, serositis and renal, neurological, hematological or immunological involvement as well as detection of antinuclear antibodies (ANA). As 4 of the 11 criteria are skin or mucous membrane manifestations (including photosensitivity), the diagnosis of SLE could be made solely on the basis of cutaneous symptoms. This can easily lead to overdiagnosing SLE, without the affected patients having the often life-threatening involvement of internal organs such as brain and kidneys typical for SLE [3]. Further, discoid lesions and butterfly erythema are not parameters independent of the photosensitivity. On the other hand, cutaneous lesions are found in up to 85% in SLE, and mild SLE forms are easily overlooked initially and misdiagnosed as CLE.

Particularly in SLE great efforts have been undertaken to open up new therapy options based on the current genetic and immunologic knowledge. It can be expected that due to many genetic and immunologic overlaps between CLE and SLE these will soon also be of relevance for CLE.

Epidemiology

Incidence

LE (CLE and SLE) is not a common disorder. Several studies have been published on the epidemiology of CLE [1, 4, 5]. The incidence of CLE is around 4.0 per 100,000 population and year, based on a Swedish study of over 1,000 patients [6]. In another Swedish survey anti-Ro/SSA-positive SCLE had an incidence of 0.7 per 100,000 population per year while SLE has an incidence of 4.8 per 100,000 population per year. The ratio between women and men in CLE in Europe appears to be 2.5–3 : 1, on the basis of a Europe-wide survey and the above-mentioned Swedish study [1, 5, 6]. The same Swedish study suggested that 12% of patients diagnosed with CLE develop SLE in the first year and 18% in the first 3 years. Women and patients with SCLE are particularly affected [6]. Other studies demonstrate that in CDLE in 10% and in SCLE in 10–15% of cases there is a transition into SLE in the course of time, with SCLE patients often already at the time of diagnosis fulfilling more than 4 ACR criteria [1, 5]. In American long-term observational studies 25% of CLE patients develop SLE within 25 years.

The incidence rate of SLE in Europe is 3.3–4.8 cases per 100,000 population and year and in the USA 2.0–7.6 [5, 7]. The incidence in women is ten times higher than in men so that usually the stated incidence rates in the total population represent average values between the genders, and the incidence in women is actually about double as high [7]. As mentioned, the majority of SLE patients (up to 85%) display cutaneous manifestations during the course of the disease.

Distribution of the subtypes

The gender ratio in CLE of 3 : 1 is the same in the various CLE subtypes with exception of patients with ICLE where 60% are women [5]. The age of manifestation of the disease is on average 43–45 years in women and men, but differs slightly in the subtypes and is, for example, the highest for SCLE with 51 years [5, 7]. CCLE accounts for about two-thirds of cases. ACLE and SCLE each affect one-third and ICLE 10% of the patients [5]. The overstepping of 100% in this calculation is due to the simultaneous presence of several subtypes in about 30% of the cases. For example, ACLE patients also have DLE lesions in one-third of the cases and in 14% of the cases SCLE lesions [5]. A recent study suggests an 80% prevalence of CDLE in all CLE forms [6].

ACR criteria

More than 40% of the patients in the study of Biazar et al. on CLE fulfill 4 and more ACR criteria for SLE [5]. Considering only the cases with CLE as the primary diagnosis (in the study also patients with the primary diagnosis SLE with additional skin lesions were included), the number was distinctly less with only 27%. The most frequent ACR criteria such as photosensitivity, discoid skin lesions and ANA titers occurred in the group with 4 and more than 4 ACR criteria distinctly more frequently than in the group with less than 4 ACR criteria. For example, patients with 4 and more criteria had in 95% an elevated ANA titer, while in the group with less than 4 criteria the ANA titer was elevated only in 40%. The ACLE patients had in all cases a butterfly erythema that hardly occurred in the other subtypes. Elevated ANA titers were found particularly in ACLE and SCLE. Frequent, not LE-specific skin lesions were diffuse alopecia, Raynaud phenomenon and nailfold telangiectases that particularly occurred in ACLE [5]. Patients with CLE had in more than two-thirds of the cases a positive history of photosensitivity [5], with ACLE and ICLE appearing to be most frequently associated with this (75–82%). In tests, however, less than one-half of the patients with a positive UV history actually reacted positively. Recently the ARA criteria were revised by the Systemic Lupus International Collaborating Clinics (SLICC) [8]. Here a total of 17 clinical and immunological criteria were presented. These SLICC criteria led in the studied cases to less falsely classified SLE patients and higher sensitivity for the diagnosis SLE in comparison to the ACR criteria [8]. Newly included, in contrast to the ACR criteria, were non-scarring alopecia and synovitis. Anemia, leucopenia and thrombocytopenia are each independent criteria in the SLICC criteria.

Gender distribution

The more frequent occurrence of CLE and SLE in women suggests that X-chromosomal or hormonal factors affect the LE pathogenesis. Studies on genetically manipulated mice with a different number of X-chromosomes demonstrated that in two X-chromosomes in comparison to only one disease severity is increased [3]. Likewise, pregnancy can increase the severity of the disease. The role of sexual hormones has not yet definitively been clarified. In fact, the estradiol and progesterone levels in the second and third trimester in LE patients are lower than in the healthy. Even though estrogen levels are not increased in lupus patients, one does find elevated levels of estrogen metabolites such as 16-α-hydroxyestrone and estriol. In the mouse model estrogens support the survival of autoreactive B cells, down-regulate the apoptosis-inducing ligand FasL on T cells and induce the immunoregulatory molecule CD40L. The estrogen receptor Erα affects the Toll-like receptor-induced activation of the IL23/IL17 signaling pathway. Thus, there is an entire series of indications that female hormones can be important in LE by impacting upon immunoregulation.

Environmental factors

Provocation by UV light plays an important role in CLE. High photosensitivity exists particularly in ACLE that is mostly associated with SLE. A further important risk factor of CLE is also smoking. There is an association between smoking and disease activity of CLE. Further, smokers respond worse than non-smokers to antimalarials in the therapy of CLE. In SLE the association with environmental factors is not well-proven. Smoking and UV light are in general viewed as causative factors [3]. Studies from the USA suggest that both ethnicity and particularly socioeconomic factors play an important role in the severity and mortality of SLE [7]. Africans and Afro-Americans develop LE distinctly more often than other groups.

Genetics

TREX1

Extensive genetic studies on LE have delivered valuable information on the pathogenesis of the disease [9]. In the recently identified mutation in the TREX1 gene that codes for a DNA-degrading exonuclease a direct association between the mutation and the occurrence of familial chilblain LE (CHLE) could be found. Mutations in the TREX1 gene were originally found in the Aicardi-Goutières syndrome, a -hereditable disorder featuring encephalopathy, increased interferon-α levels in liquor and Chilblain-like cutaneous lesions. Later TREX1 mutations were also found in families with familial chilblain LE mutations 10]. In SLE the TREX1 gene is mutated in about 2% of the cases. There are so other well-established gene mutations or other alternations associated with CLE or SLE, except for the long-known association between the very rare mutations leading to lack of the complement -factors C1q and C4 which can induce SLE and other autoimmune diseases [3].

HLA region

The majority of LE cases according to new knowledge are based on gene variants of a larger number of genes that actually do increase the disease risk, but are not alone responsible for the development [9]. The strongest genetic association still exists between the HLA (human leukocyte antigen) or MHC (major histocompatibility) locus and SLE. HLA-DRB1 demonstrates a highly significant association (p = 2.0 × 10−60) with SLE, that has to date not been exceeded by any other genetic HLA variant. The HLA region on chromosome 6 consists of 250 genes that are divided into three classes (class I–III), with individual gene variants displaying a strong linkage disequilibrium, which means that many genes are inherited in combination and where in the individual case one can not definitely say which genes cause the effect. Besides HLA-DRB1, particularly an association with HLA-DQA1 and HLA-DQB1 exists. The genes for the complement factors C4A and C4B are also found in the HLA region. In CLE also an association with the HLA region has been reported. In SCLE patients an association exists with HLA-A1, -B8, -DR3, DQ2, -DRw52, particularly in patients with positive anti-Ro/SSA antibodies. In CDLE particularly associations with HLA-A1, -B8, -DR3 and -B7, -DR2 were found.

IRF5, TNFAIP3, STAT4, BLK

In the search for genetic polymorphisms of individual nucleotides (single nucleotide polymorphisms, SNPs) that predispose to LE, large studies were performed that examined up to one million of such variants (Table 1) [9, 11]. SNP are genetic variants that also occur in the normal population, distinctly rarer here. One says that an SNP is associated with a certain disease and does not directly cause it as in a mutation.

Table 1. Summary of genetic loci associated with CLE and SLE, based on genome-wide association studies
GeneGene nameFunctionAssociation with other autoimmune diseases
ITGAMIntegrin alpha MPhagocytosis, complement receptor cell adhesionNone known
TNFAIP3Tumor necrosis factor alpha-induced proteinUbiquitination, TNF signal transduction, inhibition of the NF-κB signaling pathwayRheumatoid arthritis, celiac disease, ulcerative colitis, psoriasis
TNIP1TNFAIP3-interacting protein 1TNF signal transduction, inhibition of the NF-κB signaling pathwayPsoriasis
BLKB lymphoid tyrosine kinaseIntracellular kinase, tumor suppressor qualitiesRheumatoid arthritis
STAT4Signal transducer and activator of transcription 4T cell development and signal transduction, IL-17 expressionRheumatoid arthritis, Crohn disease, type I diabetes, Sjögren syndrome
HLA-DRB1HLA class II histocompatibility antigenAntigen presentationRheumatoid arthritis, psoriasis
IRF5Interferon regulatory factor 5Interferon regulation and production, cell differentiationType I diabetes, rheumatoid arthritis, celiac disease, Crohn disease, ulcerative colitis
IRF7Interferon regulatory factor 7Interferon regulation and productionType I diabetes
TYK2Tyrosine kinase 2Association with cytokine receptors, type I interferon signaling pathwayMultiple sclerosis

A recently published study identified in CLE associations with the genetic loci for the genes TYK2, IRF5, CTLA4 and ITGAM [12]. TYK2 codes for a tyrosine kinase in the interferon signaling pathway that phosphorylates interferon receptors. In cutaneous lesions of CCLE, SCLE and SLE an overexpression of TYK2 was found in macrophages and fibroblasts. The interferon response genes IRF5, 7 and 8 induce the production of interferons in cells and are important for central mechanisms of the immune response in LE (see below).

In SLE, due to the larger number or studies, distinctly more associated genes or gene regions have been found. New SNP analyses demonstrate an association with TNFAIP3, that also appears to play a role in other autoimmune diseases such as psoriasis and rheumatoid arthritis (RA) [9]. TNFAIP3 acts in an inhibiting fashion on the TNF signaling pathway and the NF-κB signaling pathway. When TNFAIP3 is lacking in mice, they develop a severe inflammation syndrome in a multitude of organs with lethal results. Further, it was shown that mice with a B-cell specific TNFAIP3 knockout demonstrate lupus-like autoimmune phenomena such as an increased number of B cells in the germinal centers of lymphatic organs, autoantibodies and glomerular immunoglobulin deposition. A further gene associated with SLE from this signaling pathway, TNIP1, codes for an adapter protein that also binds to the TNFAIP3-coded protein A20.

In a further SNP analysis in RA and SLE patients the transcription factor STAT4 was found as a susceptibility gene. STAT4 participates in the regulation of IL-17. The IL-23/IL17 axis plays an important role in SLE and further autoimmune diseases such as psoriasis and RA [13]. In the mouse model IL-17 is strongly -expressed in the kidneys in lupus nephritis.

In a study with over 1000 SLE patients an association with the B lymphocyte kinase (BLK) and as in CLE also with the integrin ITGAM was found [11]. The tyrosine kinase BLK, which belongs to the Src family, is limited to B cells in its expression; its exact role is not yet known. ITGAM codes for the αMβ2-integrin and, among others, is considered a receptor for the complement factor C3bi. It might be involved in the pathogenesis of CLE and SLE via disturbed complement activation.

New large multicenter studies see an association with IRF8 (interferon response factor 8) and the IKZF3, a member of the Ikaros family of transcription factors. IRF8 is involved in the development of B cells and macrophages and affects TLR9 signal transduction by binding to TRAF6, that in the end effect leads to production of type I interferons. In another large lupus cohort more than 10% of the patients had SNP in the TREX1 gene. Further papers found associations with the interferon response genes IRF8, IRF5 and IRF7 as well as TYK2 and the gene PTPN22 that codes for a phosphatase interacting with the B-cell receptor. The polymorphism in the IRF5 gene leads to a new splice variant, which implies pathogenetic relevance [9].

Altogether, a multitude of genetic associations are found pointing to active signaling pathways in LE and thus delivering new knowledge for lupus pathogenesis.

Epigenetics

The significance of epigenetic phenomena in SLE is underscored by the fact that the drugs hydralazine and procainamide inhibit epigenetic DNA methylation and simultaneously can induce SLE [3]. Further, in LE increased DNA hypomethylation in T cells has been reported. For example, the genes ITGAL (CE11a), CD40L (TNFSF5), CD70 (TNFSF7) and PPP2CA are hypomethylated and play a role in the pathogenesis of LE. Treatment of mice with trichostatin A, a histone deacetylase inhibitor, leads to an improvement of signs and symptoms in a mouse model of LE, which suggests that histone modifications also play a role in LE.

Gene expression patterns

Interferon and granulopoiesis signature

In order to gain insights on the genes actually active in CLE and SLE, gene expression patterns of many thousands of genes were analyzed using microarray technology in both diseases. Interestingly, in skin samples of patients with CLE and dermatomyositis largely overlapping gene patterns were found [14] Twenty-one of the top 25 most distinctly up-regulated genes were genes that are inducible by interferons. These include, among others, the chemokine CXCL10, IFIH1 (interferon-induced with helicase C domain 1), ISG15 (interferon-induced 15 kDA protein), C1S/R, IRF7, IDO1, MX2 (myxovirus resistance 2) and CHN1. Genes suggesting keratinocyte activation (S100A7/8/9), T-cell activation (IL2RB, CD2, TRAC, CD3D, CTLA4) and the activation of macrophages and dendritic cells were detected.

Such gene expression patterns were also found in SLE patients with the help of blood samples and in other tissues [15]. These studies demonstrate for the first time what is termed the interferon signature, i.e. gene patterns that are particularly induced by type I interferons (interferon α/β) [16, 17]. In the paper by Baechler et al. one-half of the patients had such a gene signature that demonstrated overlaps with IFN-α/β-stimulated PBMC of normal controls. Of the 161 differentially expressed genes, 23 were interferon-regulated [16]. In the study of Bennett et al. on pediatric SLE patients 26 interferon-regulated genes were identified that essentially overlapped with the first study [17]. Among the genes of the interferon signature that were found in one or both studies were IFIT1 (interferon-induced with tetratricopeptide repeats 1), IFI44 (interferon-induced, hepatitisC-associated microtubular aggregate protein), MX1 (myxovirus resistance 1), OAS1 (2',5'-oligoadenylate synthetase 1), OAS2 and OASL (2′,5′-oligoadenylate synthetase-like gene). Interestingly, in the second study a gene signature for genes of granulopoiesis was found. These included, among others, the genes for MPO (myeloperoxidase), DEF3 (defensin 3), DEFA4 (defensin A4) and FALL39 or LL37 (cathelicidin).

An interferon signature was also found in kidney biopsies of SLE patients. An 11-gene signature with 7 interferon-regulated genes was found, among others MX2, IFIT1 and ISG15; in addition, interestingly, a cluster with genes that are involved in the development of tissue fibrosis such as collagen I and IV. Further studies found an increased or altered expression of TNF/death receptor genes such as TNFRII, TRAIL (TNF-related apoptosis-inducing ligand) as well as IL1A, IL1B, IL1R2 and IL1RAP, IL8 and both IL-8 receptors CXCR1 and CXCR2, FcyR1 (CD64), PBEF and CD19. In summary, the studies have emphasized the role of type I interferons and granulocytes in CLE and SLE and, in addition, identified important immunoregulators [18].

Immunology

The immune and autoimmune processes in LE have been the subject of intensive research for a long time [19, 20]. Involved are the innate immune system, among others, with neutrophilic granulocytes, macrophages, dendritic cells, complement factors and Toll-like receptors as well as the adaptive immune system with T cells, B cells, dendritic cells and autoantibodies [19, 20]. Three basic mechanisms appear to underlie the immune or autoimmune processes: (1) an altered clearance of material containing nucleic acids (DNA/RNA) and immune complexes, (2) an excessive activation of the innate immune system with participation of Toll-like receptors (TLRs) and type I interferons, and (3) an abnormal B and T cell activation [19] (Figure 1).

Figure 1.

Schematic representation of immune mechanisms in lupus erythematosus. After decay of neutrophils by apoptosis (NETose), DNA fragments are released together with DNA-binding proteins and cathelicidin (LL-37). These fragments are recognized by auto-antibodies secreted by B cells, leading to the generation of immune complexes consisting of autoantibodies, DNA fragments, DNA-binding proteins and cathelicidin (LL-37). After binding to the Fc receptor on dendritic cells, phagocytosis is induced as well as interaction with Toll-like receptors after fusion of endolysosomes with autophagosomes. This leads to the induction of pro-inflammatory cytokines such as TNF-α, IL-1, IL-6, IL-18, IFN-α/β and B-cell activating factor BAFF (BLyS), which in turn activate B and T cells. Antigens processed by dendritic cells are also presented to T cells inducing a specific T-cell response, which involves B cells. Activated T cells in turn support the generation of autoreactive antibodies in B-cells. Based on genetic and environmental factors, this cascade is deregulated in lupus erythematosus leading to an enhanced and uncontrolled autoimmune reaction. Abbr.: pDC, plasmacytoid dendritic cell; TLR7/9, Toll-like receptors 7 and 9; FCR, Fc receptor.

Neutrophilic granulocytes

In recent times neutrophilic granulocytes have come into the focus of interest of LE. During neutrophil apoptosis there is release of what is termed neutrophil -extracellular traps (NET). Therefore, the process is also termed NETosis [20]. Here net-like DNA structures and cathelicidin (LL-37) are released that serve to capture and kill bacteria. Apoptosis is triggered by circulating immune complexes in the plasma of lupus patients being taken up by neutrophilic granulocytes via the Fc receptors and intracellularly inducing death by NETosis. The NET-DNA complexes and opsonized cell fragments, e.g. of apoptotic cells, are recognized by antibodies and then taken up by cells of the innate immune system such as macrophages and dendritic cells (DCs). Particularly plasmacytoid DCs (pDCs) appear to play a role here.

Dendritic cells

Intracellularly the nucleic acids bind to Toll-like receptors (TLRs) that fuse with the antigens from the endosomes (protein/ DNA complexes) in the autophagosomes. Here TLR9 is responsible for DNA and TLR7 for RNA complexes (Figure 2). Intracellularly there is then an activation of the TLR7/9 effector MyD88 and subsequently an activation of NF-κB and the two interferon response factors IRF5 and IRF7, as well as an induction of the proinflammatory cytokines IL-1, IL-6, IL-12, IL-18 and TNF-α as well as type I interferons and the B-cell-activating factor BAFF (BlyS) [20]. In this manner, a feed-forward loop, is formed, in which pDCs are activated by neutrophilic granulocytes that in turn again activate B cells and subsequently granulocytes. Besides the TLRs there are other intracellular RNA receptors such as e.g. RLR (RIG I-like receptor) that can stimulate interferon production via the mitochondrial adapter protein MAVS. Further DNA receptors are AIM2 (absent in melanoma 2), STING (stimulator of interferon genes) and DAI (DNA-dependent activator of interferon-regulatory factors) (Figure 2). The above-mentioned exonuclease TREX1 intervenes in these DNA sensing processes. The exact function of the factors just named is, however, not yet well-understood.

Figure 2.

Intracellular detection of nucleic acids and induction of cytokines in lupus erythematosus. DNA taken up by different mechanisms binds to specific intracellular receptors, which activate further intracellular signaling pathways via MyD88 and IRF5/7, MyD88 and NF-κB, or via the inflammasome-caspase-1 pathway inducing the production of pro-inflammatory cytokines. Similar mechanisms have been reported for RNA. Abbr.: DAI, DNA-dependent activator of interferon regulatory factors; DDX41, member of the DEXDc family of helicases; AIM2, absent in melanoma 2; MyD88, myeloid differentiation primary response 88; IRF 5/7, interferon regulatory factors 5 and 7.

The important role of DCs in lupus pathogenesis was underscored by a recently published paper with DC-depleted mice in the classical murine lupus model (MRL.FasIpr). The DC-depleted mice had a distinctly milder disease than the control mice. In the DC-depleted mice both conventional DCs (cDCs) and pDCs were depleted. The latter are the main producers of type I interferons in LE and occur particularly in the skin.

B cells

Cell remnants containing DNA can also be taken up by B cells via the B-cell receptor of autoreactive B cells that are in this manner activated and up-regulate the BAFF and APRIL receptor TACI. After this, via an interaction with TLR9 antibodies towards double-stranded DNA and through the interaction with TLR7 antibodies towards RNA are produced. The significance of this process for lupus pathogenesis is underscored by the fact that a lupus disease in the mouse model takes a distinctly milder course, when both TLRs – TLR7 and TLR9 – or their effector molecule MyD88 are lacking [19]. Additionally, there are indications that both central as well as peripheral immunologic checkpoints for the elimination of autoreactive B cells do not function adequately in LE. The phosphatase PTPN22 mentioned above appears to be involved in this B-cell tolerance defect. Additionally, follicular helper cells (TFH) known for quite some time obviously play a decisive role. They are of great importance for B-cell maturation. It could be shown that TFH present in the germinal centers of secondary lymphatic organs (e.g. lymph nodes, spleen) participate in the development of LE in the mouse system. Such TFH cells have also been identified in the human system. Further evidence for their pathogenetic role in LE comes from successful treatment attempts of lupus nephritis patients with anti-CD40L antibodies. CD40L is expressed by TFH and induces via CD40 B-cell maturation.

The subsequently developing long-living autoreactive memory B cells and plasma cells are usually found in a resting state and therefore difficult to reach by therapies targeted on cell division and immunologic activation mechanisms. According to current opinions, they survive in niches in the bone marrow and other chronically inflamed organs and can be reactivated anytime through additional inflammatory stimuli. They can not be affected by antibodies against CD20 (rituximab) or CD257/BAFF/BlyS (belimumab).

T cells

Adaptive immunity includes besides the formation of long-living effector B cells particularly the clonal expansion of lymphocytes with the formation of long-living effector T cells. T lymphocytes are activated by peptide-MHC complexes on antigen-presenting cells (macrophages, dendritic cells) (Figure 1). As described above, the strongest genetic risk alleles for LE are located in the MHC region, which suggests that there is a disturbed antigen presentation of peptides due to genetically altered MHC complexes. This has, however, not yet been studied functionally. Further, T cells of lupus patients exhibit altered signal transduction. There is an increased activation of the T-cell receptor, as CD3-ζ as part of the T-cell receptor complex is replaced by the γ-chain of the Fc receptor (FcR) which leads to a participation of the spleen tyrosine kinase (SYK) instead of the normal CD3-ζ-associated protein kinase ZAP70 [20]. Through this there is an activation of the calcium/calmodulin-dependent protein kinase type IV (CAMK4) and an increased production of IL-17 as well as an increased calcium influx into the cell. In addition to this, there is an increased expression of the costimulatory molecule CD40L and the adhesion molecule CD44 on CD4+ T cells.

In summary, in LE various mechanisms of innate and acquired immunity interact, with DCs representing an important link between both. The molecules identified here have in part already found their ways as target structures into lupus treatment. For example, with belimumab recently a monoclonal antibody towards the B cell-activating cytokine BAFF (BLyS) has been licensed for the therapy of SLE. Further molecules directed against the above-mentioned kinase SYK, and cytokine receptors are currently under clinical investigation [21].

Ancillary