Cutaneous lupus erythematosus: clinical aspects and molecular pathogenesis


Correspondence: Vilija Oke, Department of Medicine, Rheumatology Unit, Center for Molecular Medicine L8:04, Karolinska Institutet, Karolinska University Hospital, Solna 171 76, Stockholm, Sweden.

(fax: +46 8 51775562; e-mail:


Lupus erythematosus (LE) is an autoimmune disease with diverse clinical manifestations ranging from limited cutaneous (CLE) to potentially life-threatening systemic disease (SLE). Susceptibility to LE arises from genetic variation in multiple loci, and disease activity is provoked by exogenous or endogenous trigger(s), the best characterized of which is exposure to ultraviolet radiation (UVR). Amongst patients with LE, a cluster of photosensitive subjects with cutaneous lesions and positivity for anti-Ro/SSA autoantibodies have been described. The Ro52 antigen belongs to the tripartite motif protein family and has E3 ligase activity. New data reveal that Ro52 ubiquitinates interferon regulatory factors and modulates their transcriptional activity, indicating an important role for Ro52 in inflammation as a negative feedback regulator. Our findings indicate that UVR exposure induces upregulation of Ro52 in the CLE target cell, the keratinocyte, and that Ro52 is upregulated in spontaneous and UVR-induced CLE lesions. Recently described functional analysis of Ro52-deficient mice revealed that loss of Ro52 results in uncontrolled inflammation in response to minor skin injury leading to an LE-like condition. In summary, emerging data suggest that abnormal function or regulation of Ro52 contributes to the pathogenesis of UVR-induced CLE in genetically susceptible individuals. Ro52 may thus be an interesting therapeutic target, as its activation could contribute to downregulation of the chronic inflammatory process in LE. Here, we review the available data on the pathogenesis of CLE and, in particular, the role of the Ro52 autoantigen.


acute cutaneous lupus erythematosus


antigen-presenting cell


complement component


chronic cutaneous lupus erythematosus


cutaneous lupus erythematosus


dendritic cell


discoid cutaneous lupus erythematosus


high-mobility group protein B1


immune complex


intermittent cutaneous lupus erythematosus






interferon regulatory factor


‘lupus band’ test


lupus erythematosus


major histocompatibility complex


plasmacytoid dendritic cell


subacute cutaneous lupus erythematosus


systemic lupus erythematosus


tripartite motif


ultraviolet radiation


Lupus erythematosus (LE) is an autoimmune disease that has a range of clinical manifestations with varying degrees of severity and prognosis. LE can manifest solely as a dermatological disease, termed cutaneous LE (CLE). Systemic LE (SLE) commonly involves the skin, joints and cardiovascular and central nervous systems, as well as serous cavities, and is a potentially life-threatening disorder [1]. The temporal demarcation between limited cutaneous or life-threatening systemic LE is not completely clear as localized disease can progress to a systemic disorder or systemic condition may remit.

Cutaneous lupus erythematosus (CLE) is classified into several morphological subtypes that share an LE-specific histopathological pattern [2, 3], including acute (ACLE), subacute (SCLE), chronic (CCLE) and intermittent CLE (ICLE) [3-5]. Nonspecific cutaneous manifestations of LE include a heterogeneous group of dermatological disorders, as well as systemic manifestations of life-threatening SLE (e.g. vasculitis) [4, 6]. In this review, we will mainly focus on the LE-specific manifestations of CLE.

Clinical features of CLE

Cutaneous lupus erythematosus (CLE) lesions are preferentially found in sun-exposed areas, and the majority of patients report photosensitivity. The most typical manifestation of ACLE is a butterfly-shaped facial erythema over the malar eminences [4]. SCLE presents with annular or papulosquamous, psoriasis-like scaling erythematous plaques that may heal leaving abnormalities of pigmentation (Fig. 1a) [3]. There are several different subspecificities of CCLE, but discoid LE (DLE) is the most frequent type and accounts for 98% of all CCLE cases [7]. DLE is clinically characterized by scaling erythematous disc-like plaques of a scarring nature. Chilblain lupus is a variant of CCLE and typically appears as purplish-blue, tender nodules mainly involving the toes and fingers, but may also affect the heels, knees, nose and ears [4]. ICLE lesions clinically appear as indurated, succulent, urticarial-like plaques of reddish-violaceous colour, with a smooth surface [5] (Table 1). ACLE, SCLE and CCLE can be present in a patient with SLE; however, the same patient may display several different subtypes of CLE during the course of the disease [3]. ICLE seems to be a purely dermatological disease [5]. Malar rash and ACLE are exclusively associated with SLE [4, 8, 9]. SCLE and DLE lesions occur in approximately 8–21% and 11–58% of patients with SLE, respectively [8, 10]. Up to 90% of patients with SCLE and almost 25% of patients with DLE are positive for anti-Ro/SSA antibodies [11-13].

Table 1. Clinical manifestations, disease triggers and important genetic loci associated with CLE
CLE subtypeClinical featuresTriggersGenetic loci
Acute (ACLE)Facial erythema of butterfly shape localized over the malar eminences; erythematous maculae–papules

UVR [88]

Female sex hormones

Drugs: sulphasalazine, hydralazine, isoniazide, procainamide, TNF-α blockers

Chemicals: hydrazines, aromatic amines, organophosphates [88]

FCGR2A [28]
Subacute (SCLE)Annular or papulosquamous, psoriasis-like scaling erythematous plaques

UVR [88]

Drugs: thiazides, calcium channel blockers, proton pump inhibitors, terbinafine [90]

Chemicals: organophosphates [90]

C2, C4 [27, 34], IRF5 [29], TNF-α(308A) [89]
Chronic (CCLE)
a) discoid (DLE)Scaling, erythematous, typically scarring, disc-shaped plaquesUVR [88]ITGAM, CTLA4, TYK2, IRF5 [29, 30]
b) chilblain LEPurplish-blue, tender nodules involving the toes, fingers, heels, knees, nose and earsCold, humidity [88]TREX1 [91]
Intermittent (ICLE)Reddish-violaceous indurated, succulent, urticaria-like plaquesUVR [88]Not identified
Figure 1.

(a) Clinical appearance of a CLE lesion (SCLE). Photograph provided by K. Popovic. (b) Histopathology of CLE. e, epidermis; d, dermis.

Histopathology of CLE

Lupus erythematosus (LE)-specific lesions show a histopathological pattern of lichenoid tissue reaction (Fig. 1b) [3]. Histopathological changes include atrophy of the epidermis, hydropic degeneration of the basal cell layer with the presence of apoptotic keratinocytes, hyperkeratosis, follicular plugging, basement membrane thickening, dermal mononuclear cell infiltrate located at the dermo-epidermal junction, perivascularly and/or perifollicularly, and dermal oedema [2]. CLE subtypes share these histological characteristics, but some features are more typical or common for certain subtypes than others [2, 3]. Deposition of immune complexes (ICs) containing immunoglobulin (Ig)G, IgM and complement component C3 is typically observed at the dermo-epidermal junction and is defined as a positive ‘lupus band’ test (LBT) [14, 15].

Autoantibodies in CLE

A hallmark of SLE is the presence of autoantibodies against intracellular targets. Patients with CLE also frequently display positivity for certain autoantibodies. Antinuclear autoantibodies (ANA) and anti-double-stranded DNA(dsDNA) antibodies followed by anti-Ro/SSA autoantibodies are the most common types detected in patients with SLE [16]. Of note, two subspecificities of Ro/SSA have been identified and are directed against autoantigens Ro52 and Ro60 [17-19], although due to historical or technical reasons, the common term ‘anti-Ro/SSA autoantibodies’ is still commonly used in many reports without distinguishing between the two autoantibody specificities. However, determination of anti-Ro52 separately from anti-Ro60 has clinical significance and prognostic value. For example, positivity for anti-Ro52 autoantibodies has been associated with congenital heart block, severe pulmonary manifestations of autoimmune myositis and prognosis of autoimmune liver disease [20-22]. Photosensitive patients with CLE frequently have anti-Ro/SSA autoantibodies, and the levels of anti-Ro52 autoantibodies are higher than those of anti-Ro60 [7, 8, 23]. It has recently been demonstrated that autoantibodies may be detected several years before LE develops. Exposure to triggering factors is probably essential to provoke onset of the clinical disease later in life [24, 25].

Genetics of CLE and anti-Ro/SSA-positive disease

Several studies have demonstrated genetic variations associated with CLE. The reported candidate genes can be subclassified into MHC and non-MHC genes. The associations observed within the MHC locus include variations in HLA-DRB1*0301, HLA-DRB1*1501 and genes encoding for complement components C1q, C2 and C4 [2, 26] (Table 1). The variations or mutations in complement genes seem to particularly confer risk for photosensitivity, ACLE, SCLE and anti-Ro/SSA production [27]. The demonstrated associations with certain clinical phenotypes are observed in non-MHC loci, including FCGR2A (risk for ACLE) [28], TYK2, IRF5, tumour necrosis factor-α (TNF-α) (-308A) (risk for SCLE), ITGAM (risk for DLE) and TREX1 (risk for chilblain LE) [2, 26, 29, 30] (Table 1). Polymorphisms in the Ro52/TRIM21 gene have been associated with SLE and anti-Ro52 autoantibody production in patients diagnosed with Sjögren's syndrome [31, 32].

CLE and LE triggering factors

It has been suggested that genetic factors determine an individual's lifetime risk of developing LE, and environmental factors are likely to provide a trigger for the onset of clinical manifestation(s) of disease [26]. The list of exogenous factors that may trigger CLE includes exposure to ultraviolet radiation (UVR) and a variety of chemical substances including drugs and agricultural agents [2, 33] (Table 1). Tobacco smoking has also been implicated as a risk factor for CLE [34, 35].

Photosensitivity and experimental photoprovocation

In a susceptible individual, sun exposure can induce exacerbation of CLE and even induce the onset of systemic disease in a previously healthy subject. A large proportion of patients with LE are photosensitive, and indeed, photosensitivity is one of eleven American College of Rheumatology criteria for the diagnosis of SLE [36]. The observation that sun exposure can trigger CLE lesions has led to the development of photoprovocation, a method that allows induction of CLE-resembling skin lesions in an experimental setting for scientific purposes [37].

Immunological phenotype of inflammation in CLE

The cascade of events leading to flares of LE is usually initiated by an external factor of cell-death-inducing and/or proinflammatory nature (e.g. UVR or drugs) [1, 12, 33], and the observed changes in the CLE lesions include signs of ongoing inflammation and occurrence of cell death [2]. Apoptotic cells are present in the basal epidermis. Deposits of ICs can be detected at the dermo-epidermal junction and may include cell debris bound by Igs and complement components. These complexes are detected as a positive LBT in the majority of CLE lesions [14].

Proinflammatory cytokines such as high-mobility group protein B1 (HMGB1), TNF-α, interleukin (IL)-1β, interferon (IFN)λ, IL-17 and IL-18 are detected in CLE skin lesions [38-41]. These mediators might be responsible for the induction of chemokines and adhesion molecules at the site of injury and subsequently facilitate leucocyte influx [42]. The upregulated adhesion molecules observed in CLE lesions include ICAM1 and E-selectin [43, 44]. The reported data indicate that T-helper 1 (Th1)-type chemokines (CXCL9, CXCL10, CXCL11 and CXCL12) are the most strongly upregulated out of the entire chemokine family and are observed in areas in which epidermal and dermal injuries are evident [45-48]. These chemokines may home lymphocytes bearing their ligands CXCR3 and CXCR4, and cells positive for these markers are detected within lesions [47, 48]. The presence of CXCR4-expressing cells suggests accumulation of cutaneous dendritic cells (DCs) [49]. A substantial portion of the infiltrating cells are cytotoxic CD8 +  and effector CD4 +  T cells that might have been recruited via CXCR3 [46, 48].

Macrophages (CD68+) and plasmacytoid DCs (pDCs) are present amongst dermal infiltrates [48, 50-52]. Activated pDCs are potent IFNα secretors, and the observed upregulation of IFN-inducible proteins (IRF5, IRF7, MxA and also CXCL9, CXCL10 and CXCL11) could be the result of IFNα secreted by these cells [29, 44, 47, 53]. Keratinocytes are poor producers of type I or II IFNs, but it was recently demonstrated that they can produce IFNλ1 and express its receptor, both of which are upregulated in CLE lesions [41, 54].

Thus, current knowledge suggests that skin inflammation in CLE is driven by the Th1 immune response in parallel to the activated IFN system.

Biological mechanisms of UVR-induced CLE

Much of the understanding of the pathogenesis of sun-induced CLE comes from studies utilizing experimental photoprovocation. It has been demonstrated that apoptotic keratinocytes accumulate in patients with CLE up to 72 h post-UVR exposure, whereas in healthy control subjects, the increase in apoptotic cells is observed only 24 h after UVR injury, and unviable cells completely disappear within 72 h [55]. It is likely that the accumulation of apoptotic cells occurs due to clearance deficiencies. Unremoved apoptotic cells undergo secondary necrosis [56]. Prolonged induction of nitric oxide generation, as detected indirectly by the inducible nitric oxide synthase expression pattern, may contribute to the increased number of apoptotic cells, but also enhance secretion of proinflammatory cytokines and influx of leucocytes [42, 57, 58]. Expression of the IFN-inducible protein MxA has been demonstrated to increase in parallel with the development of UVR-induced CLE lesions and may also be related to the induction of an IFN signature, as observed in spontaneous CLE lesions [44, 47].

Several investigators attempted to explore whether UVR can modulate the subcellular localization of the CLE-associated autoantigens Ro52 and Ro60. It was demonstrated that Ro52, in parallel with Ro60, may translocate to the apoptotic blebs after cell exposure to UVR [59-62].

We have reported that HMGB1, an alarmin with proinflammatory cytokine-like properties, was upregulated and translocated to the extracellular space in the epidermis and dermis, infiltrating cells in the CLE lesions, and that the highest level of expression was found in the clinically most active lesions [63]. Interestingly, translocation of HMGB1 was observed even before lesion development, already 2 days after the last photoprovocation [63]. HMGB1 can be actively secreted by activated cells or passively released by necrotic cells [64, 65]. It is therefore possible that the extracellular HMGB1 observed in CLE lesions was actively secreted by keratinocytes in the epidermis and macrophages in the dermis. In addition, a proportion of HMGB1 could have been passively released by keratinocytes undergoing secondary necrosis [56, 64]. Of note, as these cells were initially directed to die by apoptosis, the released HMGB1 is most probably bound to nucleosomes [66]. It has been demonstrated that such complexes are highly immunogenic and could serve as an autoantigen [66].

Ro52 and its biological functions

Ro52 is a common target of the circulating autoantibodies in LE. The Ro52 protein contains an N-terminal RING domain then a B-box motif, a coiled-coil domain and a B30.2 (or PRYSPRY) region at the C-terminal end. Structurally, Ro52 is a member of the family of tripartite motif (TRIM) proteins and is also termed TRIM21 (Fig. 2) [67]. Like several other TRIM proteins, Ro52 has E3 ligase activity and is involved in ubiquitination [68]. The reported substrates for Ro52-mediated ubiquitination include IRF3, IRF5, IRF7 and IRF8 [69-72], and Ro52 modulates the transcriptional activity of these IRFs [69, 70, 72-74]. Ro52 is the predominantly cytoplasmic protein that can be upregulated in a proinflammatory environment, such as stimulation by type I and II IFNs. Cells exposed to reactive oxygen/nitrogen species may accumulate Ro52 in the cell nucleus [62, 75, 76]. It is the cells of the immune system that have the strongest expression of Ro52 [68].

Figure 2.

Schematic representation of the functional domains of the Ro52 protein.

Several investigators have reported that Ro52 can bind to the Fc part of any IgG with unexpectedly high affinity via the B30.2/PRYSPRY domain and that the binding affinity is comparable with that of the bacterial superantigen protein A [76].

Ro52 and CLE

Recently, we described the pattern of Ro52 expression in CLE lesions [77]. Ro52 was found to be upregulated in all active CLE lesions investigated. More specifically, cytoplasmic Ro52 was highly expressed in epidermal cells in both spontaneous and UVR-induced CLE. Of note, in some patients with CLE, we observed a particularly strong staining in the basal keratinocytes that are the zone of the autoimmune attack and where the apoptotic keratinocytes are found [2]. The increased Ro52 expression in keratinocytes might contribute to Ro52-associated autoimmunity. For example, overexpression of Ro52 in a lymphoma-derived B-cell line leads to a decreased rate of proliferation and increased susceptibility to activation-induced cell death [68]. The high Ro52 expression observed in the basal keratinocytes of CLE lesions could therefore, at least in part, account for the increased numbers of apoptotic cells [2].

It has been demonstrated in in vitro experiments that Ro52 is translocated to the blebs of apoptotic keratinocytes and thus could be recognized by the immune system [59-61]. As a substantial proportion of patients with LE have defects in the removal of unviable cells [56], it is therefore possible that Ro52 might be released by secondary necrotic cells, and importantly, increased Ro52 production in the basal keratinocytes just before cell death could contribute to the considerable load of this autoantigen [77]. Ro52 in the extracellular space, together with other highly proinflammatory molecules (e.g. HMGB1 [66]) released from secondary necrotic keratinocytes, might be recognized by antigen-presenting cells (APCs) and initiate the first step in breaking peripheral tolerance in previously anergic or low self-reactive T and/or B cells and thus lead to the induction of adaptive immunity against self in a genetically susceptible individual.

It has been demonstrated in vitro that keratinocyte exposure to UVR upregulates Ro52 expression within 24 h, but that the predominantly cytoplasmic localization of the protein is not changed [77]. Increased Ro52 levels might be required to terminate the UVR-induced cutaneous inflammation, as evidenced by the fact that Ro52 acts as a negative feedback regulator of inflammation via downregulation of the transcriptional activity of several IRFs [71, 72]. It is therefore possible that this regulation is abnormal in patients with LE. Genetic polymorphisms in the Ro52 gene have been associated with lupus and anti-Ro52-positive Sjögren's syndrome [31, 32]. Whether these polymorphisms could result in abnormal Ro52 expression levels or nonfunctional protein is not clear. Of interest, it has recently been demonstrated that patient-derived anti-Ro52 autoantibodies directed against the RING domain of Ro52 may inhibit its E3 ligase activity in vitro through steric hindrance, by blocking access of the E2 to its binding site in the RING domain [78]. It is possible that Ro52 autoantibodies do interfere with the function of their target in vivo. Alternatively, another molecule involved in the Ro52 ubiquitination pathway could be aberrantly expressed in patients with LE and impede the function of Ro52 (e.g. polymorphisms in the IRF5 and IRF7 genes are associated with LE [29, 79, 80]).

Keeble and colleagues proposed an interesting hypothesis to explain how anti-Ro52 autoantibodies might contribute to IC deposition and reduced clearance in the target organ [81]. They suggest that extracellular Ro52 could bind the Fc portion of any locally present IgG via the B30.2/PRYSPRY domain and simultaneously be bound by anti-Ro52 autoantibodies. This could result in building of massive ICs that are difficult for phagocytes to engulf.

In the dermis, approximately 80% of cells within infiltrates of CLE lesions stain positive for Ro52 [77]. The majority of these cells are activated CD4+ and CD8+ T cells and macrophages [48, 68]. It has been shown that a high level of Ro52 expression in macrophages and T cells may have dual effects, both enhancing proinflammatory properties of the cells (for example, through production of IL-12p40 and IL-2, respectively) and negatively regulating their activation [69, 72, 73]. We found that Ro52 was also upregulated in several LE-unrelated inflammatory skin diseases, such as psoriasis, atopic eczema and lichen planus [72, 77]. This finding adds to the emerging data indicating that Ro52 is a general and important regulator of inflammation.

Proposed hypothesis of CLE development

Based on the available data, a model can be proposed for the development of LE via initial injury to the skin (Fig. 3). It appears that susceptibility to LE is conferred by multiple genes involved in the regulation of the innate and adaptive immune responses and that an external trigger is needed to induce clinical manifestations of the disease. One of the primary events in the pathogenesis of CLE may be an increased number of apoptotic cells in the inflammatory environment, for example, after sun exposure.

Figure 3.

Schematic illustration of the proposed pathogenesis of CLE. (A). UVR-induced skin injury. (a) Activated keratinocytes secrete proinflammatory cytokines, express chemokines and upregulate Ro52 expression. (b) Cell cycle arrest occurs in keratinocytes due to UVR-induced DNA damage; DNA can be repaired, but the cell will undergo apoptosis if the damage is too extensive or the repair mechanisms fail. (c) Apoptotic keratinocytes that have not been removed undergo secondary necrosis and passively release intracellular constituents to the surrounding. (d) Macrophages and DCs are activated by proinflammatory cytokines and unviable cells. (e) DCs ingest cell debris and probably autoantigens too. (B). Initiation of the adaptive immune response against self. (a) DCs may present autoantigens to naïve, potentially self-reactive, T and B cells in the lymph node. (b) Influx of cells, including CD4+ and CD8+ T cells, macrophages, neutrophils, B cells and pDCs to the site of UVR-induced injury via upregulated adhesion molecules and a chemokine gradient. (C). Autoimmunity-induced skin injury. (a) Unviable cell debris, generated from unviable keratinocytes, is opsonized by Igs and complement components. ICs and possibly also Ro52–anti-Ro52 complexes are formed. (b) ICs containing HMGB1–DNA-Ig may activate pDCs and initiate IFNα secretion. (c) Cytotoxic CD8+ and effector CD4+ T cells may further activate macrophages and neutrophils; this would cause a further escalation of inflammation via cytokines and reactive oxygen/nitrogen species and facilitate further inflammatory cell influx and killing of keratinocytes. (d) ICs, including HMGB1–DNA-Igs, stimulate B cells and induce cytokine and autoantibody production and class switch.

The process of apoptosis and/or the response of the immune system to the presence of apoptotic cells is abnormal at least in a proportion of LE-susceptible individuals [82]. Apoptotic cells that are not cleared within a limited period of time undergo secondary necrosis. An external proinflammatory trigger (e.g. UVR) that induces a local transient inflammatory response in a nonsusceptible individual may induce a stronger inflammatory reaction in an LE-susceptible person. Through activation of MyD88, NFκB and inflammasomes, UVR induces production and secretion of proinflammatory cytokines such as TNF-α, IL-1β, IL-6 and IL-8 by keratinocytes (Fig. 3a) [42, 83].

Our data indicate that the Ro52 autoantigen is upregulated by UVR in CLE target cells, keratinocytes, and might increase keratinocyte sensitivity to cell death-inducing stimuli [68]. Dying keratinocytes, which upregulate Ro52 just before death (i.e. apoptosis followed by secondary necrosis), might passively release Ro52 to the extracellular space along with highly proinflammatory and immunogenic nuclear material such as HMGB1 tightly complexed with nucleosomes [66]. Circulating complement factors and Igs opsonize the cell debris and establish ICs, as detected by the LBT; however, in LE-susceptible individuals, these complexes might not be removed due to lack of certain complement components or C-reactive protein or the inability of phagocytes to recognize and engulf them [26, 27, 30]. In such a proinflammatory environment, chemokines (CXCL9–12) and adhesion molecules (ICAM1 and E-selectin) are upregulated and mediate leucocyte influx (Fig. 3a,c) [44, 48].

The presence of proinflammatory cytokines and ICs induces maturation of APCs and enables phagocytosis of unviable cell debris including possible autoantigens. Subsequently, APCs carrying autoantigens can migrate to secondary lymphoid organs, present ingested antigens to the adaptive immune system and induce autoantigen-specific secondary immune responses (Fig. 3b) [84]. The proinflammatory environment at the site of skin injury leads to the further recruitment of cytotoxic CD8+ T cells carrying granzyme B and Tia1, which can kill the target cells locally (Fig. 3c) [48]. CD4+ effector T cells might activate leucocytes and facilitate phagocytosis and also killing.

Circulating autoantibodies are likely to contribute to the formation of ICs that are deposited at the dermo-epidermal junction (as observed by the LBT). pDCs are also present at the site of skin injury and probably secrete IFNα, as evidenced by the observed ‘interferon signature’ [48, 49, 51]. ICs containing nuclear constituents might be recognized by pDCs and amplify type I IFN secretion, in particular IFNα [51, 85]. Upregulation of Ro52 in CLE lesions might reflect the presence of IFNs in the surrounding environment, and Ro52 could be expected to modulate the downregulation of the ongoing inflammation. It is possible that in a subgroup of patients with LE, such as those with Ro52 autoantibodies and/or genetic polymorphisms in the Ro52 gene, Ro52 is unable to mediate some of its functions (e.g. regulation of IRFs), and therefore, the inflammatory process cannot be terminated [78]. An uncontrollable inflammatory response to a minor skin injury due to loss of functional Ro52 has been demonstrated to lead to a lupus-like disease in an animal model [72].

An attack of the adaptive immune system via autoantibodies and effector T cells might further induce cell death and contribute to the vicious circle amplifying inflammation that subsequently results in damage to the target tissue (Fig. 3c). Escalating inflammation in a genetically susceptible individual might lead to cutaneous or even systemic manifestations of LE.


In summary, the pathogenesis of CLE is a complex, multistep process, and recent findings have contributed to major advances in understanding some of the key mechanisms involved. Ro52 is a negative regulator of inflammatory pathways (reviewed by Yoshimi et al. [86]), as it negatively regulates proinflammatory cytokine production [72, 87] and alters T- and B-cell growth and differentiation [68, 72, 86]. Thus, modulating the expression or function of Ro52 could be of therapeutic value. However, further research is essential to enable development of more specific therapies for patients with this condition.

Conflict of interest statement

The authors have no conflict of interests to declare.


We thank Karin Popovic for kindly providing the photograph in Fig. 1a.