A comprehensive review of immune-mediated dermatopathology in systemic lupus erythematosus
Introduction
Lupus erythematosus (LE) is a highly heterogeneous autoimmune disease characterized by abnormal immune cells and abundant autoantibodies. LE has a broad clinical spectrum. On the one hand, there is cutaneous lupus erythematosus (CLE), showing primarily cutaneous lesions, while on the other hand, there is systemic lupus erythematosus (SLE), characterized by severe systemic manifestations (Table 1) [1]. Generally, LE-specific cutaneous lesions are subdivided into three different categories: acute cutaneous LE (ACLE), subacute cutaneous LE (SCLE) and chronic cutaneous lupus erythematosus (CCLE) [2,3]. CCLE mainly includes five different forms of disease: discoid LE (DLE), verrucous/hypertrophic LE, LE profundus/panniculitis (LEP), LE tumidus (LET) and chilblain LE (CHLE). ACLE is usually the acute cutaneous manifestations performed by SLE patients. Moreover, these SLE patients likely have more severe systemic disease over time when compared with those SLE patients without skin involvement [4]. For this reason, clinically CCLE and SCLE are traditionally classified as CLE, while ACLE is usually included in SLE. Indeed, there is no clear line between CLE and SLE. DLE, the most typical type of CLE, rarely shows a progression from DLE to SLE (fewer than 5%). Another example is SCLE, in which 50% of patients might develop systemic damage several years after diagnosis [5]. However, even if CLE patients progress to systemic involvement, a lower prevalence of renal involvement and mild disease activity have been found in these patients [6]. These variants with different organ-involvements in LE are still unidentified. However, accumulating evidence has shown the unignorable role of dysregulated immune cells in skin biopsy and circulation in diseases. Therefore, we attempt to make a systems review about the clinical features, histological changes and laboratory abnormalities of LE with cutaneous lesions, then discuss the current findings on dysregulated immune cells involving the dermatopathology of LE, which may give us a better understanding of the immune-mediated dermatopathology in LE.
Section snippets
Epidemiology and history
Biett, a French dermatologist, was the first person to describe lupus, in 1828. In the initial decades of the history of lupus, studies showed nothing more than descriptions emphasizing skin lesions. The discoid lesions were described in 1833 by Cazenave, while the butterfly-shaped rash was noted by Hebra in 1846. More severe pathological changes besides skin lesions were first described by Kaposi in 1872, and the existence of systemic form of lupus was firmly established in 1904 by Osler.
Genetic associations
The first-degree relatives of LE patients have a significantly higher prevalence of LE, indicating the close association of LE in first-degree relatives [28]. Genetic association studies have identified a number of genes that may confer susceptibility to CLE and SLE, including HLA, complement pathway genes, TNF-α, IRF5 and TREX1. Numerous studies have been done on the association between HLA variants and LE. Among these HLA variants, the HLA B8, HLA-DR and HLA-DQ alleles appear to play more
Systemic lupus erythematosus (SLE)
Acute cutaneous lupus erythematosus (ACLE) is frequently defined as a cutaneous manifestation associated with active SLE and can be divided into localized ACLE and generalized ACLE [54]. The localized form is characterized by the ‘butterfly’ rash, which occurs over both cheeks, extends over the nasal bridge and forms the shape of butterfly (Fig. 1A). These lesions are frequently sun-induced and non-scarring and can cause dyspigmentation [55,56]. Butterfly rashes occur in up to 52% of SLE
Histopathology
The various clinical subtypes of LE (with the exception of LE profundus) often show an extensive overlap in their histological features, with degeneration of the basal layer, dermal edema, superficial or deep perivascular and periadnexal lymphocytic infiltrate and interface dermatitis. The differences in histopathology between the groups of LE mainly lie in the extent of development and are associated with the stage of cutaneous lesions. Typically, fully developed DLE exhibits most of the
Assessment of serologic autoantibodies
Auto-antibodies are frequently used as biomarkers for diagnosis and disease monitoring in LE, which is especially important in SLE. Some 95% of ACLE patients show a positive ANA, as well as a high incidence of anti-dsDNA and anti-Sm antibodies. Typically, anti-dsDNA antibodies are highly specific for SLE, and the levels of anti-dsDNA antibodies in serum tend to reflect disease activity, especially for the development of renal disease [90,91]. Anti-Ro/SSA and anti-La/SSB antibodies may play a
The aberrant distribution and function of immune cells in LE skin
Skin barrier function is the responsibility of different types of cells, including keratinocytes (KCs), endothelial cells (ECs), dendritic cells (DCs) and lymphocytes, such as T lymphocytes (T cells) and B lymphocytes (B cells). Which type of cell plays the predominant role in lupus has not been answered. However, accumulating evidence has shown that the infiltrating T and B cells in dermis might play a critical role. The majority of T cells in peripheral blood (95%) express the αβ T-cell
Prevention
Some lifestyle habits of LE patients can be a motivating or exacerbating factor of disease activity. Hence, it is necessary to give detailed health guidance for patients, especially the risks of sun exposure and the importance of sun protection. To avoid direct sun exposure, patients should be prepared for the outdoors with sunglasses, a high-sun-protection factor (>30) sunscreen, sun-blocking clothing and a wide-brimmed hat. For long-time sun-avoiding patients, the risk of vitamin D deficiency
Conclusions
Although some similarities exist at the beginning of lesion formation, the pathogenesis of skin damage in CLE and SLE patients might still have fundamental differences. The mechanisms of skin damage in LE are multifactorial, and the distribution of immune cells in lesions may vary with as the disease progresses. Different stages and severities of disease, diverse subtypes of LE, and individual variation may affect the observed results when we study the pathogenesis of LE skin damage. The
Author contributions
Qianwen Li conducted the manuscript writing. Haijing Wu, Wei Liao, Ming Zhao, Vera Chan, Linfeng Li, Min Zheng, Genhui Chen conducted editing, and Jianzhong Zhang, Chak-sing Lau and Qianjin Lu revised the manuscript.
Conflict of interest
The authors declare no conflicts of interests.
Acknowledgement
This work was supported by the National Natural Science Foundation of China (No.81220108017, No. 81522038, No. 81602767 and No. 81430074), the Programs of Science-Technology Commission of Human province (2013F J4202), the Natural Science Foundation of Hunan Province (2017JJ3453), the Fundamental Research Funds for Central Universities of Central South University (NO. 2017zzts842) and the Natural Key Clinical Specialty Construction Project of National Health and Family Planning Commission of the
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