| Abstract|| |
Background: Lupus erythematosus (LE) is a broad-spectrum, heterogeneous disease. At one end of the spectrum is the cutaneous LE (CLE) without systemic involvement, and at the other end is the systemic LE (SLE) with multisystem involvement. Analyses of clinical and immunological indicators and pathological examinations are helpful for early diagnosis, differential diagnosis, and prognosis of LE. Aim and Objectives: We described the clinical and laboratory characteristics of patients with LE and assessed the diagnostic value of immunohistochemical detection of C3d, C4d, IgG, IgG4, and CD123 in skin lesions of LE. Materials and Methods: Clinical and laboratory data of 62 patients with LE were collected. The expression levels of C3d, C4d, IgG, IgG4, and CD123 in skin lesions of LE were detected by immunohistochemistry (IHC). Results: Clinical manifestations such as hematological involvement, C3, C4, ESR, hematuresis, proteinuria, anti-Sm, anti-ribosomal P-protein, anti-U1-RNP, anti-histone, and anti-nucleosome antibodies are helpful for classificatory diagnosis of LE. The positive rate of C3d and/or C4d along the basement membrane zone in LE skin lesions by IHC was 74.6%, which was higher than that by direct immunofluorescence (47.5%) (P = 0.002). The expression of CD123 protein and the number of CD123+ plasmacytoid dendritic cells (PDCs) in skin lesions of patients with LE were higher than those of dermatomyositis (DM), while the distributed form of CD123 + PDCs in the dermis was different between LE and DM. Conclusions: The diagnosis of CLE and SLE requires a combination of clinical manifestations, laboratory indicators, and pathological examination. Immunohistochemical detection of C3d, C4d, and CD123 in skin lesions is important for the classificatory diagnosis of LE.
Keywords: Clinical and immunological characteristics, C3d, C4d, CD123, immunohistochemistry, lupus erythematosus
|How to cite this article:|
Deng M, Wu R, Zhou X, Su Y, Li Y. Analyses of the clinical and immunological characteristics of patients with lupus erythematosus. Indian J Dermatol 2022;67:205
|How to cite this URL:|
Deng M, Wu R, Zhou X, Su Y, Li Y. Analyses of the clinical and immunological characteristics of patients with lupus erythematosus. Indian J Dermatol [serial online] 2022 [cited 2022 Aug 17];67:205. Available from: https://www.e-ijd.org/text.asp?2022/67/2/205/350856
| Introduction|| |
Lupus erythematosus (LE) is a complicated chronic autoimmune inflammatory disease. There is a great variation in the clinical and immunological abnormalities of LE. The diagnosis of LE should be based on a combination of clinical manifestations, laboratory tests, and histopathologic changes in the affected tissues. Direct immunofluorescence (DIF) is an essential aid for the diagnosis of LE. However, DIF has some limitations, including the requirement of fresh skin tissues and specialized pathologists.
The complement system is widely accepted to play an important role in the pathologic process of LE. Complement C3 is the central component of the complement system in the classical and alternate pathways. C3d and C4d are the degradation products of complement factors C3 and C4, respectively. They are considered to be evidence of complement activation in an inflammatory response. Many researchers have shown that immunohistochemical (IHC) detection of C3d and C4d deposition in skin biopsy specimens is of great diagnostic value when evaluating some inflammatory skin diseases, such as bullous pemphigoid and pemphigoid gestationis.,, Several studies have established the role of immunohistochemical deposits of C3d and C4d along the basement membrane zone (BMZ) in the diagnosis of patients with LE.
Previous research has shown increased density and clustering of plasmacytoid dendritic cells (PDCs) in the lesions of LE.,,, PDCs have shown plasma cell morphology and they express CD123 in the cytomembrane. PDCs can rapidly produce high amounts of type I interferons after virus infection through TLR activation. Type I interferons derived from PDCs prompt monocytes to differentiate into dendritic cells, promoting autoimmunity in SLE. The average PDC amount in the peripheral blood shows a decrease in patients with LE, while there is an increase in activated PDCs in target organs such as the skin and renal tissues. PDCs can be immunohistochemically stained with CD123. Based on the above observations, we can evaluate the expression of PDCs in skin lesions of patients with LE through immunohistochemical CD123 staining.
The aim of this study was to summarize the clinical and immunological characteristics and the expression levels of C3d, C4d, IgG, IgG4, and CD123 proteins in skin lesions of patients with LE and to examine correlations among these factors, thus providing guidance for the diagnosis and treatment of LE.
| Materials and Methods|| |
Patients and samples
A total of 62 patients diagnosed with LE, including 23 patients with CLE (15 patients with discoid LE (DLE) and 8 patients with subacute cutaneous LE (SCLE)) and 39 patients with SLE, during the period from March 2016 to June 2018 at the Dermatology Department of Second Xiangya Hospital, Central South University, were studied. All patients met the following criteria: all of the cases were diagnosed based on clinical manifestations, laboratory tests, and histopathology of skin lesions. All patients with LE (age ≥ 18 years) had skin lesions and underwent a skin biopsy. The major exclusion criteria were as follows: (1) absence of pathologic results of skin biopsy and (2) associated with other connective tissue diseases. Patients with LE were divided into two groups according to clinical parameters: SLE and CLE groups. (1) All patients with SLE fulfilled the American College of Rheumatology (ACR) classification criteria for SLE. (2) All patients with CLE were diagnosed by clinical manifestations and serological parameters as well as histopathology of skin lesions. The specific skin lesions of DLE were discoid erythema, and the specific skin lesions of SCLE presented in two forms: scaly annular lesions (annular SCLE) or scaly papulosquamous plaques (papulosquamous SCLE). Patients with CLE tended to have less and milder systemic involvement.
Skin biopsy specimens received from patients with DM were used as disease controls (n = 15), and skin specimens from healthy persons were used as normal controls (n = 10). A total of 15 patients with DM were selected following the Bohan and Peter criteria.
IHC was performed on skin biopsy specimens, and 3–4-μm sections were used for evaluating C3d, C4d, IgG, IgG4, and CD123 deposition by IHC. Primary antibodies used the rabbit monoclonal antihuman C3d antibody (no. ab136916, dilution 1:600; Abcam, Cambridge, UK), C4d antibody (no. ab183311, dilution 1:100; Abcam), rabbit polyclonal anti-IgG antibody (ZA-0448, working solution, ZSGB-BIO, China), rabbit polyclonal anti-IgG4 antibody (ZA-0576, working solution, ZSGB-BIO), and rabbit polyclonal anti-CD123 antibody (ZM-0423, working solution, ZSGB-BIO). The secondary antibody used was from the Universal kit (mouse/rabbit polymer detection system) (PV-6000, ZSGB-BIO). Biopsies were reviewed by two experienced pathologists who were not aware of the patients' data and who observed the IHC sections and recorded the results separately.
Definition of positive results by IHC: the presence of continuous granular C3d or C4d deposition along the epidermal BMZ was considered to be positive; IgG and IgG4 on the cytoplasm and/or cell membrane of lymphocytes were stained brownish yellow; CD123 on the PDC cell membrane was stained brownish yellow. Evaluation criteria for immunohistochemical scores of IgG, IgG4, and CD123 were as follows: Based on the previously defined IgG, IgG4, and CD123 positive results. According to the proportion of positive cells, 0–4 points were calculated as 0%, 1%–25%, 26%–50%, 51%–75%, and 76%–100%, respectively. Immunostaining intensity: no staining of cells: 0, pale yellow: 1, yellow: 2, and tawny: 3. The final score was calculated by multiplying the scores of the two parts.
Samples were submitted in saline solution, and 3–4-μm sections were used for evaluating C3 and IgG deposition. Samples were fixed in 95% ethanol and then rinsed in phosphate-buffered saline. Solutions of rabbit polyclonal anti-human C3 antibody (no. GF020129, dilution 1:10; Gene Tech, Shanghai, China) and polyclonal rabbit anti-human IgG/FITC antibody (DK-2600, dilution 1:20, Glostrup, Denmark) were placed on the tissues for 1 h, and the slides were washed twice with phosphate-buffered saline. The slides were mounted with a glycergel mounting medium.
The clinical and immunological data are presented as mean ± SD for continuous variables and as numbers with percentages for categorical variables. Statistical analyses were performed using the Pearson Chi-square test, Chi-square test with Yates's correction, or Fisher's exact test and two-tailed t tests for categorical and continuous data, respectively. P < 0.05 was considered statistically significant.
| Results|| |
Among the 62 patients with LE, there were 37 women (59.7%) and 25 men (40.3%) with a female: male ratio of 1.48:1. The mean age was 41.23 ± 14.28 years (range: 12–69 years). Furthermore, 23 of 62 patients had CLE, and the mean age was 44.74 ± 14.34 years (range: 12–67 years). Of these cases, 12 were in men and 11 were in women. The remaining 39 patients had SLE, and the mean age was 39.15 ± 14.01 years (range: 16–69 years). Of these cases, 13 were in men and 26 were in women.
The disease control group with DM consisted of 5 men and 10 women. The healthy control group with normal skin included 3 men and 7 women.
Clinical manifestations and laboratory tests
The frequency of different clinical manifestations and laboratory tests in CLE and SLE is shown in [Table 1]. In terms of prevalence, common manifestations of patients with LE were lesions on the exposed sites (95.2%), photosensitivity (35.5%), alopecia (33.9%), arthritis (32.3%), oral ulcers (17.7%), fever (16.1%), myalgia (12.9%), Raynaud's phenomenon (3.2%), and neuropsychiatric LE (3.2%). The prevalence of laboratory abnormalities of LE, from high to low, was C3 decline (66.1%), C4 decline (53.2%), erythrocyte sedimentation rate (ESR) rise (51.6%), anemia (41.9%), proteinuria (37.1%), leukopenia (33.9%), hematuresis (22.6%), thrombocytopenia (12.9%), and creatine kinase rise (11.5%). The most common serum autoantibodies of LE were ANA (75.8%), anti-Ro/SSA (46.8%), anti-U1-RNP (43.5%), anti-Ro-52 (37.1%), anti-Sm (35.5%), anti-ribosomal P-protein (30.6%), anti-nucleosome (24.2%), anti-ds-DNA (21.0%), anti-histone (16.1%), anti-La/SSB (14.5%), anti-mitochondrial type 2 (11.3%), anti-centromere (3.2%), and anti-Jo-1 (3.2%). Compared with patients with CLE, patients with SLE showed a higher prevalence of C3 decline, C4 decline, ESR rise, anemia, leukopenia, proteinuria, hematuresis, anti-U1-RNP, anti-Sm, anti-ribosomal P-protein, anti-nucleosome, and anti-histone antibodies. In addition, the C3 and C4 levels of SLE were significantly lower than those of CLE [Figure 1].
|Figure 1: Comparison of serum complement C3 and C4 levels between SLE and CLE. The C3 and C4 levels in SLE were significantly lower than those in CLE (P < 0.0001, P < 0.05).|
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|Table 1: Comparison of the main clinical and immunological characteristics of cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE)|
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The correlation analysis between clinical manifestations and autoantibodies in patients with LE showed that there were associations between the anti-Sm antibody (P = 0.004), anti-U1-RNP antibody (P = 0.018), and photosensitivity; between the anti-Sm antibody (P = 0.002), anti-U1-RNP antibody (P = 0.006), and hematological damage; and between the anti-dsDNA antibody (P = 0.002), anti-Sm antibody (P = 0.025), and renal damage [Table 2].
|Table 2: Associations between autoantibodies and clinical manifestations of LE|
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The comparison of laboratory tests between LE with renal damage and without renal damage showed that the prevalences of C3 decline, C4 decline, anti-ds-DNA, anti-Sm, anti-nucleosome, and anti-histone antibodies of LE with renal damage were markedly higher than those of LE without renal damage (P < 0.05 for all comparisons) [Table S1].
Immunohistochemical expression of C3d and C4d along the BMZ
The expression of C3d along the BMZ was positive in 25 out of 39 cases of SLE and in 18 out of 23 cases of CLE (64.1% vs. 78.3%, respectively). The expression of C4d along the BMZ was positive in 17 out of 39 cases of SLE and in 12 out of 23 cases of CLE (43.6% vs. 52.2%, respectively). [Figure 2] shows that granular C3d and C4d deposited along the BMZ in DLE specimens [Figure 2]a and [Figure 2]b. The positive rates of C3d and C4d showed no meaningful difference between the CLE and SLE groups. We evaluated the expression of C3d and C4d in UV exposed and non-exposed sites in SLE and CLE, respectively. In the group of 39 patients with SLE, 67.9% (19/28) of cases with an exposed site and 54.5% (6/11) of cases with a non-exposed site showed granular, continuous C3d along the BMZ, and 50.0% (14/28) of cases with an exposed site and 27.3% (3/11) of cases with a non-exposed site showed continuous C4d along the BMZ. In the group of 23 patients with CLE, 85.7% (18/21) of cases with an exposed site and 0.0% (0/2) of cases with a non-exposed site showed granular, continuous C3d along the BMZ, and 57.1% (12/21) of cases with an exposed site and 0.0% (0/2) of cases with a non-exposed site showed continuous C4d along the BMZ. The positive rates of C3d and C4d in the exposed sites were significantly higher than those in the non-exposed sites in SLE; however, there was no statistical difference (P = 0.478, P = 0.288). The positive rates of C3d and C4d in the exposed sites were significantly higher than those in the non-exposed sites in CLE (P = 0.040, P = 0.217). The positive rates of C3d, C4d, and LBT in the non-exposed sites in SLE were higher than those in CLE.
|Figure 2: Immunohistochemistry for C3d and C4d and immunofluorescence for C3 and IgG in lupus erythematosus (LE) specimens. An example of discoid lupus erythematosus (DLE) shows granular C3d deposition along the BMZ (a). An example of DLE shows positive granular C4d deposition along the BMZ (b). However, both C3 (e) and IgG (f) were negative by immunofluorescence staining for the same case. One case of SLE shows no C3d (c) deposition along the BMZ. However, both C3 (g) and IgG (h) are significantly deposited along the BMZ by immunofluorescence staining for the same case. Another case of SLE shows no C4d (d) deposition along the BMZ. (a and c, C3d immunohistochemistry, ×200. b and d, C4d immunohistochemistry, ×200. e and g, C3 immunofluorescence, ×200. f and h, immunofluorescence, ×200.)|
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By comparing the positive rate of C3d and/or C4d along the BMZ detected by IHC (74.6%) and C3 and/or IgG detected by DIF (47.5%), we concluded that IHC displayed better sensitivity in the diagnosis of LE, and there was a meaningful difference (P = 0.002). An example of DLE shows positive granular C4d deposition along the BMZ [Figure 2]b. However, both C3, C4 [Figure 2]e, and IgG [Figure 2]f were negative by immunofluorescence staining for the same case. In contrast, one case of SLE showed no C3d or C4d [Figure 2]c deposition along the BMZ. However, both C3 [Figure 2]g and IgG [Figure 2]h were significantly deposited along the BMZ by immunofluorescence staining for the same case. Furthermore, patients with a positive LBT had a higher prevalence of C3d and/or C4d (P < 0.0001).
Immunohistochemical expression of CD123
Positive CD123 expression was detected in 56.5% of cases of LE and in 46.7% of cases of DM, and it was completely negative in normal skin [Figure 3]a. There was no statistical difference between LE and DM (P = 0.495). Immunohistochemical scores in LE and DM were 4.98 ± 4.66 and 2.80 ± 3.69, respectively. The results showed that the expression of CD123 protein in patients with LE was higher than that in patients with DM, although there was no statistical significance (P = 0.062) [Figure 4]a. The mean percentage and immunohistochemical scores of CD123 + PDCs did not show any differences between CLE and SLE [Figure 4]b. The majority of LE specimens contained clusters of PDCs [Figure 3]c and [Figure 3]d. However, in DM specimens, CD123 + PDCs were scattered in the dermis [Figure 3]b.
|Figure 3: Selected CD123 immunostaining in LE, DM, and normal skin. An example of normal skin shows no CD123 + PDCs in the epidermis and dermis (a). An example of DM shows that a small number of CD123 + PDCs (arrow) are scattered in the dermis (b). Example of DLE (c) and SLE (d) is shown. Both panels show that many CD123 + PDCs (arrows) constitute the inflammatory cell infiltrate and form prominent clusters in the dermis. (CD123 immunohistochemistry, ×200.)|
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|Figure 4: Comparison of CD123 immunohistochemical scores between CLE and SLE, LE, DM, and NC. There was no statistical difference between LE and DM (a). The expression of CD123 protein in patients with LE was higher than that in patients with DM, although there was no statistical significance (b). There was no CD123 protein in the dermis of NC.|
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The expression of IgG and IgG4 protein in the dermis of patients with LE
IgG expression was detected in 56% of all cases of LE. The positive rate of IgG in SLE and CLE was 59.0% (23/39) and 52.2% (12/23), respectively. There was no difference between the two groups. There were few IgG4+ lymphocytes in the dermis of LE, although the positive rate was somewhat low. We compared the immunohistochemical scores of IgG4 and the ratio of IgG4 to IgG in lesions between CLE and SLE, and the results showed no difference.
| Discussion|| |
Despite increasing awareness of LE, the diversity in clinical manifestations and laboratory abnormalities make its diagnosis occasionally challenging. We described the clinical and immunological characteristics of 62 Chinese patients with LE and assessed the utility of C3d, C4d, IgG, IgG4, and CD123 immunostaining in the diagnosis of LE.
LE is a heterogeneous autoimmune disease with an extensive range of clinical and immunopathological features, ranging from CLE that affects skin lesions alone to SLE with multisystem involvement, such as arthritis, nephritis, and neuropsychiatric LE. We analyzed the clinical symptoms and immunologic features of CLE and SLE. Of the 23 patients with CLE, 10 patients (43.5%) fulfilled four or more of the American College of Rheumatology (ACR) criteria for the classification of SLE. This is in accordance with a previous study. The accuracy of the ACR criteria is limited because 4 of the 11 criteria are dermatological. Therefore, even if patients with skin diseases satisfy the ACR criteria, it is crucial to combine the clinical manifestations and laboratory tests of patients to make a comprehensive diagnosis. Among the dermatological criteria, facial erythema and photosensitivity are the most common. The most common lesion sites of LE are areas exposed to UV radiation, such as the neck, upper chest, and especially the face, which are consistent with the fact that UV light is involved in the pathogenesis of LE.
Patients with SLE in this study had a similar prevalence (64.1%) of hematological abnormalities as in other studies, which have shown a prevalence ranging from 44.0% to 82.7%.[20–23] Among the 39 patients with SLE in this study, anemia was the most common abnormality, followed by leukopenia and thrombocytopenia. Our results are comparable to those of Li et al. Similar to SLE, anemia is the most common hematological abnormality of CLE, but anemia in CLE is much rarer than in SLE. Another difference is that there have been no cases of thrombocytopenia in patients with CLE.
Of the 39 SLE cases, 11 (28.2%) developed lupus nephritis, and this percentage was much lower than that in an analysis with a prevalence of 47.4% from a Chinese cohort including 2104 patients with SLE. The reason for the lower rates of patients with lupus nephritis compared to patients with SLE in other studies is that in this study, the data were evaluated at a dermatology unit where patients with SLE predominantly had skin damage along with milder systemic involvement.
Anti-ds-DNA antibody has been proven to be a pathogenic autoantibody in SLE and has been confirmed to be related to renal disorders, leukopenia, and anemia. Our study confirmed that anti-ds-DNA was associated with renal damage, which was also reported by Li et al. Li et al. and Ni et al. found that there were high correlations between the anti-Sm antibody and disease activity, renal damage, malar rash, and C3 decline. Our study revealed an association of the anti-Sm antibody not only with photosensitivity but also with renal damage. An association between the anti-U1-RNP antibody, anti-SSA antibody, and pulmonary arterial hypertension (PAH) in patients with SLE was discovered by Li et al. In the current study, we did not conduct a clinical manifestation analysis of PAH, but we found that being anti-U1-RNP antibody positive was related to a higher prevalence of photosensitivity. Previous studies have shown an association between anti-SSB and hematologic damage, and between anti-Ro-52 and photosensitivity. However, these associations were not discovered in this study. The difference may be due to different standardizations of laboratory methods and sample size. The most commonly affected organs in LE are the kidneys and skin. Previous studies have found anti-ds-DNA, anti-nucleosome, and anti-histone antibodies in kidney tissues of patients with lupus nephritis. This study also showed associations between renal damage and the three abovementioned antibodies. We found that LE with renal damage was also associated with C3 decline and C4 decline.
Apart from studies describing the sedimentation of C3d and C4d along the BMZ of skin tissue in bullous disease, there are only a few works reporting C3d or C4d in skin biopsy material with LE. Based on our study, C3d and C4d detected by IHC serve as a diagnostic adjunct in the evaluation of LE. Both SLE and CLE cases showed depositions of C3d and C4d along the BMZ. C3d expression alone had good sensitivity for the diagnosis of CLE and SLE (78.3% and 64.1%, respectively). However, C4d expression alone had poorer performance for the diagnosis of CLE and SLE (52.2% and 43.6%, respectively). In addition, the positive rates of C3d and C4d depositions and LBT in UV-exposed sites were higher than those in non-exposed sites, although not all of the differences were statistically significant. The lack of statistical difference is attributed to the small sample size of cases with non-exposed sites. UV radiation is the most obvious trigger of LE, and lesions of LE are typically photo-distributed. UV light exposure can induce DNA breaks and lead to the development of inflammatory lesions in the skin of patients with LE. The positive rates of C3d and C4d in SLE were much lower than those in a study by Magro et al., which found different positive rates and locations of C3d and C4d depositions in different subtypes of LE and indicated that the absence of C3d and C4d in SCLE skin specimens is associated with negative LBT results. This is in accordance with our observation of a positive association between positive LBT and deposition of C3d and C4d. In contrast, almost 74.6% of 62 skin specimens with LE were positive for C3d and/or C4d through IHC. The percentage of positive IHC results was higher than that of positive C3 and/or IgG through DIF (47.5%), which revealed that the diagnostic sensitivity of IHC was higher than that of DIF. Thus, the detection of C3d and C4d expression in skin lesions by IHC is an important diagnostic indicator for LE., Furthermore, IHC has the following advantages. First, it does not need fresh frozen specimens and specialized laboratories. Second, IHC is not as costly as DIF. Third, IHC can be used as a diagnostic method instead of DIF in hospitals where DIF examination is unavailable.
PDCs are rarely present in normal skin, which is consistent with our finding that all immunohistochemical CD123 stains in 10 normal skin specimens were negative. Other research confirmed that CD123+ PDCs are increased in the epidermis and dermis of LE.[27-29] In this work, CD123+ PDCs were observed in the dermis of LE and DM. The positive rate of CD123+ PDCs in the dermis showed no difference between LE and DM. This suggests that PDCs in tissue may have pathogenic implications. Similar to LE, PDCs and their product type I IFNs are involved in the pathogenesis of DM., The immunohistochemical scores of CD123 protein in patients with LE and patients with DM were not statistically different, which may be due to the small sample size of DM cases. In fact, the expression of CD123 protein in the dermis of patients with LE was higher than that in patients with DM. The result obtained is parallel to that in a report showing that CD123+ PDCs are present in greater numbers and comprise a larger percentage of the infiltrate in LE lesions compared with DM lesions. CD123+ PDCs in the dermis of patients with LE were clustered, while they were scattered in patients with DM. This is consistent with previous studies showing that the quantity and distribution of PDCs vary in different inflammatory and neoplastic diseases.[28-30] PDCs were clustered around blood vessels and appendages in LE and lymphocytic infiltrate. In other forms of dermatitis, PDCs can be found as single cells or scattered throughout the infiltrate or beneath the epidermis. Another study showed different patterns of distribution of PDCs in lesions of LE and DM; PDCs are numerous in the dermis in LE, while they favor the epidermis in DM. Therefore, the quantity, distribution, and density of PDCs in skin lesions observed by IHC may offer a useful diagnostic aid in the differential diagnosis of LE from other forms of dermatitis.,
| Conclusions|| |
Based on our research, we conclude that high positive rates of ANA, anti-Ro/SSA, anti-U1-RNP, anti-Ro-52, and anti-Sm antibodies are immunological characteristics of SLE. Distinct correlations between clinical and serologic autoantibodies are present in patients with SLE, such as a positive correlation between anti-ds-DNA, anti-Sm, anti-U1-RNP, anti-nucleosome, and anti-histone antibodies and renal damage and a positive association between anti-Sm and anti-U1-RNP antibodies and photosensitivity. Our results present a better understanding of the features of patients with LE and can help in early diagnosis and differential diagnosis. Immunohistochemical detection of C3d and C4d along the BMZ and CD123 in skin lesions has important diagnostic value for LE.
We are grateful to all the patients with LE and healthy controls who participated in this study.
Financial support and sponsorship
The National Natural Science Foundation of China [Grant No.: 81872534, 81472881] and the Natural Science Foundation for Distinguished Young Scholars of Hunan Province, China [Grant No.: 13JJ100].
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]