The expression and clinical significance of different forms of LILRA3 in systemic lupus erythematosus

Du, Yan; Sun, Fengyin; Zhou, Meiju; Wu, Xinyu; Sun, Wenjia; Jiang, Yujie; Cheng, Qi; Chen, Xiaochan; Wu, Huaxiang; Xue, Jing

doi:10.1007/s10067-019-04624-z

Cited by 9 publications

(7 citation statements)

References 22 publications

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“…Serum IL-10 and IFN-γ are positively correlated with LILRA3 levels and negatively associated with serum TNF-α and LILRA3 in patients with multiple sclerosis (12). Serum LILRA3 concentrations are also significantly upregulated in patients with rheumatoid arthritis (28), systemic lupus erythematosus (29) and Sjögren's syndrome (30), and positively correlated with disease activity and severity. In the present study, the expression of LILRAs in patients with SAA was investigated.…”

Section: Discussionmentioning

confidence: 98%

Upregulated expression of leukocyte immunoglobulin‑like receptor A3 in patients with severe aplastic anemia

Liu

Zhao

et al. 2021

Exp Ther Med

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Severe aplastic anemia (SAA) is a rare and potentially life-threatening disease characterized by pancytopenia and bone marrow (BM) hypoplasia. In a previous study by our group, increased expression of leukocyte immunoglobulin-like receptors A (LILRA), LILRA3 in myeloid dendritic cells (mDCs) and LILRA5 in CD34 + cells in SAA was detected using proteomics techniques, highlighting their potential role in disease pathogenesis. In the present study, the expression of LILRA1-6 mRNA was assessed in the BM mononuclear cells of patients with SAA using reverse transcription-quantitative (RT-q)PCR. The expression of homogenic LILRA3 and LILRA5 isoform on mDCs, as well as CD34 + , CD3 + CD8 + , CD19 + and CD14 + cells, was detected using flow cytometry. mDCs were then induced, cultured and sorted. The expression of LILRA3 was confirmed using RT-qPCR and western blot analyses. The serum levels of soluble LILRA3 were measured using ELISA. Furthermore, the relationship between LILRA3 expression and disease severity was assessed. The results indicated increased LILRA3 mRNA expression in patients with SAA. The percentage of LILRA3 + in BM mDCs and CD34 + cells was increased. Compared with controls, the relative LILRA3 mRNA expression and the relative protein intensity were highly increased in SAA mDCs. The serum LILRA3 levels in patients with SAA were also increased. The proportion of LILRA3 + CD11C + human leukocyte antigen (HLA)-DR + /CD11C + HLA-DR + cells was positively correlated with the ratio of LILRA3 + CD34 + /CD34 + cells and the expression of LILRA3 mRNA. Taken together, the expression of LILRA3 on mDCs of patients with SAA was increased, which may affect the function of mDCs. LILRA3 may have a significant role in the immune pathogenesis of SAA.

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Section: Discussionmentioning

confidence: 98%

Upregulated expression of leukocyte immunoglobulin‑like receptor A3 in patients with severe aplastic anemia

Liu

Zhao

et al. 2021

Exp Ther Med

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“…Given that the LILRA3 protein has been previously found to be elevated in both sera from patients with RA, SLE and multiple sclerosis (MS) in association with disease activity [17,21] or severity [29], it seems that the LILRA3 molecule may contribute to SS and SS related lymphoma development in younger onset populations through altered regulation of chronic inflammatory processes. In support of this hypothesis, the LILRA3 protein has been previously shown to trigger a cellular immune response, through proliferation of cytotoxic-CD8 + T and NK cells [10], both previously shown to be related to SS pathogenesis [36].…”

Section: Discussionmentioning

confidence: 99%

“…Of interest LILRA3 variants have shown great heterogeneity across races, with the LILRA3 deleted variant being the dominant allele in northeast Asia (~84%), and the functional genotype (LILRA3+/+) being dominant in Caucasian populations [19]. In a German cohort, the presence of the deleted form has been associated with SS [9] and NHL susceptibility [10], while in a Chinese population, the presence of the functional LILRA3 variant increased disease susceptibility for both SS and active systemic lupus erythematosus (SLE), along with the presence of serum anti-Ro/SSA and anti-La/SSB antibodies and leucopenia [20,21], both previously shown to serve as high risk predictors for SS related lymphoma [22,23].…”

Section: Introductionmentioning

confidence: 99%

Leukocyte Immunoglobulin-Like Receptor A3 (LILRA3): A Novel Marker for Lymphoma Development among Patients with Young Onset Sjogren’s Syndrome

Argyriou

Nezos

Ρούσσος

et al. 2021

JCM

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Background: Primary Sjogren’s syndrome (SS) is an autoimmune disease with a strong predilection for lymphoma development, with earlier disease onset being postulated as an independent risk factor for this complication. Variations of the Leukocyte immunoglobulin-like receptor A3(LILRA3) gene have been previously shown to increase susceptibility for both SS and non-Hodgkin B-cell lymphoma (B-NHL) in the general population. We aimed to investigate whether variations of the LILRA3 gene could predispose for lymphoma development in the context of SS. Methods: Study population, all of Greek origin, included 101 SS cases with a current or previous diagnosis of lymphoma (SS-lymphoma, SS-L) and 301 primary SS patients not complicated by lymphoma (SS-non-lymphoma, SS-nL). All SS patients fulfilled the 2016 SS American College of Rheumatology/European league against Rheumatism (ACR/EULAR) classification criteria. A total of 381 healthy controls (HC) of similar age/sex/race distribution were also included. On the basis of the age of SS onset and the presence or absence of adverse predictors for lymphoma development, SS patients were further stratified into younger (≤40 years) and older (>40 years) age of disease onset, as well as into high/medium and low risk groups. Polymerase chain reaction (PCR) was implemented for the detection of the following LILRA3 gene variants: homozygous non-deleted or functional wild type (+/+) heterozygous (+/−) and homozygous deleted (−/−). LILRA3 serum protein levels were quantitated by enzyme-linked immunosorbent assay (ELISA) in 85 individuals (29 SS-L, 35 SS-nL patients and 21 HC). Results: While no statistically significant differences were detected in the overall frequency of LILRA3 gene variants between SS-L, SS-nL and HC groups, LILRA3 serum protein levels were increased in the SS-L group compared to HC (1.27 ± 1.34 vs. 0.38 ± 0.34 ng/mL, p-value: 0.004). After stratification according to the age of SS onset and history of lymphoma, as well as the presence or absence of adverse predictors for lymphoma development, the prevalence of the functional LILRA3 gene variant was found to be significantly increased in the young onset SS-L group compared to the HC of similar age and sex distribution (100% vs. 82.9%, p = 0.03), as well as in the high/medium risk SS compared to the low risk SS (91.3 vs. 78.3%, p = 0.0012). Of note, young onset SS-L and SS-nL groups displayed higher LILRA3 serum levels compared to their older counterparts (p-values: 0.007 and 0.0005, respectively). Conclusion: The functional LILRA3 gene variant increases susceptibility to SS-related lymphoma development in patients with a disease onset of <40 years old, implying that genetically determined deranged immune responses in younger SS individuals could underly their pronounced risk for lymphoma development.

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“…Functional LILRA3 has been reported to be associated with susceptibility to and disease severity of many autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematous (SLE), primary Sjögren's syndrome (primary SS), ankylosing spondylitis (AS), multiple sclerosis (MS), and Takayasu arteritis, among others (8)(9)(10)(11)(12)(13)(14). A higher frequency of functional LILRA3 has been observed in Chinese patients with RA, conferring greater risk for RA in male patients and a predisposition toward anti-citrullinated protein antibody-positive RA (10).…”

Section: Introductionmentioning

confidence: 99%

“…The serum level of LIR-A3 is also significantly increased in RA patients and correlated with disease activity. Moreover, functional LILRA3 is defined as a factor of disease susceptibility in SLE and primary SS, and levels of LIR-A3 in both serum and CD14+ monocytes were significantly increased in SLE and correlated with disease activity (11,14). In addition, functional LILRA3 appears to be a strong genetic risk factor for susceptibility to AS, mainly in the Northern Han subpopulation, and typically confers an increase in the severity of disease activity (8).…”

Section: Introductionmentioning

confidence: 99%

Association of the Leukocyte Immunoglobulin‐like Receptor A3 Gene With Neutrophil Activation and Disease Susceptibility in Adult‐Onset Still’s Disease

Wang

Liu

Jia

et al. 2021

Arthritis & Rheumatology

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Objective. Adult-onset Still's disease (AOSD) is a severe autoinflammatory disease. Neutrophil activation with enhanced neutrophil extracellular trap (NET) formation is involved in the pathogenesis of AOSD. Functional leukocyte immunoglobulin-like receptor A3 (LIR-A3; gene name LILRA3) has been reported to be associated with many autoimmune diseases. We aimed to investigate the association of LILRA3 with disease susceptibility and neutrophil activation in AOSD.Methods. The LILRA3 deletion polymorphism and its tagging single-nucleotide polymorphism rs103294 were genotyped in 164 patients with AOSD and 305 healthy controls. The impact of LILRA3 on clinical features and messenger RNA expression was evaluated. Plasma levels of LIR-A3 were detected using enzyme-linked immunosorbent assay (ELISA), and the correlation between LIR-A3 plasma levels and disease activity and levels of circulating NET-DNA was investigated. LIR-A3-induced NETs were determined using PicoGreen double-stranded DNA dye and immunofluorescence analysis in human neutrophils and a neutrophil-like differentiated NB4 cell line transfected with LIR-B2 small interfering RNA.Results. The findings from genotyping demonstrated that functional LILRA3 was a risk factor for AOSD (11% in AOSD patients versus 5.6% in healthy controls; odds ratio 2.089 [95% confidence interval 1.030-4.291], P = 0.034), and associated with leukocytosis (P = 0.039) and increased levels of circulating neutrophils (P = 0.027). Functional LILRA3 messenger RNA expression was higher in the peripheral blood mononuclear cells (P < 0.0001) and neutrophils (P < 0.001) of LILRA3 +/+ patients. Plasma levels of LIR-A3 were elevated in patients with AOSD (P < 0.0001) and correlated with disease activity indicators and levels of circulating NET-DNA complexes. Finally, enhanced NET formation was identified in neutrophils from healthy controls and patients with inactive AOSD after stimulation of the neutrophils with LIR-A3. Moreover, NET formation was impaired in NB4 cells after knockdown of LILRB2 gene expression. Conclusion.Our study provides the first evidence that functional LILRA3 is a novel genetic risk factor for the development of AOSD and that functional LIR-A3 may play a pathogenic role by inducing formation of NETs.

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The expression and clinical significance of different forms of LILRA3 in systemic lupus erythematosus

Cited by 9 publications

References 22 publications

Upregulated expression of leukocyte immunoglobulin‑like receptor A3 in patients with severe aplastic anemia

Upregulated expression of leukocyte immunoglobulin‑like receptor A3 in patients with severe aplastic anemia

Leukocyte Immunoglobulin-Like Receptor A3 (LILRA3): A Novel Marker for Lymphoma Development among Patients with Young Onset Sjogren’s Syndrome

Association of the Leukocyte Immunoglobulin‐like Receptor A3 Gene With Neutrophil Activation and Disease Susceptibility in Adult‐Onset Still’s Disease

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