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ObjectiveLeucocyte immunoglobulin-like receptor A3 (LILRA3) belongs to a family of leucocyte receptors. Our previous study reported LILRA3 transcripts were markedly upregulated in neutrophils from patients with APS. We undertook this study to investigate clinical implications of LILRA3 in APS and its potential role in APS-associated thrombosis.MethodsTwo independent cohorts were studied. The first consisted of 294 APS patients, 48 asymptomatic aPL carriers and 150 healthy controls (HCs) from Peking University People’s Hospital. The second included 99 APS patients, 25 aPL carriers and 40 HCs from United States APS centres. Serum or plasma concentrations of LILRA3 and MPO-DNA complexes were measured. Additionally, 35 patients with thrombotic APS (tAPS) were evaluated to determine potential effects of immunosuppressive therapy on serum concentrations of LILRA3 and MPO-DNA complexes.ResultsBoth positivity and serum concentration of LILRA3 were significantly increased in APS patients, especially in those with tAPS. LILRA3-positive tAPS patients displayed more severe thrombotic manifestations. Serum LILRA3 was positively correlated with MPO-DNA complexes in LILRA3-positive tAPS. After immunosuppressive treatment, LILRA3 and MPO-DNA complexes were consistently decreased in tAPS patients. Key findings from the Peking cohort were confirmed in the United States cohort.ConclusionOur study provides first evidence that LILRA3 is aberrantly expressed in APS, especially in patients with tAPS. Serum LILRA3 correlated with MPO-DNA complexes, and the two indices were consistently decreased in tAPS patients after treatment. LILRA3 may play a role in thrombosis of APS and may serve as a biomarker and/or therapeutic target in tAPS.

Interleukin (IL)-24 has been considered as an inflammatory cytokine in autoimmune diseases. However, conflicting data exist and its biological function remains controversial. Additionally, little is known about its functional impact on natural killer (NK) cells. The aim of this study was to investigate the role of IL-24 in NK cell activation and its clinical implication in systemic lupus erythematosus (SLE). Serum cohort consisting of 299 SLE patients, 214 RA patients, and 159 healthy controls (HCs) and plasma cohort consisting of 70 SLE patients, 82 RA patients, and 123 HCs were included in evaluating IL-24 concentrations. Impact of IL-24 on NK cell activation was assessed in two NK cell subsets, i.e., CD56dimCD16+ and CD56brightCD16− NK cells. Human NK-92 cell line was applied to evaluate functional potential of IL-24 on NK cell migration and invasion. Serum and plasma levels of IL-24 were comparable between patients with SLE or RA and HCs. While recombinant human (rh) IL-2 consistently induced an increased expression of CD69 on both CD56dimCD16+ and CD56brightCD16− cells derived from both healthy subjects and patients with SLE, IL-24 alone was insufficient to activate the CD56dim and CD56bright NK cells. Similarly, while the migratory NK-92 cell numbers were significantly increased with rhIL-2 stimulation, IL-24 alone was unable to enhance NK-92 cell migratory and invasive capacity. Our data indicate that there were no significant differences in serum and plasma concentrations of IL-24 between SLE patients and healthy controls. Recombinant IL-24 has no effect on NK cell activation and migration.

B cells are important participants in the pathogenesis of rheumatoid arthritis (RA). Besides classical B cells, novel B cell subsets are continually to be identified in recent years. Natural killer-like B (NKB) cells, a newly recognized B cell subset, are proved to be actively involved in the anti-infection immunity. However, their role in RA and the potential mechanism remain elusive. Here, we showed that NKB cells were expanded dramatically in collagen-induced arthritis (CIA) mice, demonstrating dynamic changes during the disease progression. These cells promoted CD4+ effector T cell proliferation and Th17 cell differentiation in vitro, while adoptive transfer of these cells exacerbated the arthritis severity of CIA mice. RNA Sequencing revealed that NKB cells displayed distinct differential gene expression profile under RA circumstance, potential perpetuating the disease progression. Moreover, the frequencies of NKB cells were significantly increased in RA patients, positively correlated with the clinical and immunological features. After effective therapy, these cells could be recovered to normal levels. Taken together, our results preliminarily revealed the pathogenic role of NKB cells in RA by promoting Th17 proinflammatory responses. Targeting these cells might provide potential therapeutic strategies for this persistent disease.

Interleukin (IL)-24 has been considered as an inflammatory cytokine in autoimmune diseases. However, conflicting data exist and its biological function remains controversial. Additionally, little is known about its functional impact on natural killer (NK) cells. The aim of this study was to investigate the role of IL-24 in NK cell activation and its clinical implication in systemic lupus erythematosus (SLE).Serum cohort consisting of 299 SLE patients, 214 RA patients, and 159 healthy controls (HCs) and plasma cohort consisting of 70 SLE patients, 82 RA patients, and 123 HCs were included in evaluating IL-24 concentrations. Impact of IL-24 on NK cell activation was assessed in two NK cell subsets, i.e., CD56Serum and plasma levels of IL-24 were comparable between patients with SLE or RA and HCs. While recombinant human (rh) IL-2 consistently induced an increased expression of CD69 on both CD56Our data indicate that there were no significant differences in serum and plasma concentrations of IL-24 between SLE patients and healthy controls. Recombinant IL-24 has no effect on NK cell activation and migration. Key points • This is the first study to investigate functional potential of IL-24 on NK cell activation. • Recombinant IL-24 lacks functional capacity on NK cell activation in either CD56

Introduction: Leukocyte immunoglobulin-like receptor A3 (LILRA3) belongs to the LILR family with unique feature of a 6.7-kb deletion variation among individuals. Frequencies of the 6.7-kb deletion vary widely across populations, but so far it has not been carefully investigated among Han Chinese subpopulations. Furthermore, we previously identified the non-deleted (functional) LILRA3 as a novel genetic risk for multiple autoimmune diseases. The current study aimed to investigate (i) whether frequencies of the LILRA3 6.7-kb deletion differ within Han Chinese subpopulations and (ii) whether the functional LILRA3 is a novel genetic risk for ankylosing spondylitis (AS).Methods: The LILRA3 6.7-kb deletion was genotyped in two independent cohorts, including 1,567 subjects from Shenzhen Hospital and 2,507 subjects from People’s Hospital of Peking University. Frequencies of the 6.7-kb deletion were first investigated in combined healthy cohort according to the Chinese administrative district divisions. Association analyses were performed on whole dataset and subsets according to the geographic regions. Impact of the functional LILRA3 on AS disease activity was evaluated.Results: Frequencies of LILRA3 6.7-kb deletion were highly differentiated within Han Chinese subpopulations, being gradually decreased from Northeast (80.6%) to South (47.4%). Functional LILRA3 seemed to be a strong genetic risk in susceptibility to AS under almost all the alternative genetic models, if the study subjects were not geographically stratified. However, stratification analysis revealed that the functional LILRA3 was consistently associated with AS susceptibility mainly in Northern Han subgroup under the alternative genetic models, but not in Central and Southern Hans. Functional LILRA3 conferred an increased disease activity in AS patients (P < 0.0001 both for CRP and ESR, and P = 0.003 for BASDAI).Conclusions: The present study is the first to report that the frequencies of LILRA3 6.7-kb deletion vary among Chinese Hans across geographic regions. The functional LILRA3 is associated with AS susceptibility mainly in Northern Han, but not in Central and Southern Han subgroups. Our finding provides new evidence that LILRA3 is a common genetic risk for multiple autoimmune diseases and highlights the genetic differentiation among different ethnicities, even within the subpopulations of an ethnic group.

Background Leukocyte immunoglobulin-like receptor A3 (LILRA3) is a secreted protein belongs to LILR family. Our research group previously reported that the functional LILRA3 is a novel genetic risk for multiple autoimmune diseases including systemic lupus erythematosus (SLE). However, the function of LILRA3 in development of lupus is unclear. The bm12 model is a chronic graft-versus-host disease (cGVHD) model characterized by the lupus-like syndrome with cell subtype alteration and autoantibody production. To functionally study the role of LILRA3 in lupus pathogenesis, we constructed the LILRA3 knock-in mice and assessed the clinical manifestation and immune responses in bm12 model. Methods Human LILRA3 gene (Gene ID: 11026) was inserted into Rosa26 allele in C57BL/6 (B6) mice based on Cas9/sgRNA system. The cGVHD was induced by an intraperitoneal injection of the bm12 donor splenocytes into recipients, either B6 wild-type or knock-in mice. Mice were sacrificed on day 14 and 28. Flow cytometry was used to analyze frequencies of immunocytes from mice splenocytes. Enzyme-linked immunosorbent assay was applied to detect antibodies in serum. Results Compared with the wild-type mice, the LILRA3 knock-in mice displayed a more severe immune response on both day 14 and day 28 of post induction. Spleen mass were significantly increased in LILRA3 knock-in mice (p Conclusions Our data indicate that LILRA3 promotes lupus-like disease probably through the excessive expression of Tfh cells and GC B cells, subsequently help for the induction and maintenance of plasma cell differentiation and autoantibody production. Funding Source(s): None