Abstract Antiphospholipid syndrome (APS) is a heterogeneous autoimmune disease with persistent antiphospholipid antibodies. This study aimed to identify unrecognized APS subgroups from multicenter cohorts ( n = 760, training: n = 415; validation: n = 345). Patients are stratified through unsupervised K‐means clustering analysis. Prognostic outcomes are evaluated using Kaplan‐Meier survival analyses. Proteomic analysis is conducted on primary APS patients ( n = 36) and healthy controls ( n = 12). Key molecule insulin‐like growth factor 1 is validated using ELISA. Three clusters are identified. Cluster 1 ( n = 320, 42.1%) is completely consisted of females (100%), with predominant occurrence of pregnancy morbidity (88.8%) but low incidences of thrombocytopenia (18.4%) and thrombosis (15.0%), and a favorable prognosis. Cluster 2 ( n = 309, 40.7%) is predominantly female (99.4%) and characterized by high thrombosis (85.8%) and thrombocytopenia (46.6%), low pregnancy morbidity (13.6%), and poor prognosis. Cluster 3 ( n = 131, 17.2%) is predominantly male (99.2%), exhibiting highest thrombosis (96.2%) and moderate thrombocytopenia (32.8%), with worst prognosis. Immunological and proteomic analyses clearly differentiated three clusters. This study reveals a distinct difference between obstetric and thrombotic APS, and a sex‐based distinction within thrombotic APS. Three APS subgroups display unique clinical and molecular characteristics, and marked difference in prognostic outcomes.
Leukocyte immunoglobulin-like receptor A3 (LILRA3) belongs to the multigene LILR family with unique feature of a presence or absence of 6.7-kb variation among individuals. The frequencies of the 6.7-kbdeletion 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. We undertook current study to investigate i) the frequencies of 6.7-kb deletion among Han Chinese subpopulations. ii) whether the functional LILRA3 is a novel susceptibility factor for ankylosing spondylitis (AS), and iii) whether LILRA3 influences the disease activity in AS.
Background: Emerging evidence has emphasized the functional of microbiota in the etiopathogenesis of rheumatoid arthritis (RA). Previously we and other groups have demonstrated that the urinary infection was implicated in the pathogenesis of RA. However, the profile of urinary microbiota and its association with RA remains to be investigated.Methods: The study cohort consisted of 39 patients with RA, including 8 treatment-naïve patients, and 37 age- and sex-matched healthy controls. The clean midstreams of urine samples were collected from both groups. The microbial profiles and bacterial loads of urinary microbiota were identified and quantified by 16S ribosomal RNA (16S rRNA) gene sequencing and quantitative PCR, respectively. The compositions of urinary microbiota and its associations with clinical and molecular characteristics were analyzed. The urinary metabolites were detected by gas chromatography.Findings: Compared to healthy controls, the urinary microbiota from RA patients displayed an increase in microbial richness with a decrease in microbial dissimilarity. There were 40 altered genera with absolute quantities in patients with RA, including 31 enriched (Proteus, Faecalibacterium, Bacteroides, etc.) and 9 deficient genera (Arcanobacterium, Rothia, Megasphaera, Ureaplasma, etc.). These RA-associated urinary taxa achieved a performance power of 84.6% for discriminating RA patients from healthy controls. Notably, the RA-enriched, but not deficient genera, were correlated with elevated disease duration, anti-CCP antibodies, joint damages, and increase of circulating LPS binding protein (LBP) and soluble CD14. Furthermore, the compositions of the urinary metabolites, including proline, citric acid and oxalic acid, were significantly different in RA patients from healthy controls. These RA-associated urinary metabolites showed close correlations with urinary microbiota.Interpretation: An increased microbial richness and shifted compositional profiles are found in the urinary microbiota of RA patients, which is strongly associated with immunological and metabolic changes in RA.Funding: National Natural Science Foundation of China and Beijing Municipal Science & Technology Commission.Declaration of Interest: None to declare. Ethical Approval: Approval for the study was obtained from the Medical Ethics Committee of Peking University People’s Hospital.
To analyze the relationship between ectopic germinal centers (GCs) in the salivary glands and the clinical/laboratory characteristics of patients with Sjögren's syndrome (SS).Retrospectively, 126 patients with primary SS (pSS) and 16 patients with secondary SS (sSS) were analyzed. Minor salivary gland biopsies were evaluated for the presence of GC-like morphology by hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining for CD21. Clinical and serological data were obtained from medical records.GC-like structures were observed in 36/126 (28.6%) pSS patients and 4/16 (25.0%) sSS patients. The mean inflammatory focus score of the gland was significantly higher in GC-positive samples than in GC-negative ones in both pSS and sSS patients (P = 0.007 and 0.024, respectively). In pSS, significantly elevated titers of rheumatoid factor (RF)-IgM (P = 0.023) and antinuclear antibodies (ANA) (P = 0.036), increased levels of IgA (P = 0.012) and IgG (P = 0.017) were encountered in GC-positive patients. The GC-positive group also presented higher prevalence of anti-SSA antibodies, lower levels of white blood cells, higher levels of erythrocyte sedimentation rate and γ-globulin, although not statistically significant. In sSS patients with ectopic GC formation, ANA titers were remarkably elevated. The anticyclic citrullinated peptide (anti-CCP)-IgG titers and the prevalence of antikeratin antibody (AKA)-IgG, antiperinuclear factor (APF)-IgG were also increased, yet not significantly. GCs were found to be associated with antibody and immunoglobulin production.This study indicates that SS patients with ectopic GCs have distinct features. Ectopic GC structures were particularly noted in patients with higher focus scores, and might play an essential role in sustaining antibody production as well as B cell activation.
Objectives . IL-33, a newly found cytokine which is involved in joint inflammation, could be blocked by a decoy receptor—sST2. The expression and correlation of IL-33 and sST2 in rheumatoid arthritis (RA) are of great interest. Methods . Synovial fluid (SF) was obtained from 120 RA and 30 osteoarthritis (OA) patients, and paired sera were collected from 54 of these RA patients. The levels of IL-33 and sST2 were measured by ELISA. Results . SF IL-33 was significantly higher in RA than in OA, which was correlated with disease activity score 28, erythrocyte sedimentation rate, rheumatoid factor (RF)-IgM, RF-IgG, glucose phosphate isomerase (GPI), and immunoglobulin. Serum IL-33 was correlated positively with SF IL-33 in RA. Furthermore, it was correlated with RF-IgM and GPI. sST2 was partly detectable in RA (13 out of 54, 24.1%), while not in OA. Serum sST2 in RA had no significant correlation with serum IL-33 or SF IL-33. However, SFs from both RA and OA patients did not express sST2. Conclusions . This study supported that IL-33 played an important role in the local pathogenesis of RA. Considering the tight correlation between IL-33 and clinical features, it may become a new target of local treatment.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
Objective
To detect the anti-citrullinated alpha-enolase peptide 1(CEP-1) antibody in rheumatoid arthritis(RA).
Methods
One hundred and twenty-nine patients with RA were enrolled randomly. Thirty-one patients with primary Sjogren's syndrome (pSS), 32 patients with systemic lupus erythematosus (SLE), 32 patients with osteoarthritis (OA), and 106 healthy controls (HC) were include into this study. Anti-CEP-1 antibody was detected by enzyme-linked immunosorbent assay (ELISA). The correlations between serum anti-CEP-1 antibody and clinical features, disease activities, laboratory tests or Sharp scores of RA patients were evaluated. Mann-Whitney U test and χ2 test were used for statistical analysis.
Results
①Anti-CEP-1 antibodies were positive in 64.3%(83/129) of RA patients, 22.6%(7/32) of pSS patients, 12.5%(4/32) of SLE patients, none of OA patients (0/32) or healthy controls. The positivity of anti-CEP-1 antibody was significantly higher than those in pSS (χ2=17.7), SLE (χ2=25.7), OA (χ2=42.5), and healthy controls (χ2=102.6) (P<0.01, respectively). The specificity of anti-CEP-1 antibody in RA was 94.5%. ② In patients without anti-citrullinated protein/peptide autoantibodies (ACPA), rheumatoid factor (RF) or the patients without ACPA and RF, the positive rate of anti-CEP-1 antibody was 30.3%(10/33), 41.9%(18/43) and 22.7%(5/22), respectively. ③ Compared with patients without anti-CEP-1 antibodies, patients with anti-CEP-1 anti-bodies had higher rates of joint deformity, bone erosion and high disease activities (P<0.05, respectively). ④ Higher rate of interstitial lung disease (ILD) was found in RA patients with anti-CEP-1 antibody (19.3% vs 4.3%, χ2=5.494, P<0.05). ⑤ The patients with anti-CEP-1 anti-body had higher rates of elevated erythrocyte sedimentation rate (ESR) (χ2=6.543) and decreased serum albumin (χ2=6.59), compared to patients without anti-CEP-1 antibody (P<0.05, respectively).
Conclusion
Anti-CEP-1 antibody has high sensitivity and specificity for RA diagnosis. Combination of anti-CEP-1 antibody with other RA antibodies might improve the early diagnosis of RA. Anti-CEP-1 antibody is significantly associated with joint damage, disease activity and pulmonary interstitial fibrosis.
Key words:
Arthritis, rheumatoid; Diagnosis; Anti-CEP-1 antibody
Macrophage activation syndrome (MAS) is a rare and life-threatening disease, characterized by inappropriate activation of lymphocytes and histiocytes, leading to a cytokine storm, haemophagocytosis and multi-organ damage. Our previous studies demonstrated that the leukocyte immunoglobulin-like receptors A3 (LILRA3) plays a pathogenic role in multiple autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus and antiphospholipid syndrome. However, the role of LILRA3 in MAS has not been investigated. This study was undertaken to examine the in vivo role of LILRA3 in MAS model.
Methods
To functionally study the role of LILRA3 in MAS pathogenesis, we generated a novel LILRA3 knock-in (LILRA3-KI) mouse. Human LILRA3 gene (Gene ID: 11026) was inserted into Rosa26 allele in C57BL/6 (B6) mice based on Cas9/sgRNA system. The MAS-like disease model was induced by repeated intraperitoneal injection of CpG-ODNs in either B6 wild-type (B6-WT) or LILRA3-KI mice. Mice were assessed for the development of splenomegaly, hematological indices, immune cellular response, cytokine expression, and spleen pathology.
Results
Compared with untreated B6-WT control mice, both B6-WT and LILRA3-KI treated mice displayed decreased haemocytes; inappropriate activation of lymphocytes; increased organ damage; and elevated levels of cytokines. Notably, compared with CpG-ODN treated B6-WT mice, the treated LILRA3-KI mice displayed a less pronounced MAS-like phenotypes and immune responses, including an increase of erythrocytes, hemoglobin, and platelets; an expansion of CD4+ and CD8+ T cells; decreased spleen enlargement; less disorganized spleen architecture and inflammatory cell infiltration; and reduced serum levels of cytokines (IL-6, IL-10, IL-12p70, IL-18 and IFN-γ).
Conclusions
Our data indicate that LILRA3 plays a protective role in MAS-like disease probably through suppressing the inappropriate activation of both CD4+ and CD8+ T cells, and subsequently leading to decreased production of cytokines, less haemophagocytosis and reduced spleen impairment.
Leukocyte immunoglobulin-like receptor A3 (LILRA3) is the soluble protein of LILRs family. LILRA3 exhibits a 6.7-kb deletion variation among individuals. The deletion removes all of four Ig-like domains, resulting in a 'non-functional LILRA3'. Our research group identified the functional LILRA3 as a novel genetic risk for systemic lupus erythematosus. The aim of this study was to functionally characterize the impact of LILRA3 in the pathogenesis of SLE.
Methods
We constructed a humanized LILRA3 knock-in (LILRA3-KI) mouse in C57BL/6 (B6) mice background. The lupus-like disease was induced by repeated epicutaneous stimulation with Toll-like receptor (TLR)-7 agonist imiquimod (IMQ) on both ears of mice. All of the mice were euthanized four weeks after the initiation of treatment. The spleen and serum samples were collected. Immunocyte populations were determined by staining with fluorescently-conjugated antibodies and analysed by flow cytometry. Serum antibodies were detected by enzyme-linked immunosorbent assay (ELISA).
Results
The mice developed lupus-like disease following 4 weeks of treatment with imiquimod. LILRA3-KI mice exposed to imiquimod showed increased innate and adaptive immune response, including splenomegaly (p < 0.05) and elevated levels of serum anti-dsDNA IgG (p < 0.05), compared to WT mice. The frequencies of M1 macrophage, M2 macrophage, T follicular helper cells (Tfh), germinal center (GC) B, and plasma B cells were increased in KI mice (p < 0.05).
Conclusions
Our data demonstrated that LILRA3 promoted the TLR7-driven lupus autoimmunity with the excessive expansion of macrophages, Tfh, GC B, and plasma B cells.
Palatine tonsils are the only air-contacted lymphoid organs that constantly engage in crosstalk with commensal microorganisms and serve as the first handling sites against microbial antigens. While tonsil inflammations have been implicated in various autoimmune diseases, including rheumatoid arthritis (RA), the precise role of tonsillar microbiota in autoimmune pathogenesis remains inadequately characterized. In this study, we conducted a profiling of the tonsillar microbiota and identified a notable dysbiosis in RA patients, particularly within the Streptococcus genus. Specifically, RA patients exhibited an enrichment of pathogenic Streptococcus species, including S. pyogenes, S. dysgalactiae, and S. agalactiae. Colonization with these bacteria significantly exacerbated arthritis severity and increased autoimmune responses in collagen-induced arthritis (CIA). Furthermore, immunization with peptides derived from these pathogenic Streptococcus species directly induced experimental arthritis. Conversely, RA patients demonstrated a marked deficiency in commensal Streptococcus members, notably S. salivarius. Treatment of CIA mice with S. salivarius attenuated the progression of arthritis and downregulated autoimmune responses. These findings highlight a functional link between tonsillar microbiota and RA, shedding light on their contribution to autoimmunity.
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