Remodeled structure and reduced contractile responsiveness of ocular ciliary artery in spontaneously hypertensive rats

AIM: To investigate the alterations in both structure and contractile responsiveness of ocular ciliary artery(OCA) in spontaneously hypertensive rat(SHR).METHODS: In this experiment, 20-week-old male SHR and Wistar Kyoto rat(WKY) were studied. The heart rate(HR), the blood pressure(BP; the systolic BP and the diastolic BP) of rats with an electronic sphygmomanometer were measured. Vascular morphometry and isometric tension measurement were used to investigate the alterations in structure and contractility of OCA.RESULTS: A general narrowing of OCAs was observed in SHR compared to the control WYK. In SHR, the media of OCAs were thicker, the luminal diameters were smaller, and the media-to-lumen ratios were higher when compared with WKY(P<0.05). The contractions of OCAs evoked by norepinephrine were smaller in SHR compared to control(P<0.05). Then, OCAs were pretreated with iberiotoxin, L-NAME, or indomethacin 30 min before norepinephrineinduced contraction. Iberiotoxin(0.1 μmol/L) has not changed the norepinephrine-induced contractions in OCAs from both groups. However, L-NAME(100 μmol/L) increased the vasoconstrictions, the increased extents were similar in SHR and WKY(P>0.05). Indomethacin(10 μmol/L) decreased the contractions induced by norepinephrine in OCAs from WKY(P<0.05), but did not change those contractions in vessels from SHR(P>0.05).CONCLUSION: Our results demonstrate that the structure and function of OCAs are altered in hypertension. OCAs from SHR are remodeled with decreased lumen diameter and increased media-to-lumen ratio. Moreover, the contractile responsiveness of OCAs from SHR is diminished due to the disruption of vasoconstrictive effect of prostaglandins.

Endoscopic findings of gastrointestinal involvement in Chinese patients with Behcet's disease

AIM:To report the incidence,clinical features and outcomes of gastrointestinal(GI)involvement in Behcet’s disease(BD).METHODS:A total of 168 consecutive patients with BD were screened and upper and lower GI endoscopies were performed in 148 patients.Four hundred age-and sex-matched controls were enrolled for comparison.RESULTS:Fifty-two(35.1%)patients had GI lesions.After a mean follow-up of 10 mo,ileocecal ulcers had been confirmed in 20 patients,including active ulcer(s)in 18 patients,but no ileocecal ulceration was found in controls.GI symptoms were present in 14 patients with active ulcer(s),while 4 patients with smaller ulcer were asymptomatic.Endoscopic features of ileocecalulcer were:a single ulcer(50%),larger than 1 cm in diameter(72.2%),and round/oval or volcano-type in shape(83.3%).Compared with patients without GI involvement,less ocular lesions,lower levels of albumin,erythrocyte count and hemoglobin,and higher levels of C-reactive protein and erythrocyte sedimentation rate were confirmed in the intestinal BD group.Four patients had esophageal ulcers in the BD group but no case in controls.The other endoscopic findings were similar between the two groups.The prevalence of Helicobacter pylori infection was similar in both groups.Most patients received an immunomodulator and responded well.CONCLUSION:GI lesions commonly occur in Chinese BD patients.The most frequently involved area is the ileocecal region.Esophageal ulcer might be a rare but unique lesion.

Gut microbial metabolite targets HDAC3-FOXK1-interferon axis in fibroblast-like synoviocytes to ameliorate rheumatoid arthritis

Rheumatoid arthritis(RA)is an autoimmune disease.Early studies hold an opinion that gut microbiota is environmentally acquired and associated with RA susceptibility.However,accumulating evidence demonstrates that genetics also shape the gut microbiota.It is known that some strains of inbred laboratory mice are highly susceptible to collagen-induced arthritis(CIA),while the others are resistant to CIA.Here,we show that transplantation of fecal microbiota of CIA-resistant C57BL/6J mice to CIA-susceptible DBA/1J mice confer CIA resistance in DBA/1J mice.C57BL/6J mice and healthy human individuals have enriched B.fragilis than DBA/1J mice and RA patients.Transplantation of B.fragilis prevents CIA in DBA/1J mice.We identify that B.fragilis mainly produces propionate and C57BL/6J mice and healthy human individuals have higher level of propionate.Fibroblast-like synoviocytes(FLSs)in RA are activated to undergo tumor-like transformation.Propionate disrupts HDAC3-FOXK1 interaction to increase acetylation of FOXK1,resulting in reduced FOXK1 stability,blocked interferon signaling and deactivation of RA-FLSs.We treat CIA mice with propionate and show that propionate attenuates CIA.Moreover,a combination of propionate with anti-TNF etanercept synergistically relieves CIA.These results suggest that B.fragilis or propionate could be an alternative or complementary approach to the current therapies.

系统性红斑狼疮孕妇早产及先兆子痫发病的预测因子

Objective: The purpose of this study was to describe the outcomes of a 10- year cohort of pregnancies in patients with systemic lupus erythematosus and to evaluate clinical and laboratory markers for adverse outcomes. Study design: We reviewed all pregnancies in patients with systemic lupus erythematosus who were seen at Stanford University from 1991 to 2001. Univariate analyses were performed to identify potential risk factors for adverse outcomes. Results: Sixty-three pregnancies in 48 women were identified. Approximately 35% of the pregnancies occurred in women with previous renal disease and 10% in women with previous central nervous system disease. Flares occurred in 68% of the pregnancies, the majority of which were mild to moderate. Preeclampsia complicated 12 pregnancies. Factors that were associated with premature delivery included prednisone use at conception (relative risk, 1.8), the use of antihypertensive medications (relative risk, 1.8), and a severe flare during pregnancy (relative risk, 2.0). Thrombocytopenia was associated with an increased risk of preeclampsia (relative risk, 3.2). Conclusion: Flares, most of which were mild to moderate, occurred most of the pregnancies in our cohort of patients with systemic lupus erythematosus. Thrombocytopenia, hypertension, and prednisone use may be predictive factors for particular adverse outcomes.

SARS-CoV-2 infection of monocytes:balancing acts of antibodies and inflammasomes

In a recent study in Nature,Junqueira et al.provided evidence that severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infects human monocytes and lung macrophages.1 The infection is antibody-mediated via Fc-receptors(FcγRs),and activates NLRP3 and AIM2 inflammasomes,which in turn induce pyroptosis and halt viral replication.Infected monocytes secrete the proinflammatory cytokines interleukin-1β(IL-1β)and IL-18,which contribute to systemic inflammation and severe coronavirus disease 19(COVID-19)(Fig.1).

Infliximab therapy and outcomes in patients with polyarticular juvenile idiopathic arthritis:a single-center study in China

Background Juvenile idiopathic arthritis(JIA)is a chronic inflammatory disease that includes seven heterogeneous subgroups with different prognoses.In particular,polyarticular JIA(pJIA)has a longer period of active disease and a poorer prognosis.Tumor necrosis factor(TNF)-alpha inhibitors are effective in patients with pJIA,but the therapeutic regimen remains controversial.Here,we performed a single-center study to determine the potential correlation between TNF-alpha inhibitor(infliximab)therapy and outcomes in these patients.Methods Clinical data of 40 pJIA patients were collected at our center from January 1,2010 to January 1,2018,and patients were grouped according to the timing of infliximab therapy.The erythrocyte sedimentation rate(ESR),the number of joints with active disease,and the 27-point juvenile arthritis disease activity score(JADAS-27)were analyzed.Results The ESR,the active joint count,and the JADAS-27 decreased significantly in all groups after 3 months(P=0.041/0.415/0.008,0.022/0.030/<0.001,and 0.05/0.012/<0.001,respectively)and 6 months(P=0.036/0.045/0.041,0.076/0.037/<0.001,and 0.096/0.006/<0.001,respectively)of infliximab treatment,although the rates of change of these parameters were similar.However,after 12 months,only patients treated with infliximab within 3 months of disease onset had a stable ESR,active joint count,and JADAS-27,while these parameters increased sharply when infliximab was administered 3 months and especially 1 year after disease onset.Conclusions TNF-alpha is a pleiotropic pro-inflammatory cytokine of crucial importance in the pathogenesis of JIA.Infliximab can improve the outcomes of patients with pJIA significantly,and should be introduced early during the clinical course.

Mechanism-driven strategies for prevention of rheumatoid arthritis

In seropositive rheumatoid arthritis(RA),the onset of clinically apparent inflammatory arthritis(IA)is typically preceded by a prolonged period of autoimmunity manifest by the presence of circulating autoantibodies that can include antibodies to citrullinated protein antigens(ACPA)and rheumatoid factor.This period before clinical IA can be designated preclinical RA in those individuals who have progressed to a clinical diagnosis of RA,and an“at‐risk”status in those who have not developed IA but exhibit predictive biomarkers of future clinical RA.With the goal of developing RA prevention strategies,studies have characterized immune phenotypes of preclinical RA/at-risk states.From these studies,a model has emerged wherein mucosal inflammation and dysbiosis may lead first to local autoantibody production,which should normally be transient,but instead is followed by a systemic spread of the autoimmunity as manifested by serum autoantibody elevations,ultimately driving the development of clinically identified joint inflammation.This model can be envisioned as the progression of disease development through serial“checkpoints”that in principle should constrain or resolve autoimmunity;however,instead,the checkpoints“fail”and clinical RA develops.Herein we review the immune processes that are likely to be present at each step and the potential therapeutic strategies that could be envisioned to delay,diminish,halt,or even reverse the progression to clinical RA.Notably,these prevention strategies could utilize existing therapies approved for clinical RA,therapies approved for other diseases that target relevant pathways in the preclinical/at-risk state,or approaches that target novel pathways.

Advances in the role of follicular T helper cells in graft versus host diseases

Graft versus host disease(GVHD)is a refractory complication of allogeneic hematopoietic stem cell transplantation for the treatment of malignant and non-malignant hematopoietic diseases.Inflammatory cascade responses and cellular immune reactions are the major factors underlying GVHD pathogenesis.Cells producing the cytokine,interleukin(IL)-21 are crucial players involved in injured tissues in GVHD patients.Besides T helper 17 cells,follicular T helper(Tfh)cells are a new source of IL-21 and play a vital role in GVHD pathogenesis.Tfh cell function is mostly regulated by T-follicular regulatory(Tfr)cells that are also located in the germinal center.This review highlights recent advances in the role of Tfh and Tfr cell function in GVHD pathogenesis.New insights are provided into the potential for clinical application in GVHD prevention and treatment.

Multiplexed cytokine detection on plasmonic gold substrates with enhanced near-infrared fluorescence

Protein microarrays based on fluorescence detection have been widely utilized for high-throughput functional proteomic analysis. However, a drawback of such assays has been low sensitivity and narrow dynamic range, limiting their capabilities, especially for detecting low abundance biological molecules such as cytokines in human samples. Here, we present fluorescence-enhancing microarrays on plasmonic gold films for multiplexed cytokine detection with up to three orders of magnitude higher sensitivity than on conventional nitrocellulose and glass substrates. Cytokine detection on the gold plasmonic substrate is about one to two orders of magnitude more sensitive than enzyme-linked immunosorbent assay （ELISA） and can be multiplexed. A panel of six cytokines （Vascular endothelial growth factor （VEGF）, Interleukin 1β （IL-1β）, Interleukin 4 （IL-4）, Interleukin 6 （IL-6）, Interferon γ （IFN-γ）, and Tumor necrosis factor （TNF）） were detected in the culture media of cancer cells. This work establishes a new method of high throughput multiplexed cytokine detection with higher sensitivity and dynamic range than ELISA.

CD4＋VEGFR1HIGH T cell as a novel Treg subset regulates inflammatory bowel disease in lymphopenic mice

Regulatory T cells （Tregs） are a specialized subpopulation of T cells that control the immune response and thereby maintain immune system homeostasis and tolerance to self-antigens. Many subsets of CD4＋ Tregs have been identified, including Foxp3~, Trl, Th3, and Foxp3neg iT（R）35 cells. In this study, we identified a new subset of CD4＋VEGFR1high Tregs that have immunosuppressive capacity. CD4＋VEGFRlhigh T cells, which constitute approximately 1.0% of CD4＋ T cells, are hyporesponsive to T-cell antigen receptor stimulation. Surface marker and FoxP3 expression analysis revealed that CD4＋VEGFR1high T cells are distinct from known Tregs. CD4＋VEGFR1high T cells suppressed the proliferation of CD4＋CD25- T cell as efficiently as CD4＋CD25high natural Tregs in a contact-independent manner. Furthermore, adoptive transfer of CD4＋VEGFR1＋ T cells from wild type to RAG-2-deficient C57BL/6 mice inhibited effector T-cell-mediated inflammatory bowel disease. Thus, we report CD4＋ VEGFR1high T cells as a novel subset of Tregs that regulate the inflammatory response in the intestinal tract.