Low-dose IL-2 mitigates glucocorticoid-induced Treg impairment and promotes improvement of SLE

Dear Editor,Previous studies have proved that regulatory T cell(Treg)insufficiency contributed to the development of autoimmune conditions including systemic lupus erythematosus(SLE).Conventional immunosuppressive treatment was reported to downregulate beneficial Tregs together with pathogenic effector immune cells,which may impede a rapid achievement of optimal therapeutic effects.

Treatment of STING-associated vasculopathy with onset in infancy

To the Editor:Gain-of-function mutations in TMEM173,which encodes the protein stimulator of interferon(IFN)genes(STING),can reportedly cause an autoinflammatory syndrome termed STING-associated vasculopathy with onset in infancy(SAVI).1-3 SAVI is characterized by cutaneous necrotic lesions,growth failure,systemic inflammation,and interstitial lung disease.1,4 Therapeutic management is challenging and difficult:steroids are only partially effective,and patients respond poorly to immunosuppressants.

Efficacy and safety of low-dose interleukin-2 in combination with methotrexate in patients with active rheumatoid arthritis:a randomized,double-blind,placebo-controlled phase 2 trial

Rheumatoid arthritis(RA)is an aggressive autoimmune arthritis,and current therapies remain unsatisfactory due to low remission rate and substantially adverse effects.Low-dose interleukin-2(Ld-IL2)is potentially a therapeutic approach to further improve the disease.This randomized,double-blind,placebo-controlled trial was undertaken to evaluate the efficacy and safety of Ld-IL2 in patients with active RA.Patients were randomly assigned(1:1)to receive Ld-IL2,defined as a dose of 1 million IU,or placebo in a 12-week trial with a 12-week follow-up.Three cycles of Ld-IL2 or placebo were administered subcutaneously every other day for 2 weeks(a total of 7 doses),followed by a 2-week break.All patients received a stable dose of methotrexate(MTX).The primary outcomes were the proportion of patients achieving the ACR20,DAS28-ESR<2.6,and the change from baseline in CDAI or SDAI at week 24.Secondary endpoints included other clinical responses and safety.The primary outcomes were achieved in the perprotocol population.The improvements from baseline in CDAI and SDAI were significantly greater across time points for the LdIL2+MTX group(n=17)than for the placebo+MTX group(n=23)(P=0.018 and P=0.015,respectively).More patients achieved ACR20 response in the Ld-IL2+MTX group than those in the placebo+MTX group at week 12(70.6%vs 43.5%)and at week 24(76.5%vs 56.5%)(P=0.014).In addition,low Treg and high IL-21 were associated with good responses to Ld-IL2.Ld-IL-2 treatment was well-tolerated in this study.These results suggested that Ld-IL2 was effective and safe in RA.ClinicalTrials.gov number:NCT 02467504.

Anatomy of the perirectal fascia at the level of rectosacral fascia revisited

Background:The relative anatomical understanding of the perirectal fasciae is of paramount importance for the proper performance of total mesorectal excision(TME).This study was to demonstrate the planes of TME and validates the intraoperative findings using cadaveric observations.Methods:In this combined retrospective and prospective study,bilateral attachment of the rectosacral fascia(RSF)was observed in 28 cadaveric specimens(male,n=14;female,n=14).From January 2018 to December 2019,surgical videos of 67 patients who underwent laparoscopic TME at the Affiliated Union Hospital of Fujian Medical University(Fuzhou,China)were reviewed and interpreted with the cadaveric findings.Results:The RSF(synonym:Waldeyer’s fascia)is the end of the pre-hypogastric fascia at the level of S4 and comprises two layers(upper and lower).These two layers provide double fascial protection for the venous sacral plexus.It inserts into the fascia propria of the rectum along a broad horizontal arc that merges anterolaterally in an oblique downward direction until it meets the posterolateral merge of Denonvilliers’fascia at the lateral rectal ligament(LRL).This ligament does not look like a true ligament but is more likely to be a fascial combination that cushions the rectal innervation and middle rectal vessels.Conclusions:Understanding the lateral attachment of RSF and its contribution to LRL provides invaluable surgical guidance to dissect this critical area.Therefore,lateral dissection is proposed from the anterior to the posterior direction to find the correct plane that guarantees an intact mesorectal envelope to protect the important nearby nerve structures.

The“terminal line”:a novel sign for the identification of distal mesorectum end during TME for rectal cancer

Background:Although the clinical importance of complete,intact total mesorectal excision(TME)is the widely accepted standard for decreasing local recurrence of rectal cancer,the residual mesorectum still represents a significant component of resection margin involvement.This study aimed to use a visible intraoperative sign to detect the distal mesorectal end to ensure complete inclusion of the mesorectum and avoid unnecessary over-dissection.Methods:The distal mesorectum end was investigated retrospectively through a review of 124 operative videos at the Union Hospital of Fujian Medical University(Fujian,China)and Cleveland Clinic(Ohio,USA)by two independent surgeons who were blinded to each other.Furthermore,28 cadavers and 44 post-operative specimens were prospectively examined by hematoxylin and eosin(H&E)staining and Masson’s staining to validate and confirm the findings of the retrospective part.Univariate and multivariate analyses were carried out to detect the independent factors that can affect the visualization of the distal mesorectal end.Results:The terminal line(TL)is the distal mesorectal end of the transabdominal and transanal TME(taTME)and appears as a remarkable pearly white fascial structure extending posteriorly from 2 to 10 o’clock.Histopathological examination revealed that the fascia propria of the rectum merges with the presacral fascia at the TL,beyond which the mesorectum ends,with no further downward extension.In the retrospective observation,the TL was seen in 56.6%of transabdominal TME and 56.0%of taTME operations.Surgical approach and tumor distance from the anal verge were the independent variables that directly influenced the detection of the TL(P=0.03 and P=0.01).Conclusion: The TL is a visible sign where the transabdominal TME should end and the taTME should begin. Recognitionof the mesorectal end may impact the certainty of complete mesorectum inclusion. Further clinical trials are needed toconfirm the preliminary findings.

Identification of lipopolysaccharide-binding protein as a novel citrullinated autoantigen in rheumatoid arthritis

Background:A specific feature of the autoimmune response in rheumatoid arthritis(RA)is the presence of anti-citrullinated protein antibodies(ACPAs)in patient sera.These antibodies can appear several years before disease onset and are involved in the development of RA.Objective:We performed proteomic analysis by mass spectroscopy to identify novel citrullinated antigens and autoantibodies in RA patients.Methods:Polypeptides isolated from the sera of RA patients were identified by Orbitrap high-precision mass spectrometry and then citrulline-containing proteins were selected.The levels of ACPAs against these newly identified citrullinated autoantigens in sera of 100 RA patients and 50 healthy controls were determined by enzyme-linked immunosorbent assays.Results:A total of 135 proteins were identified in RA patients and the protein profile included 11 citrulline-containing antigens.Three of the 11 citrullinated proteins had been reported in previous studies.ACPAs against the novel citrullinated epitopes from these proteins were increased in sera from the RA patients compared with those from healthy controls.Autoantibodies against one of the citrullinated antigens,lipopolysaccharide-binding protein(LBP),was significantly increased in RA patients and associated with disease activities.The titer of anti-citrullinated LBP antibodies(anti-cLBP)was closely related to the infection incidence in RA patients.Conclusion:Serum protein analysis by high-precision proteomic technology is a feasible method to identify novel citrullinated epitopes in RA patients.Anti-cLBP antibodies are associated with disease severity and infection in RA patients.

Effect of nucleating agents on the electrical properties of cross-linked polyethylene under tensile stress

During the operation of high-voltage cables,external stress and residual stress can affect the aggregated structure of insulating materials and lead to significant deterioration in their electrical performance.To investigate the evolution characteristics of the electrical properties of cross-linked polyethylene(XLPE)under mechanical stress,this paper ex-plains the relationship between the aggregated structure of XLPE and its electrical properties and proposes a method for improving insulation performance under me-chanical stress.The results show that metallocene polyethylene used as a nucleating agent can promote crystallisation through heterogeneous nucleation and increase Young's modulus by non-uniform nucleation,increasing crystallinity and reducing interplanar spacing,resulting in more complete crystal forms and reduced damage to the aggregated structure during the tensile process.After nucleating agent modification,the XLPE crystallisation becomes more uniform,and interfacial adhesion forces increase.The weakened interface damage process between the amorphous and crystalline regions under tensile stress effectively inhibits the process of molecular chain polarisation turning and reduces trap density.The modified XLPE crystal structure shows a tendency towards densification and enhanced molecular chain interactions,which can reduce the damage to the aggregated structure under tensile stress,while the reduced free volume inside the material and the shortened average free path of carriers can weaken the damage of high-energy electrons to molecular chains,thereby inhibiting the process of electrical tree degradation.The results show that nucleating agents have great potential for maintaining the stable operation of XLPE cables under mechanical stress.