Mechanistic immunological based classification of rheumatoid arthritis

The classical autoimmunity paradigm in rheumatoid arthritis (RA) is strongly supported by immunogenetics suggesting follicular helper T-cell responses driving high titre specific autoantibodies that pre-dates disease onset. Using the immunological disease continuum model of inflammation against self with “pure” adaptive and innate immune disease at opposite boundaries, we propose a novel immune mechanistic classification describing the heterogeneity within RA. Mutations or SNPs in autoinflammatory genes including MEFV and NOD2 are linked to seronegative RA phenotypes including some so called palindromic RA cases. However, just as innate and adaptive immunity are closely functionally integrated, some ACPA+ RA cases have superimposed “autoinflammatory” features including abrupt onset attacks, severe attacks, self-limiting attacks, relevant autoinflammatory mutations or SNPs and therapeutic responses to autoinflammatory pathway therapies including colchicine and IL-1 pathway blockade. An emergent feature from this classification that non-destructive RA phenotypes, both innate and adaptive, have disease epicentres situated in the extracapsular tissues. This mixed innate and adaptive immunopathogenesis may be the key to understanding severe disease flares, resistant disease subsets that are unresponsive to standard therapy and for therapies that target the autoinflammatory component of disease that are not currently considered by expert therapeutic recommendations.     

ZnO Nanoparticles Impose a Panmetabolic Toxic Effect Along with Strong Necrosis,Inducing Activation of the Envelope Stress Response in Salmonella enterica Serovar Enteritidis

In this study, we tested the antimicrobial activity of three metal nanoparticles (NPs), ZnO, MgO, and CaO NPs, against Salmonella enterica serovar Enteritidis in liquid medium and on solid surfaces. Out of the three tested metal NPs, ZnO NPs exhibited the most significant antimicrobial effect both in liquid medium and when embedded on solid surfaces. Therefore, we focused on revealing the mechanisms of surface-associated ZnO biocidal activity. Using the global proteome approach, we report that a great majority (79%) of the altered proteins in biofilms formed by Salmonella enterica serovar Enteritidis were downregulated, whereas a much smaller fraction (21%) of proteins were upregulated. Intriguingly, all downregulated proteins were enzymes involved in a wide range of the central metabolic pathways, including translation; amino acid biosynthetic pathways; nucleobase, nucleoside, and nucleotide biosynthetic processes; ATP synthesis-coupled proton transport; the pentose phosphate shunt; and carboxylic acid metabolic processes, indicating that ZnO NPs exert a panmetabolic toxic effect on this prokaryotic organism. In addition to their panmetabolic toxicity, ZnO NPs induced profound changes in cell envelope morphology, imposing additional necrotic effects and triggering the envelope stress response of Salmonella serovar Enteritidis. The envelope stress response effect activated periplasmic chaperones and proteases, transenvelope complexes, and regulators, thereby facilitating protection of this prokaryotic organism against ZnO NPs.     

Clinical significance of high c-MYC and low MYCBP2 expression and their association with Ikaros dysfunction in adult acute lymphoblastic leukemia

Increased expression of c-MYC is observed in both Acute Myeloid Leukemia (AML) and T- cell Acute Lymphoblastic Leukemia (T-ALL). MYC binding protein 2 (MYCBP2) is a probable E3 ubiquitin ligase and its function in leukemia is unknown. IKZF1 deletion is associated with the development and poor outcome of ALL. Here, we observed significant high c-MYC expression and low MYCBP2 expression in adult ALL patients. Patients with high c-MYC expression and/or low MYCBP2 expression had higher WBC counts and a higher percentage of CD34+ or CD33+ cells, as well as splenomegaly, liver infiltration, higher BM blasts, and lower CR rate. Ikaros bound to the regulatory regions of c-MYC and MYCBP2, suppressed c-MYC and increased MYCBP2 expression in ALL cells. Expression of c-MYC mRNA was significantly higher in patients with IKZF1 deletion; conversely MYCBP2 mRNA expression was significantly lower in those patients. A CK2 inhibitor, which acts as an Ikaros activator, also suppressed c-MYC and increased MYCBP2 expression in an Ikaros (IKZF1) dependent manner in the ALL cells. In summary, our data indicated the correlation of high c-MYC expression, low MYCBP2 expression and high c-MYC plus low MYCBP2 expression with high-risk factors and proliferation markers in adult ALL patients. Our data also revealed an oncogenic role for an Ikaros/MYCBP2/c-MYC axis in adult ALL, providing a mechanism of target therapies that activate Ikaros in adult ALL.     

A High-Throughput Amplicon Screen for Somatic UBA1 Variants in Cytopenic and Giant Cell Arteritis Cohorts

Journal of Clinical Immunology -     

Clinical Outcome and Underlying Genetic Cause of Functional Terminal Complement Pathway Deficiencies in a Multicenter UK Cohort

Background

Terminal complement pathway deficiencies often present with severe and recurrent infections. There is a lack of good-quality data on these rare conditions. This study investigated the clinical outcome and genetic variation in a large UK multi-center cohort with primary and secondary terminal complement deficiencies.

Methods

Clinicians from seven UK centers provided anonymised demographic, clinical, and laboratory data on patients with terminal complement deficiencies, which were collated and analysed.

Results

Forty patients, median age 19 (range 3–62) years, were identified with terminal complement deficiencies. Ten (62%) of 16 patients with low serum C5 concentrations had underlying pathogenic CFH or CFI gene variants. Two-thirds were from consanguineous Asian families, and 80% had an affected family member. The median age of the first infection was 9 years. Forty-three percent suffered meningococcal serotype B and 43% serotype Y infections. Nine (22%) were treated in intensive care for meningococcal septicaemia. Two patients had died, one from intercurrent COVID-19. Twenty-one (52%) were asymptomatic and diagnosed based on family history. All but one patient had received booster meningococcal vaccines and 70% were taking prophylactic antibiotics.

Discussion

The genetic etiology and clinical course of patients with primary and secondary terminal complement deficiency are variable. Patients with low antigenic C5 concentrations require genetic testing, as the low level may reflect consumption secondary to regulatory defects in the pathway. Screening of siblings is important. Only half of the patients develop septicaemia, but all should have a clear management plan.

     

Well-Being Among Older Gay and Bisexual Men and Women in England: A Cross-sectional Population Study

ObjectivesLesbian, gay, and bisexual (LGB) older people present an under-represented population in research, with limited research citing higher prevelance of depression, loneliness, rejection, and overall poorer health and well-being outcomes. Our study compares well-being, defined as quality of life, life satisfaction, sexual satisfaction, and depression, among LGB people with their heterosexual peers'.DesignCross-sectional population study using data from the English Longitudinal Study of Aging (ELSA), a representative panel study of older adults aged 50 and older.Setting and ParticipantsData were from ELSA wave 6, collected 2012-2013. A total of 5691 participants were included in the analysis, with 326 (5.7%) self-identifying as LGB.MeasuresWell-being was measured using CASP-19, a quality of life questionnaire; the Satisfaction with Life Scale for life satisfaction; and the Center for Epidemiologic Studies Depression Scale for depressive symptoms. Sexual satisfaction was assessed using the question “During the past three months, how satisfied have you been with your overall sex life?” In addition, t test and chi-square tests were used to test differences in sociodemographic characteristics between LGB and heterosexual participants. Bivariate logistical regression and linear regression were used to test associations between sexual orientation and well-being outcomes.ResultsIn unadjusted models, LGB participants reported significantly lower mean quality of life and life satisfaction, and had significantly lower odds of reporting satisfaction with their overall sex life and higher odds of reporting depressive symptoms above threshold. After adjustment for sociodemographic and health-related covariates, there remained significant differences between LGB and heterosexual groups in mean quality of life scores (B = ?0.96, 95% confidence interval [CI] ?1.87 to ?0.06, P = .037) and odds of sexual satisfaction (odds ratio = 0.56, 95% CI 0.38-0.82, P = .003).Conclusions/ImplicationsLGB older people report lower quality of life and lower sexual satisfaction than their heterosexual counterparts, possibly associated with a number of unwanted social experiences.     

Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study

OBJECTIVES: This study was designed to compare two treatment strategies in patients with atrial fibrillation(AF): rhythm-control (restoration and maintenance of sinus rhythm) and rate-control (pharmacologic or invasive rate-control and anticoagulation). BACKGROUND: Atrial fibrillation is the most common arrhythmia. It is unclear whether a strategy of rhythm- or rate-control is better in terms of mortality, morbidity, and quality of life. METHODS: The Strategies of Treatment of Atrial Fibrillation (STAF) multicenter pilot trial randomized 200 patients (100 per group) with persistent AF to rhythm- or rate-control. The combined primary end point was a combination of death, cardiopulmonary resuscitation, cerebrovascular event, and systemic embolism. RESULTS: After 19.6 +/- 8.9 months (range 0 to 36 months) there was no difference in the primary end point between rhythm-control (9/100; 5.54%/year) and rate-control (10/100; 6.09%/year; p = 0.99). The percentage of patients in sinus rhythm in the rhythm-control group after up to four cardioversions during the follow-up period (rate-control group) was 23% (0%) at 36 months. Eighteen primary end points occurred in atrial fibrillation; only one occurred in sinus rhythm (p = 0.049). CONCLUSIONS: The STAF pilot study showed no differences between the two treatment strategies in all end points except hospitalizations. These data suggest that there was no benefit in attempting rhythm-control in these patients with a high risk of arrhythmia recurrence. It remains unclear whether the results in the rhythm-control group would have been better if sinus rhythm had been maintained in a higher proportion of patients, as all but one end point occurred during AF.