Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells

Susceptibility and protection against human autoimmune diseases, including type I diabetes, multiple sclerosis, and Goodpasture disease, is associated with particular human leukocyte antigen (HLA) alleles. However, the mechanisms underpinning such HLA-mediated effects on self-tolerance remain unclear. Here we investigate the molecular mechanism of Goodpasture disease, an HLA-linked autoimmune renal disorder characterized by an immunodominant CD4+ T-cell self-epitope derived from the α3 chain of type IV collagen (α3135–145)1,2,3,4. While HLA-DR15 confers a markedly increased disease risk, the protective HLA-DR1 allele is dominantly protective in trans with HLA-DR15 (ref. 2). We show that autoreactive α3135–145-specific T cells expand in patients with Goodpasture disease and, in α3135–145-immunized HLA-DR15 transgenic mice, α3135–145-specific T cells infiltrate the kidney and mice develop Goodpasture disease. HLA-DR15 and HLA-DR1 exhibit distinct peptide repertoires and binding preferences and present the α3135–145 epitope in different binding registers. HLA-DR15-α3135–145 tetramer+ T cells in HLA-DR15 transgenic mice exhibit a conventional T-cell phenotype (Tconv) that secretes pro-inflammatory cytokines. In contrast, HLA-DR1-α3135–145 tetramer+ T cells in HLA-DR1 and HLA-DR15/DR1 transgenic mice are predominantly CD4+Foxp3+ regulatory T cells (Treg cells) expressing tolerogenic cytokines. HLA-DR1-induced Treg cells confer resistance to disease in HLA-DR15/DR1 transgenic mice. HLA-DR15+ and HLA-DR1+ healthy human donors display altered α3135–145-specific T-cell antigen receptor usage, HLA-DR15-α3135–145 tetramer+ Foxp3− Tconv and HLA-DR1-α3135–145 tetramer+ Foxp3+CD25hiCD127lo Treg dominant phenotypes. Moreover, patients with Goodpasture disease display a clonally expanded α3135–145-specific CD4+ T-cell repertoire. Accordingly, we provide a mechanistic basis for the dominantly protective effect of HLA in autoimmune disease, whereby HLA polymorphism shapes the relative abundance of self-epitope specific Treg cells that leads to protection or causation of autoimmunity

ATAD5 promotes replication restart by regulating RAD51 and PCNA in response to replication stress

Maintaining stability of replication forks is important for genomic integrity. However, it is not clear how replisome proteins contribute to fork stability under replication stress. Here, we report that ATAD5, a PCNA unloader, plays multiple functions at stalled forks including promoting its restart. ATAD5 depletion increases genomic instability upon hydroxyurea treatment in cultured cells and mice. ATAD5 recruits RAD51 to stalled forks in an ATR kinase-dependent manner by hydroxyurea-enhanced protein-protein interactions and timely removes PCNA from stalled forks for RAD51 recruitment. Consistent with the role of RAD51 in fork regression, ATAD5 depletion inhibits slowdown of fork progression and native 5-bromo-2??-deoxyuridine signal induced by hydroxyurea. Single-molecule FRET showed that PCNA itself acts as a mechanical barrier to fork regression. Consequently, DNA breaks required for fork restart are reduced by ATAD5 depletion. Collectively, our results suggest an important role of ATAD5 in maintaining genome integrity during replication stress

Discrete Element Modelling of Single-Nave Churches Damaged after the 2009 Earthquake in l’Aquila, Italy

The survey of damages after recent earthquakes have shown the fragility of masonry churches against the out-of-plane overturning of the façade. This failure mechanism is currently analyzed having recourse to a rigid body model, using either limit analysis with kinematic approach, or dynamic analysis under rocking motion. However, both the aforementioned methods neglect the interaction with the lateral walls, leading to an underestimation of the effective structural capacity under seismic action. The main goal of this work is therefore to investigate the effect of the interlocking between the façade and the transversal wall and the influence of the quality of masonry in out-of-plane overturning. For this purpose, a refined model of masonry through a Discrete Element Method is developed, based on a detailed recognition of masonry units. The acceleration and displacement capacity are estimated through quasi-static pushover and pulse-based dynamic analyses and compared to those calculated for the rigid body model. The proposed methodology is then applied to a sample of three single-nave masonry churches that suffered damages during the 2009 L’Aquila, Italy earthquake

Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges

Seasonality in Major Depressive Disorder: Effect of Sex and Age

Background: Aside from the concept of seasonal affective disorder, the evidence for a seasonal pattern (SP) of major depressive disorder (MDD) is controversial. Furthermore, the effect of sex and age is still unclear. Methods: This is a nationwide, registry-based study assessing all inpatient admissions in mental health hospitals due to MDD episodes according to ICD-10 (moderate (F32/33.1), severe (F32/33.2) and severe with psychotic features (F32/33.3)) in Austria across 14 years. Calculations were based on deviations from expected monthly admissions. Results: The sample comprised 231,824 hospitalisations (36.8% men) for MDD. A significant SP (p=0.001) in moderate and severe depressive episodes in both women and men with decreased admission rates in the summer months and December was detected. In psychotic depression a significant SP was only evidenced in women (p = 0.002, men: p = 0.291). Patients older than 55 years had a reduced SP compared to those being younger. Limitations: Only anonymised admission data of inpatient treatments were available. Hospitalization rates cannot fully be equated to the occurrence of MDD. Conclusions: The current study indicates a seasonal variation in MDD symptoms that may go beyond seasonal affective disorder. Knowledge about the predictability of depressive symptoms in patients should encourage preventive strategies

Replication intermediates that escape Dna2 activity are processed by Holliday junction resolvase Yen1

Cells have evolved mechanisms to protect, restart and repair perturbed replication forks, allowing full genome duplication, even under replication stress. Interrogating the interplay between nuclease-helicase Dna2 and Holliday junction (HJ) resolvase Yen1, we find the Dna2 helicase activity acts parallel to homologous recombination (HR) in promoting DNA replication and chromosome detachment at mitosis after replication fork stalling. Yen1, but not the HJ resolvases Slx1-Slx4 and Mus81-Mms4, safeguards chromosome segregation by removing replication intermediates that escape Dna2. Post-replicative DNA damage checkpoint activation in Dna2 helicase-defective cells causes terminal G2/M arrest by precluding Yen1-dependent repair, whose activation requires progression into anaphase. These findings explain the exquisite replication stress sensitivity of Dna2 helicase-defective cells, and identify a non-canonical role for Yen1 in the processing of replication intermediates that is distinct from HJ resolution. The involvement of Dna2 helicase activity in completing replication may have implications for DNA2-associated pathologies, including cancer and Seckel syndrome

Clinical Correlates and Outcome of Major Depressive Disorder and Comorbid Migraine: A Report of the European Group for the Study of Resistant Depression

Background: The present multicenter study aimed at defining the clinical profile of patients with major depressive disorder (MDD) and comorbid migraine. Methods: Demographic and clinical information for 1410 MDD patients with vs without concurrent migraine were compared by descriptive statistics, analyses of covariance, and binary logistic regression analyses. Results: The point prevalence rate for comorbid migraine was 13.5% for female and 6.2% for male patients. MDD + migraine patients were significantly younger, heavier, more likely female, of non-Caucasian origin, outpatient, and suffering from asthma. The presence of MDD + migraine resulted in a significantly higher functional disability. First-line antidepressant treatment strategy revealed a trend towards agomelatine. Second-generation antipsychotics were significantly less often administered for augmentation treatment in migraineurs. Overall, MDD + migraine patients tended to respond worse to their pharmacotherapy. Conclusion: Treatment guidelines for comorbid depression and migraine are warranted to ensure optimal efficacy and avoid possible pitfalls in psychopharmacotherapy, including serotonin syndrome

B cell tolerance and antibody production to the celiac disease autoantigen transglutaminase 2

Autoantibodies to transglutaminase 2 (TG2) are hallmarks of celiac disease. To address B cell tolerance and autoantibody formation to TG2, we generated immunoglobulin knock-in (Ig KI) mice that express a prototypical celiac patient-derived anti-TG2 B cell receptor equally reactive to human and mouse TG2. We studied B cell development in the presence/absence of autoantigen by crossing the Ig KI mice to Tgm2 -/- mice. Autoreactive B cells in Tgm2 +/+ mice were indistinguishable from their naive counterparts in Tgm2 -/- mice with no signs of clonal deletion, receptor editing, or B cell anergy. The autoreactive B cells appeared ignorant to their antigen, and they produced autoantibodies when provided T cell help. The findings lend credence to a model of celiac disease where gluten-reactive T cells provide help to autoreactive TG2-specific B cells by involvement of gluten-TG2 complexes, and they outline a general mechanism of autoimmunity with autoantibodies being produced by ignorant B cells on provision of T cell help

SET8 is degraded via PCNA-coupled CRL4(CDT2) ubiquitylation in S phase and after UV irradiation

Degradation of the histone H4 methyltransferase SET8, which regulates chromosome compaction and genomic integrity, is regulated by the CRL4(CDT2) ubiquitin ligase to facilitate DNA replication and repair

Sex-related effects in major depressive disorder: Results of the European Group for the Study of Resistant Depression

Background: Sex-related effects on the evolution and phenotype of major depressive disorder (MDD) were reported previously. Methods: This European multicenter cross-sectional study compared sociodemographic, clinical, and treatment patterns between males and females in a real-world sample of 1410 in- and outpatients with current MDD. Results: Male MDD patients (33.1%) were rather inpatients, suffered from moderate to high suicidality levels, received noradrenergic and specific serotonergic antidepressants (ADs) as first-line AD treatment, generally higher mean AD daily doses, and showed a trend towards a more frequent administration of add-on treatments. Female MDD patients (66.9%) were rather outpatients, experienced lower suicidality levels, comorbid thyroid dysfunction, migraine, asthma, and a trend towards earlier disease onset. Conclusions: The identified divergencies may contribute to the concept of male and female depressive syndromes and serve as predictors of disease severity and course, as they reflect phenomena that were repeatedly related to treatment-resistant depression (TRD). Especially the greater necessity of inpatient treatment and more complex psychopharmacotherapy in men may reflect increased therapeutic efforts undertaken to treat suicidality and to avoid TRD. Hence, considering sex may guide the diagnostic and treatment processes towards targeting challenging clinical manifestations including comorbidities and suicidality, and prevention of TRD and chronicity