The immunology of systemic lupus erythematosus.

Understanding the pathogenesis and clinical manifestations of systemic lupus erythematosus (SLE) has been a great challenge. Reductionist approaches to understand the nature of the disease have identified many pathogenetic contributors that parallel clinical heterogeneity. This Review outlines the immunological control of SLE and looks to experimental tools and approaches that are improving our understanding of the complex contribution of interacting genetics, environment, sex and immunoregulatory factors and their interface with processes inherent to tissue parenchymal cells. Efforts to advance precision medicine in the care of patients with SLE along with treatment strategies to correct the immune system hold hope and are also examined.

Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations.

Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation.

Glutathione peroxidase 4-regulated neutrophil ferroptosis induces systemic autoimmunity.

The linkage between neutrophil death and the development of autoimmunity has not been thoroughly explored. Here, we show that neutrophils from either lupus-prone mice or patients with systemic lupus erythematosus (SLE) undergo ferroptosis. Mechanistically, autoantibodies and interferon-α present in the serum induce neutrophil ferroptosis through enhanced binding of the transcriptional repressor CREMα to the glutathione peroxidase 4 (Gpx4, the key ferroptosis regulator) promoter, which leads to suppressed expression of Gpx4 and subsequent elevation of lipid-reactive oxygen species. Moreover, the findings that mice with neutrophil-specific Gpx4 haploinsufficiency recapitulate key clinical features of human SLE, including autoantibodies, neutropenia, skin lesions and proteinuria, and that the treatment with a specific ferroptosis inhibitor significantly ameliorates disease severity in lupus-prone mice reveal the role of neutrophil ferroptosis in lupus pathogenesis. Together, our data demonstrate that neutrophil ferroptosis is an important driver of neutropenia in SLE and heavily contributes to disease manifestations.

Autoimmunity and organ damage in systemic lupus erythematosus.

Impressive progress has been made over the last several years toward understanding how almost every aspect of the immune system contributes to the expression of systemic autoimmunity. In parallel, studies have shed light on the mechanisms that contribute to organ inflammation and damage. New approaches that address the complicated interaction between genetic variants, epigenetic processes, sex and the environment promise to enlighten the multitude of pathways that lead to what is clinically defined as systemic lupus erythematosus. It is expected that each patient owns a unique 'interactome', which will dictate specific treatment.

Author Correction: The kinase TBK1 controls IgA class switching by negatively regulating noncanonical NF-κB signaling.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Phosphatase PP2A is requisite for the function of regulatory T cells.

Homeostasis of the immune system depends on the proper function of regulatory T cells (T(reg) cells). Compromised suppressive activity of T(reg) cells leads to autoimmune disease and graft rejection and promotes anti-tumor immunity. Here we report a previously unrecognized requirement for the serine-threonine phosphatase PP2A in the function of T(reg) cells. T(reg) cells exhibited high PP2A activity, and T(reg) cell-specific ablation of the PP2A complex resulted in a severe, multi-organ, lymphoproliferative autoimmune disorder. Mass spectrometry revealed that PP2A associated with components of the mTOR metabolic-checkpoint kinase pathway and suppressed the activity of the mTORC1 complex. In the absence of PP2A, T(reg) cells altered their metabolic and cytokine profile and were unable to suppress effector immune responses. Therefore, PP2A is required for the function of T(reg) cells and the prevention of autoimmunity.

The Role of Cilia and the Complex Genetics of Congenital Heart Disease.

Congenital heart disease (CHD) can affect up to 1% of live births, and despite abundant evidence of a genetic etiology, the genetic landscape of CHD is still not well understood. A large-scale mouse chemical mutagenesis screen for mutations causing CHD yielded a preponderance of cilia-related genes, pointing to a central role for cilia in CHD pathogenesis. The genes uncovered by the screen included genes that regulate ciliogenesis and cilia-transduced cell signaling as well as many that mediate endocytic trafficking, a cell process critical for both ciliogenesis and cell signaling. The clinical relevance of these findings is supported by whole-exome sequencing analysis of CHD patients that showed enrichment for pathogenic variants in ciliome genes. Surprisingly, among the ciliome CHD genes recovered were many that encoded direct protein-protein interactors. Assembly of the CHD genes into a protein-protein interaction network yielded a tight interactome that suggested this protein-protein interaction may have functional importance and that its disruption could contribute to the pathogenesis of CHD. In light of these and other findings, we propose that an interactome enriched for ciliome genes may provide the genomic context for the complex genetics of CHD and its often-observed incomplete penetrance and variable expressivity.

Recommendations for measuring and standardizing light for laboratory mammals to improve welfare and reproducibility in animal research.

Light enables vision and exerts widespread effects on physiology and behavior, including regulating circadian rhythms, sleep, hormone synthesis, affective state, and cognitive processes. Appropriate lighting in animal facilities may support welfare and ensure that animals enter experiments in an appropriate physiological and behavioral state. Furthermore, proper consideration of light during experimentation is important both when it is explicitly employed as an independent variable and as a general feature of the environment. This Consensus View discusses metrics to use for the quantification of light appropriate for nonhuman mammals and their application to improve animal welfare and the quality of animal research. It provides methods for measuring these metrics, practical guidance for their implementation in husbandry and experimentation, and quantitative guidance on appropriate light exposure for laboratory mammals. The guidance provided has the potential to improve data quality and contribute to reduction and refinement, helping to ensure more ethical animal use.

Anomalously enhanced ion transport and uptake in functionalized angstrom-scale two-dimensional channels.

Emulating angstrom-scale dynamics of the highly selective biological ion channels is a challenging task. Recent work on angstrom-scale artificial channels has expanded our understanding of ion transport and uptake mechanisms under confinement. However, the role of chemical environment in such channels is still not well understood. Here, we report the anomalously enhanced transport and uptake of ions under confined MoS2-based channels that are ~five angstroms in size. The ion uptake preference in the MoS2-based channels can be changed by the selection of surface functional groups and ion uptake sequence due to the interplay between kinetic and thermodynamic factors that depend on whether the ions are mixed or not prior to uptake. Our work offers a holistic picture of ion transport in 2D confinement and highlights ion interplay in this regime.

Twelve-hour rhythms in transcript expression within the human dorsolateral prefrontal cortex are altered in schizophrenia.

Twelve-hour (12 h) ultradian rhythms are a well-known phenomenon in coastal marine organisms. While 12 h cycles are observed in human behavior and physiology, no study has measured 12 h rhythms in the human brain. Here, we identify 12 h rhythms in transcripts that either peak at sleep/wake transitions (approximately 9 AM/PM) or static times (approximately 3 PM/AM) in the dorsolateral prefrontal cortex, a region involved in cognition. Subjects with schizophrenia (SZ) lose 12 h rhythms in genes associated with the unfolded protein response and neuronal structural maintenance. Moreover, genes involved in mitochondrial function and protein translation, which normally peak at sleep/wake transitions, peak instead at static times in SZ, suggesting suboptimal timing of these essential processes.

Retraction Note: Microglia-dependent synapse loss in type I interferon-mediated lupus.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Advancing quantitative PCR with color cycle multiplex amplification.

Quantitative PCR (qPCR) is the gold standard for detection and quantitation of known DNA targets, but the scarcity of spectrally distinct fluorophores and filter sets limits the number of detectable targets. Here, we introduce color cycle multiplex amplification (CCMA) to significantly increase the number of detectable DNA targets in a single qPCR reaction using standard instrumentation. In CCMA, presence of one DNA target species results in a pre-programmed pattern of fluorescence increases. This pattern is distinguished by cycle thresholds (Cts) through rationally designed delays in amplification. For example, we design an assay wherein Staphylococcus aureus sequentially induces FAM, then Cy5.5, then ROX fluorescence increases with more than 3 cycles between each signal. CCMA offers notably higher potential for multiplexing because it uses fluorescence permutation rather than combination. With 4 distinct fluorescence colors, CCMA theoretically allows the detection of up to 136 distinct DNA target sequences using fluorescence permutation. Experimentally, we demonstrated a single-tube qPCR assay screening 21 sepsis-related bacterial DNA targets in samples of blood, sputum, pleural effusion and bronchoalveolar lavage fluid, with 89% clinical sensitivity and 100% clinical specificity, showing its potential as a powerful tool for advanced quantitative screening in molecular diagnostics.

Colors of entangled two-photon absorption.

Multiphoton absorption of entangled photons offers ways for obtaining unique information about chemical and biological processes. Measurements with entangled photons may enable sensing biological signatures with high selectivity and at very low light levels to protect against photodamage. In this paper, we present a theoretical and experimental study of the excitation wavelength dependence of the entangled two-photon absorption (ETPA) process in a molecular system, which provides insights into how entanglement affects molecular spectra. We demonstrate that the ETPA excitation spectrum can be different from that of classical TPA as well as that for one-photon resonant absorption (OPA) with photons of doubled frequency. These results are modeled by assuming the ETPA cross-section is governed by a two-photon excited state radiative linewidth rather than by electron-phonon interactions, and this leads to excitation spectra that match the observed results. Further, we find that the two-photon-allowed states with highest TPA and ETPA intensities have high electronic entanglements, with ETPA especially favoring states with the longest radiative lifetimes. These results provide concepts for the development of quantum light-based spectroscopy and microscopy that will lead to much higher efficiency of ETPA sensors and low-intensity detection schemes.

Misregulation of mitochondria-lysosome contact dynamics in Charcot-Marie-Tooth Type 2B disease Rab7 mutant sensory peripheral neurons.

Inter-organelle contact sites between mitochondria and lysosomes mediate the crosstalk and bidirectional regulation of their dynamics in health and disease. However, mitochondria-lysosome contact sites and their misregulation have not been investigated in peripheral sensory neurons. Charcot-Marie-Tooth type 2B disease is an autosomal dominant axonal neuropathy affecting peripheral sensory neurons caused by mutations in the GTPase Rab7. Using live super-resolution and confocal time-lapse microscopy, we showed that mitochondria-lysosome contact sites dynamically form in the soma and axons of peripheral sensory neurons. Interestingly, Charcot-Marie-Tooth type 2B mutant Rab7 led to prolonged mitochondria-lysosome contact site tethering preferentially in the axons of peripheral sensory neurons, due to impaired Rab7 GTP hydrolysis-mediated contact site untethering. We further generated a Charcot-Marie-Tooth type 2B mutant Rab7 knock-in mouse model which exhibited prolonged axonal mitochondria-lysosome contact site tethering and defective downstream axonal mitochondrial dynamics due to impaired Rab7 GTP hydrolysis as well as fragmented mitochondria in the axon of the sciatic nerve. Importantly, mutant Rab7 mice further demonstrated preferential sensory behavioral abnormalities and neuropathy, highlighting an important role for mutant Rab7 in driving degeneration of peripheral sensory neurons. Together, this study identifies an important role for mitochondria-lysosome contact sites in the pathogenesis of peripheral neuropathy.

Transcriptomic congruence analysis for evaluating model organisms.

Model organisms are instrumental substitutes for human studies to expedite basic, translational, and clinical research. Despite their indispensable role in mechanistic investigation and drug development, molecular congruence of animal models to humans has long been questioned and debated. Little effort has been made for an objective quantification and mechanistic exploration of a model organism's resemblance to humans in terms of molecular response under disease or drug treatment. We hereby propose a framework, namely Congruence Analysis for Model Organisms (CAMO), for transcriptomic response analysis by developing threshold-free differential expression analysis, quantitative concordance/discordance scores incorporating data variabilities, pathway-centric downstream investigation, knowledge retrieval by text mining, and topological gene module detection for hypothesis generation. Instead of a genome-wide vague and dichotomous answer of "poorly" or "greatly" mimicking humans, CAMO assists researchers to numerically quantify congruence, to dissect true cross-species differences from unwanted biological or cohort variabilities, and to visually identify molecular mechanisms and pathway subnetworks that are best or least mimicked by model organisms, which altogether provides foundations for hypothesis generation and subsequent translational decisions.

Reverse aging to treat lupus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with multifaceted pathogenetic processes, including abnormalities of T-cell subset distribution and function. Accumulation of senescent CD4+ T cells has been found to contribute to the development of the disease. In this issue, Jiang et al. provide compelling evidence that links an expanded pool of CD4+CD57+ senescent T cells in patients with SLE to disease activity favored by interleukin-15. Importantly, treatment of lupus-prone mice with a senolytic drug resulted in decreased autoimmune pathology. The findings of this study suggest possible novel therapeutics to treat patients with SLE.

Model-based multifacet clustering with high-dimensional omics applications.

High-dimensional omics data often contain intricate and multifaceted information, resulting in the coexistence of multiple plausible sample partitions based on different subsets of selected features. Conventional clustering methods typically yield only one clustering solution, limiting their capacity to fully capture all facets of cluster structures in high-dimensional data. To address this challenge, we propose a model-based multifacet clustering (MFClust) method based on a mixture of Gaussian mixture models, where the former mixture achieves facet assignment for gene features and the latter mixture determines cluster assignment of samples. We demonstrate superior facet and cluster assignment accuracy of MFClust through simulation studies. The proposed method is applied to three transcriptomic applications from postmortem brain and lung disease studies. The result captures multifacet clustering structures associated with critical clinical variables and provides intriguing biological insights for further hypothesis generation and discovery.

Cell-type and sex-specific rhythmic gene expression in the nucleus accumbens.

Circadian rhythms are critical for human health and are highly conserved across species. Disruptions in these rhythms contribute to many diseases, including psychiatric disorders. Previous results suggest that circadian genes modulate behavior through specific cell types in the nucleus accumbens (NAc), particularly dopamine D1-expressing medium spiny neurons (MSNs). However, diurnal rhythms in transcript expression have not been investigated in NAc MSNs. In this study we identified and characterized rhythmic transcripts in D1- and D2-expressing neurons and compared rhythmicity results to homogenate as well as astrocyte samples taken from the NAc of male and female mice. We find that all cell types have transcripts with diurnal rhythms and that top rhythmic transcripts are largely core clock genes, which peak at approximately the same time of day in each cell type and sex. While clock-controlled rhythmic transcripts are enriched for protein regulation pathways across cell type, cell signaling and signal transduction related processes are most commonly enriched in MSNs. In contrast to core clock genes, these clock-controlled rhythmic transcripts tend to reach their peak in expression about 2-h later in females than males, suggesting diurnal rhythms in reward may be delayed in females. We also find sex differences in pathway enrichment for rhythmic transcripts peaking at different times of day. Protein folding and immune responses are enriched in transcripts that peak in the dark phase, while metabolic processes are primarily enriched in transcripts that peak in the light phase. Importantly, we also find that several classic markers used to categorize MSNs are rhythmic in the NAc. This is critical since the use of rhythmic markers could lead to over- or under-enrichment of targeted cell types depending on the time at which they are sampled. This study greatly expands our knowledge of how individual cell types contribute to rhythms in the NAc.