Commentary
Abstract
Rheumatoid factors (RFs) are autoantibodies directed against the tail region of IgG antibodies and are present in a majority of people with rheumatoid arthritis (RA). RF production is commonly assessed to help diagnose RA, but its performance is limited due to low specificity and sensitivity for reasons that have remained unclear. In this issue of the JCI, Hocaoğlu and Sawalha shed light on this matter using extensive phenome-, genome-, transcriptome-, and proteome-wide association analyses of RF-seropositive and -seronegative individuals. They report that RF production was controlled by a genetic signature that included HLA and non-HLA genes and an immune signature reflective of B cell dysregulation but distinct from the genetic and immune signatures associated with RA. These findings explain the limited diagnostic value of RF testing in RA and may help refine the clinical management of RA and development of interventions that prevent or delay disease.
Authors
Luc Van Kaer
Abstract
Another individual’s distress can provoke withdrawal and avoidance behaviors, yet, in social species, it can also motivate approach and caregiving behavior. In this issue, Geng et al. identified a vasopressin-sensitive neuronal circuit that converts distress signals from a cagemate into caregiving-like behavior in mice. Using fiber photometry, electrophysiological recordings, and optogenetic activation to dissect this circuit, they showed that vasopressin neurons in the paraventricular hypothalamus recruit vasopressin 1a receptor–expressing (V1aR-expressing) neurons in the medial central amygdala, which engage the ventral tegmental area to promote allogrooming and injury-directed licking. The findings link emotional state matching, prosocial action, reinforcement, and stress relief, while raising important questions about circuit specificity, sex as a biological variable, and translation.
Authors
Jonathan P. Fadok
Abstract
Autoimmune diseases share a genetic predisposition, and GWAS have identified certain HLA haplotypes as components of susceptibility. In this issue of the JCI, Eriksson et al. leveraged population-scale registry data from Sweden, encompassing 6.3 million individuals in combination with paired relatedness data from a remarkable 3.84 million sibling pairs drawn from 1.57 million nuclear families to create a unified model of the shared genetic risk across 22 common and rare autoimmune diseases. The resulting network of pairwise genetic relationships demonstrated that genetic predisposition alone could not explain the full spectrum of autoimmunity. Analyses exposed distinct patterns, confirmed expected genetic relationships, and revealed unexpected findings. By looking into the family to quantify shared genetic liability at a remarkable scale, this study not only reinforces established genetic components of autoimmune disease but also highlights variation that lacks shared genetic architecture, paving the way for future study of environmental mechanisms in autoimmunity.
Authors
Arielle Klepper, Mark S. Anderson
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is characterized by fragile, enlarged vessels with arteriovenous connections, which can form arteriovenous malformations (AVMs) that are prone to rupture. It is driven by mutations in TGF‑β pathway genes that disrupt endothelial cell responses and blood vessel remodeling. Two studies published in this issue of the JCI identify c‑KIT as a central mediator of HHT vascular pathology. Gahn et al. showed that SMAD4 loss derepressed c‑KIT, whose activity in the junctional mechanosensory receptor complex of endothelial cells reset the fluid shear stress set point to drive maladaptive vascular remodeling. Drapé et al. demonstrated that ALK1 loss in a mouse model of HHT induced a regional pro‑angiogenic c‑KIT+ endothelial state in brain AVMs. Both studies showed that pharmacologic c-KIT inhibition mitigated disease, revealing an unexpected, potentially ligand‑independent role for c‑KIT and highlighting a promising therapeutic target.
Authors
Ruilin Wu, Jason E. Fish
Abstract
Multiple myeloma is a systemic and spatially heterogeneous cancer of plasma cells. Available methods for diagnosing and monitoring disease do not fully capture its heterogeneity. For instance, bone marrow sampling is anatomically limited and [18F]FDG PET/CT reflects glucose metabolism rather than a specific target. In this issue of JCI, Gu et al. reported a prospective phase I study of [68Ga]Ga-PFBC01, a nanobody tracer targeting B cell maturation antigen (BCMA). The study presents a coherent translational pathway for [68Ga]Ga-PFBC01 PET and demonstrates high sensitivity, associations with tissue and circulating disease measures, and clinical management impact. By shifting myeloma imaging from metabolic assessment toward target biology, [68Ga]Ga-PFBC01 PET may visualize whole-body disease distribution and actionable target expression, while blood-pool activity may reflect systemic antigen biology (Figure 1).
Authors
Yangmeihui Song, Wenyu Song, Weibo Cai
Abstract
Polyendocrine metabolic ovarian syndrome (PMOS) affects one of every eight women worldwide and is associated with high rates of cardiovascular disease, type 2 diabetes, and infertility. Polycystic ovarian syndrome (PCOS), another term for this condition, reflects a historical focus on its effects on the female reproductive system. Recently, however, experts and patient groups have advocated renaming the condition PMOS, conveying increasing recognition that hyperandrogenism and insulin resistance contribute to its pathology. In this issue, Nguyen et al. took a systems genetic approach that combined data from murine models of PMOS and data from human studies, identifying the splicing factor 3b subunit 1 (SF3B1) and IGFBP2, both previously associated with metabolic disease, as molecular drivers of PMOS. SF3B1 inhibitors improved PMOS symptoms in mice, including decreased adiposity, hypoandrogenism, and insulin levels. These findings open therapeutic and mechanistic avenues in the study of PMOS, including exploration of splice variants as regulators of disease progression.
Authors
Michaela M. Morhaus, Lauren W. Yowelunh McLester-Davis, Judith A. Simcox
Abstract
Autosomal dominant polycystic kidney disease (ADPKD), mainly driven by pathogenic variants in PKD1 and PKD2, is the most common inherited cause of kidney failure. Details of ADPKD pathogenesis are incompletely resolved, but primary cilia are an integral component. There is also evidence for changes to the tubular basement membrane (TBM) in early disease. In this issue of the JCI, Mazloum and colleagues link cilia-dependent, PKD1-mediated regulation of the TBM to ADPKD pathogenesis. Using in vivo, ex vivo, tubule-on-chip, and cellular models of ADPKD, they connect cilia-dependent tubule dilation and TBM thinning to early-stage cystogenesis. Moreover, they identify a cilia-dependent TBM remodeling expression signature in affected tubules and suggest that PC1 loss compromises TBM stiffness. By integrating roles for cilia at the apical membrane and extracellular matrix at the basolateral membrane in cystogenesis, this work highlights the TBM as an additional area for investigation of therapeutic and biomarker discovery in ADPKD.
Authors
Caroline R. Sussman, Peter C. Harris
Going to the source: pancreatic lymph nodes maintain stem-like CD8+ T cells in human type 1 diabetes
Abstract
Where does autoimmune persistence reside in type 1 diabetes (T1D)? Detailed investigation of the pancreas and pancreatic lymph nodes (PLNs) may provide more definitive answers, yet most studies in these target tissues have been confined to mouse models. In nonobese diabetic (NOD) mice, disease development is prevented by PLN ablation, and these LNs harbor a stem-like population of autoreactive CD8+ T cells. In this issue, Peters et al. identified stem-like CD8+ T cell populations enriched in PLNs from humans with T1D and provide evidence for a developmental continuum linking lymphoid and pancreatic immune compartments. Their findings extend concepts previously established in NOD mice and in cancer immunology to humans with T1D, wherein self-renewing T cell populations sustain long-term immune responses. While the precise relationship between these stem-like cells and pathogenic autoreactive clones remains unresolved, this work positions the PLN as a potential reservoir of autoimmune persistence in T1D and a target for immune intervention.
Authors
Fatoumata Samassa, Sylvaine You, Roberto Mallone
Abstract
Bone formation in soft tissues, known as heterotopic ossification (HO), can occur as a complication of trauma or burn injury and can cause pain and functional limitations in the affected site. HO remains an unmet clinical challenge due to a general lack of specific medical therapies. In this issue of the JCI, a study by Moye et al. identified obesity as a risk factor for HO and further found that the association with obesity was driven not by caloric surplus, but instead by dietary omega-6 lipids, which are characteristically elevated in the Western diet. These omega-6 lipids accumulated directly at the incipient HO site, where they served as substrates for prostaglandin E2 (PGE2), fueling aberrant osteoblast differentiation. Overall, this work provides compelling support for dietary intervention or pharmacologic therapy directed at downstream PGE2 signaling as approaches to reduce HO in at-risk patients.
Authors
Peyton L. Carpen, Matthew B. Greenblatt
Abstract
Fibrosis is driven by the activation of quiescent fibroblasts into contractile, matrix-secreting myofibroblasts, a transition governed jointly by biochemical signals and by the mechanical properties of the ECM. How the physical stiffness of tissue is converted into a durable transcriptional cell fate decision has remained poorly understood. In this issue of the JCI, Kadri et al. used global phosphoproteomic profiling of primary human lung fibroblasts across a defined stiffness gradient to identify phosphorylation of NFATC4 at residues S213/S217 as a mechanosensitive switch that is both necessary and sufficient for the fibroblast-to-myofibroblast transition. They validated these predictions in an independent transcriptomic dataset from patients with idiopathic pulmonary fibrosis, showing that NFATC4 expression increased with disease severity. Prior work has implicated NFATC4 activation in cardiac and hepatic fibrosis, suggesting that this single modification may serve as a convergence point for mechanical and cytokine signals across fibrotic diseases.
Authors
Rebecca Shelley Frabotta, Purushothama Rao Tata
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