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Brief Definitive Report
A TBK1 variant causes autophagolysosomal and motoneuron pathology without neuroinflammation in mice
The ALS/FTD-associated TBK1 variant p.E696K shows a selective loss of optineurin binding. Its knock-in causes autophagolysosomal dysfunction and ALS-like symptoms in mice, while RIPK-dependent necroptosis or inflammation is absent. This highlights the role of autophagolysosomal dysfunction in TBK1-ALS/FTD.
Antigen-independent, autonomous B cell receptor signaling drives activated B cell DLBCL
This study describes and characterizes antigen-independent, autonomous signaling of the clonal B cell receptor as an intrinsic oncogenic driver in activated B cell type DLBCL. This long-sought non-genetic lymphomagenic mechanism has profound implications for development of effective novel therapies.
Article
Functional diversity of NLRP3 gain-of-function mutants associated with CAPS autoinflammation
Functional characterization of 34 NLRP3 variants identifies benign polymorphisms versus a spectrum of gain-of-function pathogenic variants with variable effects and highlights diversities in the signals controlling their activation and sensitivity to inhibitors. This study provides tools for CAPS diagnosis and anti-inflammation drug development and insights on NLRP3 control mechanisms.
Human neutrophils drive skin autoinflammation by releasing interleukin (IL)-26
Autoinflammation is marked by IL-1 cytokine overexpression and excessive infiltration by neutrophils. By studying pustular psoriasis, we identify a cascade where neutrophils release IL-26 and trigger skin autoinflammation. The mechanism entails IL-26 activation of keratinocytes and concurrently killing of skin microbiota with formation of IL-26–DNA complexes that stimulate TLR9.
Competitive fungal commensalism mitigates candidiasis pathology
This study reports robust competitive commensalism between fungi of the Kazachstania and Candida clades. Specifically, K. weizmannii exposure prevented C. albicans colonization of mice and caused C. albicans expulsion from the gut microbiome, mitigating systemic fungal spread and candidiasis.
Piezo1 channels restrain ILC2s and regulate the development of airway hyperreactivity
Piezo1 channels regulate the magnitude of ILC2-dependent type 2 lung inflammation. In murine and human ILC2s, Piezo1 channels are induced by allergen and cytokine encounter as activation decreases ILC2 effector functions and development of airway hyperreactivity in a KLF2-dependent manner.
Dietary fiber is a critical determinant of pathologic ILC2 responses and intestinal inflammation
Inulin fiber diet induces microbial dysbiosis, production of bile acids, and inflammatory ILC2s responses, triggering IL-5 production, eosinophilia, and intestinal inflammation. These studies highlight that diet and microbiota-derived metabolites are significant determinants of the balance between inflammatory versus tissue-protective ILC2s with implications for chronic inflammation.
Induction of immortal-like and functional CAR T cells by defined factors
Immortality and functionality typically do not coexist in mammalian cells. Wang et al. successfully induced CAR T cells into an immortal-like state while preserving their T cell functionality, conferring long-term functional persistence of CAR T cells in vivo.
Technical Advances and Resources
Distinct molecular profiles drive multifaceted characteristics of colorectal cancer metastatic seeds
This study delves into the complex landscape of CRC metastasis, revealing distinct molecular profiles of metastatic seeds within primary tumors. The research identifies genetic alterations and communication capabilities driving metastasis, offering insights into clinical prognosis and potential anti-metastatic therapeutic targets for CRC patients.
Insights
One in, one out: Commensal fungus protects against infection
In this issue of JEM, Sekeresova Kralova et al. identify a commensal yeast that displaced fungal pathogen Candida albicans and protected against subsequent invasive infections that originate from the gut.
Cracking the NLRP3 code: Pioneering precision medicine for inflammation
In this issue of JEM, Cossons et al. propose a novel functional classification of NLRP3 gain-of-function mutation that could inform therapeutic decisions.
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