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Brief Definitive Report

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.

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.

Perspective

Immune cells instruct the development and persistence of adaptive and maladaptive pain states by modifying neural activity in the end organs, nerves, dorsal root ganglia, spinal cord, and brain, therefore opening the neuroimmune axis as a target to treat pain.

Article

This study describes clinical features and cellular and molecular mechanisms underlying immune deficiency in seven patients with biallelic germline variants in CD4. The data reveal important roles for CD4 in host defense against a range of pathogens, particularly human papilloma virus.

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.

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.

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 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.

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.

In Special Collection: JEM Cancer Collection 2024

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

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.

Viewpoint

The cognitive side effects of cancer treatment are common. Jian Hu and Yuan Pan explore the role of hormones as mediators between cancer therapy and cognitive impairment, discussing potential future directions.

Insights

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.

In this issue of JEM, Cossons et al. propose a novel functional classification of NLRP3 gain-of-function mutation that could inform therapeutic decisions.

Pustular psoriasis is an inflammatory skin disease with features of neutrophil-mediated sterile autoinflammation. In this issue of JEM, Baldo et al. show that this autoinflammation is driven by a vicious cycle through neutrophil-derived IL-26.

Found in Translation

Jennifer S. Michaelson and Patrick A. Baeuerle discuss the use of CD19-specific T cell–engaging antibody therapies (TCEs) as therapeutics for autoimmune diseases.

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