Autoimmune encephalitis (AE) comprises immune-mediated brain disorders that may occur despite the absence of detectable neuronal antibodies. These antibody-negative presentations comprise a broader spectrum that includes antibody-negative but probable autoimmune encephalitis (ANPRA) as well as clinically defined syndromes such as definite antibody-negative autoimmune limbic encephalitis, MOG-IgG-negative ADEM, and antibody-negative Bickerstaff brainstem encephalitis. Apparent antibody-negativity may reflect assay limitations, antibodies against as-yet unidentified neural antigens, or immune-mechanisms not dominated by detectable humoral responses, including T-cell–mediated and innate-immune pathways, after alternative diagnoses have been reasonably excluded. Assay methodology, antigen panel selection and paired serum/CSF testing are critical and can reveal previously unrecognized neural reactivity in a subset of patients initially classified as antibody-negative. Emerging antigen-discovery strategies, including tissue-based screening, protein arrays, immunoprecipitation–mass spectrometry, and PhIP-Seq, may identify novel neural targets and refine disease classification. This review summarizes current knowledge and emerging approaches to improve recognition and stratification of antibody-negative AE.
Brain metastasis of lung adenocarcinoma (LUAD) worsens patient prognosis, yet the role of monocyte-derived macrophages (mo-Mac) in this process remains poorly defined. Multi-omics analyses identified mo-Mac signature genes in LUAD brain-metastatic tissues, and a prognostic model was constructed using Cox-LASSO regression. The model was trained in TCGA-LUAD and validated in the independent GSE31210 cohort with overall survival (OS) as the endpoint; the 13-gene mo-Mac model stratified patients by OS risk. In exploratory analyses, low-risk patients showed a potentially better predicted immunotherapy response, whereas high-risk mo-Mac showed SAA/IL-10-associated cell-to-cell communication signatures, and exploratory pan-cancer analysis revealed associations of uncertain clinical significance. PLEKHG2 knockdown in macrophages impaired adhesion, migration, and invasion of LUAD cells, a phenotype rescued by recombinant SAA supplementation. We constructed an OS prognostic model from mo-Mac signature genes and show that macrophage-expressed PLEKHG2 may promote in vitro LUAD cell migration and invasion via paracrine signaling.
Background: AD involves barrier dysfunction and immune imbalance. Roles of LCE3D and TGF-(31 remain unclear. Methods: Bioinformatics analysis (GEO: GSE130588), RT-qPCR, ELISA, and Western blot were performed in 30 CE patients and 30 controls, including 15 serum pairs. TNF-alpha-stimulated HaCaT and NHEK cells were used to establish an AD-like model. LCE3D knockdown and overexpression were conducted, and TGF-(31 silencing was used to explore mechanistic interaction. Results: LCE3D was upregulated in AD tissues and serum, negatively correlated with TGF-(31, and associated with disease severity and IL-4/IFN-gamma imbalance. In vitro, TNF-alpha increased LCE3D and IL-4 while decreasing IFN-gamma and TGF-(31. LCE3D knockdown increased TGF-(31, IFN-gamma, and barrier proteins (involucrin, loricrin) and reduced IL-4, whereas overexpression showed opposite effects. TGF-(31 silencing reversed these effects. Conclusions: LCE3D promotes AD progression by suppressing TGF-(31, driving Th2/Th1 imbalance and epidermal barrier dysfunction. The LCE3D/TGF-(31 axis is a potential therapeutic target.
This systematic-narrative hybrid review assessed evidence on immunoglobulin replacement therapy (IgRT) use in patients with autoimmune diseases who develop hypogammaglobulinemia and/or secondary immunodeficiency following B-cell targeted therapies (BCTT). This work builds upon a 2019 review in patients with rheumatic diseases, and informed consensus recommendations developed through a separate Delphi process. A systematic search identified literature published between 01/09/2018 (2019 review cut-off) and 27/09/2024 (present review search) in PubMed, Web of Science and Cochrane library databases, supplemented by a search for relevant guidelines. Overall, 186 studies and 154 guideline documents were identified. Evidence was synthesized across 17 core research themes.While most core themes were well represented, evidence remained limited in some areas. Despite advances in understanding and clinical practice since 2019, many similar evidence gaps remain, highlighting the need for more structured guidance on management of hypogammaglobulinemia in patients with autoimmune disorders receiving BCTT, including clear criteria for IgRT use.
