ABSTRACT Aquaporin‐4 (AQP4) antibody‐positive neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD) are distinct autoimmune inflammatory conditions of the central nervous system. Defined autoantigens characterize NMOSD and MOGAD; however, the mechanisms driving immune activation, tissue injury, and breakdown of immune tolerance differ substantially between these conditions. Both conditions reflect a breakdown of immune tolerance mechanisms, permitting the persistence and activation of autoreactive T and B cells. However, NMOSD is characterized by a more clearly defined antibody and complement‐mediated astrocytopathy, whereas MOGAD appears to require synergy with T‐cell‐driven inflammation, with a more variable contribution from complement‐mediated and innate effector pathways. This review summarizes the current understanding of innate and adaptive immune activation and mechanisms of immune tolerance failure in NMOSD and MOGAD and highlights how these features may inform emerging therapeutic strategies.
ABSTRACT Follicular helper T (Tfh) cells orchestrate germinal center (GC) derived humoral immunity by providing essential help to B cells. Despite their key role in humoral immunity, the metabolic cues that shape Tfh cell differentiation and functions in humans remain poorly understood. Here, using a human ex vivo Tfh cell differentiation model, we investigated the metabolic requirements of Tfh cell development and function through targeted metabolic perturbation of glycolysis and fatty acid metabolism, transcriptomic analyses, and metabolic rescue experiments. Unexpectedly, early glycolytic inhibition enhanced Tfh cell differentiation but markedly impaired function, including reduced IL‐21 production and diminished B‐cell help. Transcriptomic and metabolic analyses revealed that glycolytic inhibition was accompanied by suppression of fatty acid metabolism. Consistently, independent inhibition of fatty acid synthesis or oxidation suppressed Tfh cell help functions, including IL‐21 and IFN‐γ production, as well as B‐cell help potential. Interestingly, acetate supplementation partially restored IFN‐γ secretion in glycolysis‐inhibited conditions, but not IL‐21, indicating limited metabolic compensation. Together, these findings reveal distinct metabolic requirements for Tfh cell differentiation and function and identify glycolysis‐dependent fatty acid metabolism as an important determinant of human Tfh cell functional competence. This metabolic crosstalk provides new insight into the regulation of Tfh cells and Tfh‐driven humoral immunity in vaccination and autoimmunity.
ABSTRACT Here, we assessed whether spatially resolved capture of polyadenylated mRNA permitted simultaneous screening of host and viral responses in situ. Fresh‐frozen lung samples from mice infected with H1N1 influenza A strain, PR8, were processed via genome‐wide, spatial transcriptomics (ST) at 10‐μm resolution. To determine if specific cell‐types were detectable within the ST data, we first performed cellular deconvolution using publicly available, single‐cell RNA‐seq data of immune and non‐immune cells from PR8‐infected lungs. This revealed expected structures such as rings of epithelial cells lining airways, and at Day 10 post‐infection (p.i.) unexpected structures dominated by B cells. We next screened ST data alone for groups of genes displaying similar spatial expression patterns. This again identified at Day 10 p.i. cellular aggregates enriched for genes associated with B cell biology. Mapping these gene signatures to a B cell transcriptomic atlas suggested plasmablasts had emerged early in the lung, which was confirmed by flow cytometry. Finally, by mapping ST data to the influenza A genome, we observed widespread expression of all 10 viral transcripts across samples at Day 4 but not Day 10 p.i., consistent with viral clearance. Cellular deconvolution analysis at Day 4 p.i. revealed proportions of every detected cell‐type harbored viral transcripts, suggesting indiscriminate infection across the specific area of tissue examined. Subsequent whole‐section immunohistochemical assessment further supported the phenomenon of localized indiscriminate infection, with these areas found adjacent to minimally infected zones. Thus, spatial screening of mRNA in tissues can simultaneously inform upon viral pathogenesis and host responses to infection.
ABSTRACT With widespread use of mice ( Mus musculus ) in immunological research, understanding baseline immune variation between mouse models is critical. While peripheral blood immune profiles have been well‐defined, strain‐ and sex‐specific differences in leukocyte composition across other tissues remain poorly characterized. Here, we performed flow cytometric immunophenotyping of 19 leukocyte subsets and 3 T cell memory phenotypes in the blood, bone marrow, liver, spleen, and lymph nodes of seven strains of naïve adult male mice: Balb.b, BALB/c, BALB/c Ly5.1, C57BL/6J, C57BL/6J Ly5.1, BALB/c:B6J (F1), and DBA/2 J. Parallel analyses were conducted in female BALB/c and C57BL/6J mice. Each tissue contained a unique immunobiome, with conventional T and B cells enriched in the lymph nodes and spleen, unconventional T cells and innate lymphoid cells (ILCs) in the liver, and myeloid cells in the bone marrow. Generally, BALB‐derived strains displayed a helper T cell‐ and innate‐skewed profile, enriched for CD4 and regulatory T cells, neutrophils, and natural killer cells. C57BL/6J‐derived strains were typically enriched for CD8 T cells, ILC1s, and conventional dendritic cells, consistent with a cytotoxic immune bias. Small differences were detected between congenic and parental strains. F1's exhibited a mix of C57BL/6J‐biased and intermediate parental phenotypes. DBA/2 J mice were immunologically distinct, notably enriched for γδ T cells. Sex‐associated differences were minor compared to strain effects. These findings provide tissue‐specific benchmarks for leukocyte composition across commonly used mouse strains. They also highlight the importance of strain and sex selection and baseline immunophenotyping to support accurate interpretation of observed immune phenotypes in experimental contexts.
The skin microbiota has been reframed as a dynamic and active regulator of cutaneous barrier integrity and immune programming, moving beyond its traditional view as a passive microbial community. Dysbiosis represents a complex functional and ecological imbalance that disrupts barrier integrity and may promote sustained inflammatory immune remodeling. This mechanistic axis, in which disruption of the microbiota contributes to barrier failure and immune dysregulation, underpins chronic inflammatory skin conditions. Conventional antibiotic-centered therapies often fail to restore microbial homeostasis or immune balance, highlighting their limitations. Emerging precision microbiome therapeutics focus on targeted modulation of microbial function, signaling pathways, and ecological restoration to repair barrier defects and recalibrate immune responses. This review synthesizes current evidence linking skin microbiota dysbiosis with barrier dysfunction, inflammatory immune remodeling, and emerging microbiome-directed therapeutic strategies. We propose an integrative framework linking ecological disruption, epithelial barrier injury, and immune dysregulation while highlighting unresolved mechanistic, translational, and knowledge gaps, such as detailed molecular mechanisms of host-microbiota interactions and challenges in translating findings into clinically effective personalized interventions. Future research should prioritize multi-omics integration and biomarker-driven stratification to advance precision dermatology therapeutics grounded in mechanistic insights of skin microbial ecology.
