Jennifer L. Gommerman

In addition to myeloid antigen-presenting cells (APCs), CD40 also induces APC potential in astrocytes during neuroinflammation.

Existing vectored immunoprophylaxis (VIP) approaches have primarily focused on IgG, which provides systemic protection but is less specialized in mucosal immunity. In contrast, secretory IgA (sIgA) plays a central role at epithelial surfaces, promoting pathogen neutralization while limiting inflammation. Although monoclonal IgA therapies are effective, their short half-life requires repeated dosing. Thus, VIP strategies enabling sustained sIgA expression at mucosal sites could transform mucosal infection prevention and treatment. This review outlines the key challenges associated with in vivo IgA expression and discusses critical considerations for VIP-mediated IgA delivery at mucosal surfaces, with emphasis on its potential for clinical translation. We provide a detailed overview of platforms for targeted IgA expression, including adeno-associated virus (AAV), adenoviral and lentiviral vectors, and lipid nanoparticle-based systems, alongside relevant routes of administration. Additionally, we examine emerging strategies to enhance the robustness, durability, and localization of IgA expression in vivo. Overall, VIP-enabled IgA expression represents an emerging strategy for enhancing mucosal immunity, with continued advances required to establish its role in the prevention and treatment of mucosal infections.

Therapy with anti-CD20 monoclonal antibodies is highly efficacious in various autoimmune diseases including multiple sclerosis (MS), a prototypic autoimmune inflammatory disease of the central nervous system (CNS). However, which B cell subsets and altered B cell–regulating factors mediate the clinical efficacy of anti-CD20 treatment is unclear. To address this gap in knowledge, we performed longitudinal high-dimensional single-cell transcriptomic and proteomic profiling of blood, cerebrospinal fluid (CSF), and intestinal samples from people with MS (pwMS), combined with immune profiling in a preclinical autoimmune encephalomyelitis model during anti-CD20 therapy. CSF analyses were performed using previously published datasets. Multisite intestinal profiling was conducted in one anti-CD20–treated patient with MS and one control participant. By applying algorithm-guided analyses of flow cytometry, single-cell transcriptomic, and immune receptor repertoire data, we found that anti-CD20 B cell depletion was associated with increased frequencies of regulatory mucosal-derived IgA-producing B cells in the periphery and CSF, together with increased B cell receptor clonal overlap between mucosal and systemic compartments, indicating enhanced trafficking of IgA B cells from gut mucosal tissues to the systemic circulation and the CNS. Moreover, we demonstrated that higher levels of B cell–activating factor and a proliferation-inducing ligand were related to favorable outcomes in pwMS during anti-CD20 treatment. Together, our findings suggest that mucosal immune regulatory mechanisms may be harnessed by anti-CD20 B cell depletion, opening previously unknown therapeutic avenues for MS.

Existing vectored immunoprophylaxis (VIP) approaches have primarily focused on IgG, which provides systemic protection but is less specialized for mucosal immunity. In contrast, secretory IgA (sIgA) plays a central role at epithelial surfaces, promoting pathogen neutralization while limiting inflammation. Although monoclonal IgA therapies are effective, their short half-life requires repeated dosing. Thus, VIP strategies enabling sustained sIgA expression at mucosal sites could transform mucosal infection prevention and treatment. This review outlines the key challenges associated with in vivo IgA expression and discusses critical considerations for VIP-mediated IgA delivery at mucosal surfaces, with emphasis on its potential for clinical translation. We provide a detailed overview of platforms for targeted IgA expression, including adeno-associated virus (AAV), adenoviral and lentiviral vectors, and lipid nanoparticle-based systems, alongside relevant routes of administration. Additionally, we examine emerging strategies to enhance the robustness, durability, and localization of IgA expression in vivo. Overall, VIP-enabled IgA expression represents an emerging strategy for enhancing mucosal immunity, with continued advances required to establish its role in the prevention and treatment of mucosal infections.

In multiple sclerosis (MS), B cell-rich tertiary lymphoid tissues (TLTs) in the brain leptomeninges associate with cortical gray matter injury. Using a model of Th17 cell-driven experimental autoimmune encephalomyelitis in mice, we found that inhibitors of Bruton’s tyrosine kinase (BTKi) prevented TLT formation and cortical pathology in a B cell activating factor (BAFF)-dependent manner. BTKi reduced expression of lymphotoxin ligands, and cotreatment with a lymphotoxin-β receptor agonist abrogated the benefits of BTKi. TLT and cortical pathology tracked with a high CXCL13:BAFF ratio in the leptomeninges, which was reduced by BTKi. Moreover, we observed high CXCL13:BAFF ratios in post mortem cerebral spinal fluid from patients with MS and pathologically confirmed leptomeningeal inflammation, as well as in living patients with MS and radiologically confirmed paramagnetic rim lesions. In summary, using experimental autoimmune encephalomyelitis, we revealed a molecular circuit that leads to TLT formation and cortical injury with translational relevance for detection of this pathology in patients with MS.

Type 2 conventional dendritic cells (cDC2s) are functionally and phenotypically heterogenous. Previous work in mice and humans identified two cDC2 subsets (cDC2As and cDC2Bs) and a monocytic DC3 subset. However, the microenvironmental cues governing their distinct differentiation pathways remain unclear. Here, we delineate mouse cDC2 lineage relationships and the sequential signals required for cDC2A maintenance. We show that cDC2s, arising from the CLEC9A⁺ cDC progenitor, encompass T-BET-expressing cDC2As and two cDC2B subsets distinguished by MGL2 expression, with monocytic DC3s exhibiting transcriptional overlap with Mgl2⁻ cDC2Bs. Among these subsets, T-BET⁺ cDC2As dominate the spleen where they require cell-intrinsic retinoic acid signaling to sustain their differentiation via Notch signals. Lymphotoxin-β receptor signaling on splenic cDC2s limits F-actin content retaining cDC2s at sites of retinol delivery. In summary, these data establish the developmental and transcriptional relationships between diverse cDC2 subsets and identify signals that regulate their prevalence in specific lymphoid tissues.