Thomas Korn

Compartmentalized inflammation within the CNS is considered to drive progressive immunopathology in multiple sclerosis (MS) independently of relapses. Meningeal tertiary lymphoid structures (TLS) represent an immune niche associated with histological signs of immunopathology, including demyelination in the adjacent CNS parenchyma. Here, we show that the opticospinal encephalomyelitis (OSE) mouse model, in which meningeal TLS develop spontaneously based on the interaction of myelin oligodendrocyte glycoprotein (MOG)-specific T cell receptor (TCR) transgenic T cells with MOG B cell receptor (BCR) transgenic B cells, recapitulates the dynamics and the histological features of meningeal TLS observed in human MS. Based on scRNAseq datasets of meningeal TLS from OSE mice, the CD40L-CD40 pathway is highly active in the T cell-B cell interaction in this niche. Accordingly, a monoclonal antibody to CD40L, applied systemically, abrogates the T-B interaction in the systemic compartment and even more so in the meningeal compartment. This leads to near-complete clearance of meningeal TLS, concomitant with clinical improvement of the progressive disease phase of OSE mice. In contrast, systemic B cell depletion with a monoclonal antibody to CD20 does not improve signs of progressive disease in the OSE model. Treatment with anti-CD40L is more effective in disrupting T-B interaction, the more the T-B interaction relies on the CD40L-CD40 pathway, and thus leads to a "semi-selective" targeting of meningeal TLS. In addition, not only B cells but the entire antigen-presenting compartment in the CNS is remodeled in the absence of CD40 engagement. Since these effects persist even after withdrawal of anti-CD40L treatment, no rebound episodes or resumption of progression are observed. In conclusion, anti-CD40L treatment may be an effective intervention to mitigate progressive immunopathology associated with meningeal TLS. Beyond B cells, anti-CD40L treatment also modulates and likely silences other CD40-dependent antigen-presenting cells in the CNS, including myeloid cells and astrocyte subsets.

Foxp3-expressing regulatory T (T _reg ) cells protect against systemic autoimmunity. However, little is known about the significance of T _reg cells in inflammation-experienced tissues. Here, we use an experimental autoimmune encephalomyelitis model and show that T _reg cells accumulate and persist in the central nervous system (CNS) long after the resolution of the bulk of the inflammatory infiltrate. CNS-specific depletion of postinflammatory T _reg cells, but not systemic depletion of T _reg cells, results in autoimmune inflammatory flares in the CNS by residual local effector T cells. Expression of the NAD-consuming ectoenzyme CD38 is crucial for the functional adaptation of postinflammatory CNS T _reg cells to a stressful microenvironment, in which access to interleukin-2 (IL-2) is limited. CD38 counteracts ADP-ribosylation of the IL-2 receptor and thus maintains its high sensitivity to IL-2. This fully functional high-affinity IL-2 receptor prevents the loss of tissue-resident antigen-specific T _reg cells. These ‘stress-tolerant’ CNS T _reg cells impede the collapse of immune homeostasis in the CNS once acute inflammation is controlled.

Retinal optical coherence tomography (OCT) in rodent models has been used to longitudinally image retinal changes, to define end points for more costly or time-consuming experiments, and to better understand the pathophysiology underlying OCT findings in human diseases. No standardization of rodent OCT reporting currently exists. Here, we aim to establish consensus recommendation for reporting results from retinal OCT studies in rodents. Initial recommendations were developed based on the APOSTEL criteria for quantitative OCT reporting in humans by a core team. Using a modified Delphi process, an expert panel of rodent OCT researchers (N = 31) and the wider scientific community discussed, refined, and voted on these initial recommendations. The list of recommendations was then revised and approved by the expert panel. The final 7-point checklist includes reporting recommendations regarding the study protocol, OCT device, acquisition settings and modifications, scanning protocol, funduscopic imaging, postacquisition data selection and image data analyses, and qualitative and quantitative results. With a median agreement score of 3 or 4 out of 4, the scientific community agreed with these recommendations. After revisions, the expert panel accepted the final recommendations. The Advised Protocol for OCT Study Terminology and Elements for reporting OCT studies in rodents (APOSTEL-R) originates from an expert consensus. They will provide guidance throughout the experimental process and will contribute to the standardization and quality improvement of preclinical OCT studies.

Myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD) is a recently defined neurological autoimmune condition. The pathogenesis of the disease remains poorly understood, and no specific therapies are currently approved. Here, a comprehensive single-cell immunophenotyping of peripheral blood mononuclear cells from two independent cohorts of patients with MOGAD revealed pronounced immune perturbations in MOGAD when compared with healthy controls and patients with multiple sclerosis. Patients with MOGAD displayed an expansion of CXCR5 ⁻ CD21 ⁻ activated naïve and double-negative B cell subsets, a feature shared with patients with systemic lupus erythematosus. In addition, we observed altered Fc gamma receptor expression in natural killer cells, monocytes, and dendritic cells. Within the T cell compartment, CXCR3 ⁺ CD4 ⁺ memory T cells were reduced in the circulation of patients with MOGAD compared with healthy controls, and this result was mirrored in a transgenic mouse model that showed retention of these cells in the inflamed central nervous system. Together, these results demonstrate profound systemic immune cell alterations in MOGAD and contribute to a better understanding of this distinct disease entity.

Neuromyelitis optica spectrum disorder (NMOSD) is a paradigmatic autoimmune disease of the central nervous system (CNS), in which the water channel protein Aquaporin-4 (AQP4) is targeted by a self-reactive immune response. While the immunopathology of human NMOSD is largely dependent on antibodies to astrocytic AQP4, the role of AQP4-specific T cells for the localization and quality of NMOSD lesions in the CNS is not known. Only recently, we established that thymic B cells express and present AQP4 in the context of MHC class II molecules to purge the naive T cell receptor repertoire of AQP4-specific clones. Here, we exploited this finding to investigate the lesion localization in the CNS of B cell conditional AQP4-deficient (Aqp4 ^ΔB) mice, which harbor AQP4-specific precursors in their naive T cell repertoire and can be sensitized to mount a strong AQP4(201–220)-specific CD4⁺ T cell response. Sensitization of Aqp4 ^ΔB mice with AQP4(201–220) was sufficient to induce clinical disease. The spatiotemporal lesion distribution and the glial cell response in AQP4(201–220)-induced experimental autoimmune encephalomyelitis (EAE) was compared to classical MOG(35–55)-induced EAE in Aqp4 ^ΔB mice. In contrast to MOG-EAE, AQP4(201–220)-induced EAE was characterized by midline lesions in the brain, retinal pathology, and lesions at the grey matter/white matter border zone in the spinal cord. Therefore, we conclude that antigen-specific T cells dictate the localization of NMOSD-lesions in the CNS.