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Principal Investigator: MARCO COLONNA
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $587,914
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
B cells have an important pathogenic role in neurological autoimmune disorders, such as multiple sclerosis (MS)
and neuropsychiatric systemic lupus erythematosus (NP-SLE), one of the most disabling manifestations of SLE.
The relevance of B cells in central nervous system (CNS) autoimmunity is underscored by the therapeutic
efficacy of mAb-mediated B cell depletion in MS. How autoreactive B cells are generated and infiltrate the CNS
remains enigmatical. The CNS is enclosed within three membranes: pia, arachnoid, and dura. Between the
arachnoid and pia lies the subarachnoid space, which contains cerebrospinal fluid that harbors assorted immune
cells, including B cells. During neuroinflammation, blood lymphocytes infiltrate the meninges to mount local
humoral and/or cellular responses. Thus, meningeal B cells are thought to exclusively derive from the systemic
circulation. However, we recently showed that in young adult mice meningeal B cells mainly derive from the bone
marrow of cranial flat bones, known as calvaria, through special vascular channels. During aging, in contrast,
age-associated-B cells (ABC) migrate from the periphery into the dura, where they may differentiate into Ig-
secreting plasma cells. We hypothesize that meningeal B cells that derive from calvaria and differentiate locally
are tolerant to CNS-Ag. By contrast, B cells that originate from the periphery and hence are not educated by the
local antigenic milieu, may differentiate into autoreactive plasma cells upon CNS-Ag encounter. In Aim 1, we will
investigate mechanisms of meningeal B cell tolerance to local antigens under steady-state. Preliminary data
suggest that self-Ag experience during B cell development induces meningeal B cell depletion. Alongside, we
will examine meningeal B cell activation upon foreign Ag encounter. Finally, we will investigate the impact of the
microenvironment in dura B cell development, focusing on CXCL12 produced by dura fibroblasts. In Aim 2, we
will investigate autoreactivity of meningeal B cells and plasma cells in the SWAP-70/DEF6 double knock-out
(DKO) model of lupus. Preliminary data show accumulation of plasmablasts in the meninges of DKO mice. We
will compare the transcriptional profiles and B cell receptor (BCR) repertoires of B cells and plasma cells from
the dura and spleen to determine whether systemic B cells clones disseminate equally in lymphoid organs and
meninges, or whether the CNS environment recruits specific clones that further differentiate into plasma cells. In
parallel, DKO mice will be examined for behavioral alterations and CNS pathology. We will also identify the
utmost expanded BCR clones in the dura of DKO mice and generate monoclonal antibodies to ascertain
specificity for autoantigens. In Aim 3, we will obtain a single-cell transcriptomic profile of human dura immune
cells isolated from autoptic specimens, filling a critical gap in our knowledge of human meninges. Overall, this
proposal will advance our understanding of B cells in the CNS and mechanisms that promote neuroinflammation.
To achieve this, we will leverage the complementary expertise of the Colonna lab, which studies
neuroinflammation, and the Pernis lab, which studies autoimmunity in both humans and mouse models.
Terms: <Ablation><Active Follow-up><Aging><Antigens><Applications Grants><Arachnoid><Arachnoid mater><Autoantigens><Autoimmune Diseases><Autoimmune Diseases of the Nervous System><Autoimmune Responses><Autoimmune Status><Autoimmune neurologic condition><Autoimmunity><Autologous Antigens><Autoregulation><B blood cells><B cell><B cell receptor><B cell repertoire><B cells><B-Cell Activation><B-Cell Antigen Receptor><B-Cell Development><B-Cells><B-Lymphocytes><B-cell><Behavioral><Bio-Informatics><Bioinformatics><Blood><Blood Plasma Cell><Blood Reticuloendothelial System><Blood Vessels><Body Tissues><Bone Marrow><Bone Marrow Grafting><Bone Marrow Reticuloendothelial System><Bone Marrow Transplant><Bone Marrow Transplantation><Bp35><Brain><Brain Nervous System><C2B8 Monoclonal Antibody><CD20><CNS Diseases><CNS Nervous System><CNS autoimmunity><CNS disorder><CNS lupus><CXCL12><CXCL12 gene><CXCL12 protein><Calvaria><Cell Body><Cell Compartmentation><Cell Compartmentations><Cell Isolation><Cell Locomotion><Cell Migration><Cell Movement><Cell Segregation><Cell Separation><Cell Separation Technology><Cells><Cellular Migration><Cellular Motility><Central Nervous System><Central Nervous System Diseases><Central Nervous System Disorders><Central Nervous System Lupus><Central Nervous System Systemic Lupus Erythematosis><Cephalic><Cerebrospinal Fluid><Chemokine (C-X-C Motif) Ligand 12><Circulation><Clinical Treatment Moab><Clone Cells><Cranial><Data><Development><Disabling><Disease><Disorder><Disseminated Sclerosis><Dura><Dura Mater><Encephalon><Environment><Expression Signature><Fibroblasts><Gene Expression><Gene Expression Profile><Goals><Grant><Grant Proposals><Hematopoietic><Homeostasis><Homing><Human><Immune><Immune Globulins><Immune Surveillance><Immune Tolerance><Immune system><Immunes><Immunoglobulins><Immunologic Surveillance><Immunologic Surveillances><Immunologic Tolerance><Immunological Surveillance><Immunological Surveillances><Immunosurveillance><Infiltration><Invaded><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Knowledge><Leu-16><Light><Lupus><Lupus Erythematosus Disseminatus><Lymphatic cell><Lymphocyte><Lymphocytic><Lymphocytic Infiltrate><MS4A1><MS4A1 gene><MS4A2><MabThera><Marrow Transplantation><Mature B-Cell><Mature B-Lymphocyte><Mediating><Medulla Spinalis><Membrane><Meningeal><Meninges><Mice><Mice Mammals><Minor><Modeling><Modern Man><Monoclonal Antibodies><Multiple Sclerosis><Murine><Mus><Nerve Cells><Nerve Unit><Nervous System><Nervous System Autoimmune Disorders><Neural Cell><Neuraxis><Neurocyte><Neurologic Autoimmune Diseases><Neurologic Body System><Neurologic Organ System><Neurons><Neuropsychiatric Lupus><Neuropsychiatric SLE><Neuropsychiatric Systemic Lupus Erythematosus><Null Mouse><PBSF><Parabiosis><Pathogenicity><Pathology><Periosteum><Periosteums><Peripheral><Photoradiation><Physiological Homeostasis><Plasma Cells><Plasmablast><Plasmacytes><Play><Pre-B Cell Growth Stimulating Factor><Publishing><Reactive Plasma Cell><Research Specimen><Rituxan><Role><SCYB12><SDF-1><SDF-1A><SDF-1B><SDF-1alpha><SDF1><SDF1A><SDF1B><SLE><Science><Sdf1 protein><Self-Antigens><Seminal><Skull><Source><Specificity><Specimen><Spinal Cord><Spleen><Spleen Reticuloendothelial System><Stromal Cell-Derived Factor 1><Subarachnoid Space><Surface><Syndrome><Systemic Lupus Erythematosus><Systemic Lupus Erythematous><Systemic Lupus Erythmatosus><TLSF-A><TLSF-B><TPAR1><Techniques><Testing><Tissues><Treatment Efficacy><Update><Work><activated B cells><active followup><adult youth><age associated><age correlated><age dependent><age linked><age related><age specific><aged mice><aged mouse><autoimmune condition><autoimmune disease in the nervous system><autoimmune disorder><autoimmune reactivity><autoimmune-driven neurological disease><autoimmunity disease><autoreactive B cell><autoreactivity><bone><calvarial><cell motility><cell sorting><central nervous system autoimmunity><cerebral spinal fluid><confocal imaging><cranium><developmental><disseminated lupus erythematosus><elderly mice><experience><experiment><experimental research><experimental study><experiments><flat bone><follow up><follow-up><followed up><followup><gene expression pattern><gene expression signature><hIRH><hemopoietic><human model><immune system tolerance><immune unresponsiveness><immunogen><immunological paralysis><insular sclerosis><intervention efficacy><lupus-like><lymph cell><lymph organ><lymphatic organ><lymphoid organ><mAbs><membrane structure><meninge><model of human><monoclonal Abs><mouse model><murine model><neural inflammation><neuro-autoimmune disorder><neuroinflammation><neuroinflammatory><neurologic autoimmune disorder><neuronal><old mice><plasmocyte><preservation><reconstitute><reconstitution><recruit><response><rituximab><self reactive B cell><social role><spinal fluid><stromal cell-derived factor-1alpha><systemic lupus erythematosis><theories><therapeutic efficacy><therapy efficacy><transcriptional profile><transcriptional signature><transcriptomics><vascular><young adult><young adulthood>