SUMMARY The human gut is colonized by a large number of microorganisms (~1013 bacteria) that support various physiologic functions. A perturbation in healthy gut microbiome might leads to the development of inflammatory diseases including multiple sclerosis (MS). Therefore, gut commensals can provide promising therapeutic options for treating autoimmune diseases such as MS. We report identification of human gut–derived commensal bacteria, Prevotella histicola, which can suppress an autoimmune disease in HLA class-II transgenic model of experimental autoimmune encephalomyelitis (EAE); an animal model of MS. P. histicola suppresses disease through modulation of systemic immune responses. P. histicola challenge led to a decrease in pro-inflammatory Th1 and Th17 cells, and increase in the frequencies of CD4+FoxP3+ regulatory T cells, tolerogenic dendritic cells, and suppressive macrophage. Our study provides evidence that administration of gut commensals may regulate a systemic immune response and may, therefore, have a possible role in the treatment strategies for MS.
Aquaporin-4 (AQP4) water channel-specific IgG distinguishes neuromyelitis optica (NMO) from multiple sclerosis and causes characteristic immunopathology in which central nervous system (CNS) demyelination is secondary. Early events initiating the pathophysiological outcomes of IgG binding to astrocytic AQP4 are poorly understood. CNS lesions reflect events documented in vitro following IgG interaction with AQP4: AQP4 internalization, attenuated glutamate uptake, intramyelinic edema, interleukin-6 release, complement activation, inflammatory cell recruitment, and demyelination. Here, we demonstrate that AQP4 internalization requires AQP4-bound IgG to engage an astrocytic Fcγ receptor (FcγR). IgG-lacking Fc redistributes AQP4 within the plasma membrane and induces interleukin-6 release. However, AQP4 endocytosis requires an activating FcγR's gamma subunit and involves astrocytic membrane loss of an inhibitory FcγR, CD32B. Interaction of the IgG-AQP4 complex with FcγRs triggers coendocytosis of the excitatory amino acid transporter 2 (EAAT2). Requirement of FcγR engagement for internalization of two astrocytic membrane proteins critical to CNS homeostasis identifies a complement-independent, upstream target for potential early therapeutic intervention in NMO.N euromyelitis optica (NMO) is a relapsing inflammatory autoimmune demyelinating disease of the central nervous system (CNS), long considered a severe form of multiple sclerosis (MS). Attacks are generally more severe, onset of paralysis and blindness more rapid (1), and standard MS therapies can worsen NMO (2, 3). A specific serum IgG allows early distinction from MS, thus ensuring timely appropriate therapy (4, 5).The aquaporin-4 (AQP4) water channel is the CNS target (4). Outcomes documented in vitro after NMO-IgG binds to the AQP4 extracellular domain on astrocytes include AQP4 endocytosis and lysosomal degradation, loss of its physically linked major excitatory amino acid transporter 2 (EAAT2), reduced glutamate uptake, impaired water fluxes, granulocyte chemotaxis, and complement factor transcription, secretion, and activation (1, 6-11). Ensuing endothelial permeation of circulating immunoglobulins, complement components, and leukocytes magnifies the initial inflammatory response (6-12). Immunopathological analyses of NMO patients' CNS tissues attest to these events occurring in vivo and inform lesional evolution at the target astrocyte level (1). The blood-brain barrier (BBB) does not absolutely restrict IgG entry into the CNS, but it does exclude macromolecular C1q, essential for activating the classical complement cascade.Experimental studies of lesional events in vitro and in animal models of NMO have emphasized complement-mediated inflammation and astrocyte cytolysis, late events associated with extensive BBB disruption. A neglected potential initiator of NMO pathophysiology is the AQP4-IgG-activated astrocyte's response: synthesis and secretion of complement, cytokines, chemokines (12-14), and inflammatory mediators attracting NMO-characteristic gra...
Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) of presumed autoimmune origin. Of all the genetic factors linked with MS, MHC class-II molecules have the strongest association. Generation of HLA class-II transgenic mice has helped to elucidate the role of HLA class-II genes in chronic inflammatory and demyelinating diseases. We have shown that the human HLA-DRB1*0301 gene predisposes to proteolipid protein (PLP)-induced EAE, whereas HLA-DQβ1*0601 (DQ6) was resistant. We also showed that the DQ6 molecule protects from EAE in DRB1*0301.DQ6 double transgenic mice by producing anti-inflammatory interferon gamma (IFNγ). HLA-DQβ1*0302 (DQ8) transgenic mice were also resistant to PLP91-110-induced EAE, but production of pro-inflammatory IL-17 exacerbated disease in DRB1*0301.DQ8 mice. To further confirm the role of IFNγ in protection, we generated DRB1*0301.DQ8 mice lacking IFNγ (DRB1*0301.DQ8.IFNγ−/−). Immunization with PLP91-110 peptide caused atypical EAE in DRB1*0301.DQ8.IFNγ−/− mice characterized by ataxia, spasticity and dystonia, hallmarks of brain-specific disease. Severe brain specific inflammation and demyelination in DRB1*0301.DQ8.IFNγ−/− mice with minimal spinal cord pathology further confirmed brain-specific pathology. Atypical EAE in DRB1*0301.DQ8.IFNγ−/− mice was associated with increased encephalitogenicity of CD4 T cells and their ability to produce higher levels of IL-17 and GM-CSF compared to DRB1*0301.DQ8 mice. Further, areas with demyelination showed increased presence of CD68+ inflammatory cells, suggesting an important role for monocytes/microglia in causing brain pathology. Thus, our study supports a protective role for IFNγ in the demyelination of brain through down regulation of IL-17/GM-CSF and induction of neuro-protective factors in the brain by monocytes/microglial cells.
Among all the genetic factors linked with multiple sclerosis (MS), MHC class-II molecules show the strongest association. Generation of HLA class-II transgenic mice has helped to elucidate the role of HLA class-II gene in MS. We have shown that the human HLA-DR3 (DRβ1*0301) gene predisposes to proteolipid protein (PLP)-induced EAE, whereas HLA-DQβ1*0601 (DQ6) was resistant. We also showed that the DQ6 molecule protects from EAE in DR3DQ6 double transgenic mice by producing anti-inflammatory interferon gamma (IFNγ). To further confirm the role of IFNγ in protection, we generated DR3DQ8 mice lacking IFNγ (DR3DQ8.IFNγ-/-). Immunization with PLP91-110 peptide caused atypical EAE in DR3DQ8.IFNγ-/- mice characterized by ataxia and spasticity, hallmarks of brain-specific disease. Severe brain specific inflammation and demyelination in DR3DQ8.IFNγ-/- mice with minimal spinal cord pathology further confirmed brain-specific pathology. Severe disease in DR3DQ8.IFNγ-/- mice was due to increased encephalitogenicity of CD4 T cells and its ability to produce higher levels of IL-17 and GM-CSF compared to DR3DQ8 mice. Further, areas with demyelination showed increased presence of CD68+ inflammatory cells suggesting an important role for monocytes/microglia in causing brain pathology. Thus, our study supports a protective role for IFNγ in inflammatory and demyelinating disease through down regulation of IL-17 and induction of neuro-protective factors in the brain by monocytes/microglial cells.
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