No description available.

No description available.

No description available.

Experimental Autoimmune Uveitis (EAU) is the murine and rat model of the equivalent chronic inflammatory condition in humans. Tolerance to EAU can be induced via a single intra-nasal administration of the retinal autoantigen interphotoreceptor retinoid-binding protein (hIRBP_1-20). Tolerance initiation to EAU has been associated with an initial elevation of Th2-type cytokines in the cervical lymph nodes and spleens of experimental animals. Moreover, tolerance initiation was enhanced in mice with inhibited expression of the myeloid cell-regulatory protein CD200. Binding of CD300/CD200R initiates a signalling cascade that ultimately results in the down-regulation of myeloid cell activation. Therefore, enhanced tolerance initiation in the CD200-deficient mice was a paradox and the main aim of this study was to examine the molecular events leading to enhanced tolerance. The first aim of this study was the identification of the exact time-point of tolerance initiation. Because of the association of Th2-type cytokines in tolerance induction, Northern Blotting detection for the <i>Stat6</i> transcript was performed. Maximal expression of the <i>Stat6</i> transcript was observed in the spleens of the CD200-deficient mice 8 h post-tolerisation. Having identified 8 h as a potentially relevant point in tolerance initiation, a GenaArray study was performed for the analysis of global gene expression in the cervical lymph nodes of IRBP-tolerised animals in respect to the sham-terrorised controls. Furthermore, the alternative molecular pathways initiated or inhibited in the cervical lymph nodes and spleens of CD20-deficient animals in respect to the WT controls were also examined. The results obtained in the microarray study were verified by Western Blotting and qRT-PCR. The results obtained in our study demonstrated that the nasal administration of autoantigen and the shift from a WT to a CD200-deficient phenotype had more diverse biological effects than previously thought.

No description available.

Autoimmune encephalitic (AE) syndromes represent a unique manifestation of autoimmunity: the immune system recognizes the brain as foreign, and interferes with neuronal function. AE syndromes are characterized by hallucinations, paranoia, anxiety, seizures, and autonomic dysregulation, and progress over a matter of weeks as autoantibodies targeting the brain bind more densely to their CNS targets. Development of AE has been linked to peripheral tumors and infection, both of which provide structural mimetics to CNS antigens to incite an immune response in the periphery. How these brain-specific antibodies reach the CNS remains unclear. In rare cases, Group A Streptococcus (GAS, S. pyogenes) infections can cause CNS autoimmunity targeting the basal ganglia, termed post-infectious basal ganglia encephalitis (BGE), manifesting as motor (Sydenham’s chorea) and psychiatric (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus, PANDAS) abnormalities. In a mouse model of post-infectious BGE, we have shown that repeated intranasal GAS infections generate robust T cell infiltration into the CNS, concomitant with blood-brain barrier breakdown, microglial activation, and olfactory synapse degradation. However, the different T cell subtypes that enter the brain, how they enter the CNS, and their relative contributions to neural dysfunction and neuroinflammation remain unclear. Th17 lymphocytes are heavily implicated in many autoimmune diseases, but whether the inflammatory post-infectious BGE reaction induces functional deficits in odor processing and requires Th17 lymphocytes was unknown. Here we demonstrate that mice lacking Th17 lymphocytes display both reduced BBB impairment and antibody infiltration. Furthermore, multiple GAS infections induce deficits in odor processing, which are partially ameliorated in Th17 cell-deficient mice. Notably, neuroinflammation and some excitatory synaptic loss persist, due to the presence of Th1 lymphocytes. Th17 lymphocytes are therefore critical for both selective CNS entry of autoantibodies and neural circuit impairment during post-infectious BGE. By examining the regulation of chemokine ligand expression in GAS-inoculated mice, we determined that CCL20/CCR6 and CCL2/CCR2 chemokine axes are implicated in T cell homing to the brain. In chemokine receptor mutant CCR6+/- CCR2-/- mice, T cell infiltration is reduced by 86.2%, and microglial activation is blunted. These findings suggest that CCL2/CCR2 and CCL20/CCR6 signaling may play a role in T cell homing to the brain and neuroinflammation. Finally, we first assessed behavioral and immune responses in two different GAS exposure models. It was clear that while behavioral abnormalities can be recapitulated in mice given subcutaneous GAS immunizations, this elicited relatively weak cellular and humoral immune responses. By contrast, mice given intranasal GAS inoculations showed minimal behavioral abnormalities, but elicited robust humoral and cellular immune responses. Taken together, these data demonstrate the pivotal role of Th17 lymphocytes in brain pathology and olfactory processing deficits after recurrent GAS infections in our mouse model. Our intranasal inoculation model supports the conclusion that post-infectious BGE is autoimmune in nature, despite the absence of behavioral symptoms in this model. Using multiple mouse models of post-infectious BGE may allow us to study distinct facets of disease pathogenesis. Finally, this work underscores the ability of T cells to incite neuroinflammation, provides a useful clinical diagnostic test in olfactory functional assessments, and lends support to T cell immunotherapy strategies in patients with post-infectious BGEs.

No description available.

The New Zealand Black (NZB) mouse chromosome 13 (c13) is linked to development of autoimmunity. B6 mice containing a portion of NZBc13 (B6.NZBc13 (c13)) develop a lupus phenotype that includes: autoantibody production, increased B and T cell activation, and marginal zone B cell and myeloid dendritic cell expansions. c13 mice have a B cell intrinsic dsRNA-sensing defect, leading to increased TLR3 expression and survival. The role of the aberrant dsRNA sensing in the generation of the c13 autoimmune phenotype was assessed by generating c13 mice with TLR3 knocked out (c13.TLR3KO). Marginal zone B cell expansion and B cell activation were attenuated in c13.TLR3KO mice, but other cellular phenotypes were not affected. Autoantibody production was partially reduced. These results indicate that altered dsRNA-sensing contribute to a portion of the altered cellular phenotypes in c13 mice, but that other susceptibility loci in the c13 interval are required for full development of autoimmunity.

No description available.

The New Zealand Black (NZB) mouse chromosome 13 (c13) is linked to development of autoimmunity. B6 mice containing a portion of NZBc13 (B6.NZBc13 (c13)) develop a lupus phenotype that includes: autoantibody production, increased B and T cell activation, and marginal zone B cell and myeloid dendritic cell expansions. c13 mice have a B cell intrinsic dsRNA-sensing defect, leading to increased TLR3 expression and survival. The role of the aberrant dsRNA sensing in the generation of the c13 autoimmune phenotype was assessed by generating c13 mice with TLR3 knocked out (c13.TLR3KO). Marginal zone B cell expansion and B cell activation were attenuated in c13.TLR3KO mice, but other cellular phenotypes were not affected. Autoantibody production was partially reduced. These results indicate that altered dsRNA-sensing contribute to a portion of the altered cellular phenotypes in c13 mice, but that other susceptibility loci in the c13 interval are required for full development of autoimmunity.