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Meningeal Infiltration of the Spinal Cord by Non-Classically Activated B Cells is Associated with Chronic Disease Course in a Spontaneous B Cell-Dependent Model of CNS Autoimmune Disease.

Dang AK, Tesfagiorgis Y, Jain RW, Craig HC, Kerfoot SM - Front Immunol (2015)

Bottom Line: These clusters were typically found adjacent to white matter lesions and their presence was associated with a chronic disease course.Extensive investigation of these clusters by histology did not identify features of lymphoid follicles, including organization of T and B cells into separate zones, CD35(+) follicular dendritic cells, or germinal centers.Nevertheless, they were CD62L(lo) and CD80(hi) compared to lymph node B cells suggesting that they were at least partly activated and primed to present antigen.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University Canada , London, ON , Canada.

ABSTRACT
We characterized B cell infiltration of the spinal cord in a B cell-dependent spontaneous model of central nervous system (CNS) autoimmunity that develops in a proportion of mice with mutant T and B cell receptors specific for myelin oligodendrocyte glycoprotein. We found that, while males are more likely to develop disease, females are more likely to have a chronic rather than monophasic disease course. B cell infiltration of the spinal cord was investigated by histology and FACs. CD4(+) T cell infiltration was pervasive throughout the white and in some cases gray matter. B cells were almost exclusively restricted to the meninges, often in clusters reminiscent of those described in human multiple sclerosis. These clusters were typically found adjacent to white matter lesions and their presence was associated with a chronic disease course. Extensive investigation of these clusters by histology did not identify features of lymphoid follicles, including organization of T and B cells into separate zones, CD35(+) follicular dendritic cells, or germinal centers. The majority of cluster B cells were IgD(+) with little evidence of class switch. Consistent with this, B cells isolated from the spinal cord were of the naïve/memory CD38(hi) CD95(lo) phenotype. Nevertheless, they were CD62L(lo) and CD80(hi) compared to lymph node B cells suggesting that they were at least partly activated and primed to present antigen. Therefore, if meningeal B cells contribute to CNS pathology in autoimmunity, follicular differentiation is not necessary for the pathogenic mechanism.

No MeSH data available.


Related in: MedlinePlus

B cell infiltration of the spinal cord is associated with chronic disease and increased disease severity. At study endpoints (~4 weeks post disease onset), spinal cords were harvested for evaluation of pathology by immunofluorescence histology. Spinal cords from mice deemed to have either a “Monophasic” (A) or “Chonic” (B) disease course (as defined in Figure 2) were evaluated for demyelination, CD4+ T cell infiltration and meningeal cluster formation. Solid arrowheads indicate meningeal clusters. Open arrowheads indicate regions of white matter demyelination and infiltration by CD4+ cells. Scale bars represent 200 μm. The number of meningeal clusters per section (C) and cluster area (D) was evaluated using Image J software. Three sections from different regions of the spinal cord were evaluated from each mouse. **p < 0.01 as determined by Student’s t-test. Each symbol represents the average value per section from an individual mouse. (E) Cluster size was correlated with average disease score (as a measure of overall disease severity) for each individual mouse included in the study. Each symbol represents an individual mouse. A two tailed Pearson r test was performed to test for correlation.
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Figure 5: B cell infiltration of the spinal cord is associated with chronic disease and increased disease severity. At study endpoints (~4 weeks post disease onset), spinal cords were harvested for evaluation of pathology by immunofluorescence histology. Spinal cords from mice deemed to have either a “Monophasic” (A) or “Chonic” (B) disease course (as defined in Figure 2) were evaluated for demyelination, CD4+ T cell infiltration and meningeal cluster formation. Solid arrowheads indicate meningeal clusters. Open arrowheads indicate regions of white matter demyelination and infiltration by CD4+ cells. Scale bars represent 200 μm. The number of meningeal clusters per section (C) and cluster area (D) was evaluated using Image J software. Three sections from different regions of the spinal cord were evaluated from each mouse. **p < 0.01 as determined by Student’s t-test. Each symbol represents the average value per section from an individual mouse. (E) Cluster size was correlated with average disease score (as a measure of overall disease severity) for each individual mouse included in the study. Each symbol represents an individual mouse. A two tailed Pearson r test was performed to test for correlation.

Mentions: We next evaluated spinal cord pathology later in disease (>20 days post disease onset) in mice with either a chronic or monophasic disease course (as defined above). White matter pathology in monophasic mice was very limited, in that there was little CD4+ T cell infiltration or demyelination (Figure 5A). By contrast, ongoing white and gray matter inflammation by CD4+ T cells and white matter demyelination was clearly evident in mice with chronic disease (Figure 5B) demonstrating that continued disability in these mice reflects active and ongoing inflammation, rather than permanent injury incurred during the initial attack. Large meningeal clusters containing T and B cells were also common in these mice. Nevertheless, despite reduced white matter involvement, small meningeal clusters were sometimes also present in monophasic mice (Figure 5A). However, subsequent analysis confirmed that meningeal clusters were both more numerous (Figure 5C) and larger (Figure 5D) in chronic vs. monophasic mice. Further, independent of disease course classification the size of meningeal clusters correlated with disease severity (Figure 5E). This, combined with the common spatial association between clusters and underlying regions of demyelination, suggests that these structures may contribute to ongoing chronic CNS autoimmune disease in 2D2 IgHMOG mice.


Meningeal Infiltration of the Spinal Cord by Non-Classically Activated B Cells is Associated with Chronic Disease Course in a Spontaneous B Cell-Dependent Model of CNS Autoimmune Disease.

Dang AK, Tesfagiorgis Y, Jain RW, Craig HC, Kerfoot SM - Front Immunol (2015)

B cell infiltration of the spinal cord is associated with chronic disease and increased disease severity. At study endpoints (~4 weeks post disease onset), spinal cords were harvested for evaluation of pathology by immunofluorescence histology. Spinal cords from mice deemed to have either a “Monophasic” (A) or “Chonic” (B) disease course (as defined in Figure 2) were evaluated for demyelination, CD4+ T cell infiltration and meningeal cluster formation. Solid arrowheads indicate meningeal clusters. Open arrowheads indicate regions of white matter demyelination and infiltration by CD4+ cells. Scale bars represent 200 μm. The number of meningeal clusters per section (C) and cluster area (D) was evaluated using Image J software. Three sections from different regions of the spinal cord were evaluated from each mouse. **p < 0.01 as determined by Student’s t-test. Each symbol represents the average value per section from an individual mouse. (E) Cluster size was correlated with average disease score (as a measure of overall disease severity) for each individual mouse included in the study. Each symbol represents an individual mouse. A two tailed Pearson r test was performed to test for correlation.
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Figure 5: B cell infiltration of the spinal cord is associated with chronic disease and increased disease severity. At study endpoints (~4 weeks post disease onset), spinal cords were harvested for evaluation of pathology by immunofluorescence histology. Spinal cords from mice deemed to have either a “Monophasic” (A) or “Chonic” (B) disease course (as defined in Figure 2) were evaluated for demyelination, CD4+ T cell infiltration and meningeal cluster formation. Solid arrowheads indicate meningeal clusters. Open arrowheads indicate regions of white matter demyelination and infiltration by CD4+ cells. Scale bars represent 200 μm. The number of meningeal clusters per section (C) and cluster area (D) was evaluated using Image J software. Three sections from different regions of the spinal cord were evaluated from each mouse. **p < 0.01 as determined by Student’s t-test. Each symbol represents the average value per section from an individual mouse. (E) Cluster size was correlated with average disease score (as a measure of overall disease severity) for each individual mouse included in the study. Each symbol represents an individual mouse. A two tailed Pearson r test was performed to test for correlation.
Mentions: We next evaluated spinal cord pathology later in disease (>20 days post disease onset) in mice with either a chronic or monophasic disease course (as defined above). White matter pathology in monophasic mice was very limited, in that there was little CD4+ T cell infiltration or demyelination (Figure 5A). By contrast, ongoing white and gray matter inflammation by CD4+ T cells and white matter demyelination was clearly evident in mice with chronic disease (Figure 5B) demonstrating that continued disability in these mice reflects active and ongoing inflammation, rather than permanent injury incurred during the initial attack. Large meningeal clusters containing T and B cells were also common in these mice. Nevertheless, despite reduced white matter involvement, small meningeal clusters were sometimes also present in monophasic mice (Figure 5A). However, subsequent analysis confirmed that meningeal clusters were both more numerous (Figure 5C) and larger (Figure 5D) in chronic vs. monophasic mice. Further, independent of disease course classification the size of meningeal clusters correlated with disease severity (Figure 5E). This, combined with the common spatial association between clusters and underlying regions of demyelination, suggests that these structures may contribute to ongoing chronic CNS autoimmune disease in 2D2 IgHMOG mice.

Bottom Line: These clusters were typically found adjacent to white matter lesions and their presence was associated with a chronic disease course.Extensive investigation of these clusters by histology did not identify features of lymphoid follicles, including organization of T and B cells into separate zones, CD35(+) follicular dendritic cells, or germinal centers.Nevertheless, they were CD62L(lo) and CD80(hi) compared to lymph node B cells suggesting that they were at least partly activated and primed to present antigen.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University Canada , London, ON , Canada.

ABSTRACT
We characterized B cell infiltration of the spinal cord in a B cell-dependent spontaneous model of central nervous system (CNS) autoimmunity that develops in a proportion of mice with mutant T and B cell receptors specific for myelin oligodendrocyte glycoprotein. We found that, while males are more likely to develop disease, females are more likely to have a chronic rather than monophasic disease course. B cell infiltration of the spinal cord was investigated by histology and FACs. CD4(+) T cell infiltration was pervasive throughout the white and in some cases gray matter. B cells were almost exclusively restricted to the meninges, often in clusters reminiscent of those described in human multiple sclerosis. These clusters were typically found adjacent to white matter lesions and their presence was associated with a chronic disease course. Extensive investigation of these clusters by histology did not identify features of lymphoid follicles, including organization of T and B cells into separate zones, CD35(+) follicular dendritic cells, or germinal centers. The majority of cluster B cells were IgD(+) with little evidence of class switch. Consistent with this, B cells isolated from the spinal cord were of the naïve/memory CD38(hi) CD95(lo) phenotype. Nevertheless, they were CD62L(lo) and CD80(hi) compared to lymph node B cells suggesting that they were at least partly activated and primed to present antigen. Therefore, if meningeal B cells contribute to CNS pathology in autoimmunity, follicular differentiation is not necessary for the pathogenic mechanism.

No MeSH data available.


Related in: MedlinePlus