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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

Evaluation of spinal cord pathology in 2D2 IgHMOG mice. Mice were sacrificed in the acute phase of disease (<11 days post onset) and spinal cord pathology was evaluated by immunofluorescent histology. Sections were stained for myelin and invading CD4+ T cells and B220+ B cells. [(A) – wild type health control, (B) – 2D2 IgHMOG acute disease]. Infiltrating T cells (open triangles) were evident in the gray matter of diseased mice [see (B) inset box i, shown at higher magnification in (C), top panel]. Clusters containing B220+ B cells and CD4+ T cells (closed triangles) were clearly apparent in the meninges of diseased mice, while no B cells were found in healthy spinal cords [compare (A) with (B)]. Meningeal clusters were often adjacent to areas of demyelination and CD4+ T cell infiltration of the white matter (open triangles). Ongoing parenchymal invasion by T cells and macrophages/activated microglia were clearly evident, associated with regions of demyelination [open triangles, see enlarged image and serial section stained with F4/80, inset box ii, (C)]. Representative images shown (n = 5 wt, n = 5 acute phase 2D2 IgHMOG, minimum three sections taken from different regions of each spinal cord). Scale bars represent 200 μm.
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Figure 4: Evaluation of spinal cord pathology in 2D2 IgHMOG mice. Mice were sacrificed in the acute phase of disease (<11 days post onset) and spinal cord pathology was evaluated by immunofluorescent histology. Sections were stained for myelin and invading CD4+ T cells and B220+ B cells. [(A) – wild type health control, (B) – 2D2 IgHMOG acute disease]. Infiltrating T cells (open triangles) were evident in the gray matter of diseased mice [see (B) inset box i, shown at higher magnification in (C), top panel]. Clusters containing B220+ B cells and CD4+ T cells (closed triangles) were clearly apparent in the meninges of diseased mice, while no B cells were found in healthy spinal cords [compare (A) with (B)]. Meningeal clusters were often adjacent to areas of demyelination and CD4+ T cell infiltration of the white matter (open triangles). Ongoing parenchymal invasion by T cells and macrophages/activated microglia were clearly evident, associated with regions of demyelination [open triangles, see enlarged image and serial section stained with F4/80, inset box ii, (C)]. Representative images shown (n = 5 wt, n = 5 acute phase 2D2 IgHMOG, minimum three sections taken from different regions of each spinal cord). Scale bars represent 200 μm.

Mentions: 2D2 IgHMOG mice were sacrificed for histological evaluation of CNS pathology. No evidence of pathology or inflammation was evident in the CNS of wild type mice (Figure 4A) or 2D2 IgHMOG mice that did not develop disease (not shown). Consistent with previous descriptions of this model (29, 30), there was little evidence of inflammation in the brains of 2D2 IgHMOG mice that developed disease (not shown). By contrast, extensive and profound pathology was observed in the spinal cord. Evaluation of tissue harvested from mice in the acute phase of disease (<11 days post onset) revealed that extensive infiltration by CD4+ T cells (Figure 4, compare Figure 4A – wild type to Figure 4B – acute 2D2 IgHMOG) was associated with regions of reduced myelin staining (Figures 4B,C, inset box ii, middle) and F4/80+ macrophage/activated microglia (Figure 4C, bottom). CD4+ T cells were also observed in the gray matter in some mice and in these cases myelin staining of the gray matter was often altered compared to healthy mice (Figure 4C top, inset box i).


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)

Evaluation of spinal cord pathology in 2D2 IgHMOG mice. Mice were sacrificed in the acute phase of disease (<11 days post onset) and spinal cord pathology was evaluated by immunofluorescent histology. Sections were stained for myelin and invading CD4+ T cells and B220+ B cells. [(A) – wild type health control, (B) – 2D2 IgHMOG acute disease]. Infiltrating T cells (open triangles) were evident in the gray matter of diseased mice [see (B) inset box i, shown at higher magnification in (C), top panel]. Clusters containing B220+ B cells and CD4+ T cells (closed triangles) were clearly apparent in the meninges of diseased mice, while no B cells were found in healthy spinal cords [compare (A) with (B)]. Meningeal clusters were often adjacent to areas of demyelination and CD4+ T cell infiltration of the white matter (open triangles). Ongoing parenchymal invasion by T cells and macrophages/activated microglia were clearly evident, associated with regions of demyelination [open triangles, see enlarged image and serial section stained with F4/80, inset box ii, (C)]. Representative images shown (n = 5 wt, n = 5 acute phase 2D2 IgHMOG, minimum three sections taken from different regions of each spinal cord). Scale bars represent 200 μm.
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Figure 4: Evaluation of spinal cord pathology in 2D2 IgHMOG mice. Mice were sacrificed in the acute phase of disease (<11 days post onset) and spinal cord pathology was evaluated by immunofluorescent histology. Sections were stained for myelin and invading CD4+ T cells and B220+ B cells. [(A) – wild type health control, (B) – 2D2 IgHMOG acute disease]. Infiltrating T cells (open triangles) were evident in the gray matter of diseased mice [see (B) inset box i, shown at higher magnification in (C), top panel]. Clusters containing B220+ B cells and CD4+ T cells (closed triangles) were clearly apparent in the meninges of diseased mice, while no B cells were found in healthy spinal cords [compare (A) with (B)]. Meningeal clusters were often adjacent to areas of demyelination and CD4+ T cell infiltration of the white matter (open triangles). Ongoing parenchymal invasion by T cells and macrophages/activated microglia were clearly evident, associated with regions of demyelination [open triangles, see enlarged image and serial section stained with F4/80, inset box ii, (C)]. Representative images shown (n = 5 wt, n = 5 acute phase 2D2 IgHMOG, minimum three sections taken from different regions of each spinal cord). Scale bars represent 200 μm.
Mentions: 2D2 IgHMOG mice were sacrificed for histological evaluation of CNS pathology. No evidence of pathology or inflammation was evident in the CNS of wild type mice (Figure 4A) or 2D2 IgHMOG mice that did not develop disease (not shown). Consistent with previous descriptions of this model (29, 30), there was little evidence of inflammation in the brains of 2D2 IgHMOG mice that developed disease (not shown). By contrast, extensive and profound pathology was observed in the spinal cord. Evaluation of tissue harvested from mice in the acute phase of disease (<11 days post onset) revealed that extensive infiltration by CD4+ T cells (Figure 4, compare Figure 4A – wild type to Figure 4B – acute 2D2 IgHMOG) was associated with regions of reduced myelin staining (Figures 4B,C, inset box ii, middle) and F4/80+ macrophage/activated microglia (Figure 4C, bottom). CD4+ T cells were also observed in the gray matter in some mice and in these cases myelin staining of the gray matter was often altered compared to healthy mice (Figure 4C top, inset box i).

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