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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

sEAE in 2D2 IgHMOG mice can follow a monophasic or chronic disease course. (A) 2D2 IgHMOG mice were allowed to develop CNS autoimmune disease and severity was evaluated daily. Mice that developed signs of CNS autoimmune disease for at least 21 days (excluding mice that had been used experimentally or were euthanized prior to 21 days) were divided into “monophasic” or “chronic” categories based on the following criteria: chronic – no more than 1 point recovery after the acute phase as determined by the standard 5 point score system. Monophasic – recovery of at least 1 point on the severity scale and a final score <2. (B) Compared to male mice, a greater proportion of female mice develop chronic disease as determined by Chi-square analysis (p = 0.0004, df 12.65,1).
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Figure 2: sEAE in 2D2 IgHMOG mice can follow a monophasic or chronic disease course. (A) 2D2 IgHMOG mice were allowed to develop CNS autoimmune disease and severity was evaluated daily. Mice that developed signs of CNS autoimmune disease for at least 21 days (excluding mice that had been used experimentally or were euthanized prior to 21 days) were divided into “monophasic” or “chronic” categories based on the following criteria: chronic – no more than 1 point recovery after the acute phase as determined by the standard 5 point score system. Monophasic – recovery of at least 1 point on the severity scale and a final score <2. (B) Compared to male mice, a greater proportion of female mice develop chronic disease as determined by Chi-square analysis (p = 0.0004, df 12.65,1).

Mentions: 2D2 IgHMOG mice were evaluated daily for disease severity. Of those that showed signs of disease (defined as “sick”), the majority of mice had severe disability of the tail, hindlimbs, and partial involvement of the forelimbs, reminiscent of other EAE models and consistent with previous descriptions of this model (29, 30). Unlike for disease incidence (see above), there was no difference between males and females in maximum disease severity (Table 1). We observed that disease typically followed one of two courses; after the initial acute phase some mice largely recovered with little evidence of ongoing disability while others showed little sign of recovery. Therefore, we grouped mice that survived past 21 days post disease onset (i.e., that had not been used experimentally or been euthanized early due to severe disease) into one of two groups based on their final disease status: (1) chronic – mice with no more than 1 point recovery after the acute phase as determined by the standard 5 point score system, and 2) Monophasic – mice that recovered at least 1 point on the severity scale and had a final score <2 (Figure 2). Further evaluation of these populations showed that while the timing of disease onset was not different between them, the chronic group attained a significantly higher maximum disease score (Table 2). This indicates that while the populations were separated into the chronic or monophasic groups based principally on their status at the end of the study, the differences between groups manifested themselves earlier in the acute phase of disease (Figure 2A). Interestingly, while males were more likely to develop disease (see above), females were more likely to have a chronic disease course (Figure 2B).


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)

sEAE in 2D2 IgHMOG mice can follow a monophasic or chronic disease course. (A) 2D2 IgHMOG mice were allowed to develop CNS autoimmune disease and severity was evaluated daily. Mice that developed signs of CNS autoimmune disease for at least 21 days (excluding mice that had been used experimentally or were euthanized prior to 21 days) were divided into “monophasic” or “chronic” categories based on the following criteria: chronic – no more than 1 point recovery after the acute phase as determined by the standard 5 point score system. Monophasic – recovery of at least 1 point on the severity scale and a final score <2. (B) Compared to male mice, a greater proportion of female mice develop chronic disease as determined by Chi-square analysis (p = 0.0004, df 12.65,1).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4584934&req=5

Figure 2: sEAE in 2D2 IgHMOG mice can follow a monophasic or chronic disease course. (A) 2D2 IgHMOG mice were allowed to develop CNS autoimmune disease and severity was evaluated daily. Mice that developed signs of CNS autoimmune disease for at least 21 days (excluding mice that had been used experimentally or were euthanized prior to 21 days) were divided into “monophasic” or “chronic” categories based on the following criteria: chronic – no more than 1 point recovery after the acute phase as determined by the standard 5 point score system. Monophasic – recovery of at least 1 point on the severity scale and a final score <2. (B) Compared to male mice, a greater proportion of female mice develop chronic disease as determined by Chi-square analysis (p = 0.0004, df 12.65,1).
Mentions: 2D2 IgHMOG mice were evaluated daily for disease severity. Of those that showed signs of disease (defined as “sick”), the majority of mice had severe disability of the tail, hindlimbs, and partial involvement of the forelimbs, reminiscent of other EAE models and consistent with previous descriptions of this model (29, 30). Unlike for disease incidence (see above), there was no difference between males and females in maximum disease severity (Table 1). We observed that disease typically followed one of two courses; after the initial acute phase some mice largely recovered with little evidence of ongoing disability while others showed little sign of recovery. Therefore, we grouped mice that survived past 21 days post disease onset (i.e., that had not been used experimentally or been euthanized early due to severe disease) into one of two groups based on their final disease status: (1) chronic – mice with no more than 1 point recovery after the acute phase as determined by the standard 5 point score system, and 2) Monophasic – mice that recovered at least 1 point on the severity scale and had a final score <2 (Figure 2). Further evaluation of these populations showed that while the timing of disease onset was not different between them, the chronic group attained a significantly higher maximum disease score (Table 2). This indicates that while the populations were separated into the chronic or monophasic groups based principally on their status at the end of the study, the differences between groups manifested themselves earlier in the acute phase of disease (Figure 2A). Interestingly, while males were more likely to develop disease (see above), females were more likely to have a chronic disease course (Figure 2B).

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