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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

Incidence of spontaneous CNS autoimmune disease (sEAE) in 2D2 IgHMOG mice. (A) Disease onset curves for three representative sequential 4- to 6-month time-periods (Timepoint 1, 2, and 3) selected from the ~2-year period of study. The percent of mice in each group to demonstrate signs of disability as determined by the disease scoring system (see Materials and Methods) is shown (% Sick) (B,C) PTX administration increases disease incidence. (B) Single injections of 250 ng PTX i.v. were administered to ~32 days old 2D2 IgHMOG mice, which were subsequently followed for onset of disease compared to unmanipulated mice. (C) Fraction of diseased mice in PTX-untreated and -treated mice, restricted to times when the overall incidence was below 80%. Significantly more PTX-treated mice developed disease as determined by Chi-square analysis (p = 0.0003, df = 13.13,1).
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Figure 1: Incidence of spontaneous CNS autoimmune disease (sEAE) in 2D2 IgHMOG mice. (A) Disease onset curves for three representative sequential 4- to 6-month time-periods (Timepoint 1, 2, and 3) selected from the ~2-year period of study. The percent of mice in each group to demonstrate signs of disability as determined by the disease scoring system (see Materials and Methods) is shown (% Sick) (B,C) PTX administration increases disease incidence. (B) Single injections of 250 ng PTX i.v. were administered to ~32 days old 2D2 IgHMOG mice, which were subsequently followed for onset of disease compared to unmanipulated mice. (C) Fraction of diseased mice in PTX-untreated and -treated mice, restricted to times when the overall incidence was below 80%. Significantly more PTX-treated mice developed disease as determined by Chi-square analysis (p = 0.0003, df = 13.13,1).

Mentions: We followed mice bearing mutant TCR and BCR specific for MOG autoantigen for the development of CNS autoimmune disease. Mice demonstrating overt signs of physical disability were defined as “sick.” Consistent with the previous descriptions (29, 30, 33), a proportion of unmanipulated 2D2+/− IgHMOG+/+ mice (here after described as 2D2 IgHMOG) developed sEAE (Figure 1A). No disease was observed in either 2D2 (TCR) or IgHMOG (BCR) single mutant mice (Not Shown); it is clearly demonstrating that antigen recognition by both T and B cells contributes to disease development in double mutant mice. Interestingly, males were significantly more likely to develop disease than females, although there was no difference in the time of onset (Table 1). Although previous studies did not note gender differences, the incidence data presented by Krishnamoorthy et al. (30) suggest a similar trend in male bias.


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)

Incidence of spontaneous CNS autoimmune disease (sEAE) in 2D2 IgHMOG mice. (A) Disease onset curves for three representative sequential 4- to 6-month time-periods (Timepoint 1, 2, and 3) selected from the ~2-year period of study. The percent of mice in each group to demonstrate signs of disability as determined by the disease scoring system (see Materials and Methods) is shown (% Sick) (B,C) PTX administration increases disease incidence. (B) Single injections of 250 ng PTX i.v. were administered to ~32 days old 2D2 IgHMOG mice, which were subsequently followed for onset of disease compared to unmanipulated mice. (C) Fraction of diseased mice in PTX-untreated and -treated mice, restricted to times when the overall incidence was below 80%. Significantly more PTX-treated mice developed disease as determined by Chi-square analysis (p = 0.0003, df = 13.13,1).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Incidence of spontaneous CNS autoimmune disease (sEAE) in 2D2 IgHMOG mice. (A) Disease onset curves for three representative sequential 4- to 6-month time-periods (Timepoint 1, 2, and 3) selected from the ~2-year period of study. The percent of mice in each group to demonstrate signs of disability as determined by the disease scoring system (see Materials and Methods) is shown (% Sick) (B,C) PTX administration increases disease incidence. (B) Single injections of 250 ng PTX i.v. were administered to ~32 days old 2D2 IgHMOG mice, which were subsequently followed for onset of disease compared to unmanipulated mice. (C) Fraction of diseased mice in PTX-untreated and -treated mice, restricted to times when the overall incidence was below 80%. Significantly more PTX-treated mice developed disease as determined by Chi-square analysis (p = 0.0003, df = 13.13,1).
Mentions: We followed mice bearing mutant TCR and BCR specific for MOG autoantigen for the development of CNS autoimmune disease. Mice demonstrating overt signs of physical disability were defined as “sick.” Consistent with the previous descriptions (29, 30, 33), a proportion of unmanipulated 2D2+/− IgHMOG+/+ mice (here after described as 2D2 IgHMOG) developed sEAE (Figure 1A). No disease was observed in either 2D2 (TCR) or IgHMOG (BCR) single mutant mice (Not Shown); it is clearly demonstrating that antigen recognition by both T and B cells contributes to disease development in double mutant mice. Interestingly, males were significantly more likely to develop disease than females, although there was no difference in the time of onset (Table 1). Although previous studies did not note gender differences, the incidence data presented by Krishnamoorthy et al. (30) suggest a similar trend in male bias.

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