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Mast cells are essential for early onset and severe disease in a murine model of multiple sclerosis.

Secor VH, Secor WE, Gutekunst CA, Brown MA - J. Exp. Med. (2000)

Bottom Line: Using a myelin oligodendrocyte glycoprotein (MOG)-induced model of acute EAE, we show that mast cell-deficient W/W(v) mice exhibit significantly reduced disease incidence, delayed disease onset, and decreased mean clinical scores when compared with their wild-type congenic littermates.No differences were observed in MOG-specific T and B cell responses between the two groups, indicating that a global T or B cell defect is not present in W/W(v) animals.These data provide a new mechanism for immune destruction in EAE and indicate that mast cells play a broader role in neurologic inflammation.

View Article: PubMed Central - PubMed

Affiliation: Graduate Program in Immunology and Molecular Pathogenesis, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

ABSTRACT
In addition to their well characterized role in allergic inflammation, recent data confirm that mast cells play a more extensive role in a variety of immune responses. However, their contribution to autoimmune and neurologic disease processes has not been investigated. Experimental allergic encephalomyelitis (EAE) and its human disease counterpart, multiple sclerosis, are considered to be CD4(+) T cell-mediated autoimmune diseases affecting the central nervous system. Several lines of indirect evidence suggest that mast cells could also play a role in the pathogenesis of both the human and murine disease. Using a myelin oligodendrocyte glycoprotein (MOG)-induced model of acute EAE, we show that mast cell-deficient W/W(v) mice exhibit significantly reduced disease incidence, delayed disease onset, and decreased mean clinical scores when compared with their wild-type congenic littermates. No differences were observed in MOG-specific T and B cell responses between the two groups, indicating that a global T or B cell defect is not present in W/W(v) animals. Reconstitution of the mast cell population in W/W(v) mice restores induction of early and severe disease to wild-type levels, suggesting that mast cells are critical for the full manifestation of disease. These data provide a new mechanism for immune destruction in EAE and indicate that mast cells play a broader role in neurologic inflammation.

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Detection of MOG-specific IgG and IgG subclasses. Upon sacrifice, serum was obtained from wild-type (n = 16), W/Wv (n = 16), and BMMC-reconstituted W/Wv (n = 10) mice and analyzed for MOG-specific isotype and IgG subclass levels by ELISA. Results represent cumulative data from four experiments.
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Figure 6: Detection of MOG-specific IgG and IgG subclasses. Upon sacrifice, serum was obtained from wild-type (n = 16), W/Wv (n = 16), and BMMC-reconstituted W/Wv (n = 10) mice and analyzed for MOG-specific isotype and IgG subclass levels by ELISA. Results represent cumulative data from four experiments.

Mentions: While it is formally possible that W/Wv mice have T cell deficits that could account for the differences in disease parameters demonstrated between wild-type and mast cell–deficient animals, we believe this is unlikely. Thymocytes are c-kit+, and the defect in c-kit carried by W/Wv mice could potentially hinder T cell development in these animals; however, previous characterizations of W/Wv mice revealed no such T cell deficits 4445. It has also been demonstrated that IL-7, which has many activities that overlap with SCF, can direct the development of normal T cells in c-kit–deficient mice 44. In addition, we evaluated MOG-specific proliferative responses, cytokine profiles, and antibody production in both groups. Splenocytes from MOG-immunized wild-type and W/Wv mice mounted equivalent proliferative responses and IFN-γ cytokine production in response to in vitro stimulation with MOG peptide (data not shown). No IL-4 was detected in these assays. Wild-type and W/Wv mice, as well as BMMC-reconstituted W/Wv animals, produced similar levels of MOG-specific IgG (Fig. 6). MOG-specific IgG1 and IgG2b subtypes were also detected in all three groups. Interestingly, the MOG-specific IgG1 levels of W/Wv and BMMC-reconstituted W/Wv mice were significantly higher (P < 0.05, ANOVA) than those of wild-type mice. The biological significance of this observation is unclear. However, it may indicate that c-kit signaling pathways play an as yet unidentified role in B cell isotype switching. Alternatively, the kinetics of IgG1 antibody production may be altered in these mutant animals. Despite these differences in IgG1 levels, it is unlikely that this has a major effect on the development of EAE, because wild-type and BMMC-reconstituted mice exhibit similar disease courses. Also of note, total serum IgE was high in immunized animals within all groups, yet MOG-specific IgE was undetectable (data not shown). These results indicate that there are no global T or B cell deficits in W/Wv mice. Taken together with the demonstration that mast cell reconstitution with a virtually pure BMMC population restores disease susceptibility, these data support the hypothesis that it is the absence of mast cells in the W/Wv animals that predisposes them to delayed onset and less severe disease.


Mast cells are essential for early onset and severe disease in a murine model of multiple sclerosis.

Secor VH, Secor WE, Gutekunst CA, Brown MA - J. Exp. Med. (2000)

Detection of MOG-specific IgG and IgG subclasses. Upon sacrifice, serum was obtained from wild-type (n = 16), W/Wv (n = 16), and BMMC-reconstituted W/Wv (n = 10) mice and analyzed for MOG-specific isotype and IgG subclass levels by ELISA. Results represent cumulative data from four experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195850&req=5

Figure 6: Detection of MOG-specific IgG and IgG subclasses. Upon sacrifice, serum was obtained from wild-type (n = 16), W/Wv (n = 16), and BMMC-reconstituted W/Wv (n = 10) mice and analyzed for MOG-specific isotype and IgG subclass levels by ELISA. Results represent cumulative data from four experiments.
Mentions: While it is formally possible that W/Wv mice have T cell deficits that could account for the differences in disease parameters demonstrated between wild-type and mast cell–deficient animals, we believe this is unlikely. Thymocytes are c-kit+, and the defect in c-kit carried by W/Wv mice could potentially hinder T cell development in these animals; however, previous characterizations of W/Wv mice revealed no such T cell deficits 4445. It has also been demonstrated that IL-7, which has many activities that overlap with SCF, can direct the development of normal T cells in c-kit–deficient mice 44. In addition, we evaluated MOG-specific proliferative responses, cytokine profiles, and antibody production in both groups. Splenocytes from MOG-immunized wild-type and W/Wv mice mounted equivalent proliferative responses and IFN-γ cytokine production in response to in vitro stimulation with MOG peptide (data not shown). No IL-4 was detected in these assays. Wild-type and W/Wv mice, as well as BMMC-reconstituted W/Wv animals, produced similar levels of MOG-specific IgG (Fig. 6). MOG-specific IgG1 and IgG2b subtypes were also detected in all three groups. Interestingly, the MOG-specific IgG1 levels of W/Wv and BMMC-reconstituted W/Wv mice were significantly higher (P < 0.05, ANOVA) than those of wild-type mice. The biological significance of this observation is unclear. However, it may indicate that c-kit signaling pathways play an as yet unidentified role in B cell isotype switching. Alternatively, the kinetics of IgG1 antibody production may be altered in these mutant animals. Despite these differences in IgG1 levels, it is unlikely that this has a major effect on the development of EAE, because wild-type and BMMC-reconstituted mice exhibit similar disease courses. Also of note, total serum IgE was high in immunized animals within all groups, yet MOG-specific IgE was undetectable (data not shown). These results indicate that there are no global T or B cell deficits in W/Wv mice. Taken together with the demonstration that mast cell reconstitution with a virtually pure BMMC population restores disease susceptibility, these data support the hypothesis that it is the absence of mast cells in the W/Wv animals that predisposes them to delayed onset and less severe disease.

Bottom Line: Using a myelin oligodendrocyte glycoprotein (MOG)-induced model of acute EAE, we show that mast cell-deficient W/W(v) mice exhibit significantly reduced disease incidence, delayed disease onset, and decreased mean clinical scores when compared with their wild-type congenic littermates.No differences were observed in MOG-specific T and B cell responses between the two groups, indicating that a global T or B cell defect is not present in W/W(v) animals.These data provide a new mechanism for immune destruction in EAE and indicate that mast cells play a broader role in neurologic inflammation.

View Article: PubMed Central - PubMed

Affiliation: Graduate Program in Immunology and Molecular Pathogenesis, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

ABSTRACT
In addition to their well characterized role in allergic inflammation, recent data confirm that mast cells play a more extensive role in a variety of immune responses. However, their contribution to autoimmune and neurologic disease processes has not been investigated. Experimental allergic encephalomyelitis (EAE) and its human disease counterpart, multiple sclerosis, are considered to be CD4(+) T cell-mediated autoimmune diseases affecting the central nervous system. Several lines of indirect evidence suggest that mast cells could also play a role in the pathogenesis of both the human and murine disease. Using a myelin oligodendrocyte glycoprotein (MOG)-induced model of acute EAE, we show that mast cell-deficient W/W(v) mice exhibit significantly reduced disease incidence, delayed disease onset, and decreased mean clinical scores when compared with their wild-type congenic littermates. No differences were observed in MOG-specific T and B cell responses between the two groups, indicating that a global T or B cell defect is not present in W/W(v) animals. Reconstitution of the mast cell population in W/W(v) mice restores induction of early and severe disease to wild-type levels, suggesting that mast cells are critical for the full manifestation of disease. These data provide a new mechanism for immune destruction in EAE and indicate that mast cells play a broader role in neurologic inflammation.

Show MeSH
Related in: MedlinePlus