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Aberrant immune responses in a mouse with behavioral disorders.

Heo Y, Zhang Y, Gao D, Miller VM, Lawrence DA - PLoS ONE (2011)

Bottom Line: BTBR mice had significantly higher amounts of serum IgG and IgE, of IgG anti-brain antibodies (Abs), and of IgG and IgE deposited in the brain, elevated expression of cytokines, especially IL-33 IL-18, and IL-1β in the brain, and an increased proportion of MHC class II-expressing microglia compared to B6 mice.The F1 mice had intermediate levels of Abs and cytokines as well as social activity.The Th2-like immune profile of the BTBR mice and their constitutive neuroinflammation suggests that an autoimmune profile is implicated in their aberrant behaviors, as has been suggested for some humans with autism.

View Article: PubMed Central - PubMed

Affiliation: College of Natural Sciences, Catholic University of Daegu, Kyongsan-si, Republic of Korea.

ABSTRACT
BTBR T+tf/J (BTBR) mice have recently been reported to have behaviors that resemble those of autistic individuals, in that this strain has impairments in social interactions and a restricted repetitive and stereotyped pattern of behaviors. Since immune responses, including autoimmune responses, are known to affect behavior, and individuals with autism have aberrant immune activities, we evaluated the immune system of BTBR mice, and compared their immunity and degree of neuroinflammation with that of C57BL/6 (B6) mice, a highly social control strain, and with F1 offspring. Mice were assessed at postnatal day (pnd) 21 and after behavioral analysis at pnd70. BTBR mice had significantly higher amounts of serum IgG and IgE, of IgG anti-brain antibodies (Abs), and of IgG and IgE deposited in the brain, elevated expression of cytokines, especially IL-33 IL-18, and IL-1β in the brain, and an increased proportion of MHC class II-expressing microglia compared to B6 mice. The F1 mice had intermediate levels of Abs and cytokines as well as social activity. The high Ab levels of BTBR mice are in agreement with their increased numbers of CD40(hi)/I-A(hi) B cells and IgG-secreting B cells. Upon immunization with KLH, the BTBR mice produced 2-3 times more anti-KLH Abs than B6 mice. In contrast to humoral immunity, BTBR mice are significantly more susceptible to listeriosis than B6 or BALB/c mice. The Th2-like immune profile of the BTBR mice and their constitutive neuroinflammation suggests that an autoimmune profile is implicated in their aberrant behaviors, as has been suggested for some humans with autism.

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Elevated number of CD4+ T cells in various peripheral organs of BTBR mice, compared with those of B6 mice.Spleens, mesenteric lymph nodes, and peripheral blood were obtained from postnatal day 21 male or female mice (n = 3 for each sex per strain). Since there were no gender differences within a strain, the results were pooled by strain. Percentages (A) or absolute numbers (B) of CD4+ T cells among CD45+ cells were determined by flow cytometric analysis. Number of cells indicates the number per spleen, three pooled lymph nodes, or 1 ml of blood. *, BTBR vs. C57BL/6 (p<0.05).
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pone-0020912-g006: Elevated number of CD4+ T cells in various peripheral organs of BTBR mice, compared with those of B6 mice.Spleens, mesenteric lymph nodes, and peripheral blood were obtained from postnatal day 21 male or female mice (n = 3 for each sex per strain). Since there were no gender differences within a strain, the results were pooled by strain. Percentages (A) or absolute numbers (B) of CD4+ T cells among CD45+ cells were determined by flow cytometric analysis. Number of cells indicates the number per spleen, three pooled lymph nodes, or 1 ml of blood. *, BTBR vs. C57BL/6 (p<0.05).

Mentions: The various types and proportions of immune cells distributed throughout the peripheral immune organs and brain have not been previously evaluated for BTBR mice. Since some immune cell types in the periphery or CNS, such as microglial cells or CD4+ T cells, have been suggested to be associated with pathogenesis of neuroinflammatory disorders, including autism [23], [41]–[44], we evaluated proportions and actual numbers of major immune cell types in the spleen, mesenteric lymph nodes, peripheral blood, and brain of BTBR mice, and compared the levels with those for B6 mice (Tables 3 & 4, Fig. 6). Given our described result showing relatively high levels of IgG in BTBR mice, we also enumerated plasma cells. The number of CD8+ T cells was significantly greater in the mesenteric lymph nodes of the BTBR mice than those of B6 mice, but this difference was not obtained for analysis of spleens or blood (Table 3). Although the serum IgG levels were elevated in BTBR mice compared with the IgG levels of B6 mice, the pnd21 BTBR mice did not have any significant differences from B6 mice with regard to the number of B cells or plasma cells in the spleen, lymph node or blood (Table 3). BTBR and B6 mice (pnd60) also were assayed for splenic B cell numbers and the levels were still equivalent (BTBR, 38.3±2.6 and B6, 37.4±2.7×106/spleen). A subset of mice were assayed for B1 (CD19+/CD5+) cells since B1 cells are often implicated in autoimmune processes. The percentages of splenic or blood B1 cells were not different between BTBR and B6 mice (2.9±0.8% vs. 3.2±0.7% for spleen and 0.4±0.2% vs. 0.5±0.2% for blood). The percentage of plasma cells (CD45+/CD138+) cells in the bone marrow also was not significantly higher in the BTBR mice (BTBR, 4.2±0.6 and B6, 2.9±0.4%). The BTBR mice did have a greater number of CD4+ T cells in the mesenteric lymph nodes (Fig. 6). CD4+ T cell differences in both the proportions in peripheral blood (BTBR male: 30.0±1.8, BTBR female: 28.4±3.0, B6 male: 17.0±1.9, B6 female: 19.1±1.0%) and the actual numbers in mesenteric lymph nodes (BTBR male: 8.2±1.6, BTBR female: 6.8±1.0, B6 male: 3.5±0.2, B6 female: 3.2±0.3×106 cells) attained statistical significance.


Aberrant immune responses in a mouse with behavioral disorders.

Heo Y, Zhang Y, Gao D, Miller VM, Lawrence DA - PLoS ONE (2011)

Elevated number of CD4+ T cells in various peripheral organs of BTBR mice, compared with those of B6 mice.Spleens, mesenteric lymph nodes, and peripheral blood were obtained from postnatal day 21 male or female mice (n = 3 for each sex per strain). Since there were no gender differences within a strain, the results were pooled by strain. Percentages (A) or absolute numbers (B) of CD4+ T cells among CD45+ cells were determined by flow cytometric analysis. Number of cells indicates the number per spleen, three pooled lymph nodes, or 1 ml of blood. *, BTBR vs. C57BL/6 (p<0.05).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3140472&req=5

pone-0020912-g006: Elevated number of CD4+ T cells in various peripheral organs of BTBR mice, compared with those of B6 mice.Spleens, mesenteric lymph nodes, and peripheral blood were obtained from postnatal day 21 male or female mice (n = 3 for each sex per strain). Since there were no gender differences within a strain, the results were pooled by strain. Percentages (A) or absolute numbers (B) of CD4+ T cells among CD45+ cells were determined by flow cytometric analysis. Number of cells indicates the number per spleen, three pooled lymph nodes, or 1 ml of blood. *, BTBR vs. C57BL/6 (p<0.05).
Mentions: The various types and proportions of immune cells distributed throughout the peripheral immune organs and brain have not been previously evaluated for BTBR mice. Since some immune cell types in the periphery or CNS, such as microglial cells or CD4+ T cells, have been suggested to be associated with pathogenesis of neuroinflammatory disorders, including autism [23], [41]–[44], we evaluated proportions and actual numbers of major immune cell types in the spleen, mesenteric lymph nodes, peripheral blood, and brain of BTBR mice, and compared the levels with those for B6 mice (Tables 3 & 4, Fig. 6). Given our described result showing relatively high levels of IgG in BTBR mice, we also enumerated plasma cells. The number of CD8+ T cells was significantly greater in the mesenteric lymph nodes of the BTBR mice than those of B6 mice, but this difference was not obtained for analysis of spleens or blood (Table 3). Although the serum IgG levels were elevated in BTBR mice compared with the IgG levels of B6 mice, the pnd21 BTBR mice did not have any significant differences from B6 mice with regard to the number of B cells or plasma cells in the spleen, lymph node or blood (Table 3). BTBR and B6 mice (pnd60) also were assayed for splenic B cell numbers and the levels were still equivalent (BTBR, 38.3±2.6 and B6, 37.4±2.7×106/spleen). A subset of mice were assayed for B1 (CD19+/CD5+) cells since B1 cells are often implicated in autoimmune processes. The percentages of splenic or blood B1 cells were not different between BTBR and B6 mice (2.9±0.8% vs. 3.2±0.7% for spleen and 0.4±0.2% vs. 0.5±0.2% for blood). The percentage of plasma cells (CD45+/CD138+) cells in the bone marrow also was not significantly higher in the BTBR mice (BTBR, 4.2±0.6 and B6, 2.9±0.4%). The BTBR mice did have a greater number of CD4+ T cells in the mesenteric lymph nodes (Fig. 6). CD4+ T cell differences in both the proportions in peripheral blood (BTBR male: 30.0±1.8, BTBR female: 28.4±3.0, B6 male: 17.0±1.9, B6 female: 19.1±1.0%) and the actual numbers in mesenteric lymph nodes (BTBR male: 8.2±1.6, BTBR female: 6.8±1.0, B6 male: 3.5±0.2, B6 female: 3.2±0.3×106 cells) attained statistical significance.

Bottom Line: BTBR mice had significantly higher amounts of serum IgG and IgE, of IgG anti-brain antibodies (Abs), and of IgG and IgE deposited in the brain, elevated expression of cytokines, especially IL-33 IL-18, and IL-1β in the brain, and an increased proportion of MHC class II-expressing microglia compared to B6 mice.The F1 mice had intermediate levels of Abs and cytokines as well as social activity.The Th2-like immune profile of the BTBR mice and their constitutive neuroinflammation suggests that an autoimmune profile is implicated in their aberrant behaviors, as has been suggested for some humans with autism.

View Article: PubMed Central - PubMed

Affiliation: College of Natural Sciences, Catholic University of Daegu, Kyongsan-si, Republic of Korea.

ABSTRACT
BTBR T+tf/J (BTBR) mice have recently been reported to have behaviors that resemble those of autistic individuals, in that this strain has impairments in social interactions and a restricted repetitive and stereotyped pattern of behaviors. Since immune responses, including autoimmune responses, are known to affect behavior, and individuals with autism have aberrant immune activities, we evaluated the immune system of BTBR mice, and compared their immunity and degree of neuroinflammation with that of C57BL/6 (B6) mice, a highly social control strain, and with F1 offspring. Mice were assessed at postnatal day (pnd) 21 and after behavioral analysis at pnd70. BTBR mice had significantly higher amounts of serum IgG and IgE, of IgG anti-brain antibodies (Abs), and of IgG and IgE deposited in the brain, elevated expression of cytokines, especially IL-33 IL-18, and IL-1β in the brain, and an increased proportion of MHC class II-expressing microglia compared to B6 mice. The F1 mice had intermediate levels of Abs and cytokines as well as social activity. The high Ab levels of BTBR mice are in agreement with their increased numbers of CD40(hi)/I-A(hi) B cells and IgG-secreting B cells. Upon immunization with KLH, the BTBR mice produced 2-3 times more anti-KLH Abs than B6 mice. In contrast to humoral immunity, BTBR mice are significantly more susceptible to listeriosis than B6 or BALB/c mice. The Th2-like immune profile of the BTBR mice and their constitutive neuroinflammation suggests that an autoimmune profile is implicated in their aberrant behaviors, as has been suggested for some humans with autism.

Show MeSH
Related in: MedlinePlus