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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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Related in: MedlinePlus

No difference in BBB permeability in BTBR mice relative to B6 mice.Evans blue solution (50 µg/g body weight) was injected into the peritoneum; 5 h later, peripheral blood was obtained through cardiac puncture. Brains from the perfused mice were incubated in formamide solution for 72 h for extraction of the dye, and the supernatants were collected through centrifugation. Optical density of plasma or brain supernatant sample was measured at 620 nm. No statistical significance was observed between BTBR and C57BL/6J mice. Brains were removed after PBS perfusion and weighed.
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pone-0020912-g005: No difference in BBB permeability in BTBR mice relative to B6 mice.Evans blue solution (50 µg/g body weight) was injected into the peritoneum; 5 h later, peripheral blood was obtained through cardiac puncture. Brains from the perfused mice were incubated in formamide solution for 72 h for extraction of the dye, and the supernatants were collected through centrifugation. Optical density of plasma or brain supernatant sample was measured at 620 nm. No statistical significance was observed between BTBR and C57BL/6J mice. Brains were removed after PBS perfusion and weighed.

Mentions: BBB leakage or increased BBB permeability can cause extravasation of virus, immunoglobulin, or toxic molecules into brain tissues [38]–[40]. To investigate whether increased BBB permeability was a factor contributing to the increased amount of deposited IgG in the brain of the BTBR mice, we assessed leakage of Evans blue (EB) dye into the brain after intraperitoneal injection of the dye (Fig. 5). The BBB permeability index, which reflects the amount of EB dye per unit weight of brain relative to the amount of dye per unit volume of plasma, did not differ between BTBR and B6 mice.


Aberrant immune responses in a mouse with behavioral disorders.

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

No difference in BBB permeability in BTBR mice relative to B6 mice.Evans blue solution (50 µg/g body weight) was injected into the peritoneum; 5 h later, peripheral blood was obtained through cardiac puncture. Brains from the perfused mice were incubated in formamide solution for 72 h for extraction of the dye, and the supernatants were collected through centrifugation. Optical density of plasma or brain supernatant sample was measured at 620 nm. No statistical significance was observed between BTBR and C57BL/6J mice. Brains were removed after PBS perfusion and weighed.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3140472&req=5

pone-0020912-g005: No difference in BBB permeability in BTBR mice relative to B6 mice.Evans blue solution (50 µg/g body weight) was injected into the peritoneum; 5 h later, peripheral blood was obtained through cardiac puncture. Brains from the perfused mice were incubated in formamide solution for 72 h for extraction of the dye, and the supernatants were collected through centrifugation. Optical density of plasma or brain supernatant sample was measured at 620 nm. No statistical significance was observed between BTBR and C57BL/6J mice. Brains were removed after PBS perfusion and weighed.
Mentions: BBB leakage or increased BBB permeability can cause extravasation of virus, immunoglobulin, or toxic molecules into brain tissues [38]–[40]. To investigate whether increased BBB permeability was a factor contributing to the increased amount of deposited IgG in the brain of the BTBR mice, we assessed leakage of Evans blue (EB) dye into the brain after intraperitoneal injection of the dye (Fig. 5). The BBB permeability index, which reflects the amount of EB dye per unit weight of brain relative to the amount of dye per unit volume of plasma, did not differ between BTBR and B6 mice.

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