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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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Mast cells in BTBR tissues.Diagram shows the level at which mast cells were apparent in the BTBR male and female brains (approximately Bregma −2.54 mm). Metachromatic staining of mast cells (purple) was clear on the orthochromatic (blue) background in tissue sections. Mast cells were visible at perivascular spaces in the lateral posterior thalamic nucleus, at the hippocampal fissure, and at the third ventricle adjacent to choroid plexus tissues, in BTBR male and female mice. Bar is 20 µm. Mast cells were not visible at the aforementioned regions in either male or female B6 mice, an example of hippocampal fissure tissues underneath dentate granule cells is shown from male and female cells. Only the orthochromatic (Blue) staining is visible. Bar is 60 µm.
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pone-0020912-g007: Mast cells in BTBR tissues.Diagram shows the level at which mast cells were apparent in the BTBR male and female brains (approximately Bregma −2.54 mm). Metachromatic staining of mast cells (purple) was clear on the orthochromatic (blue) background in tissue sections. Mast cells were visible at perivascular spaces in the lateral posterior thalamic nucleus, at the hippocampal fissure, and at the third ventricle adjacent to choroid plexus tissues, in BTBR male and female mice. Bar is 20 µm. Mast cells were not visible at the aforementioned regions in either male or female B6 mice, an example of hippocampal fissure tissues underneath dentate granule cells is shown from male and female cells. Only the orthochromatic (Blue) staining is visible. Bar is 60 µm.

Mentions: Mast cells are rarely seen in healthy brains but have been reported to be sparsely present in the thalamus, hypothalamus, circumventricular organs, meninges and cerebral cortex of rodent brains [46]. We were unable to characterize a significant increase in the number of mast cells from cell suspensions of perfused BTBR brains by flow cytometry, we did observe a significant increase of mast cells. However, when forebrain, midbrain and cerebellar tissues encompassing Bregma +1.4 mm to Bregma −6.12 mm from male and female BTBR and B6 mice were stained with acidic toluidine blue, metachromatic mast cells were visible in the tissue from BTBR mice at the hippocampal fissure, lateral thalamic nuclei and third ventricle, but not at the caudate nucleus, cortex or cerebellum (Figure 7). The mast cells were perivascular and appeared to be entering brain parenchyma. There was a noticeable absence of mast cells in all of the aforementioned brain regions of the male and female B6 mice. Additionally, we noted increased numbers of mast cells in meningeal tissues from the BTBR mice.


Aberrant immune responses in a mouse with behavioral disorders.

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

Mast cells in BTBR tissues.Diagram shows the level at which mast cells were apparent in the BTBR male and female brains (approximately Bregma −2.54 mm). Metachromatic staining of mast cells (purple) was clear on the orthochromatic (blue) background in tissue sections. Mast cells were visible at perivascular spaces in the lateral posterior thalamic nucleus, at the hippocampal fissure, and at the third ventricle adjacent to choroid plexus tissues, in BTBR male and female mice. Bar is 20 µm. Mast cells were not visible at the aforementioned regions in either male or female B6 mice, an example of hippocampal fissure tissues underneath dentate granule cells is shown from male and female cells. Only the orthochromatic (Blue) staining is visible. Bar is 60 µm.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0020912-g007: Mast cells in BTBR tissues.Diagram shows the level at which mast cells were apparent in the BTBR male and female brains (approximately Bregma −2.54 mm). Metachromatic staining of mast cells (purple) was clear on the orthochromatic (blue) background in tissue sections. Mast cells were visible at perivascular spaces in the lateral posterior thalamic nucleus, at the hippocampal fissure, and at the third ventricle adjacent to choroid plexus tissues, in BTBR male and female mice. Bar is 20 µm. Mast cells were not visible at the aforementioned regions in either male or female B6 mice, an example of hippocampal fissure tissues underneath dentate granule cells is shown from male and female cells. Only the orthochromatic (Blue) staining is visible. Bar is 60 µm.
Mentions: Mast cells are rarely seen in healthy brains but have been reported to be sparsely present in the thalamus, hypothalamus, circumventricular organs, meninges and cerebral cortex of rodent brains [46]. We were unable to characterize a significant increase in the number of mast cells from cell suspensions of perfused BTBR brains by flow cytometry, we did observe a significant increase of mast cells. However, when forebrain, midbrain and cerebellar tissues encompassing Bregma +1.4 mm to Bregma −6.12 mm from male and female BTBR and B6 mice were stained with acidic toluidine blue, metachromatic mast cells were visible in the tissue from BTBR mice at the hippocampal fissure, lateral thalamic nuclei and third ventricle, but not at the caudate nucleus, cortex or cerebellum (Figure 7). The mast cells were perivascular and appeared to be entering brain parenchyma. There was a noticeable absence of mast cells in all of the aforementioned brain regions of the male and female B6 mice. Additionally, we noted increased numbers of mast cells in meningeal tissues from the BTBR 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