Limits...
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.

Show MeSH

Related in: MedlinePlus

Listeria monocytogenes (LM) burden of infected mice.BTBR and B6 mice were assessed for LM (cfu/organ) in liver and spleen at threes days after infection; * indicates a significant difference between the two strains.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3140472&req=5

pone-0020912-g010: Listeria monocytogenes (LM) burden of infected mice.BTBR and B6 mice were assessed for LM (cfu/organ) in liver and spleen at threes days after infection; * indicates a significant difference between the two strains.

Mentions: Since the BTBR mice expressed high levels of IgG and cytokines, we investigated humoral immunity to KLH and innate and cell-mediated immunity to LM of adult (pnd70) BTBR and B6 mice. To eliminate differences due to estrous cycle, only males were assessed. Primary and secondary anti-KLH levels were significantly higher in BTBR mice than the levels of B6 mice (Fig. 9). Immune defenses against LM were opposite of the BTBR and B6 responses observed for humoral immunity to KLH; BTBR mice had significantly less immunity and thus the cfu levels of LM were greater in livers and spleens. For BTBR mice, there were 2.1±0.3×1010 cfu LM in the liver and 4.6±0.5×108 cfu LM in the spleen, whereas B6 mice had 8.4±3.5×106 and 0.7±0.2×106 cfu LM, respectively (Fig. 10). In previous studies with BALB/c mice, which are more susceptible than B6 mice to listeriosis, there were always lower cfu values than observed with BTBR mice. Since, innate and Th1 immune responses are responsible for defenses against LM, it seems that BTBR mice have poor innate and type-1 immunity. Interestingly, at 3 days after infection, the liver levels of IL-17, TGFβ, and IL-10 were significantly greater in BTBR mice than B6 mice (data not shown). The anti-KLH and LM immune responses suggest that BTBR mice have predominantly type-2 immunity. This suggestion is supported by the constitutively high levels of IgE in the sera of BTBR mice, which were significantly greater than those of B6 mice or the F1 offspring (15.4±1.3, BTBR; 1.6±0.2, B6; 3.4±0.7, CBF1; 2.8±0.3, BCF1; mean IgE µg/mL ± SEM). These results included pooled sera from males and females; however, most BTBR females had higher IgE levels than BTBR males (males, 11.9±1.5; females, 19.4±2.0). Since the serum IgE levels of the BTBR mice were elevated to an even greater extent than that of the IgG differences of BTBR and B6 mice, we assess, whether like IgG, IgE was elevated in the brains of the BTBR mice. Additionally, mast cells have been implicated in autism [51] and in the enhancement of immune cell entrance into the brain [52], and mast cells are triggered by IgE to release neurotransmitters and cytokines. Additionally, the BTBR mice do have more mast cells surrounding and in the brain. Thus, measurement of IgE presence in brain regions is of potential relevance to the heightened neuroinflammation of BTBR mice. Interestingly, the regional proportions of IgE (Table 6) were similar to those of IgG (Table 1) in the brains of the BTBR mice; however, the differences regarding the amounts of IgG and IgE in the brain regions of BTBR and B6 mice were not similar. All brain regions of BTBR mice had more IgG than those of B6 mice, but only the CTX, FCTX and HC of BTBR mice had more IgE. It is also interesting to note that the higher serum levels of IgE in BTBR females compared to BTBR males is observed as higher levels only in the STR, SN, HC, and CB.


Aberrant immune responses in a mouse with behavioral disorders.

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

Listeria monocytogenes (LM) burden of infected mice.BTBR and B6 mice were assessed for LM (cfu/organ) in liver and spleen at threes days after infection; * indicates a significant difference between the two strains.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0020912-g010: Listeria monocytogenes (LM) burden of infected mice.BTBR and B6 mice were assessed for LM (cfu/organ) in liver and spleen at threes days after infection; * indicates a significant difference between the two strains.
Mentions: Since the BTBR mice expressed high levels of IgG and cytokines, we investigated humoral immunity to KLH and innate and cell-mediated immunity to LM of adult (pnd70) BTBR and B6 mice. To eliminate differences due to estrous cycle, only males were assessed. Primary and secondary anti-KLH levels were significantly higher in BTBR mice than the levels of B6 mice (Fig. 9). Immune defenses against LM were opposite of the BTBR and B6 responses observed for humoral immunity to KLH; BTBR mice had significantly less immunity and thus the cfu levels of LM were greater in livers and spleens. For BTBR mice, there were 2.1±0.3×1010 cfu LM in the liver and 4.6±0.5×108 cfu LM in the spleen, whereas B6 mice had 8.4±3.5×106 and 0.7±0.2×106 cfu LM, respectively (Fig. 10). In previous studies with BALB/c mice, which are more susceptible than B6 mice to listeriosis, there were always lower cfu values than observed with BTBR mice. Since, innate and Th1 immune responses are responsible for defenses against LM, it seems that BTBR mice have poor innate and type-1 immunity. Interestingly, at 3 days after infection, the liver levels of IL-17, TGFβ, and IL-10 were significantly greater in BTBR mice than B6 mice (data not shown). The anti-KLH and LM immune responses suggest that BTBR mice have predominantly type-2 immunity. This suggestion is supported by the constitutively high levels of IgE in the sera of BTBR mice, which were significantly greater than those of B6 mice or the F1 offspring (15.4±1.3, BTBR; 1.6±0.2, B6; 3.4±0.7, CBF1; 2.8±0.3, BCF1; mean IgE µg/mL ± SEM). These results included pooled sera from males and females; however, most BTBR females had higher IgE levels than BTBR males (males, 11.9±1.5; females, 19.4±2.0). Since the serum IgE levels of the BTBR mice were elevated to an even greater extent than that of the IgG differences of BTBR and B6 mice, we assess, whether like IgG, IgE was elevated in the brains of the BTBR mice. Additionally, mast cells have been implicated in autism [51] and in the enhancement of immune cell entrance into the brain [52], and mast cells are triggered by IgE to release neurotransmitters and cytokines. Additionally, the BTBR mice do have more mast cells surrounding and in the brain. Thus, measurement of IgE presence in brain regions is of potential relevance to the heightened neuroinflammation of BTBR mice. Interestingly, the regional proportions of IgE (Table 6) were similar to those of IgG (Table 1) in the brains of the BTBR mice; however, the differences regarding the amounts of IgG and IgE in the brain regions of BTBR and B6 mice were not similar. All brain regions of BTBR mice had more IgG than those of B6 mice, but only the CTX, FCTX and HC of BTBR mice had more IgE. It is also interesting to note that the higher serum levels of IgE in BTBR females compared to BTBR males is observed as higher levels only in the STR, SN, HC, and CB.

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