Aberrant Immune Responses in a Mouse with Behavioral Disorders

Cardiff University, United Kingdom
PLoS ONE (Impact Factor: 3.53). 07/2011; 6(7):e20912. DOI: 10.1371/journal.pone.0020912
Source: PubMed

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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Available from: David A Lawrence, Jul 17, 2015
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    • "Moreover, significantly reduced levels of endogenous secretory RAGE (an inhibitor of AGE formation) and elevated concentrations of its proinflammatory ligand S100A9 were found in the bloodstream of ASD patients, suggesting the presence of a dysfunctional AGE-RAGE axis (Boso et al., 2006), although peripheral and central RAGE levels may not necessarily correlate. AGE can also activate microglia (Shaikh et al., 2012), as documented in ASD brains already at 3e4 years of age (Vargas et al., 2005), as well as mast cells (Sick et al., 2010), which may contribute to ASD pathogenesis (Heo et al., 2011; Theoharides et al., 2012). Finally, AGE also stimulate apoptosis through cytoplasmic and mitochondrial pathways (Alikhani et al., 2005). "
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    ABSTRACT: Glyoxalase I (GLO1) is a homodimeric Zn(2+)-dependent isomerase involved in the detoxification of methylglyoxal and in limiting the formation of advanced glycation end-products (AGE). We previously found the rs4746 A332 (Glu111) allele of the GLO1 gene, which encodes for glyoxalase I, associated with "unaffected sibling" status in families with one or more children affected by Autism Spectrum Disorder (ASD). To identify and characterize this protective allele, we sequenced GLO1 exons and exon-intron junctions, detecting two additional SNPs (rs1049346, rs1130534) in linkage disequilibrium with rs4746. A family-based association study involving 385 simplex and 20 multiplex Italian families yielded a significant association with autism driven only by the rs4746 C332 (Ala111) allele itself (P < 0.05 and P < 0.001 under additive and dominant/recessive models, respectively). Glyoxalase enzymatic activity was significantly reduced both in leukocytes and in post-mortem temporocortical tissue (N = 38 and 13, respectively) of typically developing C332 allele carriers (P < 0.05 and <0.01), with no difference in Glo1 protein levels. Conversely, AGE amounts were significantly higher in the same C332 post-mortem brains (P = 0.001), with a strong negative correlation between glyoxalase activity and AGE levels (τ = -0.588, P < 0.01). Instead, 19 autistic brains show a dysregulation of the glyoxalase-AGE axis (τ = -0.209, P = 0.260), with significant blunting of glyoxalase activity and AGE amounts compared to controls (P < 0.05), and loss of rs4746 genotype effects. In summary, the GLO1 C332 (Ala111) allele confers autism vulnerability by reducing brain glyoxalase activity and enhancing AGE formation, but years after an autism diagnosis the glyoxalase-AGE axis appears profoundly disrupted, with loss of C332 allelic effects.
    Journal of Psychiatric Research 08/2014; 59. DOI:10.1016/j.jpsychires.2014.07.021 · 4.09 Impact Factor
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    • "+ T cells expressing V β 6 chains are selectively expanded in the spleens of BTBR mice BTBR mice have elevated numbers of CD4 + T cells, compared to B6 mice (Heo et al., 2011). Since the amount of IgG production in vitro (Fig. 3) was dependent on the presence of T cells, and in vivo there are elevated numbers of IgG-secreting cells (Fig. 4), the splenic CD4 + T cell populations from BTBR and B6 mice were assayed for their activation and expression of V β chains. "
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    ABSTRACT: Autism spectrum disorders (ASD) are neurodevelopmental disorders with unknown etiology. BTBR-T(+)tf/J (BTBR) mice, a mouse strain with behaviors that resemble autism and with elevated levels of anti-brain antibodies (Abs), have enhanced activation of peripheral B cells and CD4(+) T cells and an expanded percentage of CD4(+) T cells expressing Vβ6 chains. The CD4(+)CD25(+)Vβ6(+) and Vβ6-splenic cells of BTBR mice have elevated levels of IL-4, IFN-γ and IL-17, but there appears to be no preferential CD4(+) T subset skewing/polarization. The high level of IgG production by BTBR B cells was dependent on T cells from BTBR mice. The CD4(+) T cells of BTBR mice, especially those expressing Vβ6 become spontaneously activated and expanded in an autoimmune-like manner, which occurred in both BTBR and B6 hosts that received an equal number of BTBR and B6 bone marrow cells. BTBR mice also have an elevated percentage of peripheral blood neutrophils, which may represent their elevated inflammatory state. B6 offspring derived from B6 dams that were gestationally injected with purified IgG from sera of BTBR mice, but not IgG of B6 mice, developed significantly impaired social behavior. Additionally, B6 offspring that developed in BTBR dams had impaired social behavior, while BTBR offspring that developed in B6 dams had improved social behavior. All of the immunological and behavioral parameters of BTBR mice were compared with those of B6 mice, which have relatively normal behaviors. The results indicate maternal Abs and possibly other maternal influences affect the social behavior of offspring.
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    • "The effects of estrogen on promoting B-cells and/or T H 2 cells might account for these sex differences of IgG levels (Pauklin et al., 2009; Gonzalez et al., 2010). However, since no sex differences were observed for brain cytokine expressions, which is suggested to be highly related to impaired social behavior (Heo et al., 2011), the results indicate that the sex differences observed on behavior changes were not caused by the immune-hormone interactions, although hormones might be involved. Further experiments are required to elucidate the mechanism. "
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