Yong Heo

Aberrant immune responses in a mouse with behavioral disorders.

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 CD40hi/I-Ahi 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.

Impact of developmental lead exposure on splenic factors.

Lead (Pb) is known to alter the functions of numerous organ systems, including the hematopoietic and immune systems. Pb can induce anemia and can lower host resistance to bacterial and viral infections. The anemia is due to Pbs inhibition of hemoglobin synthesis and Pbs induction of membrane changes, leading to early erythrocyte senescence. Pb also increases B-cell activation/proliferation and skews T-cell help (Th) toward Th2 subset generation. The specific mechanisms for many of the Pb effects are, as yet, not completely understood. Therefore, we performed gene expression analysis, via microarray, on RNA from the spleens of developmentally Pb-exposed mice, in order to gain further insight into these Pb effects. Splenic RNA microarray analysis indicated strong up-regulation of genes coding for proteolytic enzymes, lipases, amylase, and RNaseA. The data also showed that Pb affected the expression of many genes associated with innate immunity. Analysis of the microarray results via GeneSifter software indicated that Pb increased apoptosis, B-cell differentiation, and Th2 development. Direct up-regulation by Pb of expression of the gene encoding the heme-regulated inhibitor (HRI) suggested that Pb can decrease erythropoiesis by blocking globin mRNA translation. Pbs high elevation of digestive/catabolizing enzymes could generate immunogenic self peptides. With Pbs potential to induce new self-peptides and to enhance the expression of caspases, cytokines, and other immunomodulators, further evaluation of Pbs involvement in autoimmune phenomena, especially Th2-mediated autoantibody production, and alteration of organ system activities is warranted.

Central nervous system cytokine gene expression: Modulation by lead

The environmental heavy metal toxicant, lead (Pb) has been shown to be more harmful to the central nervous system (CNS) of children than to adults, given that Pb exposure affects the neural system during development. Because growth factors and cytokines play very important roles in development of the CNS, we have examined the impact of Pb exposure on the expression of cytokines during CNS development. Cytokine expression was studied in post‐natal‐day 21 (pnd21) mice by microarray, real‐time RT‐PCR, Luminex, and ELISA methodologies. BALB/c mouse pups were exposed to Pb through the dams drinking water (0.1 mM Pb acetate), from gestation‐day 8 (gd8) to pnd21. Two cytokines, interleukin‐6 (IL‐6) and transforming growth factor‐β1 (TGF‐β1), displayed significantly changed transcript levels in the presence of Pb. IL‐6 and TGF‐β1 both have signal transduction cascades that can cooperatively turn on the gene for the astrocyte marker glial‐fibrillary acidic protein (GFAP). Microarray results indicated that Pb exposure significantly increased expression of GFAP. Pb also modulated IL‐6, TGF‐β1, and IL‐18 protein expression in select brain regions. The deleterious effects of Pb on learning and long‐term memory are posited to result from excessive astrocyte growth and/or activation with concomitant interference with neural connections. Differential neural expression of cytokines in brain regions needs to be further investigated to mechanistically associate Pb and neuroinflammation with behavioral and cognitive changes.

Serum IgE elevation correlates with blood lead levels in battery manufacturing workers.

Lead (Pb), an occupational and environmental toxicant, is known to induce immunomodulatory effects resulting in lowered resistance to infectious micro-organisms and altered levels of immunoglobulins in humans. Preferential activation of type-2 helper T cells and inhibition of type-1 T-cell activation is considered a cellular mechanism for the Pb-induced immune alteration, which has not been investigated well in humans. Leads influence on in vivo balance between type-1 and type-2 activities was assessed among workers exposed to Pb through battery manufacturing in Korea. Serum IgE levels were significantly higher in the workers with a blood Pb level (PbB) of ≤30 μg/dL than in the workers with a PbB of <30 μg/dL. Furthermore, the serum IgE concentrations significantly correlated with PbB although no significant relationship between PbB and serum interleukin-4 or interferon gamma levels was observed. The present study indicates that elevation of IgE levels may be an immunologic index for Pb-induced in vivo toxicities, potentially involved with progression of various allergic diseases in humans.