Allergic diseases are a group of common and often debilitating diseases, including asthma, and their prevalence has been increasing worldwide, particularly in Taiwan. The reasons for the increased prevalence are still unclear, but recent epidemiological studies have demonstrated the importance of environmental exposure in the disease susceptibility, and in some cases, the severity. This is highlighted by recent concern about the exposure to endocrine-disrupting chemicals (EDCs; commonly used plasticizers) and their impact on the development of allergic diseases. But, the mechanisms of action remain unclear and the causal relationship has been difficult to establish. To address this important public health problem, our emphasis has been on investigating the impact of exposure to environmental pollutants on the regulatory network of innate immunity. We hypothesize that exposure to EDCs targets and programs critical regulatory cell types, including dendritic cells (DCs), a front-line cell type in contact with the environment and critical in immune regulation, leading to dysregulated immune (allergic) responses. Results from our current efforts have suggested that common EDCs may target DCs and influence innate immune function via, in part, their abilities to modify signaling events and epigenetic programs, providing a foundation for our future effort in integrating epidemiology, exposure biology and epigenomic analysis to ultimately establish a causal relationship between exposure to environmental pollutants and the development of allergic diseases.

The MLL (mixed-lineage leukemia) gene encodes a histone methyltransferase that is frequently targeted by chromosomal translocations in aggressive forms of acute leukemia. MLL associated leukemias are very prominent in infants (age <12 months), and account for ~33% of therapy-related acute leukemia with balanced chromosome aberrations. Despite the availability of multi agent chemotherapy and stem cell transplantation, the survival of MLL leukemia patients remains poor. Environmental assaults such as topoisomerase inhibitors and maternal consumption of dietary flavonoids are thought to be involved in the generation of MLL rearrangement. After treatment with etoposide (a topoisomerase inhibitor) for unrelated neoplastic disease, a high proportion of patients develops translocations at the MLL locus.

Accumulating evidence suggests that MLL fusion proteins activate a leukaemogenic gene-expression program through epigenetic misregulation. Aberrant histone modifications involve methylation of histone 3 lysine 79 (H3K79), H3K4, as well as H3, H4 acetylation. In particular, MLL fusions may promote transcriptional elongation via recruitment of H3K79 methyltransferase activity. Using ChIP-chip (Chromatin Immunoprecipitation coupled with microarray), we showed that hypermethylated H3K79 spreads over large genomic domains, and higher levels of H3K79 methylation are well correlated with increased enrichment of MLL fusion proteins. To determine the genomic loci that are directly regulated by MLL fusion proteins, we employed genome-wide location analysis in combination with global gene expression profiling. Our data demonstrated that the MLL fusion proteins, as well as misregulated H3K79 methylation, are only localized to a limited portion of genomic loci occupied by the MLL wild type protein. As an aberrant chromatin modifier, MLL fusion proteins are likely to contribute to the development of acute leukemia through direct activation of a very small set of genes involved in hematopoietic stem cell differentiation and cell cycle regulation. The link between a chromatin modulator and acute leukemia is supportive of epigenetic dysregulation of gene expression as an important mechanism in the development of human cancer.

Chemokines comprise a protein family, which is responsible for the trafficking of leukocytes to the site of inflammation and the regulation of leukocyte maturation, degranulation and differentiation. The chemokine receptors are expressed on the surface of several cell types involved in the allergic inflammation, e.g. eosinophils, monocytes, Th1 and Th2 lymphocytes. Th2-dominated cytokine profile, an upregulation of Th2-induced chemokines has been associated with allergic manifestations including atopic dermatitis and asthma. Atopic dermatitis is reported to be associated with increased levels of Th2-associated eotaxin, macrophage-derived chemokine [MDC (CCL22)], thymus- and activation-regulated chemokine [TARC (CCL17)] and pulmonary- and activation-regulated chemokine [PARC (CCL18)] in children and adults. In asthma, T-helper (Th) 2 cytokine and chemokine are thought to mediate most of the allergic inflammatory responses associated with atopic asthma. But the Th1-related chemokine, interferon-inducible protein 10 (IP-10)/CXCL10, is the predominant chemokine measured during human allergic pulmonary late-phase reaction. Maternal IgE levels during and after pregnancy correlated with cord blood IgE and Th2-associated chemokine (MDC) levels. During the development of allergic disease and sensitization is reported to be associated with increased cord blood IgE and MDC levels, as well as high ratios of MDC to Th1-associated chemokine IP-10 and I-TAC (CXCL11). In medications in asthma, long-acting β2 agonist (LABA) could suppress TARC expression in bronchial epithelial cells mediated via beta2-adrenoreceptors. Formoterol at physiologic concentration could suppress LPS-induced Th1-related (IP-10) but enhance Th2-related (MDC) chemokine expression in human monocytes. LABAs may increase Th2-related chemokine expression in monocytes and the Th2 cell recruitment, and, therefore, LABA monotherapy may not be an appropriate therapeutic option for asthma. Ketotifen is effective in down-regulating LPS-induced MDC, Mig/CXCL9 and IP-10, which play important roles in the pathogenesis of airway inflammation. In conclusion, different chemokines play different roles in different allergic diseases and their medications.