Asthma is a serious chronic illness that affects many children worldwide. Exposure to cockroach allergen in early life can lead to allergic sensitization and increase the risk of developing asthma. However, the underlying immune mechanisms and genetic etiology remain unclear. Recent advances have demonstrated that members of the C-type lectin receptor (CLR) family functionally interact with allergens and are critical in controllng immune response. This offers a novel avenue to investigate their biological role in allergic responses and their genetic effects. In this regard, CD206 (MRC1), encoding mannose receptor, a major member of the CLR family, has been shown to mediate Bla g2 (cockroach allergen) uptake. Specifically, our ongoing study has led to a novel observation that CD206 is highly expressed in human monocyte-derived fibrocytes, unique cells expressing both hematopoietic cells (CD34, CD45, MHC class II) and stromal cells (collagen I and III), and functionally interacts with Bla g2. Our preliminary studies have also provided initial evidence supporting a role of CD206 in mediating cockroach allergen -induced allergic responses in a mouse model of asthma. Furthermore, our genetic analysis has demonstrated a significant association for sequence variants in CD206 and asthma in two independent populations. The stage is thus set to critically evaluate the functional significance of the cockroach allergen-CD206 axis in allergic responses. HYPOTHESIS: CLRs, particularly CD206 expressed by fibrocytes, may play a pivotal role in allergic responses to cockroach allergen.
Aim 1 proposes experiments to investigate the functional interaction of cockroach allergen and CD206 in fibrocytes. We will use a well-established ex vivo model to investigate the CD206-mediated cockroach allergen induced fibrocyte maturation, activation, and antigen presenting cell (APC) function in T cell proliferation and polarization (Th1/Th2/Th17) by using gene silencing and receptor blocking approaches.
Aim 2 proposes experiments to determine the role of CD206 and fibrocytes in cockroach allergen-induced inflammation and airway remodeling. We will use mouse models of cockroach allergic asthma to test whether CD206 deficient mice are protected from cockroach allergen-induced airway inflammation, and to study the role of fibrocytes in regulating both airway immunological and fibrotic responses and the modulatory effects of CD206 on fibrocyte function. Finally, Aim 3 proposes studies to assess association between sequence variants in CD206 and cockroach sensitization and to determine their role in gene expression and function. We will identify genetic variants in CD206 using targeted deep-sequencing and test their associations with cockroach sensitization among African Americans. We will then test for gene-environment interactions to determine the effect of cockroach exposure on the association with cockroach sensitization. We will finally determine the role of CD206 genetic variants in regulation of gene function. This will provide novel insights into the role of cockroach allergen-CD206 axis in the pathogenesis of allergic diseases and offer an opportunity for novel therapies.
Sensitization to cockroach allergen is one of the strongest predictors of asthma morbidity, and is associated with genetic basis. Mannose receptor (MR) on innate immune cells has been shown to mediate cockroach allergen uptake and immunological responses. Studies in this grant application will investigate the functional interaction of cockroach allergen and CD206 in fibrocytes, define the role of CD206 and fibrocytes in cockroach allergen induced airway inflammation in a mouse model, and examine the impact of sequence variants in CD206 on gene expression and function, and will lead to a better target for both diagnostic and therapeutic purposes.
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