Langerhans Cell Histiocytosis (LCH) is a disease in which tissue destruction is caused by accumulation of histiocytes derived from Langerhans cells (LC), the antigen presenting dendritic cells of skin. Although these pathologic LCs (PLCs) are clonal and overexpress p53, LCH's high rate of remission in response to local treatment has led to the consensus that it is not a malignancy. However, even though some LCH lesions can be localized and easily treated, lesions in a significant percentage of cases are disseminated and lead to multiorgan failure and death. LC trafficking in vivo is tightly regulated. Normal resting LCs express the chemokine receptor CCR6 which directs them to mucocutaneous inflammatory sites where its ligand is secreted. Once LCs ingest antigen and are activated, they down-regulate CCR6 and up-regulate CCR7. This attracts LCs to lymph nodes, the source of CCR7's ligands, where they present antigen to T cells. Our preliminary data demonstrate that despite having characteristics of activated LCs, PLCs show persistent expression of CCR6 perhaps explaining, in part, their accumulation at inappropriate tissue sites. The experiments in this proposal are designed to elucidate the pathobiology and pathogenesis of LCH by testing the hypotheses that: (1) Dysregulated expression of chemokines and their receptors may be responsible for the persistence of PLC's in target organs; and (2) Clonal PLC's arise from LC's because of the expression of specific genes. To test these hypotheses, I propose the following specific aims:
Specific Aim 1. Test primary LCH and other histiocytoses for abnormalities in chemokine and chemokine receptor expression. The relevance of CCR6/CCR7 co-expression by LCs to tissue infiltration patterns will be tested using transgenic mice.
Specific Aim 2. Identify genes whose expression is characteristic of LCH. Differential display will be used to clone genes showing differential expression between PLCs and LCs.
Specific Aim 3. Positionally map and identify histiocytosis susceptibility genes in Bernese mountain dogs, a breed which suffers a histiocytic disorder similar to human LCH, using blood and pedigrees from a breeder's organization.
Specific Aim 4. Construct an in vitro system for analysis of pathological LCs. Attempts will be made to immortalize LCs and PLCs by genetic manipulation so that the genes discovered in Specific Aims 1, 2, and 3 can be tested for their relevance to disease. ? ?
| Badalian-Very, Gayane; Vergilio, Jo-Anne; Degar, Barbara A et al. (2012) Recent advances in the understanding of Langerhans cell histiocytosis. Br J Haematol 156:163-72 |
| Badalian-Very, Gayane; Vergilio, Jo-Anne; Degar, Barbara A et al. (2010) Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 116:1919-23 |
| Degar, Barbara A; Rollins, Barrett J (2009) Langerhans cell histiocytosis: malignancy or inflammatory disorder doing a great job of imitating one? Dis Model Mech 2:436-9 |
