Langerhans cell histiocytosis : Detection, monitoring and pathophysiology

Abstract: Langerhans cell histiocytosis (LCH) is a rare disease that may occur at any age but mainly affects children. Clonally expanded Langerhans cells together with lymphocytes, eosinophils and macrophages form destructive granulomatous lesions in many various organs. The etiology and pathophysiology of the disease still remain elusive. The clinical course is unpredictable, varying from spontaneous regression and resolution to repeated recurrences and progression, leading to death. In children with localized disease the prognosis is favourable but with multiple organ involvement there is a great risk of permanent disabilities and poor outcome. There is thus a need for sensitive and specific methods to detect and monitor disease activity to enable optimal tuning of treatment. In addition, there is a requirement for improved understanding of the pathophysiology of the disease in order to develop novel therapeutic approaches. This thesis focuses on defining ways of monitoring disease activity, on applying new methods detecting LCH lesions and on trying to reveal novel pathogenetic mechanisms in LCH. Since LCH may be a remitting disease, easily accessible indicators of disease activity are highly desirable. The usefulness of erythrocyte sedimentation rate (ESR) and platelet counts has been evaluated and both these parameters correlated with disease activity. With the aim to improve radiological imaging in LCH, two new methods for detection of LCH lesions have been assessed. Both positron emission tomography (PET) for imaging CNS lesions and somatostatin analogue scintigraphy (Octreoscan®) for whole body examination, may provide information about the disease activity not revealed by conventional morphological investigations. It has previously been shown that cells in LCH lesions produce numerous cytokines, but the phenotypes of producer cells have not been distinctly identified. An immunohistochemical method enabling a discrimination between cytokine-producing and cytokine-binding cells has now been utilized to study IL- 11, LIF and TNF production at a protein level in cytospin preparations from LCH lesions. A majority of examined specimens revealed synthesis of IL11 and LIF in lesional Langerhans cells. TNF production could be detected in Langerhans cells in all studied samples. These observations indicate that IL-1 1, LIF and TNF are involved in the disease process, possibly mediating systemic symptoms, osteolytic activity, increased erythrocyte sedimentation rate and thrombocytosis. Successful therapeutic targeting of TNF in one child with severe LCH was achieved using soluble TNF receptor fusion protein. These results support an important role of cytokines in the pathogenesis of LCH and advocate cytokine neutralization as an additional therapy in severe LCH.