Immunological (mis)communication in Langerhans Cell Histiocytosis

Langerhans Cell Histiocytosis (LCH) affects both children and adults. The
disease is characterized by the accumulation of aberrant histiocytes
(LCH-cells) as well as inflammatory in one or more tissues or organs with bone
and skin being the most affected sites. LCH can present in many different ways.
Consequently, LCH can be misdiagnosed particularly in adults. The past five
years, several somatic mutations associated with LCH, but also with many other
types of cancer, have been identified. Based on these results., LCH is
increasingly considered to be a neoplastic disorder of myeloid origin but with
a clear immune component.
The impact of above mentioned mutations on the presentation, course and
potential recurrence of LCH after treatment is unclear. In addition, the
contribution of lymphocytes co-present in the inflamed LCH-affected tissues is
far from clear. There is a clear need from the field to identify (bio)markers
at diagnosis which can adequatly predict progression of the disease or
recurrence after treatment (LCH-reactivation). As the latter only occurs in a
small proportion of patients, there is currently a significant number of
patients who are subjected unnecessarily to prolonged therapy with steroids
and/or chemotherapy.
As LCH is a rare disease, we can only collect reliable results from patient
materials and clinical data through intensive collaboration. For this reason,
we have set up multidisciplinaire research groups in 3 different Dutch centers
(LUMC, AMC and EUR) wherein many different specialists who regularly treat LCH
patients participate. We also collaborate with the Dutch Childhood Oncology
Group (DCOG) which is participating in a large international study (LCH-IV)
regarding long term outcome of various treatment protocols for children with
LCH. Through these collaborations, we are able to enroll both new onset as well
as former LCH patients, children and adults, in our study.

The main objective of our study is to gain more insight into the molecular
processes preceding the onset and course of LCH. Moreover, we try to understand
the role of the immune system, if any, in the clearance of histiocytes which
are typically present in LCH-affected tissues.

In our laboratory we study the gene and protein expression in leasional
LCH-cells, immune cells, stromal cells as well as their presumed precursor
cells which circulate in the blood or reside in the bone marrow. The DNA from
these cells, as well as control genomic DNA extracted from a buccal swab, is
tested for the presence of somatic mutations by standard PCR-based technology.
Through these studies, we hope to understand how and where aberrant LCH cells
arise, what their function is, how they are distributed throughout the body and
why these genetic aberrant cells are usually not automatically eradicated by
the immune system. To perform these studies, we make use of the remainder of
freshly biopsied tissues which are collected for defining the diagnosis;
alternatively, we use archived tissue blocks which are provided to us by our
collaborators from the pathology department who are participating in our study
group.

A significant proportion of LCH-affected patients concerns children and
adolescents. It is therefore esstential to include especially patients below 18
years in our studies. For all patients enrolled, we aim to limit the burden and
risks associated with the collection of biological materials from these
patients as much as possible through combining the collection with routine
clinical procedures carried out during the work up or treatment of LCH. The
sole exeption is the buccal swab. To avoid extra visits to our clinique, the
collection of buccal swabs can be easily done at home at any given moment in
time.