Hemophagocytic lymphohistiocytosis (HLH)

The mononuclear-phagocyte system comprises two major cell types, the macrophages and the dendritic cells, which are mainly antigen-presenting cells. Accordingly, histiocytoses are classified as either diseases with macrophage accumulation, including (familial) hemophagocytic lymphohistiocytosis (FHL or HLH), or disorders with the antigen-presenting Langerhans cell as the central cell, with Langerhans cell histiocytosis (LCH), previously called Histiocytosis X, as the most frequent disease.

Primary (genetic) HLH / familial HLH (FHL)

We have a deep and long-lasting interest in this field. FHL is a rapidly fatal disease that most typically affects infants and young children, with a median survival of 1-2 months without treatment. We have developed the international diagnostic guidelines for HLH (1991 and 2004) and, in collaboration with clinical scientists worldwide, we coordinated the international treatment protocols HLH-94 and HLH-2004 with the major aim to improve the therapeutic results.

In 1996 we suggested that FHL might be caused by an apoptosis defect and in 1999 we were able to show that FHL is caused by a deficiency in apoptosis triggering. Subsequently, in collaboration with other research groups in 1999, mutations in the perforin gene (PRF1) were revealed in a subset of FHL patients. Additional genetic studies revealed another gene causing FHL (STX11), and a deep intronic mutation and an inversion of the gene UNC13D.

Interestingly, it appears as if mutations in FHL-causing genes may be associated with an increased risk of developing malignancies, and we have shown that this is the case also for healthy carrier of FHL-causing genes, possibly due to a moderately deficient surveillance of tumor transformed cells.

Currently we aim to improve diagnostics of FHL and to improve treatment strategies of patients with primary HLH. We are also interested in exploring if carriership of FHL genes is associated with other health problems.

Secondary (acquired) HLH

The clinical hallmark of HLH is massive inflammation (“hyperinflammation”). We are increasingly interested various forms of secondary HLH, including infection-associated HLH, malignancy-associated HLH and rheuma-associated HLH, in children as well as adults. In international collaboration, we have recently prepared recommendations for the use of etoposide-based treatment in secondary HLH, recommendations for management of HLH in adults, and recommendations for management of HLH in intensive care units (ICU).

Our current studies aim to improve survival in infection-associated HLH (including dengue-HLH), malignancy-associated HLH, rheuma-associated HLH and HLH in the ICU. We also aim to understand the underlying biology causing secondary HLH.  

We want to take advantage of our solid knowledge on HLH and hyperinflammation, and expand that knowledge to other relevant patient groups. Our ultimate goal is to improve the outcome, in all respects, of patients affected by hyperinflammation.

Langerhans Cell Histiocytosis (LCH)

Langerhans cell histiocytosis (LCH) is a potentially fatal disease with a highly variable clinical picture. Bone and skin are the most common organs affected, and other organs that may be involved include the liver, spleen, bone marrow, lungs and CNS. CNS involvement often causes endocrine affection, and sometimes a slowly progressive, potentially devastating, neurodegeneration. Together with Sahlgrenska University Hospital in Gothenburg we have developed valuable tools for assessing and monitoring neurodegenerative CNS-LCH. Our aims are to elucidate etiology and pathophysiologic mechanisms of LCH, and to reduce mortality and late effects.

The classical treatment typically involves mild chemotherapy, such as vinblastine, methotrexate, 6-mercaptopurine, corticosteroids, and vincristine, but very toxic chemotherapy such as high doses of cytarabine and 2-CdA in combination have been suggested as salvage therapy regimens.

LCH is currently viewed as an inflammatory myeloid neoplasia characterized by granulomatous lesions containing pathological CD207+ dendritic cells (DCs) with constitutively activated mitogen-activated protein kinase (MAPK) pathway signaling. Importantly, targeted inhibition of the MAPK pathway has improved survival further. The therapeutic effect in neurodegenerative CNS-LCH, which affects > 20% of all LCH patients and also causes most of the severe late effects, is still not well known.

One current aim is to improve survival and reduce late effects. We participate actively in the international multicenter study LCH-IV on treatment and natural history of pediatric LCH patients, in which we coordinate the part on CNS-LCH. We also evaluate targeted inhibition of the MAPK pathway in LCH in general and with regard to CNS-LCH. We also study inactivation of drugs used in LCH, and how to reduce such inactivation. Another current aim is to better understand the underlying biology causing LCH.