HistioNode: The MRC Rare Disease Platform Node for Histiocytic Disorders

Histiocytic disorders are rare diseases in which immune cells called macrophages (aka 'histiocytes') cause collateral damage to the body. Macrophages develop from white blood cells and normally patrol through the tissues, looking for injury and infection. They carry a potent armoury of molecular weapons to protect us from harm.

However, in histiocytosis, macrophages become abnormally activated and cause damage to tissues that can lead to life-threatening illness. In Histiocytic Neoplasms, macrophages gain a mutation in genes governing their behaviour causing them to become mutinous and make inflammation happen spontaneously. In HLH, (short for Haemophagocytic Lympho Histiocytosis) macrophages are triggered to go into overdrive, causing bone marrow failure and widespread organ dysfunction.

HLH is less well understood but is likely to be combination of inherited genetic factors and unusual behaviour of the immune system when it meets a virus or lymphoma, a type of blood cancer.

HistioNode is an initiative to bring together doctors, scientists and patient groups within the MRC Rare Disease Platform to tackle the most pressing problems caused by Histiocytic Disorders. These diseases naturally involve many different organs, and HLH is associated with multiple different triggers. HistioNode is therefore inherently linked to other rare diseases that affect specific organs.

In the five year programme, we will engage with patients and families through our patient involvement partner Histio UK to discuss the priorities of people with a lived experience of histiocytosis. To tackle research question in the laboratory we also need to collect patient samples and clinical data in a Biobank. This has been challenging especially in HLH where patients become ill very quickly, but funding through the Node will enable us to enrol participants in the UK Histiocytosis Registry and gather material for research.

We will also collaborate with the National Disease Registration Services in all four nations to find out more about the medical needs of patients with histiocytosis, including how they are treated in different regions and whether there are unexpected associations with other illnesses.

As part of the programme of research we will target three areas where we think there is a need to find out more. Two of these are in HLH because it currently has a 50% death rate in older children and adults. In patients with HLH we will use new technology to detect viral infection and lymphoma which are two of the main triggers.

It is not known why patients with HLH have an abnormal immune response to common viruses, so we will also study the patten of infection and the response of the body, to look for atypical features. In lymphoma, the diagnosis is often difficult and delayed, so we will develop DNA sequencing of blood, also known as 'liquid biopsy, to improve the chance of early detection and survival.

In the third project we will sequence the inherited DNA of all patients to see if there are genes that increase the chance of getting a histiocytic disorder. We will also look for mutations that occur in the bone marrow and blood of individual patients to see if this changes their risk or pattern of disease. In Histiocytic Neoplasms like Langerhans cell histiocytosis and Erdheim Chester disease, there are mutations in the inflamed tissues inside histiocytes.

However, not all mutations are accounted for so we will do further sequencing aiming to find a genetic diagnosis in every patient. We will also measure mutation in liquid biopsies to help with diagnosis and risk assessment.

We are already a closely collaborative network but the MRC Rare Disease Platform will enable us to drive research forward for benefit to patients much more effectively. This will improve outcomes for patients with histiocytic disorders and, through sharing our insights and skills across the Platform, have an impact on the whole spectrum of rare diseases.