Langerhans Cell Histiocytosis: Pathogenesis and clinical findings
Precursor cells differentiateàClonal expansion of abnormal (constitutive MAPK activation) CD1a+/CD207+ (Langerhans cell phenotype surface receptors) dendritic cells in tissue(s)
Somatic BRAFV600E mutation: BRAF is a kinase in the MAPK pathway
Other somatic (non- reproductive cell) mutations
Idiopathic (unknown cause)
Mutation(s) can occur in one of these precursor cell types*
Hematopoietic stem cell (earliest cell of blood cell differentiation) in bone marrow
Committed dendritic cell (type of myeloid antigen-presenting cell) precursor in bone marrow or blood
Committed dendritic cell precursor in tissue
Constitutive activation of the MAPK pathway (signalling pathway that regulates variety of cellular processes) in one of these precursor cell types
*Note: Based on the “misguided myeloid differentiation” modelàthe earlier the mutation(s) occur in the myeloid cell differentiation pathway, the more severe the disease.
Langerhans Cell Histiocytosis
Accumulation of abnormal CD1a+/CD207+ dendritic cells (Langerhans Cell Histiocytosis cells or LCH cells) with an inflammatory background in one or more organs
Authors:
Ran (Marissa) Zhang Reviewers:
Mehul Gupta
Kiera Pajunen
Yan Yu*
Lynn Savoie*
* MD at time of publication
↑ recruitment & activation of T cells, macrophages, eosinophils in tissue(s) around the body
↓ CCR7 & CXCR4 (chemokine receptors) expression on LCH cellsàinhibits migration of LCH cells to lymph nodes
↑ BCLXL (an apoptosis regulator protein) expression on LCH cellsà inhibits apoptosis of LCH cells
Immune cell infiltration & ↑ pro-inflammatory chemokine/cytokine release à dysregulated local & systemic inflammation
Accumulation of LCH cells in tissue(s) around the body
Inflammatory lesion (an area of abnormal tissue) formation in one or more organs:
In pituitary stalk
Mass effectà
obstruction of antidiuretic hormone (complex mechanisms)
In liver
Invasion & accumulation of cells foreign to liverà expands liver
Chronic local inflammation
Scarring of bile ducts
↓ bilirubin clearance from liveràbuildup into serum
↑ serum bilirubin
Jaundice
In cortical bone Cytokine production
à↑ osteoclast
(cells that break down bone) activity
↑ rate of bone loss
Osteolytic bone lesions
In bone marrow
Unclear mechanism but likely due to macrophage activation
↑ phagocytosis (ingestion & destruction) of blood cells
In spleen
Invasion & accumulation of cells foreign to spleen
Forms aggregates that expand the red pulp (functions as the blood filter in spleen)
Splenomegaly
In skin
Unclear mechanisms
Variable presentations: most commonly pinpoint erythematous (red) papules or erythematous plaques with crusting & scaling
Hepatomegaly • BRAF- B-Raf proto-oncogene, serine/threonine kinase
• CCR7- C-C motif chemokine receptor type 7
• CD1a- Cluster of differentiation 1A
• CD207- C-type lectin domain family 4 member k • CXCR4- C-X-C chemokine receptor type 4
• LCH- Langerhans Cell Histiocytosis
• MAPK- Mitogen-activated protein kinase
Diabetes Insipidus
Abbreviations:
• BCLXL- B-cell lymphoma-extra large
Anemia, thrombocytopenia &/or neutropenia
Legend:
Pathophysiology
Mechanism
Sign/Symptom/Lab Finding
Complications
Published January 13, 2022 on www.thecalgaryguide.com