In a sense, Langerhans cell histiocytosis (LCH) has always been somewhat of a mystery for doctors. As a rare multi-system disorder, LCH can affect the skin, lungs, bone marrow, spleen, or pretty much any other organ. As LCH develops, it can set off a cytokine storm – or an overactive and harmful immune reaction. But for years, doctors had not known what causes this reaction. However, according to Medical XPress, a new study performed by researchers at Mount Sinai discovered the cause of the LCH-associated cytokine storm: senescent cells. Take a look at the full study findings published in Nature Medicine.

Langerhans Cell Histiocytosis (LCH)

Langerhans cell histiocytosis (LCH) is a rare inflammatory disorder in which too many histiocytes or Langerhans cells, white blood cells that normally protect against infection, accumulate throughout the body. Ultimately, this causes the formation of small tumors called granulomas. According to MedLine Plus, an estimated 80% of patients with LCH have at least one granuloma form within the bones.

Typically, LCH affects children. Symptom onset usually occurs between ages 2-3. Risk factors include a family history of cancer or thyroid disease; frequent infections as a newborn; being Hispanic; not being vaccinated; or having a parent who was previously exposed to metal, granite, or wood dust, or certain chemicals. However, the disorder may also affect adults. Many affected adults are, or previously were, smokers. As a result, most cases of adult-onset LCH impact the lungs.

Because LCH can affect multiple organs, symptoms vary. However, some symptoms may include:

• Neurodegeneration
• Jaundice (yellowing of the skin and eyes)
• Seizures
• Swollen lymph nodes
• Red or scaly skin lesions or papules
• Abdominal pain
• Granulomas throughout the body
• Fatigue
• Anemia (low red blood cell count)
• Neutropenia (low white blood cell count)
  • Note: Neutropenia can cause frequent infections.
• Thrombocytopenia (low platelet count)
• Delayed puberty
• Bone destruction
• Irritability
• Dizziness
• Lung fibrosis and difficulty breathing
• Vision problems, including protruding or bulging eyes

Senescent Cells

For nearly 15 years, Dr. Miriam Merad, MD, PhD, who currently holds a number of roles at Mount Sinai, has been working to increase awareness around LCH. In addition to understanding the underlying cause of the disorder, Dr. Merad also sought to find effective treatment options for patients. This has been difficult. In the past, doctors believed LCH to be a myeloid neoplastic disorder. However, patients with myeloid neoplastic disorders are typically treated with chemotherapy, which is not effective for all patients with LCH. Thus, finding a new treatment solution would fill an unmet need within this patient population.

Researchers wanted to understand:

• What caused LCH
• Potential treatment options

Currently, no treatments exist to treat LCH-associated neurodegeneration.

To begin, researchers began exploring cells from patients with LCH. They determined that many patients had BRAF gene mutations. Further, certain blood cell-producing cells expressed this mutation, causing them to enter senescence. According to an article published in Nature Reviews Drug Discovery:

Cellular senescence, which is a permanent state of cell cycle arrest induced by cellular stress, has recently emerged as a fundamental ageing mechanism that also contributes to diseases of late life, including cancer, atherosclerosis and osteoarthritis.

In other words, senescence usually occurs when the body puts malignant cells to “sleep,” preventing cancerous cells or tumors from spreading. However, during senescence, the body releases inflammatory cytokines, which play a role in immune response. In patients with LCH, blood precursor cells were entering into senescence rather than becoming blood cells. As a result, lower blood cells were being created, but higher levels of inflammatory cytokines were being released.

As a result, the inflammatory cytokines began attacking the bone marrow and, later, other organs and parts of the body. Now, researchers believe that changing treatment options could benefit patients with LCH. For example, rather than treating patients with chemotherapy, patients could receive senolytics, a class of drugs designed to kill senescent cells.