Langerhans cell histiocytosis (LCH) is a rare and devastating condition that causes system-wide inflammation. Langerhans cells are a variant of dendritic cells present on the skin’s surface which aid in fighting off infections. However, mutations may arise causing the cells to proliferate and migrate to other organs causing inflammation. Common sites are skin, eyes, lungs, mouth, lymph nodes, bone marrow, and nervous system. Since the first accounts of LCH, the central nervous system (CNS) has been implicated in the condition. A growing number of LCH patients have had various CNS abnormalities identified by MRI over the past ten years. It is said that about 10% of patients with LCH develop progressive neurodegeneration (LCH-ND) which has a high morbidity rate and is characterized by increasing dysarthria, dysmetria, and ataxia. The etiology of LCH-ND has not been well defined and poses some mystery.
CT Scan Showing LCH Credit Countincr
Aged myeloid cells are the culprits
LCH is caused by hematopoietic progenitor cells which express mutations in the MAPK gene causing it to differentiate into senescent myeloid cells propelling the formation of lesions. It is said that the circulating myeloid cells invade the blood-brain barrier and cause a breakdown leading to infiltration of the cells resulting in an accumulation in the basal ganglia, cerebellum, and brainstem.
A team of neurologists and immunologists utilized this information by digging deep, they aimed to establish the mechanisms through which neuroinflammation and neurodegeneration could be triggered by MAPK activation. They also suggested that blocking the MAPK mutation pathway could halt the neurodegenerative process and prevent brain damage.
They created transgenic mice that expressed the most prevalent somatic LCH mutation, BRAFV600E+, during various phases of hematopoietic development. The mice had developed LCH and features resembling major characteristics of LCH. This was done in order to investigate supposed cellular determinants of LCH-ND. It was discovered that BRAFV600E+ myeloid cells were the main propagators of end-organ injury.
Clinical significance
Having successfully created a link between the MAPK pathway and neurodegeneration, medications targeted at this pathway could be beneficial.
The scientists instituted a combination treatment on the mice test subjects involving MAPK inhibitor (Trametinib; MEK inhibitor) and senolytic therapy (navitoclax; Bcl-xL inhibitor). Senolytic therapy is used to clear old cells from the body system to prevent the occurrence of age-related and chronic diseases like dementia and atherosclerosis. The treatment significantly reduced the number of mutated cells in the lung, liver, spleen, and brain parenchyma.
We are now at the point where we can actively slow down the effects of the aging process. Perhaps, in the future, we will be able to reverse it.
Conclusion
Neurodegenerative conditions could be traumatic not just for the patients, but for the family members and loved ones. LCH has been associated with brain damage, however, combination therapies that inhibit the process and clear the aged cells could improve the quality of life and disease outcomes.
In addition to revolutionizing our understanding of LCH-ND pathophysiology, the animal models and therapeutic trajectories created in this study pave the way for future preventive and therapeutic treatment trajectories for the disease.
References
Circulating senescent myeloid cells drive blood-brain barrier breakdown and neurodegeneration
Christian Matthias Wilk, Flurin Cathomas, Orsolya Torok, Jessica Le Berichel, Matthew D. Park, George R. Heaton, Pauline Hamon, Leanna Troncoso, Brooks P. Scull, Diana Dangoor, Aymeric Silvin, Ryan Fleischmann, Meriem Belabed, Howard Lin, Elias Merad Taouli, Steffen Boettcher, Markus G. Manz, Julia K. Kofler, Zhenyu Yue, Sergio A. Lira, Florent Ginhoux, John F. Crary, Kenneth L. McClain, Jennifer L. Picarsic, Scott J. Russo, Carl E. Allen, Miriam Merad bioRxiv 2023.10.10.561744; doi: https://doi.org/10.1101/2023.10.10.561744
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