Langerhans Hücreli Histiositozda Prognostik Önemi Olan Faktörlerin Düzenleyici T Hücreleri ile İlişkisi

Öz

Amaç: Langerhans hücreli histiositoz (LHH), dentritik hücrelerin anormal proliferasyonu ile karakterize klonal bir hastalık olup, yoğun inflamatuar bir mikroçevreye (TM) sahiptir. TM’nin, nadir görülen bu hastalığa olan katkısı hakkında bilgiler sınırlıdır. Bu çalışmada, TM deki regülatuar T hücreleri ve BRAFV600E mutasyonunu prognostik veriler ile karşılaştırmayı amaçladık. Gereç ve Yöntemler: Çalışmaya 26 olgu dahil edildi. Olguların yaş, cinsiyet, lokalizasyon, tekli-çoklu lokalizasyon, riskli organ tutulumu ve nüks durumlarına göre immünohistokimyasal olarak FOXP3+ regülatuar T hücre (Treg) sayısı ve BRAFV600E mutasyon varlığı değerlendirildi. Bulgular: Çalışmada yetişkin olgu sayısı çocuk sayısından daha fazla idi. En sık lokalizasyon kemik olup, olguların %81’i tek lokalizasyonlu idi. Riskli organ tutulumu ise 3 olguda mevcut olup, bunlardan ikisinde nüks görüldü. FOXP3+ Treg hücrelerinin sayısı; yetişkinlerde, tek lokalizasyon tutulumu olanlarda ve kemik tutulumu olanlarda yüksek olarak bulundu. Ayrıca nüks olan grupta FOXP3+ hücre sayısı nüks olmayan gruba göre daha yüksekti. BRAF V600E mutasyonu çocuklarda yetişkinlere oranla daha yüksekti (p=0.003), fakat prognostik parametreler ile karşılaştırıldığında istatiksel olarak anlamlı sonuç bulunamadı (p>0.05). Sonuç: BRAFV600E mutasyon varlığı çocuk hastalarda daha sık olmakla birlikte yetişkin hastalarda da görülmektedir. FOXP3+ Treg sayısı CD3+ ve CD4+ T hücre sayıları ile orantılıdır. TM de yer alan farklı oranlara sahip T hücreleri LHH patogenezinde önemli yere sahiptir

Anahtar Kelimeler

• Langerhans,
• histiositoz,
• düzenleyici,
• FOXP3,
• BRAF,
• mutasyon

The Relationship of Prognostic Factors with Regulatory T Cells in Langerhans Cell Histiocytosis

Öz

Aim: Langerhans cell histiocytosis (LCH), is a clonal disorder characterized by abnormal proliferation of dendritic cells, which has an intense inflammatory microenvironment. There is limited information about contribution of microenvironment to this rare disease. We aimed to compare regulatory T cells in microenvironment and BRAFV600E mutation with prognostic data. Material and Methods: Overall, 26 cases were included to the study. The number FOXP3+ regulatory T cell (Treg) and presence of BRAFV600E mutation were assessed according to age, gender, localization, unifocal or multifocal, involvement of organ at risk, and recurrence status in a histochemical manner. Results: The number of adult cases was higher than pediatric cases. Bone was the most common localization, and 81% of cases were unifocal. Risk organ involvement was observed in 3 cases, 2 of which showed recurrence. It was found that the number of FOXP3+ Tregs was higher in adults, those with unifocal localization, and those with bone involvement. In addition, the number of FOXP3+ Tregs was higher in the group with recurrence than those without recurrence. BRAFV600E mutation was higher in children when compared to adults (p=0.003), but, no significant correlation was found when compared with remaining prognostic parameters (p>0.05). Conclusion: Although BRAFV600E mutation is more common in pediatric patients, it can also be seen in adult patients. The number of FOXP3+ Tregs is proportional to CD3+ and CD4+ cells. T cells, which present at varying rates in microenvironment, play an essential role in the pathogenesis of LCH.

Anahtar Kelimeler

• Langerhans,
• histiocytosis,
• regulatory,
• FOXP3,
• BRAF,
• mutation

Kaynakça

1. Mitchell J, Jenée M., Stuart P. Berzins, Kannourakis G.. A potentially important role for T cells and regulatory T cells in Langerhans cell histiocytosis. Clinical Immunology 2018; 194: 19-25.
2. Tong C, Jia X, Jia Y, He Y. Langerhans cell histiocytosis in Chinese adults: absence of BRAF mutations and increased FOXP3(+) regulatory T cells. Int J Clin Exp Pathol. 2014; 7: 3166-3173.
3. Goyal G, Tazi A, Go RS, Rech KL, Picarsic JL, Vassallo, et al. International expert consensus recommendations for the diagnosis and treatment of Langerhans cell histiocytosis in adults. Blood. 2022; 139: 2601-2621.
4. Mitchell J, Kvedaraite E, von Bahr Greenwood T, Lourda M, Henter JI, Berzins SP, et al. Plasma Signaling Factors in Patients With Langerhans Cell Histiocytosis (LHH) Correlate With Relative Frequencies of LHH Cells and T Cells Within Lesions. Front Pediatr. 2022; 29: 872859.
5. Halbritter F, Farlik M, Schwentner R, Jug G, Fortelny N, Schnöller T, et al. Epigenomics and Single-Cell Sequencing Define a Developmental Hierarchy in Langerhans Cell Histiocytosis. Cancer Discov. 2019; 910: 1406-1421.
6. Paredes SEY, Almeida LY, Trevisan GL, Polanco XBJ, Silveira HA, Rab S, et al. Immunohistochemical characterization of immune cell infiltration in paediatric and adult Langerhans cell histiocytosis. Scand J Immunol. 2020; 92: e12950.
7. Gao XM, Li J, Cao XX. Signaling pathways, microenvironment, and targeted treatments in Langerhans cell histiocytosis. Cell Commun Signal. 2022; 19:195.
8. Senechal B, Elain G, Jeziorski E, Grondin V, Patey-Mariaud de Serre N, Jaubert F, et al. Expansion of regulatory T cells in patients with Langerhans cell histiocytosis. PLoS Med. 2007; 4: e253.

9. Mitchell J, Kannourakis G. Langerhans cell histiocytosis: A malignant myeloid neoplasm or disorder of immune regulation? Acta Paediatr. 2021; 110: 2888-2891.
10. Zeng K, Wang Z, Ohshima K, Liu Y, Zhang W, Wang L, et al. BRAF V600E mutation correlates with suppressive tumor immune microenvironment and reduced disease-free survival in Langerhans cell histiocytosis. Oncoimmunology. 2016; 5: e1185582.
11. Mitchell J, Kelly J, Kvedaraite E, von Bahr Greenwood T, Henter JI, Pellicci DG, et al. Foxp3+ Tregs from Langerhans cell histiocytosis lesions co-express CD56 and have a definitively regulatory capacity. Clin Immunol. 2020; 215: 108418.
12. Ohue Y, Nishikawa H. Regulatory T (Treg) cells in Caner: Can Treg cells be a new therapeutic target? Caner Science. 2019; 110: 2080-9.
13. Bergamini ML, Mardegan AP, DE Rosa CS, Palmieri M, Sarmento DJS, Nakamura Hiraki KR, et al. Presence of langerhans cells, regulatory T cells (Treg) and mast cells in asymptomatic apical periodontitis. Braz Oral Res. 2020; 34: e108.
14. Özer E, Yüzügüldü RI, Olgun HN, İnce DG, Sevinc A. RAF-MEKERK yolağı mutasyonları: pediatrik çağ Langerhans Hücreli Histiositozunda prognostik ve prediktif belirteçler. 27. Ulusal Patoloji Kongresi; 2017; Antalya. Güncel Patoloji Dergisi: 2017. SS30, 1-2.
15. Nagarjun Rao R, Chang CC, Tomashefski JF Jr. Lymphocyte sub-populations and non-Langerhans' cell monocytoid cells in pulmonary Langerhans' cell histiocytosis. Pathol Res Pract. 2008; 204: 315- 322.
16. Leslie C, Bowyer SE, White A, Grieu-Iacopetta F, Trevenen M, Lacopetta B, et al. FOXP3C T regulatory lymphocytes in primary melanoma are associated with BRAF mutation but not with response to BRAF inhibitor. Pathology 2015; 47: 557-563.
17. García Díaz MP, De Luca Sologaistoa A, De Paula Vernetta C, Moreno MA, Galeano Paniagua LA, et al. Langerhans cell histiocytosis of the head and neck in the pediatric population in a tertiary center: Clinical presentation, classification and treatment. Int J Pediatr Otorhinolaryngol. 2022; 155: 111073.
18. Heritier S, Emile JF, Barkaoui MA, Thomas C, Fraitag S, Boudjemaa S, et al. BRAF Mutation Correlates With High-Risk Langerhans Cell Histiocytosis and Increased Resistance to First-Line Therapy. J Clin Oncol. 2016 1; 34: 3023–3030.
19. Haupt R, Minkov M, Astigarraga I, Schafer E, Nanduri V, Jubran R, et al. Langerhans cell histiocytosis (LCH): guidelines for diagnosis, clinical work-up, and treatment for patients till the age of 18 years. Pediatr Blood Cancer. 2013; 60: 175-184.