Копия ТН17-КЛЕТКИ И ИХ РОЛЬ В РАЗВИТИИ АУТОИММУННЫХ ЗАБОЛЕВАНИЙ

Ɏɭɧɤɰɢɨɧɚɥɶɧɚɹ ɩɥɚɫɬɢɱɧɨɫɬɶ ɫɭɛɩɨɩɭɥɹɰɢɣ Ɍ-ɯɟɥɩɟɪɨɜ

Ɉɤɨɥɨ 40 ɥɟɬ ɬɨɦɭ ɧɚɡɚɞ Ɍ-ɥɢɦɮɨɰɢɬɵ ɪɚɡɞɟɥɟɧɵ ɩɨ ɮɢɡɢɨɥɨɝɢɱɟɫɤɢɦ ɚɤɬɢɜɧɨɫɬɹɦ ɧɚ ɧɟɫɤɨɥɶɤɨ ɬɢɩɨɜ ɤɥɟɬɨɤ: Ɍ-ɯɟɥɩɟɪɵ (Th), ɰɢɬɨɬɨɤɫɢɱɟɫɤɢɟ ɥɢɦɮɨɰɢɬɵ ɢ ɫɭɩɪɟɫɫɨɪɵ. ȼ 1986 ɝɨɞɭ Ɋɨɛɟɪɬ Ʉɨɮɮɦɚɧ ɢ Ɍɢɦɨɬɢ Ɇɨɫɫɦɟɧ ɜɩɟɪɜɵɟ ɨɩɢɫɚɥɢ ɩɨɞɪɚɡɞɟɥɟɧɢɟ CD4+ T-ɤɥɟɬɨɤ, ɨɫɧɨɜɚɧɧɨɟ ɧɚ ɩɪɨɢɡɜɨɞɫɬɜɟ ɪɚɡɧɵɯ ɰɢɬɨɤɢɧɨɜ ɧɚ 2 ɮɭɧɤɰɢɨɧɚɥɶɧɵɟ ɫɭɛɩɨɩɭɥɹɰɢɢ, ɧɚɡɜɚɧɧɵɟ Ɍ-ɯɟɥɩɟɪɚɦɢ 1 ɢ 2 ɬɢɩɚ (Th1 ɢ Th2), ɢ ɩɪɢ ɷɬɨɦ ɧɟɜɨɥɶɧɨ ɨɬɤɪɵɥɢ «ɹɳɢɤ ɉɚɧɞɨɪɵ» ɫɥɨɠɧɨɫɬɢ ɢ ɩɪɨɬɢɜɨɪɟɱɢɣ [1]. Ⱦɨɤɚɡɚɧɨ, ɱɬɨ ɢɦɟɟɬɫɹ, ɩɨ ɤɪɚɣɧɟɣ ɦɟɪɟ, 2 ɤɥɨɧɚ Ɍh, ɤɨɬɨɪɵɟ ɪɚɡɥɢɱɚɸɬɫɹ ɬɟɦ, ɱɬɨ Ɍh1 ɨɩɨɫɪɟɞɭɸɬ ɡɚɳɢɬɭ ɨɪɝɚɧɢɡɦɚ ɨɬ ɜɧɭɬɪɢɤɥɟɬɨɱɧɵɯ ɛɚɤɬɟɪɢɣ ɢ ɜɢɪɭɫɨɜ ɢ ɭɱɚɫɬɜɭɸɬ ɜ ɪɚɡɜɢɬɢɢ ɚɭɬɨɢɦɦɭɧɧɵɯ ɩɚɬɨɥɨɝɢɣ. Ɋɟɚɤɰɢɢ, ɨɩɨɫɪɟɞɭɟɦɵɟ Th2, ɡɚɳɢɳɚɸɬ ɨɪɝɚɧɢɡɦ ɨɬ ɜɧɟɤɥɟɬɨɱɧɵɯ ɩɚɬɨɝɟɧɨɜ ɢ ɢɧɢɰɢɢɪɭɸɬ ɚɥɥɟɪɝɢɱɟɫɤɢɣ ɢɦɦɭɧɧɵɣ ɨɬɜɟɬ. ɏɨɬɹ ɦɟɯɚɧɢɡɦɵ, ɤɨɬɨɪɵɟ ɪɟɝɭɥɢɪɭɸɬ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɭ Th1- ɢ Th2-ɤɥɟɬɨɤ ɫɟɝɨɞɧɹ ɢɡɜɟɫɬɧɵ, ɜ ɩɨɫɥɟɞɧɢɟ ɝɨɞɵ ɨɩɢɫɚɧɵ ɞɪɭɝɢɟ ɫɭɛɩɨɩɭɥɹɰɢɢ CD4+ T-ɤɥɟɬɨɤ, ɬɚɤɢɟ ɤɚɤ T-ɪɟɝɭɥɹɬɨɪɧɵɟ ɤɥɟɬɤɢ (Treg), T-ɮɨɥɥɢɤɭɥɹɪɧɵɟ ɯɟɥɩɟɪɵ (Tfh), Ɍ-ɯɟɥɩɟɪɵ

17 ɬɢɩɚ (Th17), Th22-ɤɥɟɬɤɢ, ɢ ɧɚɤɨɧɟɰ, Th9-ɤɥɟɬɤɢ [2,3].

ɏɚɪɚɤɬɟɪɧɨ, ɱɬɨ ɪɚɡɥɢɱɧɵɟ ɫɭɛɩɨɩɭɥɹɰɢɢ Th ɹɜɥɹɸɬɫɹ ɞɨɫɬɚɬɨɱɧɨ ɩɥɚɫɬɢɱɧɵɦɢ ɢ ɧɚ ɪɚɧɧɢɯ ɫɬɚɞɢɹɯ ɪɚɡɜɢɬɢɹ ɦɨɝɭɬ ɞɢɮɮɟɪɟɧɰɢɪɨɜɚɬɶɫɹ ɜ ɞɪɭɝɢɟ ɤɥɟɬɤɢ. əɪɤɢɦ ɩɨɞɬɜɟɪɠɞɟɧɢɟɦ ɩɥɚɫɬɢɱɧɨɫɬɢ Ɍh ɹɜɥɹɟɬɫɹ ɮɚɤɬ ɨɛɧɚɪɭɠɟɧɢɹ ɞɜɨɣɧɵɯ ɩɨɡɢɬɢɜɧɵɯ Foxp3+RORȖt+ Ɍ-ɥɢɦɮɨɰɢɬɨɜ, ɤɨɬɨɪɵɟ ɦɨɝɭɬ ɜ ɞɚɥɶɧɟɣɲɟɦ ɞɢɮɮɟɪɟɧɰɢɪɨɜɚɬɶɫɹ ɤɚɤ ɜ ɪɟɝɭɥɹɬɨɪɧɵɟ ɤɥɟɬɤɢ, ɩɪɟɩɹɬɫɬɜɭɸɳɢɟ ɪɚɡɜɢɬɢɸ ɚɭɬɨɢɦɦɭɧɧɵɯ ɡɚɛɨɥɟɜɚɧɢɣ (ȺɂɁ), ɬɚɤ ɢ ɜ ɩɪɨɜɨɫɩɚɥɢɬɟɥɶɧɵɟ Th17-ɤɥɟɬɤɢ [4]. ɉɨɷɬɨɦɭ, ɷɤɫɩɪɟɫɫɢɹ ɥɢɦɮɨɰɢɬɚɦɢ ɬɪɚɧɫɤɪɢɩɰɢɨɧɧɵɯ ɮɚɤɬɨɪɨɜ Foxp3+ ɢɥɢ RORȖt+ ɟɳɟ ɧɟ ɹɜɥɹɟɬɫɹ ɫɜɢɞɟɬɟɥɶɫɬɜɨɦ ɢɯ ɬɟɪɦɢɧɚɥɶɧɨɣ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɢ ɢ ɫɨɜɟɪɲɟɧɧɨ ɧɟ ɮɚɤɬ, ɱɬɨ RORȖt+ ɤɥɟɬɤɚ ɜ ɤɨɧɟɱɧɨɦ ɢɬɨɝɟ ɩɨɩɨɥɧɢɬ ɩɭɥ Th17-ɤɥɟɬɨɤ, ɚ ɧɟ Treg.

Ɍh17 – ɧɨɜɚɹ ɥɢɧɢɹ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɢ ɚɭɬɨɚɝɪɟɫɫɢɜɧɵɯ Ɍ-ɯɟɥɩɟɪɨɜ?

Ɉɬɧɨɫɢɬɟɥɶɧɨ ɧɟɞɚɜɧɨ ɨɬɤɪɵɬɵ Th17-ɤɥɟɬɤɢ, ɤɨɬɨɪɵɟ, ɩɨ ɩɟɪɜɵɦ ɷɤɫɩɟɪɢɦɟɧɬɚɦ, ɫɱɢɬɚɥɢɫɶ ɫɭɝɭɛɨ ɩɪɨɜɨɫɩɚɥɢɬɟɥɶɧɵɦɢ. ɗɬɚ ɝɢɩɨɬɟɡɚ ɨɰɟɧɟɧɚ Lawrence Steinman ɤɚɤ «ɩɨɫɩɟɲɧɵɣ ɩɪɢɝɨɜɨɪ Th17» [5]. ɂɫɬɨɪɢɹ ɨɬɤɪɵɬɢɹ ɧɨɜɨɝɨ ɩɪɟɞɫɬɚɜɢɬɟɥɹ Ɍ-ɯɟɥɩɟɪɨɜ – Ɍh17 – ɧɚɱɢɧɚɟɬɫɹ ɫ 2003 ɝ.,

ɤɨɝɞɚ A.L. Gurney et al. [6] ɩɨɤɚɡɚɥɢ, ɱɬɨ IL-23 ɫɩɨɫɨɛ-

ɫɬɜɭɟɬ ɪɚɡɜɢɬɢɸ ɢ ɚɤɬɢɜɚɰɢɢ Ɍh17-ɤɥɟɬɨɤ, ɨɬɥɢɱɚɸɳɢɯɫɹ ɨɬ Th1 ɢ Th2 ɬɟɦ, ɱɬɨ ɨɧɢ ɩɪɨɞɭɰɢɪɭɸɬ IL-17. ȼ ɬɟɱɟɧɢɟ ɩɨɫɥɟɞɭɸɳɢɯ 5 ɥɟɬ Ɍh17 ɢɧɬɟɧɫɢɜɧɨ ɢɡɭɱɚɥɢ, ɜ ɪɟɡɭɥɶɬɚɬɟ ɷɬɨɝɨ ɭɞɚɥɨɫɶ ɩɨɤɚɡɚɬɶ ɢɫɬɨɱɧɢɤɢ ɩɪɨɢɫɯɨɠɞɟɧɢɹ, ɩɭɬɢ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɢ ɢ ɱɚɫɬɶ ɮɭɧɤɰɢɨɧɚɥɶɧɵɯ ɨɫɨɛɟɧɧɨɫɬɟɣ, ɚ ɬɚɤɠɟ ɢɯ ɪɨɥɶ ɜ ɡɚɳɢɬɟ ɨɪɝɚɧɢɡɦɚ ɨɬ ɩɚɬɨɝɟɧɨɜ ɢ ɜ ɪɚɡɜɢɬɢɢ ɩɚɬɨɥɨɝɢɱɟɫɤɢɯ ɩɪɨɰɟɫɫɨɜ. Ɉɤɨɧɱɚɬɟɥɶɧɨ ɤɚɤ ɨ ɧɨɜɨɣ ɫɭɛɩɨɩɭɥɹɰɢɢ Ɍ-ɯɟɥɩɟɪɨɜ ɨ Th17-ɤɥɟɬɤɚɯ ɫɬɚɥɢ ɝɨɜɨɪɢɬɶ ɬɨɥɶɤɨ ɜ 2006–2007 ɝɝ., ɧɚɡɵɜɚɹ ɢɯ ɬɚɤɠɟ ThIL-17-ɤɥɟɬɤɚɦɢ, ɢɥɢ ɩɪɨɜɨɫɩɚɥɢɬɟɥɶɧɵɦɢ Thi (inflammatory Th) [7,8]. ɋ ɷɬɢɯ ɩɨɪ ɨ ɦɟɯɚɧɢɡɦɚɯ ɪɚɡɜɢɬɢɹ ɛɨɥɶɲɢɧɫɬɜɚ ȺɂɁ ɪɚɫɫɭɠɞɚɸɬ ɜ ɨɫɧɨɜɧɨɦ ɜ ɤɨɧɬɟɤɫɬɟ ɷɬɢɯ ɤɥɟɬɨɤ – «ɚɭɬɨɢɦɦɭɧɧɵɟ ɡɚɛɨɥɟɜɚɧɢɹ ɜ ɷɩɨɯɭ Th17-ɤɥɟɬɨɤ» ɢ ɬ.ɩ. [9]

ɉɨɤɚɡɚɧɨ, ɱɬɨ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɚ Th17-ɤɥɟɬɨɤ ɩɪɨɢɫɯɨɞɢɬ ɧɟɡɚɜɢɫɢɦɵɦ ɨɬ Th1 ɩɭɬɟɦ [10]. Ɍɚɤ, C.T. Weaver et al. [8]

ɭɫɬɚɧɨɜɢɥɢ, ɱɬɨ IL-23 ɧɟ ɜɵɡɵɜɚɟɬ ɩɪɨɞɭɤɰɢɸ IL-17 ɩɨɥɹɪɢɡɨɜɚɧɧɵɦɢ Th1-ɤɥɟɬɤɚɦɢ ɢ ɱɬɨ Ɍh1 ɧɟ ɱɭɜɫɬɜɢɬɟɥɶɧɵ ɤ IL-23. Ȼɨɥɟɟ ɬɨɝɨ, IFNȖ, ɩɪɨɞɭɤɬ Th1, ɚɤɬɢɜɧɨ ɫɭɩɪɟɫɫɢɪɭɟɬ ɪɚɡɜɢɬɢɟ Th17. ɉɚɪɚɥɥɟɥɶɧɵɟ ɧɚɯɨɞɤɢ ɫɞɟɥɚɧɵ ɢ ɞɥɹ Th2ɤɥɟɬɨɤ, ɤɨɬɨɪɵɟ ɹɜɥɹɸɬɫɹ ɧɟɱɭɜɫɬɜɢɬɟɥɶɧɵɦɢ ɤ IL-23, ɚ ɢɯ ɩɪɨɞɭɤɬ IL-4 ɢɧɝɢɛɢɪɭɟɬ ɪɚɡɜɢɬɢɟ Th17. ɍɫɬɚɧɨɜɥɟɧɨ, ɱɬɨ CD4+ Th17-ɤɥɟɬɤɢ ɷɤɫɩɪɟɫɫɢɪɭɸɬ ɯɟɦɨɤɢɧɵ ɋCR4 ɢ ɋɋR6 [11]. ɍ ɦɵɲɟɣ ɜ ɫɨɡɪɟɜɚɧɢɟ Th17 ɜɨɜɥɟɤɚɟɬɫɹ TGFȕ ɢ IL-6, ɬɨɝɞɚ ɤɚɤ ɭ ɥɸɞɟɣ ɷɬɨ ɩɪɨɢɫɯɨɞɢɬ ɩɨɞ ɜɥɢɹɧɢɟɦ IL-23 ɢ IL1ȕ, ɤɨɬɨɪɵɟ ɩɪɢɜɨɞɹɬ ɤ ɪɚɡɜɢɬɢɸ Th17, ɷɤɫɩɪɟɫɫɢɪɭɸɳɢɯ ɫɥɟɞɭɸɳɢɣ ɰɢɬɨɤɢɧɨɜɵɣ ɩɪɨɮɢɥɶ: IL-17A, IL-17F, IL-22, IL-26, IFNȖ, ɯɟɦɨɤɢɧ CCL-20 ɢ ɬɪɚɧɫɤɪɢɩɰɢɨɧɧɵɣ ɮɚɤɬɨɪ RORȖt. ȼ ɪɚɛɨɬɟ S. Nakae et al. [12], ɜ ɤɨɬɨɪɨɣ ɪɚɫɫɦɨɬɪɟɧɵ ɮɟɧɨɬɢɩɢɱɟɫɤɢɟ ɪɚɡɥɢɱɢɹ ɦɟɠɞɭ Th1 ɢ Th17 ɦɵɲɟɣ, ɢɫ-

ɩɨɥɶɡɨɜɚɧɨ ɨɤɨɥɨ 60 ɦɚɪɤɟɪɨɜ, ɫɜɹɡɚɧɧɵɯ ɫ Ɍh. ȼ ɪɟɡɭɥɶɬɚɬɟ ɩɨɤɚɡɚɧɵ ɫɭɳɟɫɬɜɟɧɧɵɟ ɪɚɡɥɢɱɢɹ ɜ ɮɟɧɨɬɢɩɟ ɢɡɭɱɟɧɧɵɯ ɩɨɩɭɥɹɰɢɣ Ɍh. Ɉɛɧɚɪɭɠɟɧɨ, ɱɬɨ ɷɤɫɩɪɟɫɫɢɨɧɧɵɣ ɩɪɨɮɢɥɶ ɩɨɜɟɪɯɧɨɫɬɧɵɯ ɦɨɥɟɤɭɥ ɧɚ Th17 ɛɨɥɟɟ ɩɨɯɨɠ ɧɚ Th1, ɱɟɦ ɧɚ

Th2. Th1-ɥɢɧɟɣɧɵɟ ɦɚɪɤɟɪɵ (IL-18R, CXCR3, T-ɤɥɟɬɨɱɧɵɣ

Ig-ɞɨɦɟɧ, ɦɭɰɢɧɨɩɨɞɨɛɧɵɣ ɞɨɦɟɧ-3 (TIM-3)), ɧɨ ɧɟ ɥɢɧɟɣɧɵɟ ɦɚɪɤɟɪɵ Ɍh2 (T1/ST2, TIM-1, TIM-2), ɷɤɫɩɪɟɫɫɢɪɨɜɚɧɵ ɧɚ Th17, ɧɨ ɢɧɬɟɧɫɢɜɧɨɫɬɶ ɷɤɫɩɪɟɫɫɢɢ ɛɵɥɚ ɪɚɡɥɢɱɧɚ [12].

ɇɟɨɛɯɨɞɢɦɨ ɨɬɦɟɬɢɬɶ, ɱɬɨ ɨɫɧɨɜɧɨɣ ɰɢɬɨɤɢɧ Th17-ɤɥɟɬɨɤ

–IL-17, – ɦɨɠɟɬ ɩɪɨɞɭɰɢɪɨɜɚɬɶ ɢ ɰɟɥɵɣ ɪɹɞ ɞɪɭɝɢɯ ɤɥɟɬɨɤ, ɧɟ ɹɜɥɹɸɳɢɯɫɹ «ɩɨɥɧɨɰɟɧɧɵɦɢ» Th17, ɚ ɱɚɫɬɶ ɢɡ ɧɢɯ ɧɚɡɵɜɚɸɬ «ɜɪɨɠɞɟɧɧɵɦɢ» Th17-ɤɥɟɬɤɚɦɢ. ɗɬɨ T-ɤɥɟɬɤɢ ɩɚɦɹɬɢ, NKT-ɤɥɟɬɤɢ, Ɍn-ɥɢɦɮɨɰɢɬɵ (Ɍ-ɥɢɦɮɨɰɢɬɵ, ɪɟɝɭɥɢɪɭɸɳɢɟ ɧɟɣɬɪɨɮɢɥɵ), ȖįɌ-ɤɥɟɬɤɢ, ɤɥɟɬɤɢ, ɫɩɨɫɨɛɧɵɟ ɢɧɞɭɰɢɪɨɜɚɬɶ ɥɢɦɮɨɢɞɧɭɸ ɬɤɚɧɶ ɷɦɛɪɢɨɧɨɜ ɱɟɥɨɜɟɤɚ (Lti

ɤɥɟɬɤɢ, Lymphoid tissue inducer cells) [13–14].

Ⱦɥɹ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɢ Th17-ɤɥɟɬɨɤ, ɤɚɤ ɢ ɞɥɹ ɥɸɛɵɯ ɞɪɭɝɢɯ Th, ɜɚɠɧɵ ɫɢɝɧɚɥɵ, ɩɨɫɬɭɩɚɸɳɢɟ ɨɬ Ɍ-ɤɥɟɬɨɱɧɨɝɨ ɪɟɰɟɩɬɨɪɚ (ɌCR) – ɫɜɹɡɵɜɚɧɢɟ TCR ɹɜɥɹɟɬɫɹ ɫɭɳɟɫɬɜɟɧɧɵɦ ɜ ɢɧɞɭɤɰɢɢ IL-17 [15]. Ɉɫɧɨɜɧɵɦ ɩɭɬɟɦ ɚɤɬɢɜɚɰɢɢ ɫ ɭɱɚɫɬɢɟɦ TCR ɹɜɥɹɟɬɫɹ ɩɪɨɞɭɤɰɢɹ ɜɧɭɬɪɢɤɥɟɬɨɱɧɨɝɨ ɤɚɥɶɰɢɹ ɢ ɚɤɬɢɜɚɰɢɹ ɬɪɚɧɫɤɪɢɩɰɢɢ ɮɚɤɬɨɪɚ NFAT (Nuclear Factor of Activated T lymphocytes). ɉɪɨɤɫɢɦɚɥɶɧɵɣ ɩɪɨɦɨɬɨɪ ɝɟɧɚ IL-17a ɱɟɥɨɜɟɤɚ ɫɨɞɟɪɠɢɬ ɞɜɚ NFAT-ɫɜɹɡɵɜɚɸɳɢɯ ɫɚɣɬɚ, ɤɨɬɨɪɵɟ ɜɚɠɧɵ ɜ ɪɟɝɭɥɹɰɢɢ IL-17 [16]. ɉɪɨɜɟɞɟɧɢɟ ɫɢɝɧɚɥɨɜ ɨɬ TCR ɢɧɞɭɰɢɪɭɟɬ ɬɪɚɧɫɤɪɢɩɰɢɨɧɧɵɟ ɮɚɤɬɨɪɵ NF-țB ɢ AP-1, ɤɨɬɨɪɵɟ, ɩɨ-ɜɢɞɢɦɨɦɭ, ɧɟɨɛɯɨɞɢɦɵ ɞɥɹ ɩɪɨɞɭɤɰɢɢ ɩɪɨɜɨɫɩɚɥɢɬɟɥɶɧɵɯ ɰɢɬɨɤɢɧɨɜ Th17-ɤɥɟɬɤɚɦɢ [16].

P.R. Mangan et al. [17] ɢɞɟɧɬɢɮɢɰɢɪɨɜɚɥɢ TGFȕ ɤɚɤ ɰɢɬɨɤɢɧ, ɤɪɢɬɢɱɧɵɣ ɞɥɹ ɨɫɭɳɟɫɬɜɥɟɧɢɹ ɪɚɡɜɢɬɢɹ Ɍ-ɯɟɥɩɟɪɧɵɯ ɤɥɟɬɨɤ, ɩɪɨɞɭɰɢɪɭɸɳɢɯ IL-17 in vitro ɢ in vivo. Ɉɞɢɧ ɢɡ ɦɟɯɚɧɢɡɦɨɜ ɫɨɡɪɟɜɚɧɢɹ Ɍh17 ɜɵɪɚɠɚɟɬɫɹ ɜ ɬɨɦ, ɱɬɨ ɫɭɳɟɫɬɜɭɟɬ ɞɢɯɨɬɨɦɢɹ ɜ ɝɟɧɟɪɚɰɢɢ Th17-ɤɥɟɬɨɤ ɢ ɪɟɝɭɥɹɬɨɪɧɵɯ CD4+CD25+Foxp3+-ɤɥɟɬɨɤ, ɬɚɤ ɤɚɤ ɨɛɚ ɬɢɩɚ ɤɥɟɬɨɤ ɩɪɨɢɫɯɨɞɹɬ ɢɡ ɧɚɢɜɧɵɯ Th, ɢ ɢɯ ɪɚɡɜɢɬɢɟ ɧɚɯɨɞɢɬɫɹ ɩɨɞ ɤɨɧɬɪɨɥɟɦ TGFȕ. ȼ ɡɚɜɢɫɢɦɨɫɬɢ ɨɬ ɫɢɝɧɚɥɨɜ, ɝɟɧɟɪɢɪɭɟɦɵɯ ɨɤɪɭɠɟɧɢɟɦ, ɜɨɡɧɢɤɚɸɬ ɥɢɛɨ ɨɛɵɱɧɨ ɜɫɬɪɟɱɚɸɳɢɟɫɹ CD4+CD25+Foxp3+ ɪɟɝɭɥɹɬɨɪɧɵɟ Ɍ-ɤɥɟɬɤɢ, ɥɢɛɨ Th17-ɤɥɟɬɤɢ. Ɍɚɤɠɟ ɜɚɠɧɨɟ ɡɧɚɱɟɧɢɟ ɜ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɟ Th17 ɢɦɟɸɬ ɮɚɤɬɨɪɵ, ɪɟɝɭɥɢɪɭɸɳɢɟ ɢɧɬɟɪɮɟɪɨɧɵ (IRFs)

–ɫɟɦɟɣɫɬɜɨ ɬɪɚɧɫɤɪɢɩɰɢɨɧɧɵɯ ɮɚɤɬɨɪɨɜ, ɪɟɝɭɥɢɪɭɸɳɢɯ ɩɪɨɞɭɤɰɢɸ ɢɧɬɟɪɮɟɪɨɧɨɜ I ɬɢɩɚ [18]. Ɍɚɤ, ɭ ɦɵɲɟɣ ɫ ɨɬɫɭɬɫɬɜɢɟɦ ɝɟɧɚ IRF4 (irf4-/-) ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɚ Th17ɤɥɟɬɨɤ ɧɟ ɩɪɨɢɫɯɨɞɢɬ, ɢ ɨɧɢ ɩɨɥɧɨɫɬɶɸ ɨɬɫɭɬɫɬɜɭɸɬ, ɱɬɨ, ɩɨ-ɜɢɞɢɦɨɦɭ, ɫɜɹɡɚɧɨ ɫ ɞɟɮɟɤɬɧɨɣ ɩɪɨɞɭɤɰɢɟɣ IL-6. ȿɳɟ ɨɞɢɧ ɮɚɤɬ, ɩɨɞɬɜɟɪɠɞɚɸɳɢɣ ɩɪɟɞɵɞɭɳɢɣ, ɩɨɤɚɡɵɜɚɟɬ, ɱɬɨ ɦɵɲɢ ɫ ɧɨɤɚɭɬɨɦ ɝɟɧɚ IRF4 (irf4-/-) ɧɟ ɱɭɜɫɬɜɢɬɟɥɶɧɵ ɤ ɷɤɫɩɟɪɢɦɟɧɬɚɥɶɧɨɦɭ ɚɭɬɨɢɦɦɭɧɧɨɦɭ ɷɧɰɟɮɚɥɨɦɢɟɥɢɬɭ (ɗȺɗ), ɬɚɤ ɤɚɤ Th17 ɹɜɥɹɸɬɫɹ ɨɫɧɨɜɧɵɦɢ ɤɥɟɬɤɚɦɢ, ɭɱɚɫɬɜɭɸɳɢɦɢ ɜ ɩɚɬɨɝɟɧɟɡɟ ɗȺɗ [18]. IRF4-ɫɜɹɡɵɜɚɸɳɢɣ ɛɟɥɨɤ (IBP), ɤɨɬɨɪɵɣ ɧɟɞɚɜɧɨ ɛɵɥ ɢɡɨɥɢɪɨɜɚɧ, ɨɛɥɚɞɚɟɬ ɫɩɨɫɨɛɧɨɫɬɶɸ ɛɥɨɤɢɪɨɜɚɬɶ IRF4 ɢ ɬɟɦ ɫɚɦɵɦ ɩɪɟɩɹɬɫɬɜɨɜɚɬɶ ɪɚɡɜɢɬɢɸ Th17. ɍ ɦɵɲɟɣ, ɞɟɮɢɰɢɬɧɵɯ ɩɨ IBP, ɛɵɫɬɪɨ ɪɚɡɜɢɜɚɸɬɫɹ ɚɭɬɨɢɦɦɭɧɧɵɟ ɡɚɛɨɥɟɜɚɧɢɹ, ɫɨɩɪɨɜɨɠɞɚɸɳɢɟɫɹ ɪɟɡɤɨ ɩɨɜɵɲɟɧɧɵɦ ɭɪɨɜɧɟɦ IL-17 ɢ IL-21 [19].

Th17 ɱɟɥɨɜɟɤɚ ɨɬɥɢɱɚɸɬɫɹ ɨɬ Th17 ɦɵɲɢ ɬɟɦ, ɱɬɨ ɩɪɨɞɭ-

ɰɢɪɭɸɬ ɢɧɨɣ ɧɚɛɨɪ ɰɢɬɨɤɢɧɨɜ. Ɍɚɤ, Th17 ɦɵɲɢ ɩɪɨɞɭɰɢɪɭ-

ɸɬ IL-17A, IL-17F, IL-21, ɬɨɝɞɚ ɤɚɤ Ɍh17 ɱɟɥɨɜɟɤɚ – IL-17A, IL-17F, IL-22 ɢ IL-26 [3, 9]. Ʉɪɨɦɟ IL-17, ɜɚɠɧɨɟ ɡɧɚɱɟɧɢɟ ɢɦɟɟɬ ɩɪɨɞɭɤɰɢɹ IL-21, ɤɨɬɨɪɵɣ ɹɜɥɹɟɬɫɹ ɩɨɬɟɧɰɢɚɥɶɧɵɦ ɢɦɦɭɧɨɦɨɞɭɥɹɬɨɪɨɦ ɢ ɢɦɟɟɬ ɩɥɟɣɨɬɪɨɩɧɵɟ ɷɮɮɟɤɬɵ ɧɚ ɜɪɨɠɞɟɧɧɵɣ ɢ ɩɪɢɨɛɪɟɬɟɧɧɵɣ ɢɦɦɭɧɧɵɟ ɨɬɜɟɬɵ. T. Onoda et al. [20] ɩɨɥɭɱɢɥɢ ɞɚɧɧɵɟ, ɫɜɢɞɟɬɟɥɶɫɬɜɭɸɳɢɟ, ɱɬɨ Th17 ɦɵɲɟɣ ɩɪɨɞɭɰɢɪɭɸɬ IL-21, ɚ ɜ ɥɚɛɨɪɚɬɨɪɢɢ V.K. Kuchroo ɩɨɥɭɱɟɧɵ ɞɚɧɧɵɟ [21], ɫɜɢɞɟɬɟɥɶɫɬɜɨɜɚɜɲɢɟ, ɱɬɨ IL-21 ɢ TGFȕ ɬɪɟɛɭɸɬɫɹ ɞɥɹ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɢ Th17 ɤɥɟɬɨɤ ɱɟɥɨɜɟɤɚ. IL-21 ɭɫɢɥɢɜɚɟɬ ɩɪɨɥɢɮɟɪɚɰɢɸ ɥɢɦɮɨɰɢɬɨɜ, ɰɢɬɨɬɨɤɫɢɱɧɨɫɬɶ CD8+T-ɤɥɟɬɨɤ ɢ ɟɫɬɟɫɬɜɟɧɧɵɯ ɤɢɥɥɟɪɨɜ, ɚ ɬɚɤɠɟ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɭ ȼ-ɤɥɟɬɨɤ ɜ ɩɥɚɡɦɨɰɢɬɵ. ɂ ɧɚɨɛɨɪɨɬ, IL-21 ɢɦɟɟɬ ɩɪɹɦɵɟ ɢɧɝɢɛɢɬɨɪɧɵɟ ɷɮɮɟɤɬɵ ɧɚ ɚɧɬɢɝɟɧ-ɩɪɟɞɫɬɚɜɥɹɸɳɭɸ ɮɭɧɤɰɢɸ ɞɟɧɞɪɢɬɧɵɯ ɤɥɟɬɨɤ ɢ ɦɨɠɟɬ ɛɵɬɶ ɩɪɨɚɩɨɩɬɨɬɢɱɧɵɦ ɞɥɹ ȼ-ɥɢɦɮɨɰɢɬɨɜ ɢ NKɤɥɟɬɨɤ. IL-21 ɹɜɥɹɟɬɫɹ ɤɪɢɬɢɱɟɫɤɢɦ ɪɟɝɭɥɹɬɨɪɨɦ ɪɚɡɜɢɬɢɹ Th17. ɋɨɜɫɟɦ ɧɟɞɚɜɧɨ ɩɨɤɚɡɚɧɨ, ɱɬɨ IL-21 ɩɪɨɞɭɰɢɪɭɟɬɫɹ Th17-ɤɥɟɬɤɚɦɢ ɜ ɡɚɜɢɫɢɦɨɣ ɨɬ STAT3-ɦɚɧɟɪɟ [22]. A. Sato [23] ɩɨɥɭɱɢɥ ɞɚɧɧɵɟ, ɱɬɨ Th17-ɤɥɟɬɤɢ, ɧɚɯɨɞɹɫɶ ɜ ɭɫɥɨɜɢɹɯ ɩɨɥɹɪɢɡɚɰɢɢ (ɧɚɩɪɚɜɥɟɧɢɟ ɤɨɧɟɱɧɨɣ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɢ), ɩɪɨɞɭɰɢɪɭɸɬ IL-17A ɢ IL-17F, ɧɨ, ɬɟɦ ɧɟ ɦɟɧɟɟ, 60% ɷɬɢɯ ɤɥɟɬɨɤ ɩɪɨɞɭɰɢɪɭɸɬ ɧɟ IL-17, ɚ IL-21.

Ɋɚɡɜɢɬɢɟ Th17 ɬɟɫɧɨ ɫɜɹɡɚɧɨ ɫ ɟɳɟ ɨɞɧɢɦ ɰɢɬɨɤɢɧɨɦ – IL-23. ɇɟ ɢɫɤɥɸɱɟɧɚ ɜɨɡɦɨɠɧɨɫɬɶ, ɱɬɨ IL-23 ɞɟɣɫɬɜɭɟɬ ɫɨɜɦɟɫɬɧɨ ɫ TGFȕ ɜ ɪɚɡɜɢɬɢɢ Th17 – ɨɬɫɭɬɫɬɜɢɟ IL-23 ɢ TGFȕ ɩɪɢɜɨɞɢɥɨ ɤ ɩɪɨɞɭɤɰɢɢ ɦɚɥɨɝɨ ɤɨɥɢɱɟɫɬɜɚ Th17-ɤɥɟɬɨɤ. ɉɪɢ ɧɚɥɢɱɢɢ ɨɞɧɨɝɨ IL-23 ɞɟɮɢɰɢɬ Th17 ɧɟ ɜɨɫɩɨɥɧɹɥɫɹ [17]. ȼɨɡɦɨɠɧɨ, ɱɬɨ ɧɚɢɛɨɥɟɟ ɭɛɟɞɢɬɟɥɶɧɵɦ ɞɨɤɚɡɚɬɟɥɶɫɬɜɨɦ ɪɨɥɢ IL-23 ɜ ɪɚɡɜɢɬɢɢ Th17 ɛɵɥɢ ɞɚɧɧɵɟ, ɩɨɤɚɡɚɜɲɢɟ, ɱɬɨ ɞɟɥɟɰɢɹ ɝɟɧɚ IL-23 ɢɥɢ ɟɝɨ ɛɥɨɤɢɪɨɜɚɧɢɟ ɩɪɢɜɨɞɢɬ ɤ ɨɬɫɭɬɫɬɜɢɸ Th17, ɱɬɨ ɫɨɩɪɨɜɨɠɞɚɟɬɫɹ ɪɟɡɢɫɬɟɧɬɧɨɫɬɶɸ ɤ ɪɹɞɭ ɚɭɬɨɢɦɦɭɧɧɵɯ ɡɚɛɨɥɟɜɚɧɢɣ (ɗȺɗ, ɪɟɜɦɚɬɨɢɞɧɨɦɭ ɚɪɬɪɢɬɭ) [24].

Ɋɨɥɶ ɪɟɬɢɧɨɟɜɵɯ orphan-ɪɟɰɟɩɬɨɪɨɜ ɜ ɪɚɡɜɢɬɢɢ Th17ɤɥɟɬɨɤ

ɇɟɫɦɨɬɪɹ ɧɚ ɛɨɥɶɲɨɟ ɱɢɫɥɨ ɦɨɥɟɤɭɥ, ɷɤɫɩɪɟɫɫɢɪɭɟɦɵɯ Th17-ɤɥɟɬɤɚɦɢ ɢ ɩɪɟɬɟɧɞɭɸɳɢɯ ɧɚ ɪɨɥɶ ɢɯ ɦɚɪɤɟɪɨɜ, ɩɨɠɚɥɭɣ, ɧɚɢɛɨɥɟɟ ɧɚɞɟɠɧɵɦɢ ɹɜɥɹɸɬɫɹ ɬɪɚɧɫɤɪɢɩɰɢɨɧɧɵɟ ɮɚɤɬɨɪɵ, ɨɬɧɨɫɹɳɢɟɫɹ ɤ ɹɞɟɪɧɵɦ orphan-ɪɟɰɟɩɬɨɪɚɦ [25]. ɋɭɩɟɪɫɟɦɟɣɫɬɜɨ ɹɞɟɪɧɵɯ ɪɟɰɟɩɬɨɪɨɜ (əɊ) ɩɪɟɞɫɬɚɜɥɟɧɨ ɭ ɩɨɡɜɨɧɨɱɧɵɯ ɩɨɱɬɢ 50 ɛɟɥɤɚɦɢ, ɤɨɬɨɪɵɟ ɢɦɟɸɬ ɫɯɨɞɧɭɸ ɫɬɪɭɤɬɭɪɧɨ-ɮɭɧɤɰɢɨɧɚɥɶɧɭɸ ɨɪɝɚɧɢɡɚɰɢɸ ɢ ɢɫɩɨɥɧɹɸɬ ɪɨɥɶ ɥɢɝɚɧɞ-ɚɤɬɢɜɢɪɭɟɦɵɯ ɪɟɝɭɥɹɬɨɪɨɜ ɬɪɚɧɫɤɪɢɩɰɢɢ ɝɟɧɨɜ. ɉɟɪɜɵɦ ɨɩɢɫɚɧɧɵɦ əɊ ɛɵɥ ɪɟɰɟɩɬɨɪ ɝɥɸɤɨɤɨɪɬɢɤɨɫɬɟɪɨɢɞɨɜ [26]. ȼ ɞɚɥɶɧɟɣɲɟɦ, ɛɥɚɝɨɞɚɪɹ ɪɚɡɥɢɱɧɵɦ ɩɪɨɟɤɬɚɦ ɩɨ ɢɫɫɥɟɞɨɜɚɧɢɸ ɝɟɧɨɦɚ, ɢɞɟɧɬɢɮɢɰɢɪɨɜɚɧɵ ɝɟɧɵ, ɩɪɨɞɭɤɬɵ ɤɨɬɨɪɵɯ – ɩɨɥɢɩɟɩɬɢɞɵ ɛɥɢɡɤɨɣ ɫɬɪɭɤɬɭɪɵ

– ɫɮɨɪɦɢɪɨɜɚɥɢ ɫɟɦɟɣɫɬɜɨ əɊ. Ⱦɥɹ ɦɧɨɝɢɯ əɊ ɩɪɨɛɥɟɦɵ ɢɞɟɧɬɢɮɢɤɚɰɢɢ ɷɧɞɨɝɟɧɧɨɝɨ ɥɢɝɚɧɞɚ ɧɟ ɫɭɳɟɫɬɜɨɜɚɥɨ, ɨɧɢ ɛɵɥɢ ɢɡɜɟɫɬɧɵ ɟɳɟ ɞɨ ɜɵɹɫɧɟɧɢɹ ɫɬɪɭɤɬɭɪɵ ɫɚɦɨɝɨ ɪɟɰɟɩɬɨɪɚ; ɷɬɨ, ɤ ɩɪɢɦɟɪɭ, ɪɟɰɟɩɬɨɪɵ ɬɢɪɟɨɢɞɧɵɯ ɝɨɪɦɨɧɨɜ (TRĮ/ȕ), ɪɟɬɢɧɨɟɜɨɣ ɤɢɫɥɨɬɵ (RɈRs), ɷɫɬɪɨɝɟɧɨɜɵɟ ɪɟɰɟɩɬɨɪɵ (ERs) ɢ ɪɟɰɟɩɬɨɪɵ ɤ 3-ɤɟɬɨɫɬɟɪɨɢɞɚɦ (GRs, MRs, PgRs, ARs), ɜɢɬɚɦɢɧɭ D (VDRs). Ⱦɥɹ ɞɪɭɝɢɯ əɊ ɷɧɞɨɝɟɧɧɵɟ ɥɢɝɚɧɞɵ ɛɵɥɢ ɢɞɟɧɬɢɮɢɰɢɪɨɜɚɧɵ ɩɨɡɞɧɟɟ, ɱɟɦ ɭɫɬɚɧɨɜɥɟɧɚ ɫɬɪɭɤɬɭɪɚ ɫɚɦɨɝɨ ɪɟɰɟɩɬɨɪɚ, ɚ ɞɥɹ ɧɟɤɨɬɨɪɵɯ ɥɢɝɚɧɞɵ

ɧɟɢɡɜɟɫɬɧɵ ɢ ɩɨ ɫɟɣ ɞɟɧɶ. ɗɬɚ ɩɨɫɥɟɞɧɹɹ ɝɪɭɩɩɚ ɛɟɥɤɨɜ ɢ ɛɵɥɚ ɧɚɡɜɚɧɚ orphan-ɪɟɰɟɩɬɨɪɚɦɢ (ɚɧɝɥ. orphan – ɛɟɡɪɨɞɧɵɣ, ɫɢɪɨɬɚ). Ɍɚɤ, ɤ ɩɪɢɦɟɪɭ, ɭ ɱɟɥɨɜɟɤɚ ɢɞɟɧɬɢɮɢɰɢɪɨɜɚɧɵ ɥɢɝɚɧɞɵ 23 ɹɞɟɪɧɵɯ ɪɟɰɟɩɬɨɪɨɜ, ɚ ɞɥɹ 25 ɪɟɰɟɩɬɨɪɨɜ ɨɧɢ ɩɪɟɞɩɨɥɚɝɚɟɦɵ ɢɥɢ ɧɟɢɡɜɟɫɬɧɵ (ɫɨɛɫɬɜɟɧɧɨ orphanɪɟɰɟɩɬɨɪɵ). Ɍɟɦ ɧɟ ɦɟɧɟɟ, ɞɥɹ ɦɧɨɝɢɯ orphan-ɪɟɰɟɩɬɨɪɨɜ ɭɫɬɚɧɨɜɥɟɧɵ ɷɤɡɨɝɟɧɧɵɟ ɚɝɨɧɢɫɬɵ ɢ ɚɧɬɚɝɨɧɢɫɬɵ, ɢ, ɫɨɨɬɜɟɬɫɬɜɟɧɧɨ, ɮɚɪɦɚɤɨɥɨɝɢɱɟɫɤɢɟ ɷɮɮɟɤɬɵ, ɫɜɹɡɚɧɧɵɟ ɫ ɛɥɨɤɚɞɨɣ ɢɥɢ ɚɤɬɢɜɚɰɢɟɣ ɷɬɢɯ ɪɟɰɟɩɬɨɪɨɜ [27].

əɞɟɪɧɵɟ ɪɟɰɟɩɬɨɪɵ ɥɨɤɚɥɢɡɭɸɬɫɹ ɜ ɰɢɬɨɩɥɚɡɦɟ (ɬɢɩ I) ɢɥɢ ɤɨɧɫɬɢɬɭɬɢɜɧɨ ɩɪɢɫɭɬɫɬɜɭɸɬ ɜ ɹɞɪɟ (ɫɨɛɫɬɜɟɧɧɨ ɹɞɟɪɧɵɟ ɪɟɰɟɩɬɨɪɵ, ɬɢɩ II) ɢ ɨɫɭɳɟɫɬɜɥɹɸɬ ɪɟɝɭɥɹɰɢɸ ɦɧɨɠɟɫɬɜɚ ɮɭɧɤɰɢɣ ɜ ɦɧɨɝɨɤɥɟɬɨɱɧɵɯ ɨɪɝɚɧɢɡɦɚɯ (ɪɨɫɬ, ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɭ, ɚɤɬɢɜɚɰɢɸ, ɚɩɨɩɬɨɡ ɢ ɩɪ.) ɩɭɬɟɦ ɩɪɹɦɨɝɨ ɤɨɧɬɪɨɥɹ ɷɤɫɩɪɟɫɫɢɢ ɝɟɧɨɜ ɢ ɪɹɞɚ «ɧɟɝɟɧɨɦɧɵɯ» ɷɮɮɟɤɬɨɜ. Ⱥɤɬɢɜɧɨɫɬɶ ɪɟɰɟɩɬɨɪɨɜ ɤɨɧɬɪɨɥɢɪɭɸɬɫɹ ɫɥɟɞɭɸɳɢɦ ɦɟɯɚɧɢɡɦɨɦ [28]: ɰɢɬɨɩɥɚɡɦɚɬɢɱɟɫɤɢɣ ɪɟɰɟɩɬɨɪ ɫɜɹɡɵɜɚɟɬɫɹ ɫɨ ɫɩɟɰɢɮɢɱɟɫɤɢɦ ɥɢɝɚɧɞɨɦ, ɤɨɬɨɪɵɣ ɜ ɩɨɞɚɜɥɹɸɳɟɦ ɛɨɥɶɲɢɧɫɬɜɟ ɩɪɟɞɫɬɚɜɥɟɧ ɧɟɛɨɥɶɲɨɣ ɥɢɩɨɮɢɥɶɧɨɣ ɦɨɥɟɤɭɥɨɣ (ɫɬɟɪɨɢɞɵ, ɚɪɚɯɢɞɨɧɚɬɵ, ɪɟɬɢɧɨɢɞɵ, ɜɢɬɚɦɢɧ D), ɞɚɥɟɟ ɩɪɨɢɫɯɨɞɢɬ ɞɢɫɫɨɰɢɚɰɢɹ ɤɨɦɩɥɟɤɫɚ ɪɟɰɟɩɬɨɪɚ ɫ ɛɟɥɤɚɦɢ ɬɟɩɥɨɜɨɝɨ ɲɨɤɚ HSP-90, ɝɨɦɨɞɢɦɟɪɢɡɚɰɢɹ (ɝɟɬɟɪɨɞɢɦɟɪɢɡɚɰɢɹ), ɩɪɢɫɨɟɞɢɧɟɧɢɟ ɤɨɚɤɬɢɜɚɬɨɪɚ, ɬɪɚɧɫɤɥɨɤɚɰɢɹ ɜ ɹɞɪɨ

ɢɜɡɚɢɦɨɞɟɣɫɬɜɢɟ ɫ ɨɬɜɟɱɚɸɳɢɦ ɦɨɬɢɜɨɦ ȾɇɄ. ɋɨɛɫɬɜɟɧɧɨ ɹɞɟɪɧɵɟ ɪɟɰɟɩɬɨɪɵ ɤɨɧɫɬɢɬɭɬɢɜɧɨ ɷɤɫɩɪɟɫɫɢɪɭɸɬɫɹ ɜ ɹɞɪɟ ɩɨɫɥɟ ɫɜɹɡɵɜɚɧɢɹ ɥɢɝɚɧɞɚ ɢ ɝɟɬɟɪɨɞɢɦɟɪɢɡɚɰɢɢ ɢɥɢ ɜ ɦɨɧɨɦɟɪɧɨɣ ɮɨɪɦɟ ɜɡɚɢɦɨɞɟɣɫɬɜɭɸɬ ɫ ȾɇɄ. Ⱥɤɬɢɜɚɰɢɹ/ ɩɨɞɚɜɥɟɧɢɟ ɬɪɚɧɫɤɪɢɩɰɢɢ ɝɟɧɨɜ ɨɫɭɳɟɫɬɜɥɹɟɬɫɹ ɛɥɚɝɨɞɚɪɹ ɩɪɢɫɨɟɞɢɧɟɧɢɸ ɤ ɥɢɝɚɧɞ-ɫɜɹɡɚɧɨɣ ɮɨɪɦɟ ɪɟɰɟɩɬɨɪɚ ɪɚɡɥɢɱɧɵɯ ɛɟɥɤɨɜ ɤɨɚɤɬɢɜɚɬɨɪɨɜ/ɤɨɪɟɩɪɟɫɫɨɪɨɜ.

Ɋɟɰɟɩɬɨɪɵ, ɚɫɫɨɰɢɢɪɨɜɚɧɧɵɟ ɫ ɪɟɰɟɩɬɨɪɚɦɢ ɪɟɬɢɧɨɟɜɨɣ ɤɢɫɥɨɬɵ, ɢɥɢ ɪɟɬɢɧɨɟɜɵɟ orphan-ɪɟɰɟɩɬɨɪɵ (Retinoic acidrelated orphan receptors, RORs) ɩɪɟɞɫɬɚɜɥɟɧɵ ɬɪɟɦɹ ɨɫɧɨɜɧɵɦɢ ɩɨɞɬɢɩɚɦɢ: RORĮ (NR1F1), RORȕ (NR1F2) ɢ RORȖ (NR1F3) [29]. ȾɇɄ-ɫɜɹɡɵɜɚɸɳɢɣ ɞɨɦɟɧ RORs, ɫɨɞɟɪɠɚɳɢɣ 66 ɚɦɢɧɨɤɢɫɥɨɬ, ɜɵɫɨɤɨ ɤɨɧɫɟɪɜɚɬɢɜɟɧ, ɱɬɨ ɩɪɟɞɩɨɥɚɝɚɟɬ ɟɞɢɧɵɣ ɭɱɚɫɬɨɤ ɫɜɹɡɵɜɚɧɢɹ (ROR response element, RORE)

ɞɥɹ ɜɫɟɯ ɬɪɟɯ ɪɟɰɟɩɬɨɪɨɜ. ɂɡ ɧɢɯ RORĮ ɲɢɪɨɤɨ ɷɤɫɩɪɟɫɫɢɪɨɜɚɧ ɜ ɪɚɡɥɢɱɧɵɯ ɬɤɚɧɹɯ: ɫɤɟɥɟɬɧɵɯ ɦɵɲɰɚɯ, ɹɢɱɤɚɯ, ɤɥɟɬɤɚɯ ɉɭɪɤɢɧɶɟ ɜ ɦɨɡɠɟɱɤɟ, ɫɟɬɱɚɬɤɟ, ɚ ɬɚɤɠɟ ɜ ɫɟɥɟɡɟɧɤɟ. RORĮ ɬɚɤɠɟ ɢɝɪɚɟɬ ɜɚɠɧɭɸ ɪɨɥɶ ɜ ɪɚɡɜɢɬɢɢ ɥɢɦɮɨɰɢɬɨɜ. Ɍɚɤ, ɭ RORĮ-ɞɟɮɢɰɢɬɧɵɯ ɦɵɲɟɣ ɫɟɥɟɡɟɧɤɚ ɢ ɬɢɦɭɫ ɦɟɧɶɲɟ, ɱɟɦ ɜ ɤɨɧɬɪɨɥɟ [30]. ɉɪɟɞɩɨɥɚɝɚɟɬɫɹ, ɱɬɨ RORĮ ɜɥɢɹɟɬ ɧɚ ɷɤɫɩɪɟɫɫɢɸ IKBĮ, ɧɟɝɚɬɢɜɧɨɝɨ ɪɟɝɭɥɹɬɨɪɚ NFțB ɫɢɝɧɚɥɶɧɨɝɨ ɩɭɬɢ, ɨɝɪɚɧɢɱɢɜɚɹ ɬɚɤɢɦ ɨɛɪɚɡɨɦ ɭɪɨɜɟɧɶ ɜɨɫɩɚɥɢɬɟɥɶɧɨɣ ɪɟɚɤɰɢɢ ɢ ɚɞɚɩɬɢɜɧɨɝɨ ɢɦɦɭɧɧɨɝɨ ɨɬɜɟɬɚ. ɗɤɫɩɪɟɫɫɢɹ RORȕ ɨɝɪɚɧɢɱɟɧɚ ɡɨɧɚɦɢ ɐɇɋ, ɨɬɜɟɬɫɬɜɟɧɧɵɦɢ ɡɚ ɩɪɨɰɟɫɫɢɧɝ ɫɟɧɫɨɪɧɨɣ ɢɧɮɨɪɦɚɰɢɢ ɜ ɫɩɢɧɧɨɦ ɦɨɡɝɟ, ɬɚɥɚɦɭɫɟ ɢ ɫɟɧɫɨɪɧɨɣ ɤɨɪɟ. RORȖ ɲɢɪɨɤɨ ɷɤɫɩɪɟɫɫɢɪɨɜɚɧ ɜ ɬɢɦɭɫɟ, ɦɵɲɰɚɯ, ɦɨɡɝɟ, ɫɟɪɞɰɟ, ɥɟɝɤɢɯ, ɩɨɱɤɚɯ. Ɉɞɧɚ ɢɡ ɢɡɨɮɨɪɦ, RORȖ2 (RORȖt), ɜɩɟɪɜɵɟ ɨɛɧɚɪɭɠɟɧɚ ɜ ɬɢɦɭɫɟ

ɢɧɨɫɢɬ ɧɚɡɜɚɧɢɟ TOR (thymus orphan receptor). Ɉɞɧɚɤɨ ɜ ɩɨɫɥɟɞɭɸɳɟɦ ɷɤɫɩɪɟɫɫɢɹ RORȖt ɨɛɧɚɪɭɠɟɧɚ ɢ ɜ ɩɟɪɢɮɟɪɢɱɟɫɤɢɯ ɨɪɝɚɧɚɯ ɢɦɦɭɧɧɨɣ ɫɢɫɬɟɦɵ – ɥɢɦɮɨɰɢɬɚɯ ɫɟɥɟɡɟɧɤɢ, ɥɢɦɮɚɬɢɱɟɫɤɢɯ ɭɡɥɨɜ, ɥɢɦɮɨɢɞɧɵɯ ɮɨɥɥɢɤɭɥɨɜ ɬɨɧɤɨɣ ɤɢɲɤɢ ɢ ɞɪ. ɉɪɟɞɩɨɥɨɠɢɬɟɥɶɧɨ, ɥɢɝɚɧɞɚɦɢ RORĮ

ɹɜɥɹɟɬɫɹ ɯɨɥɟɫɬɟɪɢɧ ɢ ɫɭɥɶɮɚɬ ɯɨɥɟɫɬɟɪɢɧɚ, ɚ ɥɢɝɚɧɞɚɦɢ RORȕ ɢ RORȖ – ɧɟɤɨɬɨɪɵɟ ɪɟɬɢɧɨɢɞɵ [31].

ɉɨɫɥɟɞɧɢɟ ɢɫɫɥɟɞɨɜɚɧɢɹ ɨɛɧɚɪɭɠɢɥɢ ɤɪɢɬɢɱɟɫɤɭɸ ɪɨɥɶ RORȖ/RORȖt ɜ ɪɟɝɭɥɹɰɢɢ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɢ Th17-ɤɥɟɬɨɤ [32,33]. Ivanov, Littman ɢ ɢɯ ɤɨɥɥɟɝɢ ɩɟɪɜɵɦɢ ɫɨɨɛɳɢɥɢ, ɱɬɨ RORȖt ɧɟɨɛɯɨɞɢɦ ɞɥɹ ɞɢɮɮɟɪɟɧɰɢɚɰɢɢ ɧɚɢɜɧɵɯ CD4+ T-ɤɥɟɬɨɤ ɜ ɤɥɟɬɤɢ Th17 [34]. ɗɬɨ ɛɵɥɨ ɩɨɞɬɜɟɪɠɞɟɧɨ ɨɬɤɪɵɬɢɹɦɢ ɧɟɫɤɨɥɶɤɢɯ ɞɪɭɝɢɯ ɥɚɛɨɪɚɬɨɪɢɣ [24,35]. ɍɫɬɚɧɨɜɥɟɧɨ, ɱɬɨ RORȖt ɢɧɞɭɰɢɪɭɟɬɫɹ ɜɨ ɜɪɟɦɹ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɢ ɚɧɬɢɝɟɧ-ɫɬɢɦɭɥɢɪɨɜɚɧɧɵɯ Ɍh ɜ ɧɚɩɪɚɜɥɟɧɢɢ Th17 ɜ ɨɬɜɟɬ ɧɚ IL-6 ɢ TGFȕ. Ʉɥɟɬɤɢ ɫ ɧɟɞɨɫɬɚɬɤɨɦ IL-6 ɧɟ ɷɤɫɩɪɟɫɫɢɪɭɸɬ

RORȖt, ɧɟ ɫɢɧɬɟɡɢɪɭɸɬ IL-17F ɢ IL23R [24]. IL-6 ɨɩɨɫɪɟɞɭɟɬ ɫɜɨɟ ɞɟɣɫɬɜɢɟ ɫ ɩɨɦɨɳɶɸ ɚɤɬɢɜɚɰɢɢ STAT3. ɇɟɞɨɫɬɚɬɨɤ STAT3 ɫɢɥɶɧɨ ɧɚɪɭɲɚɟɬ ɚɤɬɢɜɚɰɢɸ ɷɤɫɩɪɟɫɫɢɢ RORȖt ɢ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɭ Th17, ɢɡ ɱɟɝɨ ɦɨɠɧɨ ɫɥɟɥɚɬɶ ɜɵɜɨɞ, ɱɬɨ ɷɬɚ ɢɧɞɭɤɰɢɹ STAT3-ɡɚɜɢɫɢɦɚɹ [36]. Ⱦɨɩɨɥɧɢɬɟɥɶɧɵɟ ɞɨɤɚɡɚɬɟɥɶɫɬɜɚ ɪɨɥɢ RORȖt ɜ ɪɚɡɜɢɬɢɢ Th17 ɛɚɡɢɪɭɸɬɫɹ ɧɚ ɢɫɫɥɟɞɨɜɚɧɢɹɯ, ɩɨɤɚɡɵɜɚɸɳɢɯ, ɱɬɨ Th, ɢɡɨɥɢɪɨɜɚɧɧɵɟ ɨɬ RORȖt-ɞɟɮɢɰɢɬɧɵɯ ɦɵɲɟɣ, ɯɚɪɚɤɬɟɪɢɡɭɸɬɫɹ ɡɚɦɟɬɧɵɦ ɭɦɟɧɶɲɟɧɢɟɦ ɫɩɨɫɨɛɧɨɫɬɢ ɤ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɟ ɜ ɧɚɩɪɚɜɥɟɧɢɢ Th17 [37]. Ʉɪɨɦɟ ɬɨɝɨ, RORȖt ɨɬɤɪɵɬ ɤɚɤ ɮɚɤɬɨɪ, ɪɟɝɭɥɢɪɭɸɳɢɣ ɷɤɫɩɪɟɫɫɢɸ ɝɟɧɨɜ ɜ ɬɟɱɟɧɢɟ ɪɚɡɜɢɬɢɹ Ɍ-ɤɥɟɬɨɤ ɬɢɦɭɫɚ [38]. ȼɵɫɨɤɢɣ ɭɪɨɜɟɧɶ ɷɤɫɩɪɟɫɫɢɢ ɨɛɧɚɪɭɠɢɜɚɟɬɫɹ ɜ ɞɭɛɥɶ-ɩɨɡɢɬɢɜɧɵɯ ɬɢɦɨɰɢɬɚɯ, ɷɤɫɩɪɟɫɫɢɹ ɫɧɢɠɚɟɬɫɹ ɧɚ ɷɬɚɩɟ ɩɨɡɢɬɢɜɧɨɣ ɫɟɥɟɤɰɢɢ, ɚ ɜ ɨɞɢɧɚɪɧɨ-ɩɨɡɢɬɢɜɧɵɯ ɬɢɦɨɰɢɬɚɯ ɢ ɡɪɟɥɵɯ Ɍ-ɤɥɟɬɤɚɯ RORȖ/RORȖt ɜɵɹɜɥɹɟɬɫɹ ɪɟɠɟ, ɡɚ ɢɫɤɥɸɱɟɧɢɟɦ ɩɨɩɭɥɹɰɢɢ Ɍ-ɯɟɥɩɟɪɨɜ 17 ɬɢɩɚ [39]. ɍɫɬɚɧɨɜɥɟɧɨ, ɱɬɨ ɭ ɦɵɲɟɣ ɫ ɞɟɮɟɤɬɨɦ RORȖ/RORȖt ɝɟɧɨɜ ɫɨɞɟɪɠɚɧɢɟ ɬɢɦɨɰɢɬɨɜ, ɢɡ-ɡɚ ɢɯ ɢɧɬɟɧɫɢɜɧɨɝɨ ɚɩɨɩɬɨɡɚ, ɫɧɢɠɚɟɬɫɹ ɩɨɱɬɢ ɧɚ 90% [40]. ȼ ɫɜɨɸ ɨɱɟɪɟɞɶ, ɠɢɜɨɬɧɵɟ ɫ ɝɢɩɟɪɷɤɫɩɪɟɫɫɢɟɣ RORȖt ɜ ɡɪɟɥɵɯ Ɍ-ɥɢɦɮɨɰɢɬɚɯ, ɪɚɜɧɨ ɤɚɤ ɢ RORȖ/RORȖt-ɷɤɫɩɪɟɫɫɢɪɭɸɳɢɟ ɤɥɟɬɤɢ Ɍ-ɝɢɛɪɢɞɨɦ, ɯɚɪɚɤɬɟɪɢɡɭɸɬɫɹ ɝɢɩɨɪɟɚɤɬɢɜɧɨɫɬɶɸ ɩɪɢ ɫɬɢɦɭɥɹɰɢɢ TCR, ɫɧɢɠɟɧɧɵɦ ɭɪɨɜɧɟɦ ɚɤɬɢɜɚɰɢɨɧɧɨ-ɢɧɞɭɰɢɪɨɜɚɧɧɨɝɨ ɚɩɨɩɬɨɡɚ [41]. Ɇɟɯɚɧɢɡɦɵ RORȖ/RORȖt-ɡɚɜɢɫɢɦɨɝɨ ɤɨɧɬɪɨɥɹ ɫɨɡɪɟɜɚɧɢɹ ɬɢɦɨɰɢɬɨɜ ɨɤɨɧɱɚɬɟɥɶɧɨ ɧɟ ɹɫɧɵ, ɨɞɧɚɤɨ ɭɫɬɚɧɨɜɥɟɧɨ, ɱɬɨ RORȖt ɪɟɝɭɥɢɪɭɟɬ ɷɤɫɩɪɟɫɫɢɸ ɚɧɬɢɚɩɨɩɬɨɬɢɱɟɫɤɨɝɨ ɛɟɥɤɚ Bcl-XL, ɚ ɭ RORȖt-ɞɟɮɢɰɢɬɧɵɯ ɦɵɲɟɣ ɧɚɛɥɸɞɚɟɬɫɹ ɭɫɢɥɟɧɧɵɣ ɚɩɨɩɬɨɡ ɬɢɦɨɰɢɬɨɜ ɢɡ-ɡɚ ɭɦɟɧɶɲɟɧɢɹ ɷɤɫɩɪɟɫɫɢɢ Bcl-XL [41]. ɋɭɳɟɫɬɜɟɧɧɨ, ɱɬɨ ɩɨɦɢɦɨ ɪɟɡɤɨɝɨ ɭɫɢɥɟɧɢɹ ɚɩɨɩɬɨɡɚ ɬɢɦɨɰɢɬɨɜ ɭ RORȖ/RORȖt-/- ɦɵɲɟɣ ɧɚɛɥɸɞɚɟɬɫɹ ɜɵɫɨɤɚɹ ɱɚɫɬɨɬɚ Ɍ- ɤɥɟɬɨɱɧɵɯ ɥɢɦɮɨɦ, ɱɬɨ ɫɜɹɡɚɧɨ ɫ ɩɨɹɜɥɟɧɢɟɦ Ɍ-ɥɢɦɮɨɰɢɬɨɜ, ɢɦɟɸɳɢɯ ɞɟɮɟɤɬɵ ɤɨɧɬɪɨɥɹ ɤɥɟɬɨɱɧɨɝɨ ɰɢɤɥɚ ɢ ɜɵɫɨɤɨɱɭɜɫɬɜɢɬɟɥɶɧɵɯ ɤ ɨɧɤɨɝɟɧɧɵɦ ɜɢɪɭɫɚɦ [42].

RORȖ/RORȖt ɹɜɥɹɟɬɫɹ ɤɪɢɬɢɱɧɵɦ ɬɪɚɧɫɤɪɢɩɰɢɨɧɧɵɦ ɮɚɤɬɨɪɨɦ ɢ ɞɥɹ ɪɚɡɜɢɬɢɹ ɜɬɨɪɢɱɧɵɯ ɥɢɦɮɨɢɞɧɵɯ ɨɪɝɚ-

ɧɨɜ. Ɍɚɤ, LTi-ɤɥɟɬɤɢ (Lymphoid tissue inducer cells) ɢɝɪɚɸɬ ɜɚɠɧɭɸ ɪɨɥɶ ɜ ɪɚɡɜɢɬɢɢ ɩɟɪɢɮɟɪɢɱɟɫɤɢɯ ɥɢɦɮɨɢɞɧɵɯ ɨɪɝɚɧɨɜ – ɫɟɥɟɡɟɧɤɢ, ɥɢɦɮɚɬɢɱɟɫɤɢɯ ɭɡɥɨɜ, ɥɢɦɮɨɢɞɧɵɯ ɛɥɹɲɟɤ ɤɢɲɟɱɧɢɤɚ. ɇɟɞɚɜɧɢɟ ɢɫɫɥɟɞɨɜɚɧɢɹ ɩɨɤɚɡɚɥɢ, ɱɬɨ LTi-ɤɥɟɬɤɢ ɨɬɫɭɬɫɬɜɭɸɬ ɜ ɫɟɥɟɡɟɧɤɟ, ȻɅɍ ɢ ɤɢɲɟɱɧɢɤɟ ɭ RORȖ-/- ɷɦɛɪɢɨɧɨɜ, ɱɬɨ ɫɜɢɞɟɬɟɥɶɫɬɜɭɟɬ ɨ ɤɪɢɬɢɱɟɫɤɨɣ ɪɨɥɢ RORȖt ɜ ɝɟɧɟɪɚɰɢɢ ɢ ɜɵɠɢɜɚɧɢɢ LTi-ɤɥɟɬɨɤ [43]. ɍ ɦɵɲɟɣ, ɞɟɮɢɰɢɬɧɵɯ ɩɨ RORȖt, ɤɨɥɢɱɟɫɬɜɨ Th17-ɤɥɟɬɨɤ ɜ ɥɢɦɮɨɢɞɧɵɯ ɛɥɹɲɤɚɯ ɤɢɲɟɱɧɢɤɚ ɛɵɥɨ ɫɧɢɠɟɧɨ ɜ 10 ɪɚɡ

ɩɨ ɫɪɚɜɧɟɧɢɸ ɫ ɦɵɲɚɦɢ ɞɢɤɨɝɨ ɬɢɩɚ. Ɏɨɪɫɢɪɨɜɚɧɧɚɹ ɷɤɫɩɪɟɫɫɢɹ RORȖt ɜ ɧɚɢɜɧɵɯ Ɍ-ɤɥɟɬɤɚɯ ɩɪɢɜɨɞɢɥɚ ɤ ɩɪɨɞɭɤɰɢɢ ɢɦɢ IL-17, IL-17F ɢ IL-22 [43].

ɉɪɨɜɟɞɟɧɨ ɢɦɦɭɧɨɮɥɸɨɪɟɫɰɟɧɬɧɨɟ ɜɵɹɜɥɟɧɢɟ ɷɤɫɩɪɟɫɫɢɢ RORȖt ɜ ɤɥɟɬɤɚɯ ɛɟɥɨɣ ɩɭɥɶɩɵ ɫɟɥɟɡɟɧɤɢ ɭ ɤɪɵɫ ɫ ɷɤɫɩɟɪɢɦɟɧɬɚɥɶɧɵɦ ɫɬɪɟɩɬɨɡɨɬɨɰɢɧɨɜɵɦ ɞɢɚɛɟɬɨɦ (ɗɋȾ). ɋɪɟɞɢ ɢɞɟɧɬɢɮɢɰɢɪɨɜɚɧɧɵɯ RORȖt-ɢɦɦɭɧɨɩɨɡɢɬɢɜɧɵɯ ɤɥɟɬɨɤ ɞɥɹ ɩɨɫɥɟɞɭɸɳɟɝɨ ɚɧɚɥɢɡɚ ɨɬɛɢɪɚɥɢ ɬɨɥɶɤɨ ɤɥɟɬɤɢ ɫ ɜɵɫɨɤɨɣ ɤɨɧɰɟɧɬɪɚɰɢɟɣ RORȖt (ɛɨɥɶɲɟ 0,3 ɟɞɢɧɢɰ ɢɧɬɟɧɫɢɜɧɨɫɬɢ ɮɥɸɨɪɟɫɰɟɧɰɢɢ – ȿɂɎ). ɍɫɬɚɧɨɜɥɟɧɨ, ɱɬɨ ɪɚɡɜɢɬɢɟ ɗɋȾ ɞɥɢɬɟɥɶɧɨɫɬɶɸ 28 ɢ 38 ɞɧɟɣ ɫɨɩɪɨɜɨɠɞɚɟɬɫɹ ɞɨɫɬɨɜɟɪɧɵɦ ɭɜɟɥɢɱɟɧɢɟɦ ɩɥɨɬɧɨɫɬɢ ɩɨɩɭɥɹɰɢɢ RORȖt+- ɤɥɟɬɨɤ ɜ ɥɢɦɮɨɢɞɧɵɯ ɮɨɥɥɢɤɭɥɚɯ (ɜ 6,5–11,2 ɪɚɡɚ, ɪ<0,05), ɦɚɪɝɢɧɚɥɶɧɨɣ ɡɨɧɟ (ɜ 2–2,4 ɪɚɡɚ, ɪ<0,05) ɢ ɩɟɪɢɚɪɬɟɪɢɚɥɶɧɵɯ ɥɢɦɮɨɢɞɧɵɯ ɦɭɮɬɚɯ (ɉȺɅɆ) ɫɟɥɟɡɟɧɤɢ (ɜ 3,3–3,6 ɪɚɡɚ, ɪ<0,05) ɩɨ ɫɪɚɜɧɟɧɢɸ ɫ ɤɨɧɬɪɨɥɟɦ. Ƚɢɩɨɤɫɢɱɟɫɤɢɟ ɬɪɟɧɢɪɨɜɤɢ (10 ɧɚ ɜɵɫɨɬɟ 6 ɤɦ) ɞɢɚɛɟɬɢɱɟɫɤɢɯ ɤɪɵɫ ɧɟ ɜɥɢɹɸɬ ɧɚ ɤɨɥɢɱɟɫɬɜɨ RORȖt+-ɤɥɟɬɨɤ ɜ ɥɢɦɮɨɢɞɧɵɯ ɮɨɥɥɢɤɭɥɚɯ ɢ ɩɪɢɜɨɞɹɬ ɤ ɞɨɫɬɨɜɟɪɧɨɦɭ ɫɧɢɠɟɧɢɸ ɢɯ ɩɥɨɬɧɨɫɬɢ ɜ ɦɚɪɝɢɧɚɥɶɧɨɣ ɡɨɧɟ (ɧɚ 28%, ɪ<0,05) ɢ ɉȺɅɆ (ɧɚ 25%, ɪ<0,05). Ⱦɚɧɧɵɟ ɢɡɦɟɧɟɧɢɹ ɧɟ ɬɨɥɶɤɨ ɫɨɯɪɚɧɹɸɬɫɹ, ɧɨ ɢ ɭɜɟɥɢɱɢɜɚɸɬɫɹ ɩɨ ɢɫɬɟɱɟɧɢɸ 10-ɞɧɟɜɧɨɝɨ ɩɨɫɬɝɢɩɨɤɫɢɱɟɫɤɨɝɨ ɩɟɪɢɨɞɚ.

Ⱥɭɬɨɢɦɦɭɧɧɵɟ ɡɚɛɨɥɟɜɚɧɢɹ ɢ Th17-ɤɥɟɬɤɢ. Ɋɨɥɶ Th17 ɜ ɩɚɬɨɝɟɧɟɡɟ ɫɚɯɚɪɧɨɝɨ ɞɢɚɛɟɬɚ 1 ɬɢɩɚ

ɇɚɤɨɩɥɟɧɨ ɛɨɥɶɲɨɟ ɱɢɫɥɨ ɞɚɧɧɵɯ, ɫɜɢɞɟɬɟɥɶɫɬɜɭɸɳɢɯ, ɱɬɨ ɤɥɟɬɤɢ Th17 ɩɪɢɱɚɫɬɧɵ ɤ ɪɚɡɜɢɬɢɸ ɪɚɡɥɢɱɧɵɯ ɚɭɬɨɢɦɦɭɧɧɵɯ ɡɚɛɨɥɟɜɚɧɢɣ ɱɟɥɨɜɟɤɚ, ɬɚɤɢɯ ɤɚɤ ɫɢɫɬɟɦɧɚɹ ɤɪɚɫɧɚɹ ɜɨɥɱɚɧɤɚ, ɪɟɜɦɚɬɨɢɞɧɵɣ ɚɪɬɪɢɬ, ɚɬɨɩɢɱɟɫɤɢɣ ɞɟɪɦɚɬɢɬ, ɪɚɫɫɟɹɧɧɵɣ ɫɤɥɟɪɨɡ, ɩɫɨɪɢɚɡ, ɚɫɬɦɚ ɢ ɫɚɯɚɪɧɵɣ ɞɢɚɛɟɬ 1 ɬɢɩɚ [9,44]. IL-17 ɢɧɞɭɰɢɪɭɟɬ ɫɟɤɪɟɰɢɸ ɰɟɥɨɝɨ ɪɹɞɚ ɰɢɬɨɤɢɧɨɜ, ɯɟɦɨɤɢɧɨɜ, ɦɟɬɚɥɥɨɩɪɨɬɟɢɧɚɡ ɢ ɞɪɭɝɢɯ ɩɪɨɜɨɫɩɚɥɢɬɟɥɶɧɵɯ ɦɟɞɢɚɬɨɪɨɜ ɢ ɫɩɨɫɨɛɫɬɜɭɟɬ ɩɪɢɜɥɟɱɟɧɢɸ ɧɟɣɬɪɨɮɢɥɨɜ ɤ ɨɪɝɚɧɭ-ɦɢɲɟɧɢ. Ɇɵɲɢ ɫ ɨɬɫɭɬɫɬɜɢɟɦ ɩɪɨɞɭɤɰɢɢ IL-17 ɧɟɜɨɫɩɪɢɢɦɱɢɜɵ ɤ ɤɨɥɥɚɝɟɧ-ɢɧɞɭɰɢɪɨɜɚɧɨɦɭ ɚɪɬɪɢɬɭ (CIA) ɢ ɷɤɫɩɟɪɢɦɟɧɬɚɥɶɧɨɦɭ ɚɭɬɨɢɦɦɭɧɧɨɦɭ ɷɧɰɟɮɚɥɨɦɢɟɥɢɬɭ (EAE), ɦɨɞɟɥɢ ɪɚɫɫɟɹɧɧɨɝɨ ɫɤɥɟɪɨɡɚ. ɇɟɣɬɪɚɥɢɡɚɰɢɹ IL-17 ɚɧɬɢɬɟɥɚɦɢ ɩɨɞɚɜɥɹɟɬ ɚɭɬɨɢɦɦɭɧɧɨɟ ɜɨɫɩɚɥɟɧɢɟ ɐɇɋ [44]. ɉɟɪɟɧɨɫ Th17-ɤɥɟɬɨɤ, ɧɚɩɪɨɬɢɜ, ɭɫɭɝɭɛɥɹɟɬ ɬɟɱɟɧɢɟ ɡɚɛɨɥɟɜɚɧɢɹ. ɇɟɞɚɜɧɢɟ ɢɫɫɥɟɞɨɜɚɧɢɹ ɫ ɢɫɩɨɥɶɡɨɜɚɧɢɟɦ ɷɤɫɩɟɪɢɦɟɧɬɚɥɶɧɨɣ ɦɨɞɟɥɢ ɤɨɥɢɬɚ ɩɨɤɚɡɚɥɢ, ɱɬɨ ɩɟɪɟɧɨɫ Ɍ-ɤɥɟɬɨɤ ɫ ɨɬɫɭɬɫɬɜɢɟɦ RORȖt ɧɟ ɭɜɟɥɢɱɢɜɚɥ ɭɪɨɜɟɧɶ ɫɢɧɬɟɡɚ IL-17

ɭɦɵɲɟɣ ɢ ɧɟ ɢɧɞɭɰɢɪɨɜɚɥ ɤɨɥɢɬ, ɬɨɝɞɚ ɤɚɤ ɜɨɡɞɟɣɫɬɜɢɟ IL17A ɜɨɫɫɬɚɧɨɜɢɥɨ ɤɥɢɧɢɤɭ ɤɨɥɢɬɚ [45]. ɗɬɢ ɢɫɫɥɟɞɨɜɚɧɢɹ ɩɨɤɚɡɵɜɚɸɬ, ɱɬɨ ɩɨɬɟɪɹ ɮɭɧɤɰɢɢ RORȖt ɫɢɥɶɧɨ ɭɦɟɧɶɲɚɟɬ ɜɨɫɩɪɢɢɦɱɢɜɨɫɬɶ ɤ ɪɚɡɜɢɬɢɸ ɚɭɬɨɢɦɦɭɧɧɨɝɨ ɡɚɛɨɥɟɜɚɧɢɹ

ɭɦɵɲɟɣ ɢ ɩɨɡɜɨɥɹɸɬ ɩɪɟɞɩɨɥɨɠɢɬɶ, ɱɬɨ, ɤɨɧɬɪɨɥɢɪɭɹ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɭ Th17 ɢ ɷɤɫɩɪɟɫɫɢɸ IL-17, RORȖt ɢɝɪɚɟɬ ɤɪɢɬɢɱɟɫɤɭɸ ɪɨɥɶ ɜ ɪɟɝɭɥɹɰɢɢ ɜɨɫɩɚɥɢɬɟɥɶɧɵɯ ɢ ɚɭɬɨɢɦɦɭɧɧɵɯ ɩɪɨɰɟɫɫɨɜ. ɋɥɟɞɨɜɚɬɟɥɶɧɨ, RORȖt ɦɨɠɟɬ ɹɜɥɹɬɶɫɹ ɩɨɬɟɧɰɢɚɥɶɧɨɣ ɮɚɪɦɚɤɨɥɨɝɢɱɟɫɤɨɣ ɦɢɲɟɧɶɸ ɞɥɹ ɥɟɱɟɧɢɹ ɚɭɬɨɢɦɦɭɧɧɵɯ ɡɚɛɨɥɟɜɚɧɢɣ.

J. Emamaullee ɢ ɤɨɥɟɝɢ (2009) ɨɛɧɚɪɭɠɢɥɢ ɜɵɫɨɤɢɟ ɭɪɨɜɧɢ ɂɅ-17 ɜ ɫɵɜɨɪɨɬɤɟ ɤɪɨɜɢ ɭ NOD-ɦɵɲɟɣ, ɹɜɥɹɸɳɢɯɫɹ ɦɨɞɟɥɶɸ ɋȾ 1 ɬɢɩɚ [46]. ɉɪɢ ɷɬɨɦ ɜɜɟɞɟɧɢɟ ɧɟɣɬɪɚɥɢɡɭɸɳɢɯ ɚɧɬɢ-ɂɅ-17 ɚɧɬɢɬɟɥ ɩɪɟɞɨɬɜɪɚɳɚɥɨ ɭ ɧɢɯ ɪɚɡɜɢɬɢɟ

ɞɢɚɛɟɬɚ, ɪɟɡɤɨ ɫɧɢɠɚɹ ɭɪɨɜɟɧɶ ɥɢɦɮɨɢɞɧɨɣ ɢɧɮɢɥɶɬɪɚɰɢɢ ɩɚɧɤɪɟɚɬɢɱɟɫɤɢɯ ɨɫɬɪɨɜɤɨɜ – ɢɧɫɭɥɢɬ. ɂɧɬɟɪɟɫɧɨ, ɱɬɨ ɩɪɢ ɷɬɨɦ ɭɜɟɥɢɱɢɜɚɥɫɹ ɭɪɨɜɟɧɶ ɢɧɮɢɥɶɬɪɚɰɢɢ ɨɫɬɪɨɜɤɨɜ CD4+/ CD25+/Foxp3+ Treg-ɤɥɟɬɤɚɦɢ, ɨɤɚɡɵɜɚɸɳɢɦɢ ɜɵɪɚɠɟɧɧɨɟ ɫɭɩɪɟɫɫɨɪɧɨɟ ɞɟɣɫɬɜɢɟ ɧɚ ɩɪɨɝɪɟɫɫɢɸ ɞɢɚɛɟɬɚ, ɢ ɫɧɢɠɚɥɨɫɶ ɤɨɥɢɱɟɫɬɜɨ CD4+ ɢ CD8+ Ɍ-ɤɥɟɬɨɤ. Ɍɚɤɢɦ ɨɛɪɚɡɨɦ, ɢɧɝɢɛɢɪɨɜɚɧɢɟ Th17-ɤɥɟɬɨɤ ɜɥɢɹɟɬ ɧɚ ɛɚɥɚɧɫ Th17/Treg, ɭɜɟɥɢɱɢɜɚɹ ɢ ɪɚɫɲɢɪɹɹ ɩɨɩɭɥɹɰɢɸ Treg-ɤɥɟɬɨɤ ɢ ɩɪɨɬɢɜɨɞɟɣɫɬɜɭɹ ɪɚɡɜɢɬɢɸ ɚɭɬɨɢɦɦɭɧɧɨɝɨ ɩɪɨɰɟɫɫɚ ɜ ɷɬɨɣ ɦɨɞɟɥɢ. Ʉɪɨɦɟ ɬɨɝɨ, ɩɪɢɦɟɧɟɧɢɟ ɚɧɬɢ-ɂɥ-17-ɚɧɬɢɬɟɥ ɩɪɟɞɨɬɜɪɚɳɚɟɬ ɨɛɪɚɡɨɜɚɧɢɟ ɚɭɬɨɚɧɬɢɬɟɥ ɤ ɨɞɧɨɦɭ ɢɡ ɨɫɬɪɨɜɤɨɜɵɯ ɚɧɬɢɝɟɧɨɜ – ɝɥɭɬɚɦɚɬɞɟɤɚɪɛɨɤɫɢɥɚɡɟ GAD65 [46]. ɗɬɢ ɞɚɧɧɵɟ ɩɨɡɜɨɥɹɸɬ ɩɪɟɞɩɨɥɨɠɢɬɶ, ɱɬɨ Th17 ɤɥɟɬɤɢ ɭɱɚɫɬɜɭɸɬ ɜ ɩɪɨɝɪɟɫɫɢɪɨɜɚɧɢɢ ɋȾ 1 ɬɢɩɚ, ɚ ɢɧɝɢɛɢɪɨɜɚɧɢɟ ɢɯ ɮɭɧɤɰɢɣ ɦɨɠɟɬ ɩɪɟɞɨɬɜɪɚɬɢɬɶ ɨɛɪɚɡɨɜɚɧɢɟ ɚɭɬɨɚɧɬɢɬɟɥ ɤ ɩɚɧɤɪɟɚɬɢɱɟɫɤɢɦ ɚɧɬɢɝɟɧɚɦ.

ȼɚɠɧɭɸ ɪɨɥɶ ɜ ɩɚɬɨɝɟɧɟɡɟ ȺɂɁ ɢɝɪɚɟɬ ɧɟ ɬɨɥɶɤɨ ɂɅ-17, ɧɨ ɢ ɞɪɭɝɢɟ ɰɢɬɨɤɢɧɵ, ɩɪɨɞɭɰɢɪɭɟɦɵɟ Th17 ɤɥɟɬɤɚɦɢ, ɜ

ɱɚɫɬɧɨɫɬɢ, IL-21 ɢ IL-22. Ɍɚɤ, R. Spolski et al. [47] ɭɫɬɚɧɨ-

ɜɢɥɢ ɧɟɨɛɯɨɞɢɦɨɫɬɶ IL-21 ɞɥɹ ɢɧɢɰɢɚɰɢɢ ɦɨɥɟɤɭɥɹɪɧɵɯ ɢɡɦɟɧɟɧɢɣ, ɤɨɬɨɪɵɟ ɜɵɡɵɜɚɸɬ ɤɥɟɬɨɱɧɭɸ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɭ Th17. ȼ ɫɜɨɸ ɨɱɟɪɟɞɶ, ɫɢɝɧɚɥɢɡɚɰɢɹ, ɨɫɭɳɟɫɬɜɥɹɟɦɚɹ ɱɟɪɟɡ IL-21, ɹɜɥɹɟɬɫɹ ɤɪɢɬɢɱɟɫɤɨɣ ɞɥɹ ɪɚɡɜɢɬɢɹ ɞɢɚɛɟɬɚ ɢ ɮɨɪɦɢɪɨɜɚɧɢɹ ɢɧɫɭɥɢɬɚ ɭ ɦɵɲɟɣ NOD. ɂɧɬɟɪɟɫ ɤ IL-21 ɤɚɤ ɩɨɬɟɧɰɢɚɥɶɧɨɦɭ ɦɟɞɢɚɬɨɪɭ ɚɭɬɨɢɦɦɭɧɧɨɝɨ ɞɢɚɛɟɬɚ ɨɫɧɨɜɵɜɚɟɬɫɹ ɧɚ ɬɨɦ ɮɚɤɬɟ, ɱɬɨ ɝɟɧ IL21 ɧɚɯɨɞɢɬɫɹ ɜ ɩɪɟɞɟɥɚɯ ɥɨɤɭɫɚ Idd3, ɫ ɤɨɬɨɪɵɦ ɚɫɫɨɰɢɢɪɨɜɚɧɨ ɪɚɡɜɢɬɢɟ ɞɢɚɛɟɬɚ ɭ NOD-ɦɵɲɟɣ, ɧɚɩɨɦɢɧɚɸɳɟɟ ɩɨ ɬɟɱɟɧɢɸ ɋȾ 1 ɬɢɩɚ ɭ ɱɟɥɨɜɟɤɚ, ɢ ɭɪɨɜɧɢ IL-21 ɢ ɷɤɫɩɪɟɫɫɢɢ IL-21R ɛɵɥɢ ɩɨɜɵɲɟɧɵ ɭ ɷɬɢɯ ɷɤɫɩɟɪɢɦɟɧɬɚɥɶɧɵɯ ɠɢɜɨɬɧɵɯ [47]. ȼ ɱɚɫɬɧɨɫɬɢ, ɭ IL- 21R-ɧɨɤɚɭɬɧɵɯ ɦɵɲɟɣ NOD ɨɬɫɭɬɫɬɜɨɜɚɥɚ ɥɢɦɮɨɰɢɬɚɪɧɚɹ ɢɧɮɢɥɶɬɪɚɰɢɹ ɩɚɧɤɪɟɚɬɢɱɟɫɤɢɯ ɨɫɬɪɨɜɤɨɜ, ɢ ɬɨɥɶɤɨ ɭ 1 ɢɡ 20 ɠɢɜɨɬɧɵɯ ɧɚɛɥɸɞɚɥɚɫɶ ɝɢɩɟɪɝɥɢɤɟɦɢɹ ɩɨ ɫɪɚɜɧɟɧɢɸ ɫ ɩɨɜɵɲɟɧɧɨɣ ɝɥɸɤɨɡɨɣ ɭ 60% ɨɛɵɱɧɵɯ ɦɵɲɟɣ NOD. IL-21 ɷɤɫɩɪɟɫɫɢɪɭɟɬɫɹ ɬɚɤɠɟ ɧɚ Th2-ɤɥɟɬɤɚɯ, ɮɨɥɥɢɤɭɥɹɪɧɵɯ Ɍ-ɯɟɥɩɟɪɚɯ, NKT-ɤɥɟɬɤɚɯ ɢ ɩɪɨɹɜɥɹɟɬ ɫɜɨɟ ɞɟɣɫɬɜɢɟ ɧɚ ɩɪɨɥɢɮɟɪɚɰɢɸ, ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɭ ɢ ɷɮɮɟɤɬɨɪɧɵɟ ɮɭɧɤɰɢɢ Ɍ-, ȼ-, NK- ɢ ɞɟɧɞɪɢɬɧɵɯ ɤɥɟɬɨɤ ɢ ɫɩɨɫɨɛɫɬɜɭɟɬ ɭɱɚɫɬɢɸ Th17 ɜ ɨɪɝɚɧɨɫɩɟɰɢɮɢɱɟɫɤɢɯ ɚɭɬɨɢɦɦɭɧɧɵɯ ɡɚɛɨɥɟɜɚɧɢɹɯ, ɬɚɤɢɯ ɤɚɤ ɪɚɫɫɟɹɧɧɵɣ ɫɤɥɟɪɨɡ, ɪɟɜɦɚɬɨɢɞɧɵɣ ɚɪɬɪɢɬ, ɞɢɚɛɟɬ ɢ ɞɪɭɝɢɟ [48]. R. Nurieva et al. [49] ɩɨɤɚɡɚɥɢ, ɱɬɨ ɨɫɧɨɜɧɚɹ ɚɭɬɨɤɪɢɧɧɚɹ ɪɟɝɭɥɹɰɢɹ IL-21 ɫɜɹɡɚɧɚ ɫ ɭɜɟɥɢɱɟɧɢɟɦ ɱɢɫɥɚ ɩɪɨɜɨɫɩɚɥɢɬɟɥɶɧɵɯ Ɍ-ɤɥɟɬɨɤ.

ȿɳɟ ɨɞɢɧ ɰɢɬɨɤɢɧ Th17-ɤɥɟɬɨɤ, IL-22, ɚɤɬɢɜɢɪɭɟɬ ɩɪɨɞɭɤɰɢɸ ɚɧɬɢɦɢɤɪɨɛɧɵɯ ɩɟɩɬɢɞɨɜ ȕ-ɞɟɮɟɧɡɢɧɚ 2, ɤɚɬɟɥɢɰɢ-

ɞɢɧɚ, S100A9, S100A7 ɢ S100A8 [50] ɢ ɢɝɪɚɟɬ ɜɚɠɧɭɸ ɪɨɥɶ ɜ ɪɚɡɜɢɬɢɢ ɚɭɬɨɢɦɦɭɧɧɵɯ ɩɨɜɪɟɠɞɟɧɢɣ ɤɨɠɢ ɱɟɥɨɜɟɤɚ, ɜ ɱɚɫɬɧɨɫɬɢ ɩɫɨɪɢɚɡɚ. ɉɫɨɪɢɚɬɢɱɟɫɤɢɟ ɩɨɪɚɠɟɧɢɹ ɢɧɮɢɥɶɬɪɢɪɨɜɚɧɵ Th17, ɤɨɬɨɪɵɟ ɩɪɨɞɭɰɢɪɭɸɬ IL-17A ɢ IL-22. Ȼɨɥɟɟ ɬɨɝɨ, IL-17 ɢ IL-22 ɪɟɝɭɥɢɪɭɸɬ ɩɪɨɞɭɤɰɢɸ ɚɧɬɢɦɢɤɪɨɛɧɵɯ ɛɟɥɤɨɜ ɜ ɫɥɢɡɢɫɬɨɣ ɷɩɢɬɟɥɢɹ. IL-22 ɨɛɥɚɞɚɟɬ ɤɚɤ ɩɪɨ-, ɬɚɤ ɢ ɩɪɨɬɢɜɨɜɨɫɩɚɥɢɬɟɥɶɧɵɦɢ ɫɜɨɣɫɬɜɚɦɢ. ȼ ɬɟɱɟɧɢɟ ɜɨɫɩɚɥɢɬɟɥɶɧɨɝɨ ɩɪɨɰɟɫɫɚ IL-22 ɩɪɟɞɨɬɜɪɚɳɚɟɬ ɩɨɪɚɠɟɧɢɟ ɬɤɚɧɟɣ [50]. Ɍɚɤ, ɨɬɫɭɬɫɬɜɢɟ IL-22 ɩɪɢɜɨɞɢɬ ɤ ɨɫɬɪɨɦɭ ɝɟɩɚɬɢɬɭ, ɚ ɜɨɫɫɬɚɧɨɜɥɟɧɢɟ ɟɝɨ ɷɤɫɩɪɟɫɫɢɢ Th17-ɤɥɟɬɤɚɦɢ ɨɛɟɫɩɟɱɢɜɚɟɬ ɡɚɳɢɬɭ ɩɪɨɬɢɜ ɜɨɫɩɚɥɢɬɟɥɶɧɨɝɨ ɩɨɜɪɟɠɞɟɧɢɹ

ɩɟɱɟɧɢ. L.A. Zenewicz et al. [51] ɩɨɤɚɡɚɥɢ, ɱɬɨ ɭ ɦɵɲɢ IL-22

ɩɪɨɞɭɰɢɪɭɟɬɫɹ Th17-ɤɥɟɬɤɚɦɢ ɢ ɩɨɩɭɥɹɰɢɟɣ NK-ɤɥɟɬɨɤ, ɤɨɬɨɪɵɟ ɭɱɚɫɬɜɭɸɬ ɜ ɡɚɳɢɬɟ ɨɪɝɚɧɢɡɦɚ ɨɬ ɜɨɫɩɚɥɢɬɟɥɶɧɵɯ ɡɚɛɨɥɟɜɚɧɢɣ ɤɢɲɟɱɧɢɤɚ. IL-22, ɤɚɤ ɷɮɮɟɤɬɨɪɧɵɣ ɰɢɬɨɤɢɧ, ɩɪɨɞɭɰɢɪɭɟɦɵɣ Ɍ-ɤɥɟɬɤɚɦɢ, ɨɩɨɫɪɟɞɭɟɬ ɜɡɚɢɦɨɞɟɣɫɬɜɢɟ (crosstalk) ɦɟɠɞɭ ɢɦɦɭɧɧɨɣ ɫɢɫɬɟɦɨɣ ɢ ɷɩɢɬɟɥɢɚɥɶɧɵɦɢ ɤɥɟɬɤɚɦɢ [52]. IL-17 ɢ IL-22 ɜɧɨɫɹɬ ɫɜɨɣ ɜɤɥɚɞ ɜ ɡɚɳɢɬɭ ɱɟɥɨɜɟɤɚ ɨɬ ɦɢɤɨɛɚɤɬɟɪɢɚɥɶɧɨɣ ɢɧɮɟɤɰɢɢ [52].

ɍ ɞɟɬɟɣ ɫ ɋȾ 1 ɬɢɩɚ ɧɚɛɥɸɞɚɟɬɫɹ ɭɜɟɥɢɱɟɧɢɟ ɫɟɤɪɟɰɢɢ ɢ ɷɤɫɩɪɟɫɫɢɢ IL-17 ɢ IL22 Ɍ-ɥɢɦɮɨɰɢɬɚɦɢ ɩɟɪɢɮɟɪɢɱɟɫɤɨɣ ɤɪɨɜɢ [53], ɚ ɦɨɧɨɰɢɬɵ, ɜɵɞɟɥɟɧɧɵɟ ɨɬ ɩɚɰɢɟɧɬɨɜ ɫ ɋȾ 1 ɬɢɩɚ, ɫɩɨɧɬɚɧɧɨ ɫɟɤɪɟɬɢɪɭɸɬ ɩɪɨɜɨɫɩɚɥɢɬɟɥɶɧɵɟ ɰɢɬɨɤɢɧɵ IL-1ȕ ɢ IL-6, ɤɨɬɨɪɵɟ, ɤɚɤ ɢɡɜɟɫɬɧɨ, ɫɬɢɦɭɥɢɪɭɸɬ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɭ Th17-ɤɥɟɬɨɤ [54]. ɉɪɢ ɷɬɨɦ ɢɧɞɭɤɰɢɹ ɨɛɪɚɡɨɜɚɧɢɹ Th17-ɥɢɦɮɨɰɢɬɨɜ IL-17-ɫɟɤɪɟɬɢɪɭɸɳɢɦɢ ɦɨɧɨɰɢɬɚɦɢ ɨɬ ɩɚɰɢɟɧɬɨɜ ɫ ɋȾ 1 ɬɢɩɚ ɛɵɥɚ ɭɦɟɧɶɲɟɧɚ in vitro ɜ ɫɥɭɱɚɟ ɩɪɢɦɟɧɟɧɢɹ ɤɨɦɛɢɧɚɰɢɢ IL-6-ɛɥɨɤɢɪɭɸɳɢɯ ɚɧɬɢɬɟɥ ɢ ɚɧɬɚɝɨɧɢɫɬɚ IL-1R. ɗɬɢ ɞɚɧɧɵɟ ɩɪɟɞɩɨɥɚɝɚɸɬ, ɱɬɨ ɜɪɨɠɞɟɧɧɚɹ ɢɦɦɭɧɧɚɹ ɫɢɫɬɟɦɚ, ɝɞɟ ɨɞɧɢɦɢ ɢɡ ɨɫɧɨɜɧɵɯ ɷɮɮɟɤɬɨɪɧɵɯ ɤɥɟɬɨɤ ɹɜɥɹɸɬɫɹ ɦɨɧɨɰɢɬɵ ɢ ɦɚɤɪɨɮɚɝɢ, ɭɩɪɚɜɥɹɟɬ ɭɪɨɜɧɟɦ ɚɞɚɩɬɢɜɧɨɝɨ ɢɦɦɭɧɧɨɝɨ ɨɬɜɟɬɚ, ɭɜɟɥɢɱɢɜɚɹ ɷɤɫɩɚɧɫɢɸ Th17-ɤɥɟɬɨɤ [54].

ȼɚɠɧɨɟ ɡɧɚɱɟɧɢɟ ɜ ɪɚɡɜɢɬɢɢ ȺɂɁ ɢɝɪɚɟɬ ɫɨɨɬɧɨɲɟɧɢɟ ɦɟɠɞɭ ɱɢɫɥɨɦ Th17 ɢ Treg-ɤɥɟɬɨɤ. Ɍɚɤ, J. Van den Brandt et al. ɩɨɤɚɡɚɥɢ, ɱɬɨ ɫɩɨɧɬɚɧɧɨɟ ɪɚɡɜɢɬɢɟ ɞɢɚɛɟɬɚ 1 ɬɢɩɚ ɭ ɤɪɵɫ ɥɢɧɢɢ DP-BB (Diabetes-prone BioBreeding rats) ɨɛɭɫɥɨɜɥɟɧɨ ɧɚɪɭɲɟɧɢɟɦ ɛɚɥɚɧɫɚ ɦɟɠɞɭ ɫɭɛɩɨɩɭɥɹɰɢɹɦɢ Th17 ɢ Tregɤɥɟɬɨɤ [55]. Ʉɥɟɬɤɢ Treg ɢ Th17 ɜɡɚɢɦɧɨ ɪɟɝɭɥɢɪɭɸɬɫɹ ɩɪɢ ɭɱɚɫɬɢɢ ɧɟɫɤɨɥɶɤɢɯ ɩɨɥɨɠɢɬɟɥɶɧɵɯ ɢ ɨɬɪɢɰɚɬɟɥɶɧɵɯ ɪɟɝɭɥɹɬɨɪɧɵɯ ɫɟɬɟɣ [56]. Ɋɚɜɧɨɜɟɫɢɟ ɦɟɠɞɭ ɷɤɫɩɪɟɫɫɢɟɣ ɬɪɚɧɫɤɪɢɩɰɢɨɧɧɵɯ ɮɚɤɬɨɪɨɜ RORȖt ɢ FOXɪ3 ɢɝɪɚɟɬ ɤɪɢɬɢɱɟɫɤɭɸ ɪɨɥɶ ɜ ɨɩɪɟɞɟɥɟɧɢɢ, ɛɭɞɭɬ ɥɢ ɧɚɢɜɧɵɟ CD4+ Ɍh ɞɢɮɮɟɪɟɧɰɢɪɨɜɚɬɶɫɹ ɜ Treg ɢɥɢ ɜ Th17. ɂɧɞɭɤɰɢɹ ɢɥɢ ɷɤɡɨɝɟɧɧɚɹ ɷɤɫɩɪɟɫɫɢɹ FOXɪ3 ɩɨɞɚɜɥɹɟɬ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɭ Th17. Ɋɟɝɭɥɹɰɢɹ ɷɤɫɩɪɟɫɫɢɢ FOXɪ3, ɩɪɨɢɡɜɨɞɢɦɚɹ TGFȕ ɢ IL-6 ɢɝɪɚɟɬ ɤɪɢɬɢɱɟɫɤɭɸ ɪɨɥɶ ɜ ɜɵɛɨɪɟ ɧɚɩɪɚɜɥɟɧɢɹ Treg ɢɥɢ Th17 [57]. ȿɫɥɢ ɧɚɢɜɧɵɟ Ɍh ɩɨɞɜɟɪɝɚɸɬɫɹ ɫɨɜɦɟɫɬɧɨɦɭ ɞɟɣɫɬɜɢɸ IL-6 ɢ TGFȕ1, ɢɧɞɭɰɢɪɭɟɬɫɹ ɢɯ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɚ ɜ ɫɬɨɪɨɧɭ Th17, ɜɤɥɸɱɚɸɳɚɹ ɚɤɬɢɜɚɰɢɸ ɝɟɧɨɜ IL-21, RORĮ, RORȖt, IL-17, IL-17F, IL-22, ɢ IL23R. ȿɫɥɢ ɠɟ ɞɟɣɫɬɜɭɟɬ ɬɨɥɶɤɨ TGFȕ, ɢɧɞɭɰɢɪɭɟɬɫɹ ɬɪɚɧɫɤɪɢɩɰɢɨɧɧɵɣ ɮɚɤɬɨɪ FOXɪ3 ɢ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɚ ɜ ɫɬɨɪɨɧɭ Treg, ɩɪɢɱɟɦ FOXɪ3 ɫɢɥɶɧɨ ɢɧɝɢɛɢɪɭɟɬ ɨɛɪɚɡɨɜɚɧɢɟ Th17-ɤɥɟɬɨɤ. ɏɨɬɹ TGFȕ ɦɨɠɟɬ ɭɦɟɪɟɧɧɨ ɭɫɢɥɢɜɚɬɶ ɷɤɫɩɪɟɫɫɢɸ RORĮ ɢ RORȖt, ɷɤɫɩɪɟɫɫɢɸ FOXɪ3 ɨɧ ɢɧɞɭɰɢɪɭɟɬ ɧɚ ɧɚɦɧɨɝɨ ɛɨɥɟɟ ɜɵɫɨɤɢɯ ɭɪɨɜɧɹɯ, ɬɟɦ ɫɚɦɵɦ ɫɞɜɢɝɚɹ ɛɚɥɚɧɫ ROR/FOXɪ3 ɜ ɫɬɨɪɨɧɭ FOXɪ3 ɢ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɢ Treg [56,57]. Ⱦɨɛɚɜɥɟɧɢɟ IL-6 ɢɥɢ IL-21 ɢɧɝɢɛɢɪɭɟɬ ɢɧɞɭɤɰɢɸ FOXɪ3, ɜɵɡɜɚɧɧɭɸ TGFȕ ɢ ɚɤɬɢɜɢɪɭɟɬ ɷɤɫɩɪɟɫɫɢɸ RORĮ ɢ RORȖt, ɬɟɦ ɫɚɦɵɦ ɫɞɜɢɝɚɹ ɛɚɥɚɧɫ ROR/FOXɪ3 ɜ ɫɬɨɪɨɧɭ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɢ Th17. Ɋɹɞ ɞɪɭɝɢɯ ɰɢɬɨɤɢɧɨɜ ɢ ɬɪɚɧɫɤɪɢɩɰɢɨɧɧɵɯ ɮɚɤɬɨɪɨɜ ɬɚɤɠɟ ɜɥɢɹɸɬ ɧɚ ɛɚɥɚɧɫ ɦɟɠɞɭ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɨɣ ɜ ɫɬɨɪɨɧɭ Treg

ɢTh17. ȼ ɱɚɫɬɧɨɫɬɢ, IL-2 ɢɧɝɢɛɢɪɭɟɬ ɷɤɫɩɪɟɫɫɢɸ RORȖt

ɢɞɢɮɮɟɪɟɧɰɢɪɨɜɤɭ Th17 [34]. IL-10, ɤɪɨɦɟ ɢɧɝɢɛɢɪɨɜɚɧɢɹ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɢ Th1, ɬɚɤɠɟ ɩɨɞɚɜɥɹɟɬ ɨɛɪɚɡɨɜɚɧɢɟ Th17

ɢɷɤɫɩɪɟɫɫɢɸ RORȖt ɢ IL-17 [56]. ɂ ɧɚɨɛɨɪɨɬ, ɷɤɫɩɪɟɫɫɢɹ

RORȖt ɢ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɚ Th17 ɭɫɢɥɟɧɚ ɜ ɤɥɟɬɤɚɯ ɫɟɥɟɡɟɧɤɢ IL-10-/-ɞɟɮɢɰɢɬɧɵɯ ɠɢɜɨɬɧɵɯ. ɗɤɫɩɪɟɫɫɢɢ RORĮ, RORȖt ɢ IL-17 ɫɢɥɶɧɨ ɭɦɟɧɶɲɟɧɵ ɜ ɤɥɟɬɤɚɯ ɫ ɧɟɞɨɫɬɚɬɤɨɦ ɢɧɬɟɪɮɟɪɨɧɪɟɝɭɥɢɪɭɸɳɟɝɨ ɮɚɤɬɨɪɚ 4 (IRF4), ɬɨɝɞɚ ɤɚɤ ɷɤɫɩɪɟɫɫɢɹ FOXɪ3 ɭɜɟɥɢɱɟɧɚ, ɱɬɨ ɝɨɜɨɪɢɬ ɨ ɬɨɦ, ɱɬɨ IRF4 ɬɚɤɠɟ ɢɝɪɚɟɬ ɪɨɥɶ ɜ ɪɟɝɭɥɹɰɢɢ ɛɚɥɚɧɫɚ ɦɟɠɞɭ Th17 ɢ Treg [18]. Ɍɚɤɢɦ ɨɛɪɚɡɨɦ, ɛɚɥɚɧɫ ɦɟɠɞɭ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɨɣ Th17 ɢ Treg ɧɚɯɨɞɢɬɫɹ ɩɨɞ ɤɨɦɩɥɟɤɫɧɵɦ ɤɨɧɬɪɨɥɟɦ, ɜ ɤɨɬɨɪɨɦ ɩɪɢɧɢɦɚɸɬ ɭɱɚɫɬɢɟ ɦɧɨɠɟɫɬɧɨ ɬɪɚɧɫɤɪɢɩɰɢɨɧɧɵɯ ɮɚɤɬɨɪɨɜ [58].

ɉɨɦɢɦɨ ɜɡɚɢɦɨɞɟɣɫɬɜɢɹ Th17 ɢ Treg-ɤɥɟɬɨɤ, ɤɨɬɨɪɨɟ ɹɜɧɨ ɚɧɬɚɝɨɧɢɫɬɢɱɟɫɤɨɟ ɢ ɩɪɢɜɨɞɢɬ ɤ ɩɪɨɬɢɜɨɩɨɥɨɠɧɵɦ ɷɮɮɟɤɬɚɦ, ɡɚɫɥɭɠɢɜɚɟɬ ɜɧɢɦɚɧɢɟ ɜɡɚɢɦɨɞɟɣɫɬɜɢɟ Th17 ɢ Th1-ɥɢɦɮɨɰɢɬɨɜ, ɹɜɥɹɸɳɢɯɫɹ ɨɫɧɨɜɧɵɦɢ ɷɮɮɟɤɬɨɪɚɦɢ ɚɭɬɨɢɦɦɭɧɧɵɯ ɡɚɛɨɥɟɜɚɧɢɣ ɢ ɞɟɣɫɬɜɭɸɳɢɯ, ɤɚɡɚɥɨɫɶ ɛɵ, ɫɢɧɟɪɝɢɱɧɨ [59]. ɏɚɪɚɤɬɟɪɧɨ, ɱɬɨ Th17 ɢ Th1 ɤɥɟɬɤɢ – 2 ɫɭɛɩɨɩɭɥɹɰɢɢ ɧɚɢɛɨɥɟɟ ɩɪɨɞɢɚɛɟɬɨɝɟɧɧɵɯ ɤɥɟɬɨɤ. ɉɪɢ ɷɬɨɦ, ɟɫɥɢ ɩɪɟɨɛɥɚɞɚɸɬ Th17-ɤɥɟɬɤɢ, ɬɨ ɢɧɮɢɥɶɬɪɚɰɢɹ ɩɚɧɤɪɟɚɬɢɱɟɫɤɢɯ ɨɫɬɪɨɜɤɨɜ ɩɪɟɢɦɭɳɟɫɬɜɟɧɧɨ ɧɟɣɬɪɨɮɢɥɶɧɚɹ (ɚɫɫɨɰɢɢɪɨɜɚɧɧɵɟ ɯɟɦɨɤɢɧɵ CXCL1, CXCL2, CXCL5), ɚ ɟɫɥɢ Th1 ɤɥɟɬɤɢ – ɦɚɤɪɨɮɚɝɚɥɶɧɚɹ (ɚɫɫɨɰɢɢɪɨɜɚɧɧɵɟ ɯɟɦɨɤɢɧɵ CXCL9, 10, 11). ȿɫɬɶ ɦɧɟɧɢɟ, ɱɬɨ Th17 ɤɥɟɬɤɢ ɩɪɨɜɨɰɢɪɭɸɬ ɪɚɡɜɢɬɢɟ ɢɧɫɭɥɢɬɚ ɭ NOD ɦɵɲɟɣ ɬɨɥɶɤɨ ɩɨɫɥɟ ɤɨɧɜɟɪɫɢɢ ɜ ɩɪɨɞɭɰɢɪɭɸɳɢɟ IFNȖ Th1 ɤɥɟɬɤɢ [60]. ȼɦɟɫɬɟ ɫ ɬɟɦ, ɟɫɬɶ ɧɟɦɚɥɨ ɩɪɢɦɟɪɨɜ ɚɧɬɚɝɨɧɢɫɬɢɱɟɫɤɨɝɨ ɜɡɚɢɦɨɨɬɧɨɲɟɧɢɹ ɷɬɢɯ ɫɭɛɩɨɩɭɥɹɰɢɣ Ɍ-ɯɟɥɩɟɪɨɜ: ɩɪɨɞɭɤɰɢɹ IL-17 ɭɜɟɥɢɱɟɧɚ ɭ IFN-Ȗí/í-ɧɨɤɚɭɬɧɵɯ ɦɵɲɟɣ, ɚ ɩɪɨɞɭɤɰɢɹ IFNȖ ɜɨɡɪɚɫɬɚɟɬ, ɫɨɨɬɜɟɬɫɬɜɟɧɧɨ, ɭ IL-17í/í-ɧɨɤɚɭɬɧɵɯ ɦɵɲɟɣ. Ʉɪɨɦɟ ɬɨɝɨ, ɨɫɧɨɜɧɨɣ ɰɢɬɨɤɢɧ, ɧɚɩɪɚɜɥɹɸɳɢɣ ɞɢɮɮɟɪɟɧɰɢɪɨɜɤɭ Th1 (IL-12_ ɢɧɝɢɛɢɪɭɟɬ ɨɛɪɚɡɨɜɚɧɢɟ Th17 [59,60].

ȼɕȼɈȾɕ

Ɉɛɡɨɪ ɞɚɧɧɵɯ ɩɨɤɚɡɵɜɚɟɬ, ɱɬɨ Th17-ɤɥɟɬɤɢ ɫɭɳɟɫɬɜɟɧɧɨ ɨɬɥɢɱɚɸɬɫɹ ɩɨ ɝɟɧɨɬɢɩɭ, ɮɟɧɨɬɢɩɭ ɢ ɮɢɡɢɨɥɨɝɢɢ ɨɬ ɞɪɭɝɢɯ ɫɭɛɩɨɩɭɥɹɰɢɣ Th. Th17 ɢɦɟɸɬ ɨɪɢɝɢɧɚɥɶɧɵɟ ɪɟɰɟɩɬɨɪɵ, ɬɪɚɧɫɤɪɢɩɰɢɨɧɧɵɣ ɮɚɤɬɨɪ, ɧɚɛɨɪ ɩɪɨɞɭɰɢɪɭɟɦɵɯ ɰɢɬɨɤɢɧɨɜ. Th17 ɹɜɥɹɸɬɫɹ ɤɥɟɬɤɚɦɢ, ɭɱɚɫɬɜɭɸɳɢɦɢ ɜ ɜɨɫɩɚɥɢɬɟɥɶɧɵɯ ɢ ɚɭɬɨɢɦɦɭɧɧɵɯ ɩɪɨɰɟɫɫɚɯ, ɚ ɬɚɤɠɟ ɨɫɭɳɟɫɬɜɥɹɸɬ ɡɚɳɢɬɭ ɨɪɝɚɧɢɡɦɚ ɨɬ ɜɧɟɤɥɟɬɨɱɧɵɯ ɛɚɤɬɟɪɢɣ ɢ ɩɚɪɚɡɢɬɨɜ.

Ɉɬɤɪɵɬɢɟ Th17 ɩɪɨɢɡɨɲɥɨ ɫɨɜɫɟɦ ɧɟɞɚɜɧɨ, ɨɫɧɨɜɧɵɟ ɪɚɛɨɬɵ ɩɨɹɜɢɥɢɫɶ ɜ 2006–2008 ɝɝ., ɢ ɦɧɨɝɢɟ ɩɚɪɚɦɟɬɪɵ ɫɭɳɟɫɬɜɨɜɚɧɢɹ ɷɬɢɯ ɤɥɟɬɨɤ ɩɨɤɚ ɧɟ ɹɫɧɵ. Ɍɟɦ ɧɟ ɦɟɧɟɟ, ɭɠɟ ɫɟɣɱɚɫ ɦɨɠɧɨ ɫɤɚɡɚɬɶ, ɱɬɨ Th17 – ɨɞɧɢ ɢɡ ɨɫɧɨɜɧɵɯ ɷɮɮɟɤɬɨɪɨɜ ɪɚɡɜɢɬɢɹ ȺɂɁ, ɩɨɷɬɨɦɭ ɹɜɥɹɸɬɫɹ ɜɚɠɧɨɣ ɮɚɪɦɚɤɨɥɨɝɢɱɟɫɤɨɣ ɦɢɲɟɧɶɸ ɞɥɹ ɫɨɡɞɚɧɢɹ ɧɨɜɵɯ ɥɟɱɟɛɧɵɯ ɩɨɞɯɨɞɨɜ.

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