T helper17 cells
Download as PPTX, PDF9 likes3,040 views
T helper 17 (Th17) cells, identified in 2007, produce interleukin 17 (IL-17) and are involved in autoimmune diseases and inflammation. The study compares Th17 cell characteristics in hyper IgE syndrome (HIES) and chronic granulomatous disease (CGD), revealing absent Th17 cells in HIES and elevated numbers in CGD, likely due to defective neutrophils. Bone marrow transplantation in CGD normalizes Th17 cell numbers and IL-17 production, highlighting the role of Th17 cells in fighting infections like candidiasis and staphylococcal infections.
T helper17 cells
- 1. T helper-17 cells Jafar Ali M.Phil 2nd QUAID-i-AZAM UNIVERSITY ISLAMABAD
- 2. Th 17 cells T helper 17 cells (Th17) are a subset of T helper cells producing interleukin 17 (IL-17) discovered in 2007. distinct from Th1 and Th2 cells defence play a role in inflammation and tissue injury autoimmune disease such as multiple sclerosis Rheumatoid arthritis
- 3. Subset of t cells
- 4. Th17 cell lineage development . RORγT STAT-3 Naive CD4 APC Th17 IL-17 IL-22 IL-21 IL23-APC IL-6 TGF-β Pre-Th17
- 6. Steps in the generation of Th17 cells. The activation of naive T cells in the presence of TGF-β and IL-6 initiates the Th17 differen The activation of naive T cells in the presence of TGF-β and IL-6 initiates the Th17 differentiation pathway. Th17 cells produce IL-21, which further amplifies Th17 generation in an autocrine manner. IL-21 also induces the IL-23R on differentiated Th17 cells to make them responsive to IL-23 signaling. IL-23 stabilizes the Th17 phenotype by secreting IL- 17A, IL-17F and IL-22 and helping Th17 cells to acquire effector functions. h further amplifies Th17 generati (Awasthi and Kuchroo, International Immunology, 2009)
- 7. Transcriptional regulation RORᴽt……….. necessary and sufficient to induce IL-17 expression ROR∞….. With RORᴽt promotes differntiation of Th 17 cells Runx1, to Il17 promoter and RORᴽt will give optimal IL- 17expression in CD4+ Interleukin regulatory factor 4 (IRF4)….. TH17 induction STAT3………… TH17 cell development and function is also critically dependent
- 8. Disturbances in the homeostasis of Th17 lymphocytes in patients with hyper IgE syndrome (HIES) and chronic granulomatous disease (CGD) Horvath R.1, Lastovicka J.1, Polouckova A.1, Sedlacek P.2, Bartunkova J.1, Sediva A.1, Spisek R.1 1Department of Immunology, Charles University, 2nd Medical School and Faculty Hospital Motol, Prague, Czech Republic
- 9. Th 17 cell functions Production of IL-17 cytokines family (IL-17, IL-21, IL-22) which leads to the chemoattraction of neutrophils Accumulating Th17 are highly pro - inflammatory and that Th17 cells with specificity for self-antigens lead to severe autoimmunity- (psoriasis, Crohn´s disease, multiple sclerosis)
- 10. Initially, from studies in mice, Th17 cells were thought to play an important role in host defense against extracellular pathogens, which are not efficiently cleared by Th1-type and Th2- type immunity However, identity of pathogens cleared by Th17 was unknown Direct evidence for understanding physiological target of Th17 cells came from studies of patients with mutations in STAT-3, a critical transcription factor for the differentiation of Th17 cells Physiological role of Th17 cells in humans
- 11. Defective Th17 cells in Hyper IgE syndrome Primary immunodeficiency caused by mutations in STAT-3 transcription factor, NEJM 2007 Dermatitis, boils, cyst-forming pneumonias, retained primary dentition, bone abnormalities and elevated serum IgE levels Abnormal and devastating susceptibility to a narrow spectrum of infections, most commonly Staphylococcus aureus and Candida albicans Abrogated numbers of Th17 cells, Nature 2008, JEM 2008 nonspecific stimulation
- 12. Studies in Hyper IgE point to a critical role of Th17 cells in the response against candidal and staphylococcal infections However, there are other diseases with similar spectrum of dominant pathogens where the characteristics of Th17 have not been tested We thus decided to test Th17 cells compartment in chronic granulomatous disease Defective Th17 cells in Hyper IgE syndrome
- 13. Clinical mimicry of HIES with other primary immunodeficiencies – Chronic granulomatous disease (CGD) Primary immunodeficiency Mutations in the NADPH oxidase system Profound defect of respiratory burst in myeloid cells Recurrent infections, organ granulomas Dominant susceptibility to staphylococcal and candidal infections
- 14. Aim of the study Analyze and compare the characteristics of Th17 compartment in HIES and CGD patients Patients and methods 4 patients from 3 families with HIES 7 patients with CGD (2 patients underwent allo-BMT) Mutations in STAT-3 and NADPH oxidase - genetics ELISA
- 15. 0 10 2 10 3 10 4 10 5 0 10 2 10 3 104 10 5 4.12 0.51 0 10 2 10 3 10 4 10 5 0 10 2 10 3 104 10 5 0.13 1.67 0 10 2 10 3 10 4 10 5 0 10 2 103 104 10 5 2.32 1.98 0 10 2 10 3 10 4 10 5 0 102 103 10 4 10 5 5.91 0.49 0 10 2 10 3 10 4 10 5 0 102 103 10 4 10 5 0.078 3.5 0 10 2 10 3 10 4 10 5 0 10 2 103 104 10 5 1.25 2.87 0 10 2 10 3 10 4 10 5 0 102 103 10 4 10 5 6.51 0.76 0 10 2 10 3 10 4 10 5 0 102 103 10 4 10 5 6.97 0.36 0 10 2 10 3 10 4 10 5 0 102 103 10 4 10 5 1.91 1.55 0 0,5 1 1,5 2 2,5 3 3,5 Controls HIES CGD %ofIL-17+CD4+cells 0 2 4 6 8 10 12 14 Controls HIES CGD%ofIFNgamma+CD4+cells IFNgamma-PE IL-17 A647 Controls HIES CGD A B Results – Th17 numbers in CGD and HIES p<0,05 p<0,05 p<0,05 p=0,39 p<0,05 p=0,05 • absent Th17 cells in HIES • high frequencies of Th17 in CGD
- 16. Results – cytokine production IL-17 0 200 400 600 800 1000 1200 pg/ml Controls HIES CGD A IL-21 0 500 1000 1500 2000 2500 pg/ml Controls HIES CGD p<0,05 p<0,05 p<0,05 p=0,06 p=0,29 p=0,14 IL-23 0 200 400 600 800 1000 1200 pg/ml Controls HIES CGD p<0,05 p<0,05 p<0,05 •low levels of IL-17 and IL-21 in HIES B •high levels of IL-17 and IL-21 in CGD •extremely elevated levels of IL-23 in HIES •elevated levels of IL-23 in CGD Th17 effector cytokines Polarization cytokine
- 17. 0 102 103 104 105 0 102 103 104 105 0.84 8.64 0 102 103 104 105 0 102 103 104 105 0.12 1.83 IFNgamma-PE IL-17 A647 A Correction of defect in Th17 cells in two CGD patients after successful BMT 0 ,5 1 1,5 2 2,5 3 %ofCD4pos.Tcells Th17 CGD HIES Controls 0 2 4 6 8 10 12 14 %ofCD4pos.Tcells IFN-g B p#1 p#2 pre-BMT pre-BMT CGD after BMT • normalized numbers of Th17 cells after BMT p=0,52 p=0,24 post-BMT post-BMT
- 18. Results – cytokine production after allo-BMT CGD HIES Controls 0 200 400 600 800 1000 1200 1400 pg/ml IL-17 0 250 500 750 1000 1250 1500 1750 2000 pg/ml IL-21 p=0,24 0 200 400 600 800 1000 pg/ml IL-23 A Th17 effector cytokines Polarization cytokine B pre-BMT pre-BMT pre-BMT CGD after BMT p=0,33 p=0,12 •decreased production of IL17,21 and 23 after BMT post-BMT post-BMT post-BMT
- 19. Possible theoretical explanations Healthy Th17APC IL-23 IL-17,22,21 etc Neutro Lympho Mono Eradication Candida S.aureus HIES Th17APC IL-23 IL-17,22,21 etc Candida S.aureus STAT3 mutation In-efficient immune cells attraction Pathogen persistence CGD Th17APC IL-23 IL-17,22,21 etc Neutro Lympho Mono In-efficient eradication Candida S.aureus NADPH mutation Pathogen persistence
- 20. Conclusions We identified disturbances in the homeostasis of Th17 lymphocytes in HIES and CGD patients Absent Th17 cells in STAT-3 deficient HIES patients Significantly higher frequencies of Th17 cells in CGD Increase of Th17 cells in CGD is likely to be secondary as a result of defect in neutrophils BMT leads to the normalization of elevated Th17 cell numbers and coresponding IL-17 production Positive pro-inflammatory loop caused by Th17 cells contributes to the formation of granulomas These findings confirm the critical role of Th17 lymphocytes in the elimination of candidal and staphylococcal infections