Mechanisms Regulating Th17 T Cells Implicated in the Pathogenesis of Autoimmune Conditions Like Arthritis

Jacob Moser

Introduction. Many chronic inflammatory diseases like asthma, rheumatoid arthritis, and many others owe their pathogenicity to ‘typical’ inflammatory cytokines like TNFa, and can be targeted clinically by widely used drugs like Adalimumab (Humira). But recently discovered types of asthma, rheumatoid arthritis, and others that did not respond adequately to normal TNFa targeted treatment, were shown to have abnormally high amounts of IL-17.1  Methods. In 14 new cases and 41 established RA patients compared to 22 healthy controls, the percentages of Th17, Th1 and dual Th17/Th1 cells were determined by flow-cytometry and their correlations were investigated with disease activity score (DAS28).1 Moreover, serum levels of IL-6 and IL-17 as inducer and functional cytokines for Th17 were investigated. Finally, serum levels of anti-citrullinated protein antibody (ACPA) and rheumatoid factor (RF) were assessed.4 Results. Once IL-17 pathogenicity has been proved, we look at the JAK-STAT pathway. Once the different cytokines (TGF-b, IL-23, IL-6, and IL-21) bind to the undifferentiated T helper cell, they activate the JAK – STAT pathway – specifically the STAT3 transcription factor. Rorc is then expressed and transcribes gene specific for Th17 differentiation.3 And the Simone study shows that STAT3 is primarily activated by IL-23, but can also be activated by IL-6 and IL-21.4 Ming-Hong Lin and other researchers showed that B lymphocyte-induced maturation protein 1 (BLIMP-1) has a role in differentiation of Th17 (and Th1) cells, and plays a crucial role in the induction and pathogenesis of EAE (experimental autoimmune encephalomyelitis).3 Discussion/Conclusion. IL-23 directly upregulates BLIMP-1 in a STAT3 dependent manner, which was essential for downregulating IL-2 (inducer of Treg cells through FOXP3) and maintaining the stability of the pathogenic TH17 cells. In the absence of BLIMP-1, Th17 cells did not produce IFNy and GM-CSF and did not promote EAE and other chronic inflammatory responses. But BLIMP-1 has been shown to be needed for CD8+ cell activation. Thus, there is a dangerous side effect if BLIMP-1 inactivation were to be used systematically.3 BLIMP-1 has not yet been used clinically, but researchers were able to regulate its levels, there could be great potential to prevent chronic inflammatory diseases specific for Th17 cells.

  1. Bazzazi H, Aghaei M, Memarian A, Asgarian-Omran H, Behnampour N, Yazdani Y. Th1-Th17 Ratio as a New Insight in Rheumatoid Arthritis Disease. Iranian journal of allergy, asthma, and immunology. https://www.ncbi.nlm.nih.gov/pubmed/29512371. Published February 2018. Accessed April 4, 2019.
  2. Castro G, Liu X, Ngo K, et al. RORγt and RORα signature genes in human Th17 cells. PloS one. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538713/. Published August 1, 2017. Accessed April 4, 2019.
  3. Lin M-H, Yeh L-T, Chen S-J, et al. T cell-specific BLIMP-1 deficiency exacerbates experimental autoimmune encephalomyelitis in nonobese diabetic mice by increasing Th1 and Th17 cells. Clinical immunology (Orlando, Fla.). https://www.ncbi.nlm.nih.gov/pubmed/24568746. Published April 2014. Accessed April 4, 2019.
  4. Simone VD, Franzè E, Ronchetti G, et al. Th17-type cytokines, IL-6 and TNF-α synergistically activate STAT3 and NF-kB to promote colorectal cancer cell growth. Nature News. https://www.nature.com/articles/onc2014286. Published September 1, 2014. Accessed April 4, 2019.