Novel Th17 Lymphocyte Populations, Th17.1 and PD1+Th17, are Increased in Takayasu Arteritis, and Both Th17 and Th17.1 Sub-Populations Associate with Active Disease

Abstract

Purpose We evaluated T helper lymphocyte profile, including novel Th17 subsets Th17.1 (secrete IFN-γ, associate with corticosteroid resistance) and PD1+Th17 (secrete TGF-β1, implicated in fibrosis), and related cytokines in peripheral blood of Takayasu arteritis (TAK). Materials and Methods We evaluated circulating Th1, Th2, Th17, Th17.1, PD1+CD4+ T lymphocytes, PD1+Th17, and Treg lymphocytes, inflammatory (IFN-γ, IL-4, IL-6, IL-17A, IL-23, IL-1β, TNF-α) and regulatory (IL-10, TGF-β1) cytokines in peripheral blood of TAK (n = 57; median age 35 (interquartile range 26–45) years; 40 females) in a cross-sectional design. We studied inflammatory and regulatory cytokines in culture supernatant of peripheral blood mononuclear cells (PBMCs) from TAK following stimulation with anti-CD3/anti-CD28 and their modulation by tacrolimus (immunosuppressive) with/without tadalafil (anti-fibrotic). Furthermore, we followed up immunosuppressive-naïve active TAK (n = 16) and compared T helper lymphocyte populations and cytokines before and after immunosuppressive therapy. Healthy controls (HC, n = 21) and sarcoidosis (disease control, n = 11) were compared against TAK. Results TAK had higher Th17, Th17.1 and PD1+Th17 lymphocytes than HC (p < 0.001), and higher PD1+CD4+ T lymphocytes than sarcoidosis (p < 0.001). Th17 lymphocytes associated with active TAK after multivariable-adjusted logistic regression (p = 0.008). TAK had greater cytokine secretion from PBMCs (IFN-γ, IL-17A, IL-10 versus HC; IL-6, TNF-α, IL-1β versus HC or sarcoidosis) (p < 0.05). In-vitro, PBMCs from TAK showed reduced secretion of all inflammatory cytokines with tacrolimus, with synergistic reduction in IL-17A, IL-6, IL-1β and IL-10 following addition of tadalafil to tacrolimus. Serial follow-up of immunosuppressive-naïve TAK (n = 16) showed reduction in serum IL-6 and TGF-β1 (p < 0.05) and IL-6 in culture supernatant (p < 0.05) following immunosuppressive therapy. Conclusion Novel Th17 sub-populations (Th17.1 and PD1+Th17) are elevated in TAK. Th17 lymphocytes associate with active TAK. In-vitro experiments on cultured PBMCs suggest promise for further evaluation of a combination of immunosuppressive tacrolimus with anti-fibrotic tadalafil (or other anti-fibrotic therapies) in clinical trials of TAK.

The Th17 Pathway in Vascular Inflammation: Culprit or Consort?

“…Recently, an increase in Th17.1 cells producing both IL-17 and IFNγ was observed in TAK patients compared with healthy controls. Similar results were described for PD1 + Th17 cells ( 72 ). Finally, IL-17A and Th17-related cytokines trigger neutrophil recruitment and activation that could contribute to vascular lesions ( 73 ).…”

Outcome Measures and Biomarkers for Disease Assessment in Takayasu Arteritis

“…A recent study comparing 30 patients with active TAK with 27 patients with inactive TAK reported increased Th17 and Th17.1 lymphocytes in active TAK on univariable analyses. However, Th17 lymphocytes (but not Th17.1 lymphocytes) remained associated with active TAK after adjustment for CRP and Th1, Th2, and T regulatory lymphocyte populations [ 109 ]. Another study analyzed gene expression on peripheral blood mononuclear cells in eleven patients with active TAK compared with nine with inactive TAK (disease activity assessed using the NIH criteria).…”

“…A further study compared serum cytokines in 29 TAK with active disease with 27 with inactive disease. The levels of inflammatory or regulatory cytokines were not significantly different between these two groups [ 109 ]. Another study compared various inflammatory and regulatory cytokines (including IL-6) between 15 TAK with the active disease and 17 with inactive disease.…”

Neuroinflammation: Extinguishing a blaze of T cells

“…Unveiling the contribution of Th17.1 cells to induce and sustain inflammatory responses has been a significant breakthrough to decipher autoimmune processes far beyond the neuroinflammation field. [63][64][65] 2.1.4 | Th5/ThGM-CSF: making space for newcomers…”

“…Although GM‐CSF production is not exclusive to the ex‐Th17 subset, the high activity and trafficking of these cells, as well as their co‐production of potent inflammatory cytokines make them key promoters of neuroinflammation. Unveiling the contribution of Th17.1 cells to induce and sustain inflammatory responses has been a significant breakthrough to decipher autoimmune processes far beyond the neuroinflammation field 63‐65 …”