Glucocorticoid Resistance – Takayasu Arteritis
A study published in the Arthritis & Rheumatology journal is perhaps the first to demonstrate that T helper (Th)1 and Th17 cells and cytokine pathways may play central role in driving systemic inflammation in Takayasu arteritis.
The first case of Takayasu’s arteritis was described in 1908 by Dr. Mikito Takayasu at the Annual Meeting of the Japan Ophthalmology Society. Dr. Takayasu described a peculiar “wreathlike” appearance of blood vessels in the back of the eye (retina).
Takayasu arteritis (TA) is a rare type of vasculitis that affects mostly middle-aged women, with greater frequency in Asia, South America and the Mediterranean countries.
It is characterized by a granulomatous inflammation of the aorta and its major branches, and is associated with high cellular infiltrates including T helper and cytotoxic T cells, macrophages and neutrophils.
Takayasu arteritis (TAK), a large vessel vasculitis affecting aorta and its major branches, associates with considerable morbidity. Pathology is characterized by granulomatous vascular inflammation resulting in intimal hyperplasia, thickening of the media with inflammatory cell infiltrate and adventitial fibrosis. Vascular obstruction might result from either inflammatory wall thickening or fibrosis of the hitherto inflamed arterial wall. Less commonly, aneurysms develop in affected vessels.
Assessment of disease activity and evaluation of biomarkers is challenging due to difficulty in accessing affected vessels other than during vascular bypass surgeries, therefore, relies on surrogate biomarkers, peripheral blood populations and cytokines.
Glucocorticoids (GCs) are anchor drugs for this disease and few previous studies raised the possibility that Th1 and Th17 cells may be involved in the pathogenesis of Takayasu arteritis (Chikashi Terao et al., 2014).
However, the nature and type of T cells driving inflammation in TA and how GCs affect different components of cellular immunity in this condition remain largely unknown.
In the study published in the Arthritis & Rheumatology, David Saadoun and colleagues from the Pierre and Marie Curie University, Paris, France evaluated 41 patients under the American College of Rheumatology criteria for TA.
The authors report that Th1- and Th17-related cytokines are increased in TA patients and correlate with disease activity.
The immunohistochemical analysis of vascular infiltrates revealed the presence of IFN-γ, IL-6 and IL-17A producing cells. Of note, when serum from active TA patients was added to CD4+ T cells culture of healthy donors, an increased production of IL-17 and IFN-γ was observed.
Importantly, the study also showed that TA patients under GCs therapy had decreased circulating Th1-related cytokines such as TNF-α, IL-2 and IFN-γ.
However, the inhibitory effect of GCs spared Th17-related cytokines, corroborating previous studies that point out the glucocorticoid resistance of Th17 cells as a hallmark of the pathogenic, pro-inflammatory nature of these cells.
Thus, the Saadoun et al. study may also indicate that therapies aimed at Th17 cells should be considered for optimal control of Takayasu arteritis.
Source: Arthritis & Rheumatology, 2014. Accepted manuscript.doi: 10.1002/art.39037
Read more: Arthritis & Rheumatology
An Update
In a new study published in the Journal of Inflammation Research
This study identified higher circulating overall Th17 lymphocytes and novel Th17 lymphocyte populations viz. Th17.1 and PD1+Th17 lymphocytes in Takayasu arteritis when compared with healthy controls. PD1+CD4+ T lymphocytes were elevated in TAK when compared with disease control of sarcoidosis.
Cytokines secreted by adaptive [IFN-γ (by Th1 and Th17.1), IL-17A (by Th17), IL-10 (by Treg), when compared with healthy controls] and innate immune cells (IL-6, TNF-α and IL-1β, when compared with healthy controls or sarcoidosis) were elevated in Takayasu arteritis.
Th17 and Th17.1 lymphocyte populations associated with active Takayasu arteritis on univariable analyses. However, only Th17 lymphocytes remained associated with active Takayasu arteritis after multivariable-adjusted logistic regression analyses.
had greater cytokine secretion from PBMCs (IFN-γ, IL-17A, IL-10 versus HC; IL-6, TNF-α, IL-1β versus HC or sarcoidosis).
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Cover Image Credit: Johns Hopkins Vasculitis Center, https://www.hopkinsvasculitis.org/types-vasculitis/takayasus-arteritis/. A normal aortic arch on the left, with narrow, smooth blood vessels. On the right is an example of an abnormal aortic arch in a patient with Takayasu’s, with obvious dilation of the ascending aorta on the left side of the picture.
