The autoimmune aspect of cardiovascular disease and Th17/Treg imbalance

Cardiovascular disease, an inflammatory disorder, is a leading cause of death and the autoimmune component is one of the most important and in general practice, overlooked, aspects. Consider this paper published not long ago in the journal Clinical Immunology. As the authors state,

"Atherosclerosis is a chronic inflammatory disease regulated by T lymphocyte subsets." ['T lymphocyte subsets' refers to the different categories of lymphocytes that participate in immune reactions.]

Regulatory T cells (Treg) 'referee' the immune response and quiet inflammation. Vitamin D is necessary for their production. Th1 refers to the lymphocytes that express the 'innate', cell-mediated aspect of the immune response; Th2 is the 'adaptive', humoral (antibody) mediated aspect. Th17 cells are a more recently recognized subtype that play a potent role in the immune system's inflammatory attack.

"Recently, CD4+CD25+Foxp3+ regulatory T (Treg) cells and Th17 cells have been described as two distinct subsets from Th1 and Th2 cells and have the opposite effects on autoimmunity. Th17/Treg balance controls inflammation and may be important in the pathogenesis of plaque destabilization and the onset of acute coronary syndrome [ACS, including unstable angina (UA) and acute myocardial infarction (AMI)]."

The authors investigated this by assessing Th17/Treg functions by cell numbers, related cytokine secretion and their  transcription factors in patients suffering from heart attacks, angina and control subjects free of heart disease. Their data made a strong impression:

"The results demonstrated that patients with ACS revealed significant increase in peripheral Th17 number, Th17 related cytokines (IL-17, IL-6 and IL-23) and transcription factor levels and obvious decrease in Treg number, Treg related cytokines (IL-10 and TGF-β1) and transcription factor (Foxp3) levels as compared with patients with SA and controls. Results indicate that Th17/Treg functional imbalance exists in patients with ACS, suggesting a potential role for Th17/Treg imbalance in plaque destabilization and the onset of ACS."

In other words, the inflammatory process of cardiovascular disease that culminates in the rupture of a vulnerable plaque, which is the precipitating event for a heart attack, expresses this Th17/Treg functional imbalance.You may have read earlier posts discussing oxidized LDL (ox-LDL) as a fundamental feature of cardiovascular disease and a valuable laboratory marker. This fascinating paper published recently in the journal Biochemical and Biophysical Research Communications that reports on the relationship between ox-LDL and Th17/Treg balance.

"Oxidized low-density lipoprotein (ox-LDL) is an instrumental factor in atherogenesis...CD4+CD25+ regulatory T (Treg) cells and Th17 cells, subsets of T-helper cells, play important roles in peripheral immunity and their imbalance leads to the development of tissue inflammation and autoimmune diseases...To explore the shift of Th17/Treg balance in ACS [acute coronary syndrome] patients and the effect of ox-LDL on the balance, we examined the frequencies of Th17 and Treg cells, key transcription factors and relevant cytokines in patients with AMI [acute myocardial infarction = heart attack], UA [unstable angina], stable angina (SA) and controls."

What did their data show about the connection between these immune cells and inflammatory cardiovascular disease?

"Our study demonstrated that ACS patients have shown a significant increase of Th17 frequency, RORγt expression and serum Interleukin 17 (IL-17), and a obvious decline of Treg frequency, Foxp3 expression, suppressive function, and serum IL-10. Serum ox-LDL positively correlated with the frequency of Th17 cells and negatively correlated with the frequency of Treg cells.... Treg and Th17 cells from ACS patients were significantly more susceptible to ox-LDL-mediated alterations."

Take a moment to appreciate the profound significance of this for the evaluation and treatment of cardiovascular disease. Cholesterol levels can be high in the absence of CVD, but when it is damaged by oxidation it somehow participates in the inflamed lesions of the vessel wall that are the basic characteristic of condition...

"Th17/Treg numerical and functional imbalance exists in ACS patients, and ox-LDL has a direct effect on Th17/Treg imbalance which may contribute to the occurrence of ACS."

How else might Th17/Treg imbalance manifest in cardiovascular disease? A study published this year in the Scandinavian Journal of Immunology reveals its role in idiopathic dilated cardiomyopathy, a fairly common cause of heart failure (the enlarged heart fails to pump properly).

"To assess whether Treg/Th17 balance was broken in patients with idiopathic dilated cardiomyopathy (DCM). We studied 25 patients who were diagnosed as idiopathic DCM (18 men and seven women, mean age 35.6 ± 5.2) and 25 normal persons (18 men and seven women, mean age 33.8 ± 4.9). Then, we detected Treg/Th17 functions on different levels including cell frequencies, related cytokine secretion and key transcription factors in patients with idiopathic DCM and controls."

What did their data show?

"The results demonstrated that patients with idiopathic DCM revealed significant increase in peripheral Th17 number, Th17-related cytokines (IL-17, IL-6, IL-23) and transcription factor (RORγt) levels and obvious decrease in Treg number, Treg-related cytokines (TGF-β1 and IL-10) and transcription factor (Foxp3) levels when compared to normal persons. Results indicated that Treg/Th17 functional imbalance existed in patients with idiopathic DCM, suggesting a potential role for Treg/Th17 imbalance in the development of idiopathic DCM."

We can also see that this is a mechanism promoting adverse cardiovascular events when uric acid increases in the bloodstream, such as when people undergo dialysis, from a paper published not long ago in the journal Nephrology.

"Adverse cardiovascular events resulting from accelerated atherosclerosis are the leading cause of mortality in uraemic patients on maintenance haemodialysis (MHD). Chronic inflammation due to antigen-specific responses is an important factor in the acceleration of atherosclerosis...The aim of the present study was to assess the Treg/Th17 pattern in uraemic patients on MHD and to explore the significance of Treg/Th17 imbalance in the development and outcome of acute cardiovascular events."

Their findings offer fascinating insight into the link between uric acid and cardiovascular inflammation:

"Patients with uraemia exhibited an obvious imbalance of Treg/Th17 function when compared to the normal control group, displaying increased peripheral Th17 frequency, Th17-related cytokines (interleukin [IL]-17, IL-6 and IL-23) and RORγt mRNA levels. These patients also displayed decreased Treg frequency, Treg-related cytokines (IL-10, transforming growth factor-β1) and Foxp3 mRNA levels...It was also observed that the imbalance of Treg/Th17 was not only consistent with the cardiovascular disease but also correlated with a microinflammatory state."

Clinicians and patients should bear their concluding point in mind:

"This Th17/Treg imbalance might act synergistically with microinflammation on immune-mediated atherosclerosis and contribute to the high incidence of adverse cardiovascular events."

I would like to note the evidence that Th17/Treg imbalance also plays a role in autoimmune disease associated with organ transplantation since a case this year involving autoimmune attack on the nerves regulating the heartbeat followed by another autoimmune inflammatory reaction to the pacemaker (Dressler's syndrome). The authors of a paper published in Clinical and Experimental Immunology state:

"...it can be proposed that skewing of responses towards Th17 or Th1 and away from Treg may be responsible for the development and/or progression of AD [autoimmune disease] or acute transplant rejection in humans. Blocking critical cytokines in vivo, notably IL-6, may result in a shift from a Th17 towards a regulatory phenotype and induce quiescence of AD or prevent transplant rejection..."

They sum up their extensive review by concluding:

"Interleukin 17 is a pleiotropic cytokine with multiple proinflammatory functions that is likely to be involved in either the causation or progression of inflammatory diseases and transplant rejection in humans. Regulatory T cells are an anti-inflammatory lineage of T cells... It is possible that acute flares of autoimmune diseases or acute episodes of transplant rejection may be explained by a change in the relative dominance of these pathways..."

What resources can we turn to for correcting Th17/Treg imbalances? A fascinating paper just published in the European Journal of Immunology explains how the proinflammatory cytokine IL-6 (Interleukin-6) is a regulator of Th17/Treg.

"IL-6 is a pleiotropic cytokine involved in the physiology of virtually every organ system. Recent studies have demonstrated that IL-6 has a very important role in regulating the balance between IL-17-producing Th17 cells and regulatory T cells (Treg). The two T-cell subsets play prominent roles in immune functions: Th17 cell is a key player in the pathogenesis of autoimmune diseases and protection against bacterial infections, while Treg functions to restrain excessive effector T-cell responses."

The authors explain the pivotal role played by IL-6 in determining the relative balance of autoimmune inflammation-promoting Th17 versus the anti-inflammatory Treg cells:

"IL-6 induces the development of Th17 cells from naïve T cells together with TGF-β; in contrast, IL-6 inhibits TGF-β-induced Treg differentiation. Dysregulation or overproduction of IL-6 leads to autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA), in which Th17 cells are considered to be the primary cause of pathology."

Their conclusion offers a welcome insight in that we have evidence-based physiological interventions that act to regulate IL-6:

"Given the critical role of IL-6 in altering the balance between Treg and Th17 cells, controlling IL-6 activities is potentially an effective approach in the treatment of various autoimmune and inflammatory diseases."

Further evidence for the pivotal role of IL-6 in regulating T17 and Treg balance is found in an interesting paper published in the journal Mucosal Immunology that points out the same process in inflammatory bowel disease:

"T helper (Th)17 cells have been shown to play a role in the pathogenesis of inflammatory and autoimmune diseases including inflammatory bowel diseases (IBD). It is now well established that although transforming growth factor (TGF)-beta alone induces FoxP3+ regulatory T (Treg) cells, TGF-beta and interleukin (IL)-6, acting in concert, induce differentiation of mouse naive T cells into Th17."

Going a step further, they were able to discern that IL-6 can act alone in promoting the development of Th17 cells:"We found that upon activation, Treg cells induce CD4+CD25- naive T cells or Treg cells themselves to differentiate into Th17 in the presence of IL-6 alone without exogenous addition of TGF-beta."Another clue to some of the therapies we can use is suggested by a study published in the Journal of Immunology on the ability of retinoic acid (RA), a metabolite of Vitamin A, to inhibit the expression of IL-6. The authors first observe:

"The de novo generation of Foxp3+ regulatory T (Treg) cells in the peripheral immune compartment and the differentiation of Th17 cells both require TGF-β, and IL-6 and IL-21 are switch factors that drive the development of Th17 cells at the expense of Treg cell generation."

The authors elucidate the pathways by which Treg can be promoted and IL-6 inhibited by retinoic acid (RA):

"Herein we show that RA enhances TGF-β signaling...and this results in increased Foxp3 [Treg] expression even in the presence of IL-6 or IL-21. RA also inhibits the expression of IL-6R{alpha}...and thus inhibits Th17 development. In...experimental autoimmune encephalomyelitis...RA suppresses the disease very efficiently by inhibiting proinflammatory T cell responses, especially pathogenic Th17 responses."

Their conclusion is well worth keeping in mind when we are researching a treatment plan for the autoimmune component of cardiovascular disease or any other autoimmune condition:

"These data not only identify the signaling mechanisms by which RA can affect both Treg cell and Th17 differentiation, but they also highlight that in vivo during an autoimmune reaction, RA suppresses autoimmunity mainly by inhibiting the generation of effector Th17 cells."