Acute rheumatic fever triggered by pharyngeal Streptococcus pyogenes infection can lead to rheumatic heart valve disease (RHVD). This autoimmune response causes irreversible damage to the heart valves, primarily mitral valves, while sparing myocardium and other organs. Like many other autoimmune diseases, RHVD predominantly affects women.
Elena Aikawa, MD, PhD, Naoki Miwa distinguished chair in Cardiovascular Medicine in the Heart and Vascular Center at Brigham and Women’s Hospital, Livia S.A. Passos, PhD, a research fellow in the center, and colleagues have identified a protein that contributes to chronic RHVD immunopathogenesis and has a role in the female predisposition to RHVD.
In Circulation, the researchers report other findings that have implications for potential development of a therapeutic vaccine for RHVD.
Identification of ProTα
The researchers analyzed human valves obtained from failing but nondiseased transplant hearts (six aortic valves, six mitral valves) or during valve replacement surgeries for RHVD (four aortic valves, nine mitral valves). Five aortic valves being replaced because of calcific disease were included as controls.
Prothymosin alpha (ProTα) was identified as an RHVD biomarker. It was more abundant in rheumatic valves than in nondiseased valves, suggesting it has a role in RHVD development.
ProTα is ubiquitously expressed and mediates immune responses when secreted within cells. It’s known to have immunoenhancing activity; in fact, it’s being studied as an adjuvant to cancer immunotherapy. In autoimmune diseases, though, it may exacerbate the dysfunctional immune response.
ProTα, ERα and CD8+ T Cells
All immune cells highly express estrogen receptor alpha (ERα), which is being studied to see whether it has a role in autoimmune disease. Furthermore, research published in Oncogene showed estradiol increases ProTα expression.
In the current study, expression of ERα by CD4+ and CD8+ T cells positively correlated with ProTα expression in patients with RHVD and not in healthy individuals. Moreover, the number of CD8+ T cells correlated positively with ProTα expression in both blood and valve tissue.
When the researchers used a highly selective antagonist to block ERα on CD8+ T cells, they observed decreased expression of cytotoxic molecules induced by ProTα. That finding implies a role for ProTα in RHVD sex predisposition.
Other Key Findings
Activated T cells can recognize host epitopes that resemble bacterial structures evoking autoimmune responses, a phenomenon called molecular mimicry. ProTα facilitated CD8+ T-cell recognition of type 1 collagen, which showed molecular mimicry with S. pyogenes and the ability to elicit immune responses in those cells.
Fibroblasts can have antigen-presenting capacity, and valvular interstitial cells (VICs) are fibroblast-like. When applied to VICs, recombinant ProTα increased the expression of human leukocyte antigen (HLA)-A, -B, and -C. Thus, VICs are a clear potential target of the CD8+ T-cell–mediated tissue pathology that ProTα helps to induce.
A Potential New Treatment Strategy
Antibiotics are effective against S. pyogenes infection. However, in resource-poor countries, factors including repeated exposure to the bacteria often lead to acute rheumatic fever and RHVD. There are no effective medical therapies for RHVD, and valve replacement surgery is an unrealistic option for most patients in those regions.
The ideal strategy to relieve the burden of RHVD would be a therapeutic vaccine that could resolve or control the ongoing T-cell self-reactive responses. Indiscriminate immunosuppression can lead to serious side effects, so targeting the disease-specific pathogenic T cells identified in this research is a more promising way to develop immunotherapies for RHVD.