Abstract
Bacille Calmette–Guerin (BCG) vaccination is widely practiced around the world to protect against the mycobacterial infection tuberculosis. BCG is also effective against the pathogenic mycobacteria that cause leprosy and Buruli’s ulcer. BCG is part of the standard of care for bladder cancer where, when given as an intravesicular irrigant, BCG acts as an immunomodulating agent and lessens the risk of recurrence. Mycobacterium avium ss. paratuberculosis (MAP) causes a fatal enteritis of ruminant animals and is the putative cause of Crohn’s disease of humans. MAP has been associated with an increasingly long list of inflammatory/autoimmune diseases: Crohn's, sarcoidosis, Blau syndrome, Hashimoto’s thyroiditis, autoimmune diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis, lupus and Parkinson’s disease. Epidemiologic evidence points to BCG providing a “heterologous” protective effect on assorted autoimmune diseases; studies using BCG vaccination for T1D and MS have shown benefit in these diseases. This article proposes that the positive response to BCG in T1D and MS is due to a mitigating action of BCG upon MAP. Other autoimmune diseases, having a concomitant genetic risk for mycobacterial infection as well as cross-reacting antibodies against mycobacterial heat shock protein 65 (HSP65), could reasonably be considered to respond to BCG vaccination. The rare autoimmune disease, relapsing polychondritis, is one such disease and is offered as an example. Recent studies suggesting a protective role for BCG in Alzheimer’s disease are also explored. BCG-induced energy shift from oxidative phosphorylation to aerobic glycolysis provides the immunomodulating boost to the immune response and also mitigates mycobacterial infection—this cellular mechanism unifies the impact of BCG on the disparate diseases of this article.
Highlights
Bacille Calmette–Guerin (BCG) vaccination was developed nearly one hundred years ago and remains the only vaccine to fight tuberculosis (TB), the result of infection by Mycobacterium tuberculosis
BCG vaccination induces two types of responses; the classic antigen-specific immune response leading to protection against TB and non-tuberculous mycobacteria (NTM), and an adaptive “trained” immunity-based upon reprogramming of phagocytes that extends beyond protection against TB to other infections [86]
In 2014 Netea summed up current thinking about the expanded therapeutic use of BCG: “ . . . despite the epidemiological evidence for heterologous protective effects of BCG vaccination, the perceived lack of biological plausibility has been a major obstacle in recognizing and in investigating these effects.” [164]
Summary
Bacille Calmette–Guerin (BCG) vaccination was developed nearly one hundred years ago and remains the only vaccine to fight tuberculosis (TB), the result of infection by Mycobacterium tuberculosis. BCG has been shown to benefit both T1D and MS a result that has been termed “heterologous” effects of BCG vaccination [6]. This paper will review the use of BCG in TB as well as examine BCG in mycobacterial infections other than TB. It will discuss BCG use as an adjunct to bladder cancer treatment. It will discuss the heterologous effects of BCG vaccination as it relates to autoimmune diseases T1D and MS and propose that the benefit is due to MAP mitigation in these diseases. This paper will suggest a therapeutic role for BCG vaccination in the rare autoimmune disease, relapsing polychondritis as well as explore its newfound therapeutic prospects in the very common Alzheimer’s disease
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