A potential antigenic mimicry between viral and human proteins linking Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) with autoimmunity: the case of HPV immunization, by Jody Phelan, Anna D Grabowska, Nuno Sepulveda in Autoimmunity Reviews Vol 19, no. 4, April 2020,
1. Introduction
ME/CFS is a complex disease of unknown aetiology, but there is an increasing evidence which suggests an autoimmune component after a viral infection [1]. In the quest of understanding disease pathogenesis, Gherardi et al provided a thorough review of the role of adjuvants in the development of ME/CFS after vaccination [2]. As highlighted by the authors, many cases of vaccination-induced macrophagic myofasciitis could be alternatively classified as patients with ME/CFS using the 1994 CDC criteria [3].
In addition, vaccination against the human papillomavirus (HPV) seems to have the capacity of triggering different autonomic dysfunctions including ME/CFS [4]. Under the concept of Autoimmunity/Inflammation Syndrome Induced by Adjuvants (ASIA) [5], Gherardi et al [2] suggested that ME/CFS after vaccination results from a chronic and systemic inflammation triggered by a persistence and diffusion of adjuvants in the body.
As a general principle, vaccination uses attenuated versions of natural infections in order to generate immunological memory against a specific harmful microorganism. However, vaccination as well as a natural infection has also the potential to trigger an autoimmune response via molecular mimicry, as recently discovered for Pandemrix (a vaccine against H1N1 influenza A virus) and type 1 narcolepsy [6]. Another important example of molecular mimicry with potential devastating adverse events for vaccinated individuals has been discussed for the L1 proteins included in the bivalent Cervarix and the quadrivalent Gardasil [7,8], two vaccines against HPV discussed in Gherardi at el [2].
Antigen mimicry has also been hypothesized as the cause of a case suffering from pancreatitis after HPV immunization [9]. We revisited this topic in the context of ME/CFS by performing a stringent bioinformatic analysis of these vaccine proteins.
3. Discussion
In summary, our bioinformatic analysis identified a potential antigenic mimicry between HPV L1 and different human proteins. Two of our candidate epitopes are included in a long list pentapeptides and hexapeptides from HPV L1 proteins already identified in previous studies [7–9]. The first one is the pentapeptide KFLLQAG from HPV16_L1, which has a high sequence homology with ANKDR16 human protein [7]. The second one is the hexapeptide ASSSRLL found in HPV6_L1 and HPV11_L1 proteins [9], which has already been validated experimentally as a strong inducer of virus-specific CD4+ T-cell responses [14]. The remaining epitopes identified here are novel and possibly so because of sequence variations in the L1 proteins used in this and previous studies.
From a standpoint of human genetics, HPV-vaccinated individuals who are carriers of either HLA-DRB1*01:01, HLA-DRB1*07:01, or HLA-DRB5*01:01 alleles might be at a higher risk of ME/CFS due to the suggested molecular mimicry. This genetic specificity is in line with several disparate associations between ME/CFS and different HLA genes reported in the literature [15,16]. However, given the numerous infection triggers of the disease [17], we foresee a problem of irreproducibility in future studies investigating these genetic associations. To overcome this problem, we suggest that researchers should make the effort of routinely collecting data and reporting on infection triggers of the disease in their study participants.
… In conclusion, the suggested molecular mimicry as a trigger of ME/CFS in HPV-vaccinated individuals is another piece of evidence supporting an autoimmune origin of the disease [1]. A fundamental question should be then addressed: what is the difference between ME/CFS and known autoimmune diseases? In this regard, Tregs might hold the answer to this question since these cells are thought to be key players in supressing deleterious autoreactive immune responses [27].
In addition, several studies reported an increased percentage of these cells in patients with ME/CFS when compared to healthy controls or autoimmune patients [28–30]. The overlooked role of these cells in ME/CFS will be discussed elsewhere [34].
