Vaccines Cause Auto-Immune Disease
Vaccines are a prototypic source for natural immune stimulation, but may be involved in pathogenic disease in the setting of aberrant immune system function. Possibly, the burden on the immune system resulting from simultaneous multiple vaccines and even the different types of vaccines may also be an overwhelming challenge in the autoimmune prone individual (Shoenfeld et al., 2008). In this review, we discuss the evidence for the development of autoimmune diseases following infections.
In studies of more than 10 patients, the reported manifestations following hepatitis B vaccination were arthritis, thrombocytopenia, demyelinating encephalitis, and demyelinating neuropathy. A case-control study of 265 newly diagnosed lupus patients did not show that HBV vaccine was a risk factor for developing SLE [odds ratio (OR)-1.4] (Schattner, 2005). In a current study, 10 lupus patients were diagnosed within several days and up to one year following hepatitis B vaccination (Agmon-Levin et al., 2009). Previously, 11 cases were reported in the literature regarding the onset or exacerbation of SLE post hepatitis B vaccination (Schattner, 2005).
In concordance, a latency period of less than one week and up to 2 years between vaccination and SLE onset was reported. The classical period between vaccination and autoimmunity was considered to be several weeks, similarly to the time frame suggested in the past for post-infectious autoimmunity phenomena. Interestingly, in this case series, 70% of patients continued their immunization protocol although adverse events were documented. Similarly, in previously reported cases, the affected subjects continued to be vaccinated and aggravation of their condition by additional doses had been documented (Agmon-Levin et al., 2009). Overall, SLE patients presented post hepatitis B vaccination with mild to moderate disease and without life threatening organ involvement.
Multiple sclerosis
Neurological manifestations are common following vaccinations (Huynh et al., 2008). In a case-control epidemiological study for serious adverse events reported in the hepatitis B vaccination exposed group compared to those that received tetanus vaccine, MS was prominent with an odds ratio of 5.2 (P<0.0003). Optic neuritis was also very commonly encountered (OR-14, p< 0.0002) (Geier et al., 2005).
Guillain-Barré syndrome
In GBS, activated macrophages invade intact myelin sheaths resulting in myelin damage and demyelination (Vucic et al., 2009).
Vaccines reported as associated with GBS are diverse (Schonberger et al., 1979; Hemachudha et al., 1988; Khamaisi et al., 2004; CDC, 2006; Slade et al., 2009; Haber et al., 2009). The evidence of casual relationship with GBS is strongest with the swine flu (H1N1) vaccine that was used in 1976-7. An increased relative risk [relative risk (RR)-4-8] to develop GBS 6-8 weeks after the injection was encountered in the vaccinated group compared to the non vaccinated group. The risk for GBS was slightly less than 1 excess case of GBS per 100,000 vaccinated individuals, and hence the vaccine program was suspended (Schonberger et al., 1979). Further studies substantiated the association between the H1N1 vaccine and an increased relative risk (RR-7/1) for GBS 6 weeks after the vaccine (Safranek et al., 1991). The pathophysiology is unclear but may be related to vaccine induced anti-ganglioside antibodies (GM1) (Nachamkin et al., 2008).
The vaccine against Neisseria meningitides is for use among individuals aged 11-55 years old. The VAERS published a warning of a possible association between the Meningococcal Polisaccharide Diphteria Toxoid Conjugated Vaccine (MCV4) and GBS, because of 5 cases of GBS following the MCV4 vaccine, and later 12 additional cases were reported (CDC, 2005). Based on reports, statistical analysis did not show any significant increase in the rate of GBS occurring 6 weeks after the MCV4 vaccine compared to non-vaccinated population. However, it is recommended that individuals with a history of GBS should not be vaccinated with MCV4 unless they are in a high risk for meningococcal infection.
Vaccine induced myopathies
The reports on vaccine induced inflammatory myopathies are sporadic and include cases of following immunization with HBV, bacillus Calmette-Guérin, tetanus, influenza, smallpox, polio, diphtheria, or combinations with diphtheria (Orbach et al., 2009). There is no statistically significant increase in the incidence of polymyositis or dermatomyositis after any mass vaccination. Among 289 patients with inflammatory myopathies followed in the Mayo Clinic, no recent immunization was recorded (Winkelman, 1968; Winkelmann, 1982).
Macrophagic myofasciitis
Macrophagic myofasciitis is a reaction to intramuscular injections of vaccines containing aluminum hydroxide as an adjuvant and affects mainly adults. The symptoms are usually myalgia, arthralgia, asthenia and, less frequently, muscle weakness and fever, in the presence of elevated creatine kinase and erythrocyte sedimentation rates. The electromyogram has a unique pathologic pattern characterized mainly by focal infiltration of the epimysium, perimysium, and perifascicular endomysium by sheets of large, non-epithelioid macrophages, which show fine granular staining for periodic acid-Schiff (PAS) stain that appear as small, osmiophilic, spiky structures on electron microscopy, representing the aluminum hydroxide crystals (Gherardi et al., 2001). Immunizations containing aluminum may trigger Macrophagic myofasciitis in the context of an HLA-DRB1*01 genetic background (Guis et al., 2002). Frequently, patients improve with steroid therapy.
Vasculitis
Numerous case reports reported a possible association between polyarteritis nodosa (PAN) and hepatitis B vaccination. Overall, 25 cases of PAN were submitted to VAERS over an 11 year period until 2001. Among them, only 10 individuals were diagnosed as definite or possible PAN and are discussed here. The median age of patients was 45 years old and 5 patients were hospitalized. A modal peak of 2 weeks and median of 2.8 weeks post-vaccination was noted. All cases received at least 2 doses of vaccine prior to symptom onset. Hepatitis B surface antigenemia frequently follows hepatitis B vaccination and is detected many days after the 20 microgram vaccine. This could explain related immune-complex disease. Recently, there were less than 20 reports on the development of vasculitis following influenza vaccination. Small, medium, and large vessels were involved (Begier et al., 2004). All in all, this would be considered a rare event.
Rheumatoid arthritis
A total of 48 out of 898 (5.3%) of patients with early inflammatory polyarthritis reported an immunization in the 5 weeks prior to symptom onset. There were no important clinical or demographic differences between the 48 immunized patients and 185 consecutive patients who did not report prior immunization. The frequencies of HLA DRB1 *01 and *04 and the shared epitope in 33 of the immunized patients were no different in the non- immunized patients compared to healthy controls. Possibly, in a small number of susceptible individuals, immunization may act as a trigger for RA (Harrison et al., 1997).
HPV vaccine and autoimmune manifestations
The recently released vaccine for human papillomavirus (HPV) offers an opportunity to assess the development of autoimmune phenomena in a high risk population of young women. Hence, we chose to investigate and report separately on this vaccine.
Recently developed vaccines against human papillomavirus (HPV) and hepatitis B virus (HBV) contain a novel Adjuvant System, AS04, which is composed of 3-O-desacyl-4′ monophosphoryl lipid A and aluminum salts. All randomized, controlled trials of HPV-16/18, herpes simplex virus (HSV), and HBV vaccines were analyzed in an integrated analysis of individual data (N = 68,512). A separate analysis of the HPV-16/18 vaccine trials alone was also undertaken (N = 39,160). The reported rates of overall autoimmune events were around 0.5% and did not differ between the AS04 and control groups. The relative risk (AS04/control) of experiencing any autoimmune event was 0.98 (95% confidence intervals 0.80, 1.21) in the integrated analysis and 0.92 (0.70, 1.22) in the HPV-16/18 vaccine analysis. This integrated analysis of over 68,000 participants who received AS04 adjuvant vaccines or controls demonstrated a low rate of autoimmune disorders, without evidence of an increase in relative risk associated with AS04 adjuvanted vaccines (Verstraeten et al., 2008).
In the Danish Civil Registration system, among approximately half a million adolescent girls, 414 autoimmune disorders were listed. The 5 most common autoimmune diseases occurring within 6 weeks of vaccination among 100,000 girls were: type I diabetes, juvenile arthritis, Crohn’s disease, Henoch-Schonlein disease, and ulcerative colitis (Sutton et al., 2009).
A most probable causality occurred between exposure to swine flu vaccine and the development of GBS. In addition, MMF occurred following exposure to aluminum containing adjuvant. Vaccines, like infections, activate immune mediated mechanisms to induce a protective effect. Hence, a complex vaccine may theoretically be more immunogenic than a simple vaccine. Vaccines harbor added complex agents, for example, adjuvants including aluminum, which may induce autoimmune disease. Preservatives are more often found in viral vaccines compared to bacterial vaccines suggesting that the preservatives may be the inciting culprits (Israeli et al., 2009).
A comprehensive strategy is required to develop a new vaccine that will not induce autoimmune manifestations as previously proposed.
Perhaps, the assessment of autoantibody and HLA status prior to immunization will serve as a marker for individuals at risk. More research is required to identify those individuals who may develop autoimmune diseases following immunizations.
Self-Organized Criticality Theory of Autoimmunity
Methodology/Principal Findings
Repeated immunization with antigen causes systemic autoimmunity in mice otherwise not prone to spontaneous autoimmune diseases. Overstimulation of CD4+ T cells led to the development of autoantibody-inducing CD4+ T (aiCD4+ T) cell which had undergone T cell receptor (TCR) revision and was capable of inducing autoantibodies. The aiCD4+ T cell was induced by de novo TCR revision but not by cross-reaction, and subsequently overstimulated CD8+ T cells, driving them to become antigen-specific cytotoxic T lymphocytes (CTL). These CTLs could be further matured by antigen cross-presentation, after which they caused autoimmune tissue injury akin to systemic lupus erythematosus (SLE).
Conclusions/Significance
Systemic autoimmunity appears to be the inevitable consequence of over-stimulating the host’s immune ‘system’ by repeated immunization with antigen, to the levels that surpass system’s self-organized criticality.
Source: Tsumiyama K, Miyazaki Y, Shiozawa S (2009) Self-Organized Criticality Theory of Autoimmunity. PLoS ONE 4(12): e8382. doi:10.1371/journal.pone.0008382 – Tsumiyama K, Miyazaki Y, Shiozawa S (2009) Self-Organized Criticality Theory of Autoimmunity. PLoS ONE 4(12): e8382. doi:10.1371/journal.pone.0008382.
