Vaccination and Autoimmune Diseases

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Introduction

At a time when vaccines save annually millions of child’s lives, it is paradoxical that in many industrialized countries more public attention is given to the possible risks of adverse effects of vaccination than to its beneficial effects. This attitude often leads to reducing vaccination coverage in some countries or particular communities and may result in disease outbreaks.

Autoimmune diseases, that is, diseases caused by immune responses against host self-antigens, are often at the center of such controversies. This is reflected in the large number of publications that describe cases of autoimmune disease arising following vaccination. Most of the time, these are cases characterized by a temporal relationship between two events but without demonstration of causality. The risk of fortuitous coincidence is particularly brought up by the increase of adolescent and young adult vaccination since several autoimmune diseases are often initially diagnosed in these age groups. In these circumstances, it is critical to properly estimate the real risk of a causal relationship between a particular vaccination and autoimmune events.

Autoimmune diseases might be either tissue-specific (eg, thyroiditis, type 1 diabetes, multiple sclerosis), or systemic (systemic lupus erythematosus, vasculitis). Collectively, disease manifestations caused by an autoimmune process may affect 5–9% of the population in Western countries. These disorders represent a growing burden as their incidence significantly increased over the last years. For example, the annual incidence of type 1 diabetes is increasing globally by 2.3% per year. A similar increase is seen for multiple sclerosis.

It is generally assumed that autoimmune disorders result from complex interactions between genetic traits and environmental factors. Although there is a frequent concordance of autoimmune diseases among monozygotic twins, the concordance rate is lower-than-expected. Similarly, changes in the incidence of type I diabetes and multiple sclerosis when children from a given population migrate from one region to another strongly suggest a critical role for environmental causes in addition to genetic predisposition. In most autoimmune diseases the trigger has not been formally identified, leaving room for hypotheses and allegations not always substantiated by facts.

Mechanisms leading to autoimmune responses and to their occasional translation into autoimmune diseases are now better understood. Autoimmune responses result from the combined effects of antigen-specific stimulations of the immune system and of an antigen-nonspecific activation of antigen-presenting cells in the context of a genetically determined predisposition and of a somewhat deficient immune regulation. Most often such responses are not followed by any clinical manifestations unless additional events favor disease expression, for example, a localized inflammatory process at tissue level. Therefore the demonstration of autoantibodies or autoreactive T cells does not imply their involvement in a disease process. The role of infections has been occasionally demonstrated either as etiologic factor or as triggering event in autoimmune diseases. Prototypic examples are the poststreptococcal rheumatic heart disease or the Guillain-Barré syndrome that follows Campylobacter jejuni infections. Such observations have emphasized the multifactorial immunological pathogenesis of secondary autoimmune pathology. First, there is a potential role of antigenic similarities between some microbial molecules and host antigens. Second, infection-related signals that trigger innate immunity appear to play an essential role in enhancing the immunogenicity of host antigens or of host-mimicking epitopes, and in possibly overcoming regulatory mechanisms that limit autoimmune responses. It should be stressed that postinfectious autoimmune responses are not infrequent whereas associated autoimmune diseases remain rare events and often require additional infection-related inflammatory processes.

It is on the basis of such observations that questions were raised regarding the potential risk of autoimmune responses and autoimmune diseases following vaccination that include exposure to microbial products or antigens. Is there a significant risk that some vaccines may induce autoimmune responses through the introduction of microbial epitopes that cross-react with host antigens? Can adjuvant-containing vaccines trigger the clinical expression of an underlying autoimmune process through a “nonspecific” activation of antigen-presenting cells and the release of inflammatory cytokines? Until now, answers to these questions have been largely based on data collected during pharmacovigilance studies in the context of postmarketing surveillance Many autoimmune diseases have a relatively low natural incidence. Although rheumatoid arthritis may reach 1% prevalence, others such as multiple sclerosis or systemic lupus erythematosus are much less frequent (around 0.1%) and many others are rare diseases. Therefore, only large epidemiological studies or huge clinical trials may allow for a consistent assessment of the relative risk of vaccine-related effects.

Understanding the mechanisms by which autoimmune responses are generated and how they may or not lead to autoimmune diseases is of paramount importance for defining the real risk of vaccine-associated autoimmune reaction. During the course of vaccine development, comprehensive and multidisciplinary approaches may help to reduce to a minimum the risk that a new vaccine would induce autoimmune manifestations. Later, once the new vaccine is largely used in public health programmes, systems are now in place in many countries to readily assess observations or allegations of unexpected autoimmune adverse effects. Although in the last few years, there was a dramatic increase in the number of allegations regarding links between vaccination and autoimmune disease, it was somehow reassuring that autoimmune adverse effects were confirmed in only very few instances.

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Understanding infection-associated autoimmunity

Several autoimmune diseases are known to result from an infection. This is the case for rheumatic fever, including rheumatic heart disease, which appears in up to 0.3% of children following infection by group A Streptococcus . A neurologic disease, the axonal form of Guillain-Barré syndrome, can occur in the course of Campylobacter jejuni enteritis. Similarly, autoimmunity was demonstrated in HTLV-1-associated myelopathy/tropical spastic paraparesis. Although there is suggestive evidence that viruses might contribute to the pathogenesis of type I diabetes and multiple sclerosis, a clear-cut relation between the onset of tissue-specific autoimmunity and viral infection has not been firmly established. On the other hand, the role of infections in the exacerbation of a preexisting autoimmune disorder is rather well established. For example, in multiple sclerosis, epidemiological data strongly suggest that relapses of the disease can be triggered by both bacterial and viral infections.

There is now a better understanding of immunological mechanisms in infection-associated autoimmunity. This is helpful to assess and reduce the potential risk of inducing autoimmune diseases with vaccines that aim at preventing these infections. The main characteristic of the immune system is its capacity to recognize a considerable number of antigenic moieties due to highly efficient gene rearrangement mechanisms during the maturation of B- and T cells. Antibody responses to multiple infectious agents demonstrate the remarkable recognition capacity of the B cell repertoire. A parallel recognition of autologous antigenic moieties is largely avoided by tolerogenic signals during early steps of B cell development. However structural homology with autoimmune consequences has been identified. Rheumatic heart disease which appears following infection by group A Streptococcus is associated with the an antistreptococcal immune response that cross-reacts with host cardiac myosin The axonal form of Guillain-Barré syndrome that occurs in the course of Campylobacter jejuni enteritis is mediated by antibacterial lipopolysaccharide antibodies that cross-react with human gangliosides. Similarly, antibodies directed against the Tax protein of the human T-lymphotropic virus type 1 (HTLV-1) that cross-react with the heterogeneous nuclear ribonucleoprotein-A1 (hnRNP-A1) self-antigen were demonstrated in HTLV-1-associated myelopathy/tropical spastic paraparesis. More recently, antibodies to influenza nucleoprotein were shown to cross-react with the human hypocretin receptor 2 and proposed to contribute to the pathogenesis of narcolepsy occurring after administration of an influenza pandemic vaccine. Therefore, it is obvious that B cell epitope cross-reactivity between host and microbial proteins can occur and occasionally lead to pathological consequences. Cross-reacting B-cell epitopes are more likely to generate autoimmune responses when they are linked with T-cell microbial epitopes that can recruit efficient T-cell help.

It is generally assumed that activation and clonal expansion of autoreactive T lymphocytes represent critical steps in the pathogenesis of cell-mediated autoimmune diseases. Infections might be responsible for these key events through several nonmutually exclusive mechanisms including molecular mimicry, enhanced presentation of self-antigens, bystander activation, and impaired T-cell regulation.

The molecular mimicry hypothesis is based on sequence homologies between microbial peptides and self-antigen epitopes. At the T-cell level, this concept was initially established in an experimental model in which rabbit immunization with a hepatitis B virus polymerase peptide containing a 6 amino-acid sequence of rabbit myelin basic protein (MBP) elicited an anti-MBP T-cell response leading to autoimmune encephalomyelitis. It was also suggested that a viral infection in itself could lead to autoimmune pathology caused by cross-reactive T cells in herpes simplex keratitis in which pathogenic autoreactive T-cell clones were shown to cross-react with a peptide from the UL6 protein of the herpes simplex virus.

However, the significance of T-cell epitope mimicry is limited. We know that the recognition of self peptide-MHC (pMHC) complexes play an essential role in positive and negative selection of maturing T cells in the thymus. Only T cells with a sufficient affinity for self-MHC peptides presented by cortical thymic epithelial cells will survive. Shaping the T-cell repertoire is then pursued in the thymic medulla. T cells undergo a negative selection that leads to the elimination of T cells with a high affinity for self pMHC complexes presented on medullar epithelial and dendritic cells. At the end of this process, weakly autoreactive T cells will leave the thymus and constitute the T-cell repertoire. These T cells will react to diverse microbial attacks essentially through cross-reactions. Therefore, one could consider that without any host cross-reactivity, the immune system would not be able to cope with infections.

Infection can also promote processing and presentation of self-antigens by several mechanisms. First, cellular damages locally induced by viral or bacterial infection can result in the release of sequestered self-antigens that stimulate autoreactive T cells. This was clearly demonstrated in autoimmune diabetes induced by coxsackievirus B4 infection in mice. Second, the local inflammatory reaction elicited in tissues by microbial products can trigger dendritic cell maturation, which represents a key step in the induction phase of immune responses. Microbial products that engage toll-like receptors on dendritic cells can induce the upregulation of membrane expression of MHC and costimulatory molecules and the secretion of cytokines, which promote T-cell activation and differentiation. Third, a T-cell response directed toward a single self-peptide can “spread” to other self epitopes during an inflammatory reaction. This process of “epitope spreading” has been well documented in murine models of encephalomyelitis.

Special attention has been paid to cytokines of the IL-12 family as those mediators can promote bystander activation of memory T cells and occasionally trigger autoimmune reactions when such autoreactive cells do preexist. Using murine models of encephalomyelitis, Shevach et al. demonstrated that quiescent autoreactive T cells could differentiate into pathogenic Th1 effectors in presence of microbial products that induce IL-12 synthesis. Likewise, it was shown that viral infections inducing IL-12 production could elicit relapses of autoimmune encephalomyelitis (EAE), in a nonantigen specific manner, in myelin-primed animals. A salient feature of bystander activation is its limited duration. In order to observe an exacerbation of EAE one should provide the triggering signal within a relatively restricted window of time after the aetiological stimuli that “primed” the animal for disease. In addition disease exacerbation occurs within weeks after bystander activation and it is not usually seen after longer delays. In recent years, much attention has been paid to IL-23, another member of the IL-12 family that is induced by microbial products and emerged as a key mediator of several human autoimmune diseases.

The development of pathogenic autoimmune T-cell responses is largely reflecting individual defects in regulatory mechanisms that control the activation of autoreactive T-cell clones. Regulatory T cells are instrumental in controlling autoreactive T cells both in neonates and adults. It is clear that infectious agents can have profound influences, either positive or negative, on the balance between effector and regulatory T cells, as recently reviewed in the context of skin disorders.

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