From Tolerance to Autoimmunity: Is There a Risk in Early Life Vaccination?

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Summary

The potential for vaccines to act as triggers of autoimmune reactions has received much recent attention. Such an association is very poorly defined mechanistically, but may potentially involve epitope mimicry between vaccinal and self antigen, or the immuno-stimulatory effects of vaccine adjuvant. If such reactions occur, they are more likely to involve adults than infants in early life, as a reflection of the immunological immaturity of the newborn. There has been a recent focus in immunology on the link between innate and adaptive immunity provided by dendritic cells and the range of Toll-like receptors (TLRs) that are the point of first contact of these cells with microbial antigen. These interactions appear to determine the nature of the subsequent adaptive immune response and whether it may be mediated by Th1, Th2, Th17 or T regulatory populations. TLR interactions may also be significant in the induction of vaccinal immunity and agonists of these receptors are being developed as potential vaccine adjuvants. There are differences in cytokine production of adult and newborn dendritic cells, and these differences must be considered in the application of such novel adjuvants to products intended for either age group.

Introduction

In human medicine, wide attention has been given to the proposed associations between autoimmune inflammatory events and vaccination, although the scientific proof for such cause and effect is limited. The immaturity of the newborn immune system is generally considered as a safeguard against the development of this type of reaction following neonatal immunization. However, as vaccine technology progresses the potential for early life triggering of such aberrant immunological events should not be dismissed.

Section snippets

Mechanisms of Vaccine-Associated Autoimmunity

Two main hypotheses have been proposed to explain this immunological association: epitope mimicry and the effect of adjuvant. Epitope mimicry implies that one of the antigens included in a given vaccine may share structural similarities with self-antigens. Consequently, the immune response to this vaccine antigen may subsequently extend to one directed against the host cells that express the self-antigen.

Alternatively, it is now recognized that certain types of adjuvant may drive the

Toll-Like Receptors and the Innate Response to Microbes

A set of highly conserved receptor molecules, the TLRs, respond to a variety of microbial molecules, which act as ligands for these receptors. This occurs during the early phase of exposure to microbes, which corresponds to the activation of innate immunity. By setting in motion biochemical cascades involving adaptor molecules, kinases and sequences of phosphorylation events, this gives rise to the activation of transcription factors and the production of a large array of proteins, which

The Role of Toll-Like Receptors in the Induction of T-cell responses

DCs, the professional APCs to naïve cells of the immune system, receive signals through a wide variety of pattern recognition receptors such as TLRs. Thus in addition to presenting antigen to naïve T cells in an appropriate MHC context, the range of co-stimulatory signals delivered to the T-cell by the APC is determined by TLR ligation.

Molecules of microbial origin, named pathogen associated molecular patterns (PAMPs), engage the TLR and bind to it, thereby eliciting a cellular programme (the

Autoimmune Diseases and TLR Signalling

In certain experimental settings, the activation of TLRs results in an autoimmune disease. Experimental autoimmune encephalomyelitis (EAE) is the animal model for the study of multiple sclerosis in which there is auto-reactivity to antigens such as myelin. A selection of recent papers shows that in animals tolerant to myelin antigens, but harbouring T cells able to recognize these antigens, the inoculation of ligands to TLR4 or TLR9 triggers the development of EAE (Waldner et al., 2004). A

TLR Agonists as Vaccine Adjuvants

Newer vaccines, some of which are already available, are based on adjuvants that engage some of the previously mentioned TLRs. Monophosphoryl lipid A is now included in several vaccine formulations (e.g. papillomavirus vaccine). This molecule is the ligand for TLR4 on myeloid DCs. Vaccines against cancer and against allergic diseases, currently undergoing clinical trials, contain CpG DNA, a ligand for TLR9 on plasmacytoid DCs. A molecule named Resiquimod (R-848), engages TLR7/8, and has

Th17: Changing the Picture

A new subset of CD4+ T cells was identified in 2005, now named the Th17 subset (Wynn, 2005). Production of IL-23 by mature DCs plays a major role in the maintenance and amplification of Th17 T cells. These Th17 effector T cells produce IL-17, a very important pro-inflammatory cytokine, which acts upon a large number of cell types. Evidence is now accumulating which indicates that the most important cytokines for autoimmune reactions are not IL-12 and IFN-γ but IL-23 and IL-17. This paradigm

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