INTRODUCTION

The lymphocytes of the adaptive immune system are programmed to recognize foreign antigens through their antigen-specific receptor molecules. Each individual carries lymphocytes of a wide range of specificities, such that all antigens that may be encountered throughout a lifetime can initiate an immune response. Generally, these are protective immune responses to infection by pathogens, but occasionally the immune system responds inappropriately to innocuous environmental antigens (allergens) to mount hypersensitivity responses leading to allergic disease. All individuals also carry lymphocytes with the potential to react against constituents of their own body (autoantigens). In the majority of normal people and animals, those lymphocytes that are potentially self-reactive are kept tightly controlled to prevent autoimmunity from occurring.

However, in some individuals this system fails and autoimmune disease arises. Autoimmune diseases have a major impact on human health. Diseases such as rheumatoid arthritis or type I diabetes mellitus have a major social and economic impact. Fortunately, autoimmune disease appears less common in dogs, and is poorly documented in cats. Nevertheless, autoimmune disease does occur in a proportion of our patients, and the number of disease syndromes that are recognised as having an autoimmune basis is growing.

Despite many years of research, what triggers an inappropriate immune response to self antigens is not known. Our current thinking is that autoimmunity arises in an individual exposed to three overlapping background factors. The first of these is genetic background. Autoimmunity clearly runs in human families and canine pedigrees and has a strong genetic component. Genes that encode molecules involved in the immune response (e.g., histocompatibility antigens, cytokines) often have specific alleles that are positively associated with autoimmunity--but no particular 'autoimmunity gene' has yet been identified. The second contributory factor is immune dysregulation. The immune system has developed several mechanisms that keep autoreactive lymphocytes tightly controlled--and when these break down, autoimmunity ensues.

The final predisposing factor is the influence of environment. This might include a range of background factors such as diet, stress or exposure to pollutants, but the single most significant environmental influence on the development of autoimmunity is microbial infection.

There has long been anecdotal evidence that infection either precedes, or is concurrent with, the onset of autoimmune disease. That an infectious agent might trigger the autoimmune process, which then persists even when the infectious agent is eliminated, can be reconciled with the definition of autoimmune disease that states that there should be no identifiable secondary factor. There are many examples of infectious diseases that have a known immunopathological component--and we are happy to classify these as 'immune-mediated' diseases triggered by infection. This new slant on autoimmunity suggests that we should not perhaps be so rigorous in distinguishing between an 'autoimmune' and 'immune mediated' disease. The question arises: Does all autoimmunity have an infectious trigger?

MICROBE-ASSOCIATED IMMUNE MEDIATED DISEASE

There are numerous examples of infectious diseases in which apparent autoimmune reactions occur during the infection, or in the post-infection stages. A range of immunological mechanisms accounts for these processes. Many infectious agents will give rise to immune complexes of microbial antigen-antibody-complement, and these immune complexes may circulate and lodge in capillary beds of the eye, skin, joint, glomerulus or brain. Clinically, we can recognize immune complex glomerulonephritis, uveitis or polyarthritis that may have arisen secondary to infection. In other instances, an easily identified infection might be associated with the production of antibodies that react with self tissues--to all intents and purposes these are auto-antibodies--but they arise in the presence of an infection.

Particularly good examples of infectious agents that initiate autoimmunity in animals are the arthropod-transmitted infections. In diseases such as leishmaniasis or monocytic ehrlichiosis there are complex multisystemic clinical manifestations. These are often related to over-activity of B lymphocytes, giving rise to the hypergammaglobulinaemia that characterises these infections. Both infections may be characterised by immune complex glomerulonephritis, arthritis or uveitis--and these may involve complexes of leishmanial or ehrlichial antigen and antibody. Animals with these infections may be antinuclear antibody positive, or have Coombs' positive anaemia, or thrombocytopenia with antiplatelet antibodies. The specificity of these anti-red cell and platelet antibodies has not been determined, but these may be truly self-reactive antibodies that recognize self components of the target cells rather than antigens derived from the infectious agent expressed on their surface. This latter phenomenon has been proven in canine Babesia gibsoni infection. The red-cell bound antibodies in these Coombs' positive dogs have been shown to bind to red cell membrane components and not to Babesia antigen.

DISEASES WE CONSIDER TO BE AUTOIMMUNE

At this time in veterinary medicine, we continue to recognize animals that are categorised as having primary, idiopathic autoimmune disease. In these cases there is no apparent underlying cause, no evidence of infection, autoantibodies or autoreactive lymphocytes can be demonstrated to cause tissue pathology, and there is a clinical and immunological response to immuno-suppressive therapy. In this respect, the way that we diagnose and manage such cases is not about to change. What may change, is simply the recognition that many (or all?) of these cases may actually have an infectious trigger that we cannot identify, either because the infection has resolved, or because the infection is difficult to diagnose. There are infectious agents that have a cryptic or latent phase in the host with low numbers of organisms 'hidden' in specific sites within the host. Such infectious agents may cause recurrent disease in the future, given appropriate trigger factors (e.g., stress). Modern diagnostic techniques such as polymerase chain reaction (PCR) testing might enable these hidden agents to be identified, even in their cryptic phase. In animals with immune-mediated haemolytic anaemia or thrombocytopenia, we would now routinely screen for arthropod-borne pathogens by PCR (e.g., Leishmania, Ehrlichia, Anaplasma, Babesia, Rickettsia) if they had traveled to an area in which these diseases were endemic.

HOW DO INFECTIOUS AGENTS TRIGGER AUTOIMMUNITY?

There are a number of possible ways that infection might trigger autoimmunity, and many of these immunological mechanisms have been proven in experimental systems. A very simple mechanism involves polyclonal B cell activation. Many infectious agents have molecules (e.g., bacterial lipopolysaccharide) that are able to bind in a non-specific fashion to B lymphocytes, and to activate these cells. As activation does not occur via the antigen specific B cell receptor (surface antibody), numerous B cells of numerous different antigenic specificities, can be activated. Some of these cells may be potentially autoreactive--so the infection has bypassed the normal immunological control that prevented these cells from becoming activated. In this instance, the patient would develop hypergammaglobulinaemia--and a proportion of this antibody would be autoantibody.

In similar fashion, many microbes express a variety of structural or toxic molecules that are known as 'superantigens' (e.g., staphylococcal enterotoxins). Superantigens are capable of non-specific activation of both T and B lymphocytes--again not via the normal antigen-specific receptor mechanism that would normally stimulate these cells. Lymphocytes of a range of specificities (including autoreactive cells) can be activated by superantigens.

Another potential mechanism is that of 'bystander destruction'. In this case the end effect appears to be autoimmune in nature, but the mechanism does not involve the induction of true self-reactivity. The best example of this effect is that of an infectious agent (e.g., feline haemoplasmas) that are present on the surface of red blood cells. An appropriate immune response to the infectious agent results in inappropriate destruction of the red cell, simply because the organism is attached to it. Preliminary evidence suggests that in feline haemoplasmosis, true erythrocyte membrane-specific autoantibody might also be induced by the infection and contributes to haemolysis (akin to canine B. gibsoni infection).

The most interesting of these mechanisms is 'molecular mimicry'. In this instance the microbe expresses an epitope that is a 'molecular mimic' of an epitope found in self tissue. In the case of a B lymphocyte (or antibody) this might be a relatively large, structural epitope and give rise to 'cross-reactive' antibodies that could bind to either the infectious agent or to the self antigen. For example in neuroborreliosis, anti-Borrelia flagellin antibody cross-reacts with CNS neuroaxonal proteins and may have a role in the pathogenesis of disease.

In the case of T lymphocytes, the molecular mimic would be a small peptide sequence from the microbe that would be able to bind to the T cell receptor of a potentially self-reactive T cell and trigger autoimmunity to the homologous tissue peptide. For example, recent studies have shown that a peptide derived from Borrelia burgdorferi is homologous to a peptide from the self molecule LFA-1, and that an initial reaction to the Borrelia peptide triggers a subsequent autoimmune reaction to the same portion of LFA-1. This accounts for the persistent arthritis in a proportion of patients with borreliosis in which there is no evidence of current infection by PCR of synovial tissue. Such activation of T cells might in fact be relatively easily achieved. Whereas it was once believed that T cells in the body were relatively unique in terms of their antigen specificity, we now know that each T cell might be activated by in the order of 30 different peptides (a phenomenon known as T cell receptor 'degeneracy').

CAN THESE MECHANISMS ACCOUNT FOR SOME CASES OF VACCINE-ASSOCIATED AUTOIMMUNITY?

We now recognize that vaccines (particularly multicomponent, modified live products) appear to be able to trigger a range of immune-mediated and autoimmune diseases. For example, much attention has recently focused on vaccines as an initiator of immune-mediated haemolytic anaemia in the dog. The mechanism by which this effect occurs is not well investigated. In theory, three separate components of the vaccine might be involved. Many vaccines contain adjuvant (particularly alum), the function of which is, in part, to non-specifically activate the immune system. It is theoretically possible that this activation might include autoreactive lymphocytes, and as alum is very effective at stimulating antibody responses, the activation of B cells and their particular helper T cells (Th2 cells) might readily arise.

Another vaccine constituent might be small residual fragments of cell lines or tissue culture proteins in which the viral components were grown. Recent studies have suggested that such remnants of the feline kidney cell line in which some feline viral vaccines are prepared, might trigger autoimmune responses to renal antigens and contribute to feline chronic renal disease. Similar mechanisms might underlie the autoantibody responses to thyroglobulin that occur in vaccinated dogs.

Finally, it is possible that the microbial components of the vaccine might trigger autoimmunity via the mechanisms described above--particularly molecular mimicry. These are testable hypotheses and require further research activity.

References

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