Autoimmunity to nucleosomes related to viral infection: a focus on hapten-carrier complex formation

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Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disorder with unknown aetiology. The major hallmark of this disease is the presence of antibodies against nuclear components, including double-stranded (ds)DNA and histones. The disease affects different organs, particularly the skin, kidneys and the nervous system. Although the exact molecular mechanisms underlying the pathophysiological processes in SLE remain unknown, several inherent and environmental factors seem to be involved in the ethiopathogenesis of this disorder. Viruses may be one of the factors that induce the production of autoreactive antibodies although the involved mechanisms are still incompletely understood. One proposed mechanism for virus-induced production of autoantibodies is molecular mimicry. Another mechanism derives from studies with the human polyomavirus BK. In these studies, in vivo binding of the polyomaviruses large T-antigen to chromatin of infected cells may render chromatin immunogenic. The large T-antigen–chromatin complex may thus function as a hapten-carrier model with subsequent production of anti-chromatin antibodies, including anti-dsDNA and anti-histones antibodies. This review focuses on the recent findings suggesting that this model may be applicable for other human viruses associated with SLE.

Introduction

Failure in the homeostasis of the immune system can lead to the development of autoimmune diseases. Whereas in a normal immune system host antigens are tolerated or ignored, in autoimmune diseases tolerance or unresponsiveness to self-antigens fails and leads to the activation of self-reactive T cells and the production of autoantibodies. Autoimmunity may be affecting single cell types such as β-cells in the pancreatic islets in insulin-dependent diabetes mellitus or distinctive organ systems such as the central nervous system in multiple sclerosis [1], [2]. In these situations autoantibodies are organ specific and thereby induce a type 2 immune-mediated tissue disease. Autoimmunity can also be more devastating when multiple tissues are involved (e.g. skin, kidneys, and central nervous system) as is the case in systemic lupus erythematosus (SLE) [3].

SLE is an autoimmune disorder with a prevalence of about 1 in 2000 [4]. The disease can manifest at any age but is more prominent at the age of sexual maturation. SLE is predominantly affecting women, with a female to male ratio of >8:1 [5]. The disorder is serologically characterized by the presence of anti-nuclear antibodies including antibodies against the nucleosome. The nucleosome consists of pairs of histone peptides H2A, H2B, H3, and H4 around which double-stranded (ds)DNA is wrapped. Currently, the disease activity in SLE patients is associated with the presence of anti-dsDNA antibodies. These antibodies are therefore used as a diagnostic marker [4], [6]. The progression of the disease is associated with general clinical manifestations and damage to tissue and organs, probably resulting from deposition of immune complexes or by cross-reaction of antibodies directly to tissue antigens [7], [8]. An immunological process that has the potential to induce nephritis may be fatal for the patients.

The aetiology of SLE is poorly understood, but genetic, hormonal, environmental and immunoregulatory factors, as well as infectious agents can contribute to the manifestation of the disease [4], [9], [10], [11], [12], [13], [14]. Genome-wide screens of families predisposed to SLE have shown that multiple genes confer susceptibility to this disorder. Several loci on different chromosomes are associated with SLE, including chromosomes 1, 2, 4, 6, 7, 11–14, 16, 18–20. These possible susceptibility loci for SLE encompass genes encoding factors in the complement pathway, proteins of the human major histocompatibility complex, cytokines, Fc receptors, and apoptosis factors [15]. Dysregulated clearance of apoptotic cells has been suggested to drive the autoimmune reaction in SLE patients. The aberrant clearance of apoptotic cells might expose otherwise inaccessible immunogens, like nucleosomal fragments, to the immune system [16]. Furthermore, it is well established that sex hormones, such as oestrogens, are involved in the development or the susceptibility of the disease [4], [17]. The dysfunction of T cell oestrogen receptors has been suggested for female SLE patients [18]. In addition, environmental factors like ultra-violet (UV) light and viral infections may cause exacerbation of the disease [19], [20].

The disorder is characterized by its humoral and cell-mediated autoimmunity to cell nuclear antigens. More specifically, it has become clear that the nucleosome is the major autoantigen that drives this T cell-dependent autoimmune response. Nevertheless, our knowledge on the molecular mechanisms that contribute to the production of autoantibodies and the development of the disease is still limited. However, changes in the control of autoimmune B and T cells, Ca2+concentrations, cAMP/cAMP-dependent protein kinase activities, and mitogen-activated protein kinase signalling in B and T cells may account for impaired immune responses in SLE patients [17], [21], [22], [23], [24], [25]. Some of these mechanisms may explain the effect of distinct environmental factors such as UV light. UV light can induce apoptosis through activation of the mitogen-activated protein kinase signalling pathway, which can be associated with degradation of autoantigens and subsequent exposure of novel or cryptic antigenic determinants [17], [25].

Section snippets

Viruses as environmental triggers of autoimmunity

The effect of a viral infection depends on the subtle balance between the possibility of the virus to replicate and the capacity of the host to eliminate the virus by developing a protective immune response. The outcome between viral spread and the control of the virus by the immune response determines whether the virus will be eliminated or if the infected host cells will show pathological features due to protective immune responses. Although some viruses can trigger diseases in the majority

Infection-related initiation of autoimmunity

The immune system has developed diverse mechanisms to maintain self-tolerance despite its continuous exposure to self-antigen, while preserving the capacity to respond to a diverse array of pathogens. Breaking this self-tolerance is a critical event leading to autoimmune diseases. Viruses and other infectious agents have been implicated in triggering the loss of self-tolerance, although precise mechanisms remain unclear. Several mechanisms have evolved from studies mostly based on animal

Mechanisms for virus-induced autoimmunity

The two most common strategies used by the immune system to clear viruses are illustrated in Fig. 1. In the first mechanism, a virus may infect a host cell and viral protein fragments will be presented in complex with MHC class I on the surface of the infected cells (Fig. 1A). These complexes are recognized by specific T cell receptors of cytotoxic T cells (TC) together with the CD8 T cell surface protein. The TCcell will then destroy the infected cell. Alternatively, an antigen presenting cell

Viruses associated with SLE

Several viruses have been suggested to inflict the development of SLE and humoral autoimmunity (see Table 1). Two major mechanisms for such virus-induced autoimmunity have been proposed. One mechanism, molecular mimicry, implies that viral proteins share antigenic determinants similar with host proteins. If B cells recognize this determinant within the viral polypeptide chain, they bind, internalize and present genuine non-self peptides derived from this viral protein to specific T cells

The biology of the human polyomaviruses BK and JC

The human polyomaviruses BK and JC are small dsDNA viruses that were named after the initials of the patients in which these viruses were first isolated. Almost the entire human population is infected with one or both of these viruses as shown by serological studies. Primary infection occurs predominantly during childhood and seems, with few exceptions, to be asymptomatic. Primary infection is normally followed by a life-long silent persistence or latency. Neither the route of infection, nor

Human polyomaviruses and autoimmunity to nucleosomes

Worldwide serological studies have shown that by the age of 10, antibodies against the major capsid protein VP1 could be detected in 63–100% of the children examined. However, less than 1% of the humans are seropositive for LT-ag [53]. In an initial experiment aimed at raising antibodies against BKV, autoantibodies against DNA and histones were observed in the sera of immunologically normal rabbits inoculated with purified BKV [91]. DNA is known to be a poor antibody-inducing molecule. In order

Clinical studies of polyomavirus infection and autoimmunity to nucleosomes

Because anti-dsDNA antibodies are a hallmark for SLE and human polyomaviruses are common in the human population, we investigated whether these viruses could be involved in the induction of autoantibodies in SLE patients. Hence, 20 patients were followed over a 1-year observation period for reactivation of BKV or JCV. Sixteen of twenty (80%) patients had one or several episodes of BKV (12 patients) or JCV (4 patients) reactivation, while no viral reactivation was observed in the matched control

Viral DNA-binding proteins and autoantibodies: lessons from other human viruses

Is the mechanism for induction of anti-DNA antibodies by a viral DNA-binding protein described for human polyomaviruses specific for these viruses or is it a common process linked to particular viruses that encode DNA or nucleosome-binding proteins? Table 1 presents viruses that have been reported to be associated with SLE and that encode proven or putative DNA-binding proteins. So far, it has not been investigated whether the expression of these proteins in human is linked to the development

Conclusions

In conclusion, data from several laboratories have provided two models that may explain infection-induced autoimmunity. One mechanism, known as molecular mimicry, assumes the presence of self-determinants within non-self polypeptides (cognate intramolecular help). Another mechanism, referred to as hapten-carrier model, implies a complex of self and non-self determinants localized on separate molecules (intermolecular help). This review focused on the latter model that is illustrated by studies

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