Infection in systemic lupus erythematosus: friend or foe?

Abstract

Infectious agents have long been implicated in the pathogenesis of systemic lupus erythematosus. Common viruses, such as the Epstein-Barr virus, transfusion transmitted virus, parvovirus and cytomegalovirus, have an increased prevalence in patients with systemic lupus erythematosus. They may contribute to disease pathogenesis through triggering autoimmunity via structural or functional molecular mimicry, encoding proteins that induce cross-reactive immune responses to self antigens or modulate antigen processing, activation, or apoptosis of B and T cells, macrophages or dendritic cells. Alternatively, some infectious agents, such as malaria, Toxoplasma gondii and Helicobacter pylori, may have a protective effect. Vaccinations may play dual roles by protecting against friend and foe alike.

Figure 1. Molecular mimicry in virus induced autoimmunity

Viruses can influence adaptive immunity through molecular mimicry (i.e., homology between exogenous and endogenous epitopes). Peptide sequences common to a virus (e.g., EBV protein) and a target lupus autoantigen (e.g., Sm) can induce autoantibodies [2,3]. HIV tat upregulates Rab4 producing functional mimicry [4]. EBV protein regulates apoptosis by making a bcl-2-like protein, which is also an example of functional mimicry. EBV: Epstein–Barr virus; TTV: Transfusion-transmitted virus.

Figure 2. Role of interferons in virus-induced autoimmune disease

Cells recognize PAMPs using pathogen recognition receptors such as TLRs. Necrotic debris from the apoptotic pathways, bacterial lipopolysaccharide, viral RNA and viral DNA act on TLRs. Plasmacytoid dendritic cells produces type 1 IFNs, which are important in host defense against viruses, and there is overproduction of IFNs in systemic lupus erythematosus. TLRs activate plasmacytoid dendritic cells leading to the release of IFN-α/β. IFN-α results in the maturation of antigen presenting cells and augmented T-cell activation, including excessive helper activity. Natural killer cells produce significant amounts of cytokines, for example IFN-γ, that can influence the development of T cells [7]. IFN: Interferon; PAMP: Pathogen-associated molecular patterns; TLR: Toll-like receptor.

Figure 3. Mechanisms by which infectious agents induce or protect against systemic lupus erythematosus

Infectious agents lead to the pathogenesis of SLE through several mechanisms, including molecular mimicry, apoptosis (programmed cell death) and IFN-α. On the other hand, some infections, such as malaria, can act as protective agents. Vaccinations may act as protective agents by preventing some of the infections that can induce SLE. IFN-β and IFN-γ may also have a protective effect. SLE: Systemic lupus erythematosus.

Figure 4. Regulation of apoptosis pathways by viral proteins

Oxidants, ultraviolet light and corticosteroids trigger apoptosis by damage of mitochondria, which in turn leads to caspase activating factors. This process is inhibited by viral bcl-2 and its homologs. Release of ROIs causes increased production of Fas ligand and DNA fragmentation. HIV-1 tat increases mitochondrial ROI production, thereby increasing apoptosis. The tat protein induces oxidative stress and increases surface expression of Fas ligand resulting in accelerated signaling through the Fas pathway. ROI: Reactive oxygen intermediate.