Drugs

Procainamide and hydralazine have been linked conclusively to SLE; the resulting syndrome is called ‘drug-induced lupus’ . Human and mouse models have shown that these drugs may cause epigenetic modifications, including decreased DNA methylation. These epigenetic changes can induce autoreactivity in CD4 ⁺ T cells and the expression of anti-nuclear factors, resulting in signs and symptoms of SLE .

More recently, a new variety of drugs, the anti-tumour necrosis factor-alpha (TNF-alpha) blockers, have been used to treat autoimmune diseases such as RA and ankylosing spondylitis. Although these drugs are used in autoimmune conditions, paradoxically, due to the role of TNF-alpha as regulator of the immune system, these drugs can deregulate the immune system, inducing autoantibodies, as anti-nuclear antibodies (ANAs), anti-double-stranded DNA (dsDNA), anti-nucleosomes and anti-cardiolipin . However, while the infliximab (an anti-TNF-alpha monoclonal antibody) causes a higher incidence of autoantibodies than other anti-TNF-alpha drugs (etanercept and adalimumab), the occurrence of clinical manifestations of lupus (fever, skin rash, arthralgias, malaise and leucocytoclastic vasculitis) is similar with all anti-TNF-alpha drugs .

Infectious agents

A number of mechanisms by which an infection can lead to an autoimmune process have been described, such as molecular mimicry, activation of T cells by microbial superantigens and expansion of previously activated T cells at an inflammatory site (bystander activation) . These mechanisms are not mutually exclusive; for instance, molecular mimicry can trigger the initial activation of autoreactive T cells and/or induce expansion of a memory T-cell population, while superantigens can reactivate autoreactive T cells and induce relapses .

A classic example of molecular mimicry inducing autoimmune disease is rheumatic fever. In this disease, pharyngeal infection with group A streptococci in a susceptible host is followed by an autoimmune response, which is caused by cross-reactivity between host (human) epitopes and similar epitopes in the infectious organism. This results in an acute febrile illness that can involve the heart, joints and/or central nervous system . The streptococcal M protein has significant sequence homology with several human proteins, the best studied of which is cardiac myosin. However, cross-reactivity of the M protein with other structurally related proteins, including tropomyosin, laminin and keratin, may also be relevant .

Molecular mimicry may also be involved in one of the most studied associations between infection and autoimmune disease, which is that of Epstein–Barr virus (EBV) infection and SLE, respectively. EBV has been associated with autoimmune diseases since 1971, when a high prevalence of EBV infection was observed among SLE patients . EBV infection may contribute to the pathogenesis of SLE via molecular mimicry. Specifically, EBV’s nuclear antigen 1 (EBVNA-1) can initiate the production of lupus-associated autoantibodies, such as anti-Sm and anti-Ro .

Microbial superantigens can stimulate a high proportion of T cells without the need for antigen processing by non-specifically binding to the variable domain of the T-cell receptor (TCR)-beta chain. At the same time, superantigens bind to major histocompatibility (MHC) class II molecules, resulting in a non-specific immune response . Previous studies have shown that microbial superantigens may play a role in the pathogenesis of RA, psoriatic arthropathy and SLE .

Animal studies have demonstrated the importance of bystander activation. The loss of tolerance for T cells and the development of autoimmune diseases can be virally induced by tissue damage with the release of sequestered antigen, which activates non-antigen-specific autoreactive lymphocyte clones that were not directly involved in the initial reactivity to the virus . This mechanism underlies the encephalomyelitis induced in mice by Theiler’s murine encephalomyelitis virus and the type 1 diabetes induced by coxsackie B4 virus .

Smoking

Cigarette smoking affects both the cell-mediated and humoural immune responses, inducing the release of TNF-alpha, TNF-alpha receptors, interleukin (IL)-1, IL-6, IL-8 and granulocyte-macrophage colony-stimulating factor . On the other hand, smoking has also been associated with decreased IL-6 production through Toll-like receptors (TLR) 2 and 9, decreased IL-10 production via TLR-2 activation and decreased IL-1b, IL-2, TNF-alpha and IFN-gamma production by mononuclear cells .

The mechanism through which smoking leads to autoimmune diseases is not fully known, but some potential mechanisms have been proposed . The release of intracellular antigens via tissue hypoxia or toxin-mediated cellular necrosis may precipitate an immune reaction in susceptible individuals. Smoking may also augment B-cell autoreactivity and stimulate the proliferation of peripheral T-lymphocytes.

Although some studies present conflicting evidence regarding the role of cigarette smoking in the development and severity of autoimmune disease, strong evidence links smoking to diseases such as RA and SLE . Epidemiological studies suggest that smoking is an independent risk factor for RA, particularly in rheumatoid factor-positive individuals . Smokers with RA also appear likely to have more severe disease . A possible mechanism is that long-term exposure to cigarette smoke induces mechanisms that accelerate deimination of arginine to citrulline in pulmonary autoantigens, possibly via up-regulation of peptidylarginine–deiminase activity in macrophages . In genetically susceptible individuals, the presence of antibodies to citrullinated protein antigens may be accompanied by an increase in proinflammatory cytokines without clinical signs of disease .

Smoking has been studied as an environmental risk factor for the development of SLE , and it appears to be a more significant risk factor in patients with the HLA-DR3 allele . Investigators have demonstrated that current smokers with SLE have significantly higher disease activity, higher titres of anti-double-stranded DNA, more serious cutaneous involvement and more frequent episodes of pleuritis, peritonitis and neuropsychiatric symptoms than former smokers or never-smokers .

Vaccination and adjuvants

A relationship between vaccines and autoimmune diseases has been described, but a mechanism for this relationship has never been clearly elucidated. Molecular mimicry and/or bystander activation may be involved, much like the mechanisms which cause the autoimmune diseases associated with infectious agents . To establish the association of vaccination with an autoimmune condition, a temporal relationship must exist. This time period has been generally defined to occur within a few weeks following vaccination; however, it has recently been suggested that vaccine-related autoimmune disease can develop months or years after vaccination .

There are almost 25 cases in the literature relating SLE and vaccination. The vaccines described in these reports include parenteral typhoid-paratyphoid A and B, scarlet fever Streptococcus toxin and hepatitis B . More recently, the existence of a new syndrome, referred to as ‘ASIA’ (autoimmune/inflammatory syndrome induced by adjuvants), has been proposed. ASIA includes siliconosis, Gulf War syndrome, macrophagic myofasciitis syndrome and post-vaccination phenomena . Adjuvants increase innate immune responses by mimicking evolutionarily conserved molecules and binding to Toll-like receptors. In addition, adjuvants augment the activities of dendritic cells, lymphocytes and macrophages and activate the intracellular Nalp3 inflammasome system . An example of an adjuvant acting as a trigger of autoimmune disease is tetramethylpentadecane (pristane), which is capable of inducing a lupus-like disease in a murine model .

Those authors described many clinical similarities among these four conditions, including adjuvant effects. The proposed criteria for the diagnosis of ASIA are shown in Table 1 .

Other factors

Occupational exposures also have been related to autoimmune conditions. For example, exposure to silica has been associated with the development of RA, SLE and systemic sclerosis . Silica is cytotoxic and produces inflammation in the lungs, causing a loss of self-tolerance and the production of autoantibodies .

In SLE, sunlight exposure can both trigger the disease and exacerbate it . In addition, there are many reports of oestrogen exacerbating SLE or increasing the risk of developing the disease. In the Nurses’ Health Study, oral contraceptive use and the use of postmenopausal hormone replacement therapy were associated with an increased risk of developing SLE .

The effects of vitamin D have been broadly studied, especially non-calcaemic effects, such as modulation of the immune response, effect observed in RA, SLE, multiple sclerosis and autoimmune thyroid diseases . An interesting example is the association of vitamin D and anti-phospholipid syndrome (APS) identified by Agmon-Levin and colleagues . The authors were able to demonstrate significantly lower vitamin D levels in APS patients than controls, and the lower serum levels of vitamin D correlated with thrombotic events . The physiopathological link between vitamin D and thrombotic events in APS patients was demonstrated in the same study, with vitamin D operating as a potent inhibitor of anti-β2GPI, antibody considered pathogenic, interfering with homeostasis of the endothelial cells and platelets .

Studies suggest that stress can exacerbate autoimmune disease; in turn, disease exacerbations may provoke additional stress in patients . Presumably, stress triggers the release of neuroendocrine hormones. Increased levels of these hormones may lead to immune deregulation by altering or amplifying cytokine production, thereby resulting in autoimmune diseases. Various transmitters in the neuroendocrine-immune network have been implicated in the development of autoimmunity, including the following: epinephrine, norepinephrine, acetylcholine, substance P, vasoactive intestinal peptide, glucagon, insulin, cytokines, growth factors and many other substances . Unfortunately, a vicious cycle is created by not only the stress-causing disease but also the disease itself causing a great deal of stress in patients. Stress levels and general socio-psychological factors have a major impact on the severity of pain and social functioning in patients with autoimmune diseases. The quality of family relationships and other social factors have been found to be useful prognostic factors in patients with RA .