Infektion osuus autoimmuunitaudeissa:
The role of infections in autoimmune disease
4 © 2008 British Society for Immunology,
Clinical and Experimental Immunology, 155: 1?15
A. M. Ercolini and S. D. Miller
Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Feinberg School of
Medicine, Chicago, IL, USA
Autoimmunity occurs when the immune system recognizes and attacks host tissue. In addition to genetic factors, environmental triggers (in particular viruses, bacteria and other infectious pathogens) are thought to play a major role in the development of autoimmune diseases. In this review, we (i) describe the ways in which an infectious agent can initiate or exacerbate autoimmunity; (ii) discuss the evidence linking certain infectious agents to autoimmune diseases in humans; and (iii) describe the animal models used to study the link between infection and autoimmunity.
Keywords: autoimmune disease, molecular mimicry, virus infection
Accepted for publication 27 October 2008
Correspondence: S. D. Miller, Department of
University, Tarry 6-718, 303 E. Chicago Avenue,
Chicago, IL 60611, USA.
There are more than 80 identified autoimmune diseases . Multiple factors are thought to contribute to the development of immune response to self, including genetics, age and environment. In particular, viruses, bacteria and other infectious pathogens are the major postulated environmental triggers of autoimmunity. Multiple arms of the immune system may be involved in autoimmune pathology. Antigens are taken up by antigenpresenting cells (APCs) such as dendritic cells (DCs) and processed into peptides which are loaded onto major histocompatibility complex (MHC) molecules for presentation to T cells via clonotypic T cell receptors (TCRs). Cytolytic T cells (Tc, activated by MHC Class I on APC) can directly lyse a target, while T helper cells (Th, activated by MHC class II) release cytokines that can have direct effects or can activate macrophages, monocytes and B cells. B cells themselves have surface receptors that can bind surface antigens. Upon receiving signals from Th cells, the B cell secretes antibodies specific for the antigens. Antibody may bind its specific target alone or may bind to and activate macrophages simultaneously via the Fc receptor.
There are multiple mechanisms by which host infection by a pathogen can lead to autoimmunity (Fig. 1). The pathogen may carry elements that are similar enough in amino acid sequence or structure to self-antigen that the pathogen acts as a self-?mimic?. Termed ?molecular mimicry?, T or B cells that are activated in response to the pathogen are also crossreactive to self and lead to direct damage and further activation of other arms of the immune system. The pathogenmay also lead to disease via epitope spreading. In this model the immune response to a persisting pathogen, or direct lysis by the persisting pathogen, causes damage to self-tissue. Antigens released from damaged tissue are taken up by APCs, and this initiates a self-specific immune response. ?Bystander activation? describes an indirect or non-specific activation of autoimmune cells caused by the inflammatory environment present during infection. A domino effect can occur, where the non-specific activation of one armof the immune system leads to the activation of other arms. Lastly, infection may lead autoimmunity through the processing and presentation of ?cryptic antigens?. In contrast to dominant antigenic determinants, subdominant cryptic antigens are normally invisible to the immune system. The inflammatory environment that arises after infection can induce increased protease production and differential processing of released self-epitopes by APCs.
In this review, we discuss the evidence available for the involvement of specific pathogens in the initiation or exacerbation of representative autoimmune diseases. As will be mentioned, there is evidence for the involvement of different arms of the immune systems by many mechanisms, in both human disease and in animal models.
In the United States, Lyme disease is caused by the tick-borne spirochete Borrelia burgdorfeii (Bb). Sixty per cent of untreated patients develop arthritis that can last for several years, mainly in large joints such as the knee . These patients have high titres of Bb-specific antibodies, and Bb DNA can be detected in the joint fluid by PCR . Treatment of these patients with antibiotics usually ameliorates the arthritis, which indicates that bystander inflammatory response to the spirochete is responsible for early Lyme arthritis .A subset of patients will progress from acute to chronic arthritis despite treatment with antibiotics and lack of detectable Bb DNA in synovial fluid [85?87]. Antibioticresistant Lyme arthritis is associated with the MHC class II alleles human leucocyte antigen (HLA)-DRB1*0401, *0101 and *0404, indicating that its mechanism is T cell-mediated and distinct from acute Lyme arthritis .
Cellular and humoral responses to outer surface protein A (OspA) of Bb develop in around 70% of patients with antibiotic-resistant Lyme arthritis, often at the beginning of prolonged arthritic episodes [89?92]. T cell and humoral responses to OspA, but not to other spirochete antigens, were found to correlate with the presence or severity of arthritis [92,93]. Specifically, antibiotic-resistant patients responded preferentially to the T cell epitope OspA165?173, and T cells responsive to this epitope were expanded in the joint fluid compared with peripheral blood in HLA-DRB1*0401-positive patients [89,94,95]. An initial computer algorithm search identified lymphocyte function-associated antigen (LFA)1aL332?340, a peptide derived from the light chain of human leucocyte adhesion molecule, as homologous to OspA165?173, and able to bind HLA-DRB1*0401 . Synovial fluid mononuclear cells from patients with antibiotic-resistant arthritis produced IFN-g in response to both OspA165?173 and LFA1aL332?340, suggesting that mimicry between these two proteins may cause the inflammation associated with arthritis. LFA-1a has also been identified in the synovia of patients with antibiotic- resistant Lyme arthritis .
However, other studies showed that in treatment-resistant patients, LFA1aL332?340 was a weak agonist for OspA165?173- specific T cells and mainly induced the Th2-type cytokine IL-13 . LFA1aL332?340 binds well to HLA-DRB*0401, but not to the more commonly associated allele HLADRB1* 0101 . In addition, although cross-reactive T cells were identified in the majority of patients in one study, there was no correlation between T cell response to LFA1aL332?340 and clinical status . These studies weaken the argument that LFA1aL332?340 cross-reactivity is important in the pathology of antibiotic-resistant Lyme arthritis. On the other hand, Maier et al. identified 15 other human and murine selfpeptides that could stimulate an OspA165?173-specific T cell hybridoma , so other peptides may prove to be more important in disease pathology.
There are several rodent models in which arthritis is induced upon infection with Bb [102?105]. In C3H mice, joints are infiltrated with neutrophils 10?14 days after infection and, at the peak of arthritis (3?5 weeks), synovial lesions show leucocyte infiltration with mononuclear cells . C57BL/6-beige mice, which have impaired macrophage motility and chemotaxis, develop severe arthritis , whereas C57BL/6 mice develop minimal arthritis unless deficient in IL-10 and IL-6 [107,108]. These studies indicate that macrophage-derived anti-inflammatory cytokines protect these mice from severe joint inflammation. Transferring Bb-specific T cells alone in the absence of B cells will exacerbate and accelerate the onset of arthritis in C57/BL6-SCID mice . Rodentmodels are helpful only in studying acute Lyme arthritis, as the arthritis resolves within a few weeks and is not antibiotic-resistant.
Neurological complications, including myelitis and peripheral neuropathy, can occur in 10?12% of untreated patients infected with Bb and can arise even after antibiotic treatment . Patients with chronic neuroborreliosis have been reported to have antibodies reactive to nerve axons in their serum , as well as antibodies and T cells specific for myelin basic protein (MBP) in spinal fluid [112,113]. Patient serum that was reactive to axons and neuroblastoma cells was also cross-reactive with Bb flagellin [111,114]. Next, it was discovered that a mAb for flagellin was cross-reactive with human heat shock protein 60 and with neuroblastoma cell lines [115,116] and slowed neurite outgrowth in culture . Antibody crossreactivity has also been described between human central nervous system (CNS) proteins and Bb OspA . Several host neural peptides were identified as cross-reactive with Bb-specific T cells from CSF of a patient with chronic neuroborreliosis using peptide libraries and biometric data analysis . However, studies such as those in nonhuman primates suggest that bystander inflammatory responses to the persistently infective pathogen may explain more clearly the CNS complications of this disease [120?122].
Multiple sclerosis (MS) is characterized by a loss of the myelin sheath surrounding axons in the CNS . Demyelination is associated with elevated levels of CD4+ T cells specific for major myelin proteins, and the disease is generally thought to be autoimmune [202?204]. Although it is not known precisely what triggers the development of MS, it is well established that relapses or disease flares in patients diagnosed with the relapsing?remitting form of MS are often associated with exogenous infections, particular upper respiratory infections. In total, more than 24 viral agents have been linked to MS [205,206]. Most of the associations have been circumstantial, but some studies have found evidence of specific pathogens in human tissue. Antigens from herpesvirus type 6 were found in MS plaques but not from tissues from other neurological disorders . Similarly, compared with CSF from patients with other neurological diseases, CSF from MS patients was shown to have higher levels of the bacteria Chlamydia pneumoniae . In vitro studies have also provided evidence linking MS and infectious agents. MS patients have activated T cells specific for MBP [209?211]. Eight pathogen-derived peptides, including epitopes from HSV, adenovirus and human papillomavirus, were identified that are able to activate MBP-specific T cell clones derived from MS patients . Significantly, these peptides were found to be presented most efficiently by subtypes of HLA-DR2 that are associated with susceptibility to MS. Despite the difficulty in linking MS to any one pathogen, the amount of epidemiological evidence reported over the years shows that environmental factors play a strong role in disease development, and suggests that a cumulative lifetime exposure to certain microorganisms can influence disease development [213?216]. In addition, a recent study showed that the degree of concordance for monozygotic twins (generally reported at 40% or less) was influenced by environmental factors .
There are numerous rodent models of demyelination which, although not identical to the human disease, are used to study MS. The major infectious models in mice are Theiler?s murine encephalomyelitis virus (TMEV), murine hepatitis virus (MHV) and Semliki Forest virus (SFV). Each has distinct immunopathological mechanisms and illustrate the various potential ways pathogens may induce MS. There are two strains of TMEV (TMEV-DA and TMEV-BeAn) which cause an initial acute grey matter disease followed by a chronic progressive demyelination in the white matter of the spinal chord known as TMEV-induced demyelinating disease (TMEV-IDD) [205,218,219].
Although the two strains induce slightly different diseases, the key characteristics of TMEV-IDD (abnormal gait and spastic hindlimb paralysis) remain the same. Intracerebral (i.c.) injection of virus leads to persistent CNS infection; the level of infectious virus is low during the chronic phase, but abundant amounts of viral RNA and viral antigen can be detected throughout the lifetime of the mouse [220?222]. The immune response is initiated by the presentation of persistent viral antigens by CNS-resident APCs to Th1-type CD4+ T cells, but reactivity to myelin does not appear until after the onset of clinical symptoms (30?35 days post-infection) [223?226]. Thus, TMEV-IDD is caused by epitope spreading from viral determinants to self-myelin determinants. Interestingly, in SJL mice, reactivity appears to multiple myelin peptides starting with the immunodominant epitope and spreading at later time-points to other subdominant myelin determinants in a hierarchical manner [226,227]. In contrast to TMEV, mice inoculated with neurotropic strains of MHV will have a single major symptomatic episode (ataxia, hindlimb paresis, paralysis) from which the majority will recover . CNS infection results in an influx of immune cells that for the most part will clear the virus, although virus does persist in low amounts . Demyelination begins about 1 week post-infection and peaks at week 3, after which lesion repair and remyelination generally occurs [230?232]. The exact mechanism of demyelination in this model is somewhat controversial, but appears to be bystander myelin destruction by the immune response recruited initially to the CNS to control viral infection.There is no evidence of self-specific immunity in the CNS of MHV-infected mice . T and B-cell deficient RAG1-/- mice, which were resistant to demyelination, developed histological disease after adoptive transfer with splenoctyes from MHV-inoculated mice, which involved the recruitment of activated macrophages/microglia to sites of demyelination in the spinal cord . Chemokine receptor knock-out mice (CCR5-/-) showed reduced demyelination that correlated with reducedmacrophage but not T cell infiltration into the CNS of MHV-infected mice . CD4- deficient mice showed less severe disease than CD8-deficient mice [236,237]. Collectively, these studies suggest that macrophages are responsible primarily for myelin destruction in the MHV model, but that T cells are required to recruit macrophages into the CNS. Like MHV, SFV leads to a transient clinical disease [238,239]. The virus is, for the most part, cleared from the CNS by day 6 post-infection, while demyelination peaks at day 14 and then wanes [240,241]. Demyelination is not seen in nude or SCID mice, demonstrating that it is T cell-mediated [240,242]. In BALB/c mice it is thought that demyelination is due to cytolytic damage of virus-infected oligodendrocytes, although this has not been proved definitively. Depletion of CD8+ T cells virtually abolished lesions of demyelination, whereas depletion of CD4+ T cells did not have that effect . Other studies in BALB/c mice have shown that Th1-type cytokines are involved in viral clearance but not demyelination [244,245]. In C57/Bl6 mice, molecular mimicry may also play a role in demyelination. Infected mice have MBP-reactive T cells , and antibodies reactive to MBP and myelin oligodendrocyte protein (MOG) . Computer algorithms uncovered homology between an epitope in the SFV surface protein E2 and MOG18?32 . Mice primed with either peptide develop paralytic symptoms with histopathology resembling that of mice infected with SFV. The authors of that study concluded that the cross- eactive antibody response was mainly responsible for the demyelinating lesions.
Summary and perspectives
The immune system has evolved checks and balances to prevent the destruction of host tissue. It is perhaps not surprising that a strong immune response to an invading pathogen could disrupt this regulation and lead to autoimmunity. As outlined above, there is significant evidence suggesting that different classes of pathogens (bacteria, viruses and parasites) are involved in triggering or propagating selfreactive immune responses. However, the evidence for a definitive link for infection-induced autoimmunity is stronger for certain diseases than for others.
The argument for infection-induced pathology is much stronger for diseases associated with one or two specific pathogens than for diseases with multiple causal associations. For example, the fact that infection with C. jejuni is a common antecedent to GBS makes a strong argument that this disease is infection-triggered. In contrast, for diseases such as TID and MS that have been associated with dozens of pathogens, but none in particular, much more needs to be done to make a convincing case. The most compelling proof would be the disappearance of symptoms with the clearance of the infection. This is the case in Lyme disease, where treatment with antibiotics alleviates acute arthritis.However, as outlined previously in this paper, there are many ways a pathogen can cause disease even after the infection has been cleared. In these cases, epidemiological studies showing that people infected with a particular agent have an increased incidence of these diseases compared with people never infected, while not wholly definitive, would certainly strengthen the infection-induced autoimmunity argument.
In human autoimmune diseases, where direct evidence for a role for a particular pathogen is weak, it is all the more important to have supporting animal models. The strongest support comes from animal models in which infection with the agent thought to induce disease in humans causes similar symptoms in animals, as exemplified by induction of heart disease in mice infected with T. cruzi and CVB and arthritis in mice infected with Bb. In other animal models, disease can be shown to be induced by priming with a pathogen-derived antigen, thus strengthening the argument for the involvement of that pathogen in the human disease. The ability to induce heart disease in rats primed with Streptococcal M protein is strong evidence that S. pyogenes causes heart disease in humans via molecular mimicry. Although the link between S. pyogenes infection and neurological disorders in humans is uncertain, at best, the fact that movement and behaviour disorders can be induced in mice primed with S. pyogenes homogenate also lends credibility to that theory. In cases where it is uncertain whether a disease pathology is actually autoimmune (such as uveitis and myocarditis following CVB infection), animal models have played a crucial role in elucidating the potential mechanisms of disease induction.
The heterogeneity of the human population, rather than the weakness of the data, may be in play in instances where the evidence linking infection and autoimmunity is tenuous or even conflicting. It is not difficult to imagine that some people may be more susceptible to developing autoimmune disease following a particular infection than others, or that mimic peptides derived from different infectious agents may be able to trigger a particular autoimmune disease depending on the ability of the infected individual to present various epitopes in the context of their various HLA molecules. Defining the genetic markers that predispose patients to different autoimmune diseases with a suspected infectious
trigger would be an important contribution to defining the underlying disease pathogenesis.
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