15-25 Infection can lead to autoimmune disease by providing an environment that promotes lymphocyte activation.
How might pathogens contribute to autoimmunity? While an infection is in progress, inflammatory mediators released from activated antigen-presenting cells and lymphocytes and the increased expression of co-stimulatory molecules can affect so-called bystander cells—lymphocytes that are not themselves specific for the antigens of the infectious agent. Self-reactive lymphocytes can become activated in these circumstances, particularly if tissue destruction by the infection leads to an increase in the availability of the self antigen (Fig. 15.42, left panels). Furthermore, pro-inflammatory cytokines, such as IL-1 and IL-6, impair the suppressive activity of regulatory T cells, allowing self-reactive naive T cells to become activated to differentiate into effector T cells that can initiate an autoimmune response.
The perpetuation or exacerbation of autoimmune disease by viral or bacterial infections has been shown in experimental animal models. For example, the severity of type 1 diabetes in NOD mice is exacerbated by Coxsackie virus B4 infection, which leads to inflammation, tissue damage, the release of sequestered islet antigens, and the generation of autoreactive T cells.
We discussed earlier the ability of self ligands such as unmethylated CpG DNA and RNA to directly activate autoreactive B cells via their TLRs and thus break self-tolerance (see Section 15-4 and Fig. 15.25). Microbial ligands for TLRs may also promote autoimmunity by stimulating dendritic cells and macrophages to produce large quantities of cytokines that cause local inflammation and help stimulate already activated autoreactive T and B cells. This mechanism might be relevant to the flare-ups of inflammation that follow infection in patients with autoimmune vasculitis associated with anti-neutrophil cytoplasmic antibodies.
One example of how TLR ligands can induce local inflammation derives from an animal model of arthritis in which injection of bacterial CpG DNA, which is recognized by TLR-9, into the joints of mice induces an arthritis characterized by macrophage infiltration. These macrophages express chemokine receptors on their surface and produce large amounts of CC chemokines, which promote leukocyte recruitment to the site of injection.
and self molecules can lead to antiself responses and autoimmune disease.
Infection with certain pathogens is associated with autoimmune sequelae. Some pathogens express antigens that resemble host molecules, a phenomenon called molecular mimicry. In such cases, antibodies produced against a pathogen epitope may cross-react with a self molecule (see Fig. 15.42, right panels). Such structures do not necessarily have to be identical: it is sufficient that they be similar enough to be recognized by the same antibody. Molecular mimicry may also activate autoreactive T cells and result in an attack on self tissues if a processed peptide from a pathogen antigen is similar to a host peptide. A model system to demonstrate molecular mimicry has been generated by using transgenic mice expressing a viral antigen in the pancreas.
Inject LCMV into mouse. NP-speciÿc CD8 T cells are activated by LCMV infection Activated CD8 T cells inÿltrate islets and kill ˜ cells expressing NP; this results in diabetes Make transgenic mice that express NP only in the pancreatic ˜ cells pancreas NP is expressed only in ˜ cells and provokes no T-cell response
Normally, there is no response to this virus-derived ‘self’ antigen, but upon infection with the virus that was the source of the transgenic antigen, mice develop diabetes, because the virus activates T cells that are cross-reactive with the ‘self’ viral antigen (Fig.15.43).