There are many indications that environmental factors also are involved in the pathogenesis of SLE.
• Exposure to UV light exacerbates the disease in many individuals. UV irradiation may induce apoptosis and also may alter DNA and make it immunogenic, perhaps http://ebooksmedicine.net by enhancing its recognition by TLRs. In addition, UV light may modulate the immune response, for example, by stimulating keratinocytes to produce IL-1, a cytokine that promotes inflammation.
The gender bias of SLE is partly attributable to actions of sex hormones and partly related to genes on the X chromosome, independent of hormone effects.
Drugs such as hydralazine, procainamide, and D-penicillamine can induce an SLE-like disorder.
Recent studies in animal models and patients have revealed several immunologic aberrations that collectively may result in the persistent and uncontrolled activation of self-reactive lymphocytes.
Failure of self-tolerance in B cells results from defective elimination of self-reactive B cells in the bone marrow or defects in peripheral tolerance mechanisms.
CD4+ helper T cells specific for nucleosomal antigens also escape tolerance and contribute to the production of high-affinity pathogenic autoantibodies. The autoantibodies in SLE show characteristics of T cell–dependent antibodies produced in germinal centers, and increased numbers of follicular helper T cells have been detected in the blood of SLE patients.
Type I interferons. Blood cells show a striking molecular signature that indicates exposure to interferon-α (IFNα), a type I interferon that is produced mainly by plasmacytoid DCs. Some studies have shown that such cells from SLE patients produce abnormally large amounts of IFN-α.
TLR signals. Studies in animal models have shown that TLRs that recognize DNA and RNA, notably the DNA-recognizing TLR9 and the RNA-recognizing TLR7, produce signals that activate B cells specific for self nuclear antigens.
Other cytokines that may play a role in unregulated B-cell activation include the TNF family member BAFF, which promotes survival of B cells. In some patients and animal models, increased production of BAFF has been reported, and this has led to modest success of an antibody that blocks BAFF as a therapy for SLE.
It is clear from this discussion that the immunologic abnormalities in SLE—both documented and postulated—are varied and complex. Nevertheless, an attempt can be made to synthesize results from human studies and animal models into a hypothetical model of the pathogenesis of SLE (
Fig. 5.23 ). UV irradiation and other environmental insults lead to the apoptosis of cells. Inadequate clearance of the nuclei of these cells results in a large burden of nuclear antigens. Underlying abnormalities in B lymphocytes and T lymphocytes are responsible for defective tolerance, because of which self-reactive lymphocytes survive and remain functional. These lymphocytes are stimulated by nuclear self antigens, and antibodies are produced against the antigens. Complexes of the antigens and antibodies bind to Fc receptors on B cells and dendritic cells, and may be internalized. The nucleic acid components engage TLRs and stimulate B cells to produce more auto-antibodies. TLR stimuli also activate dendritic cells to
SUSCEPTIBILITY EXTERNAL TRIGGERS GENES (e.g., UV radiation)
Defective clearance of apoptotic bodies
B and T cells specific for Increased burden of self nuclear antigens nuclear antigens