How do autoantigens induce anti-dsDNA antibody production via TLR9 activation?

From the Guidelines

Autoantigens induce anti-dsDNA antibody production via TLR9 activation by mimicking microbial molecules and triggering an aberrant immune response.

Mechanism of Action

• The fundamental driver of SLE is an abnormal immune response against self-antigen, which is hypothesized to develop in part from exposure to unidentified infectious agents 1.
• The aberrant immune response may be mediated by antigen-dependent mechanisms such as molecular mimicry or antigen-independent mechanisms such as interactions between the Toll-like receptors (TLR) of antigen-presenting cells and microbial molecules 1.
• TLR9 is a receptor that recognizes microbial DNA and triggers an immune response, and it is possible that autoantigens mimic microbial molecules and activate TLR9, leading to the production of anti-dsDNA antibodies.

Role of Anti-dsDNA Antibodies

• Anti-dsDNA autoantibodies are listed as one of the classification criteria for systemic lupus erythematosus (SLE) and are relatively effective indicators for monitoring disease activity and treatment response 1.
• However, the use of anti-dsDNA antibodies is not free from controversy, and their determination still lacks proper standardization 1.
• Anti-dsDNA antibodies are a heterogeneous group of antibodies that target multiple and different DNA structures, and their clinical relevance should be established in extensive studies of homogenous cohorts, using standardized assays 1.

Clinical Implications

• The presence of anti-dsDNA autoantibodies is associated with SLE, but also with several other diseases, and their use as a biomarker and pathogenic factor of SLE and lupus nephritis seems to have given rise to a general misconception 1.
• A deeper knowledge of the etiopathogenic role of anti-dsDNA is necessary, and it should be clarified why some patients remain seropositive and asymptomatic 1.

From the Research

Autoantigen Induction of Anti-dsDNA Antibody Production

• Autoantigens, such as double-stranded (ds) DNA, can induce anti-dsDNA antibody production via Toll-like receptor 9 (TLR9) activation 2, 3.
• TLR9 is a receptor for CpG DNA and has been implicated in the activation of autoreactive B cells in vitro 2.
• The generation of anti-dsDNA and antichromatin autoantibodies is specifically inhibited in TLR9-deficient lupus-prone mice, suggesting a critical role for TLR9 in autoantibody formation in vivo 2.

Mechanism of TLR9 Activation

• DNA-specific B cells take up mammalian DNA through their B cell receptor, and this DNA is subsequently transported to an endosomal compartment where it can potentially engage TLR9 4.
• Anti-DNA antibodies can show preference for binding to certain native dsDNA fragments of differing sequence, which can influence autoreactive B cell responses 4.
• The binding preference of anti-DNA antibodies for CpG-rich DNA fragments does not correlate directly with the presence of CpG dinucleotides, suggesting a complex mechanism of TLR9 activation 4.

Role of TLR9 in Autoimmunity

• TLR9 plays a crucial role in the pathology of systemic lupus erythematosus (SLE), and its abnormal expression on peripheral blood B cells is correlated with disease activity 3.
• The interaction between TLR9 and CpG DNA can enhance the production of anti-dsDNA antibody and IL-10, contributing to the development of autoimmunity 3.
• Other TLRs, such as TLR2, may also contribute to autoreactivity to DNA by promoting IL-6 secretion and synergizing with self-DNA in the activation of autoreactive B cells 5.