Toll-like Receptor 2 Induces Th17 Myeloperoxidase Autoimmunity While Toll-like Receptor 9 Drives Th1 Autoimmunity in Murine Vasculitis (1)
When T-cells are activated, CD4 cells differentiate into subsets (Th1, Th2, and Th17) that recruit different immune effector cells andresult in different patterns of organ injury. Both Th1 and Th17 cells have been implicated in the development of autoimmunity and organ inflammation.
In anti-neutrophil cytoplasmic antibody–associated vasculitis (AAV), the cytokine profile suggests that Th1 responses drive MPO ANCA autoimmunity. However, patients with AAV have increased numbers of Th17-producing lymphocytes,and Th17-associated serum cytokine levels correlate with disease activity. TLR activation can exacerbate autoimmunity in clinical and experimental settings, including vasculitis and renal diseases. TLRs provide a link between infection and disease initiation and relapse in AAV, potentially as a conse-quence of enhanced adaptive autoimmunity.
NOTE: Since LPS is an activator of TLR4, activators to TLR2 and TLR9 may be more efficient to induce autoimmune diseases in mice.
Wild-type mice were immunized with MPO alone, MPO and TLR-2 ligand, Pam3CSK4, or MPO and TLR-9 ligand,CpG ODN, and assessed 6 days and 28 days later. TLR-2 ligand induced IL-2 and IL-17 on day 6, and TLR-9 ligand induced IL-2 and IFN-g significantly. Immunization with the combination of a TLR ligand and MPO was necessary for increased immune response and
renal injury. The results indicated that the linking macrophages to Th1-mediated proliferative glomerulonephritis and neutrophils to Th17-mediated glomerulonephritis. Treating mice immunized with MPO and TLR-2 ligands with anti-IFN mAb did not influence disease. Similarly, treating mice immunized with MPO and TLR-9 ligand with anti–IL-17A mAb did not attenuate renal injury, confirming the specificity of these responses.
IgG subclass analyses demonstrated increased IgG1 responses in mice immunized with MPO and TLR-2 ligand, while immunization with MPO and TLR-9 ligand induced the Th1-associated antibody subclasses IgG2b and IgG2c.
Mice were immunized with MPO alone, MPO and TLR-2 ligand, or MPO and TLR-9 ligand. On day 14, when autoimmune responses had developed, mice were injected with sheep anti-mouse GBM globulin. Experiments ended 4 days later. The mice immunized with MPO alone did not develop an increase in albuminuria and demonstrated similar mild histologic injury. However, immunization with MPO and TLR-2 ligand or MPO and TLR-9 ligand resulted in significant histologic and functional renal injury, with increased albuminuria, abnormal glomeruli, and glomerular fibrin deposition. The TLR-9 ligand may have more potential to induce the nephritogenic effects.
Infection with gram-positive organisms, in- cluding Staphylococcus aureus, can ligate TLR-2, which potentially enhances innate and adaptive immune responses. In fact, ligation of TLR-2 can exacerbate experi- mental autoimmune encephalomyelitis. Hypomethylated DNA from bacterial or viral microbes can ligate TLR-9, which subsequently results in DC activation and the promotion of Th1-polarized adaptive immune responses. TLR-9 is expressed on B cells and can influence humoral autoimmunity.