Figure 9.

Illustration of the possible immunopathogenesis of erythema nodosum leprosum (ENL) based on the present findings. Based on the finding of this study, the immunopathogenesis of ENL can be illustrated using the following key steps: (1) spontaneous activation of T-cells leading to activation of macrophages that are already loaded with intact Mycobacterium leprae. Then, the activation of macrophages produces three key events: processing M. leprae and releasing of the processed antigens; antigen presentation to Th1 and production of pro-inflammatory cytokines such as IFN-γ and TNF-α and other inflammatory molecules. The causes of spontaneous T-cell activation should be investigated in the future. (2) Antigen presentation to Th1 stimulates Th1 to produce chemokines, which recruits macrophages to the site of antigen deposition, pro-inflammatory cytokines (IFN-γ, TNF-α), and other inflammatory mediators that increase expression of vascular adhesion molecules. (3) The processed and released antigens bind to the presynthesized antibody leading to antigen–antibody complex formation, which in turn recruits C1q complement and hence immune-complex formation. Following the immune-complex formation, neutrophils will be recruited to the site of immune-complexes. (4) Once immune-complex is formed, it amplifies the immune response which leads to aggressive antigen presentation, immunoglobulin synthesis, and activation of other inflammatory T-cells. (5) The pro-inflammatory cytokines and other inflammatory molecules released from macrophages, Th17, and Th1 and the immune-complex formation beyond clearance lead to tissue damage as sketched above.