Figure 4.

The relationships between LTA4H gene polymorphisms, the LXA₄/LTB₄ ratios and TNF-α production to the outcome of Mycobacterium leprae infection. (A) Individuals homozygous for LTA4H locus with two low activity alleles display a higher concentration of LXA₄ than LTB₄ (high LXA₄/LTB₄ ratio). This would impair the production of TNF-α resulting in increased susceptibility to M. leprae. The higher levels of LXA₄ not only inhibit the expression of TNFA but also block the immune-inflammatory responses. In addition, the lower levels of TNF-α do not stimulate the expression of LTA4H and therefore do not increase the synthesis of LTB₄. (B) Subjects homozygous for LTA4H locus with two high activity alleles display a higher concentration of LTB₄ than LXA₄ (low LXA₄/LTB₄ ratio). The increased abundance of LTB₄ stimulates the expression of TNFA and production of TNF-α. Increased levels of TNF-α further enhance expression of LTA4H. Thus, an intense immune-inflammatory response to M. leprae would occur resulting in damage to the host tissue. (C) Individuals heterozygous for LTA4H locus, with a high and a low activity allele, synthesize a balanced amount of LXA₄ and LTB₄ (moderated LXA₄/LTB₄). This results in the production of TNF-α to levels that promote an effective immune-inflammatory response against M. leprae and promote a balance in the LXA₄/LTB₄ ratio. This balance in product abundance or gene expression is represented by the purple font. The red font represents an increased abundance of a product or increased gene expression, while the blue font symbolizes an attenuation of product abundance or gene expression. Arrows with solid lines indicate that the production of a lipid mediator or cytokine is favored, while an arrow with a hashed line indicates that the production is not favored. (⊢)Indicates that LXA₄ attenuates or impairs the expression of TNF-α.