02578nas a2200301   4500000000100000008004100001260001600042653001200058653002900070653002500099653002200124653004600146100002200192700001800214700001500232700001400247700001600261700001400277700001500291700002000306700001400326700002000340700001500360245010600375300001100481520177000492022001402262       2025                            d  bElsevier BV10aLeprosy10aTLR1/2-driven macrophage10aHost immune response10aImmune modulation10aPaucibacillary and multibacillary leprosy1 aChebli-de-Abreu N1 aCarvalho AMRS1 aMenezes YR1 aMacedo JM1 aFrança SDT1 aAssis BPN1 aMinozzo JC1 aThomaz-Soccol V1 aLages ATC1 aMenezes-Souza D1 aRocha MODC00aTLR1/2-driven macrophage polarization shapes memory CD4+ T-cell responses across the leprosy spectrum  a1078703 a<p>Leprosy presents a clinical-immunological spectrum determined by the host immune response to Mycobacterium leprae. While paucibacillary (PB) patients mount a T<sub>H</sub>1-polarized response with effective bacillary control, multibacillary (MB) forms are associated with T<sub>Reg</sub>/T<sub>H</sub>2 dominance and bacterial persistence. This study investigated the role of Toll-like receptor (TLR) 1/2 expression and signaling in monocyte-derived macrophages, and their influence on memory CD4<sup>+</sup>&nbsp;T cell polarization across the leprosy spectrum. Peripheral blood mononuclear cells from PB (<em>n</em> = 17), MB (<em>n</em> = 15), and healthy controls (<em>n</em> = 32) were stimulated with M. leprae antigen and analyzed by flow cytometry. PB patients exhibited enhanced TLR1/2 activation, with higher frequencies of IL-12<sup>+</sup>&nbsp;and IL-1β<sup>+</sup>&nbsp;macrophages, and increased IL-12 production (measured by mean fluorescence intensity, MFI) compared to MB patients. This robust cytokine response correlated with T<sub>H</sub>1-skewed CD4<sup>+</sup>&nbsp;T cell. In contrast, MB patients displayed impaired TLR1/2 signaling with reduced IL-12/IL-1β and predominant IL-10 production, resulting in a markedly elevated IFN-γ/IL-10 ratio in PB patients. These findings demonstrate that TLR1/2-mediated macrophage activation is associated with adaptive polarisation, with suppressed signalling driving immune deviation in MB patients. The mechanistic link between TLR1/2 dysfunction and the T<sub>H</sub>1/Treg balance highlights the IFN-γ/IL-10 ratio as a potential biomarker for clinical stratification and supports TLR1/2 signaling pathways as promising targets for host-directed immunomodulation in leprosy.</p>
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