Serum Th1/Th2 and macrophage lineage cytokines in leprosy; correlation with circulating CD4⁺CD25^highFoxP3⁺ T‐regs cells

Abstract

Not only macrophages, T-helper (Th)1 and Th2, but also CD4(+) CD25(high) FoxP3(+) regulatory T cells (T-regs) are involved in immune response to Mycobacterium leprae. We aimed to evaluate serum interleukin (IL)-1β and IL-12p70 (macrophage cytokines), interferon-γ (IFN-γ) (Th1 cytokine), IL-4 (Th2 cytokine) and circulating CD4(+) CD25(high) FoxP3(+) T-regs, in untreated leprosy patients. Forty three patients and 40 controls were assessed for the mentioned cytokines using ELISA. Patients were assessed for circulating T-regs using flow cytometry. Patients were subgrouped into tuberculoid (TT), pure neural leprosy (PNL), borderline cases, lepromatous (LL), type 1 reactional leprosy (RL1) and erythema nodosum leprosum (ENL). Serum IL-12p70, IFN-γ and IL-4 were significantly higher in patients versus controls (P < 0.05). Serum IL-4 was highest in LL and lowest in RL1 (P = 0.003). Serum IL-1β levels was significantly higher in multibacillary versus paucibacillary patients (P = 0.006). Significantly higher T-regs levels was detected in TT, RL1 and PNL, while the lowest levels in ENL(P < 0.001), with significant differences versus controls (P < 0.05). FoxP3 expression% was significantly lower in PNL than other patients and controls (P < 0.05). T-regs/T-effs was lowest in ENL(P < 0.05). IFN-γ correlated positively with T-regs but negatively with IL-1β (P = 0.041&0.046 respectively), which correlated positively with T-effs%( P = 0.05). IL-4 correlated positively with T-regs FoxP3 expression% (P = 0.009). We concluded that: Circulating T-regs were increased in TT, RL1 and PNL patients, known of relatively high cell-mediated immunity. This finding was supported by low FoxP3 expression (in PNL) and correlation between T-regs count and IFN-γ level. Overproduction of IL-4 in LL may infer liability to develop ENL, with disease progression and immune hyperactivation, marked by deficient T-regs and increased T-regs FoxP3 expression%. IL-1β probably has a pro-inflammatory role in multibacillary patients as correlated with T-effs%.

Advances in the Immunology and Genetics of Leprosy

“…Comparing to other forms of leprosy and healthy controls, T2R showed lowest circulating Treg frequency, which was consistent with the high Th17 frequency in T2R (58,76). But it is not the case for T1R, several studies have demonstrated that T1R showed a significantly higher frequency of Treg compared to nonreactional leprosy in both PBMC and skin lesions (58,74,(76)(77)(78). One possible explanation for the increase of Treg in T1R is that the increase of Treg in T1R is a self-protection mechanism to reduce the tissue damage caused by the exacerbated cell-mediated immune responses.…”

“…Since T1R and T2R are both acute inflammation reactions, it is reasonable to discover a higher frequency of Th17 in both T1R and T2R compared to non-reactional leprosy considering the inflammation functions of Th17 cells (73)(74)(75). Comparing to other forms of leprosy and healthy controls, T2R showed lowest circulating Treg frequency, which was consistent with the high Th17 frequency in T2R (58,76). But it is not the case for T1R, several studies have demonstrated that T1R showed a significantly higher frequency of Treg compared to nonreactional leprosy in both PBMC and skin lesions (58,74,(76)(77)(78).…”

“…This cytokine pattern in leprosy lesions is very similar to the murine Th1/Th2 model. In addition, cytokine profiles of PBMCs from leprosy patients also showed a polar pattern according to leprosy type (57,58). Although half of PBMCs from subjects showed non-discriminating Th0 responses upon M. leprae antigen stimulation, the remaining L-lep presented Th2 responses while T-lep showed Th1 cytokine responses (57).…”

Interaction of Mycobacterium leprae with the HaCaT human keratinocyte cell line: new frontiers in the cellular immunology of leprosy

“…These findings may be of great relevance since keratinocytes play a key role in the initiation of primary immune responses in the skin (19). Furthermore, Abdallah M. et al (60) showed higher serum IL1β levels in multibacillary leprosy patients when compared to paucibacillary patients, suggesting a proinflammatory role for IL1β in multibacillar leprosy. TNFα and IL1β are important cytokines inducing the emigration of Langerhans cells (LC) from lymphoid tissues (61).…”

A Systematic Review of Immunological Studies of Erythema Nodosum Leprosum

“…Therefore, the observation of lower numbers of Tregs in ENL could account for the relatively higher proportion of T cells previously described in multiple ENL studies. Two more publications from the same group addressed the frequency of Tregs in ENL, defined as CD4 + CD25 high FoxP3 + cells and reported the ratio of Treg/Teffector cells to be low in ENL (109, 110). These results should be interpreted with caution since dichotomizing cells into CD25 high and CD25 low to identify Tregs is highly subjective.…”