Anti-TLR4 monoclonal antibody, clone 87C468.2 [PE]

Inhibitory receptors are crucial immune regulators and are essential to prevent exacerbated responses, thus contributing to immune homeostasis. Leukocyte associated immunoglobulin like receptor 1 (LAIR-1) is an immune inhibitory receptor which has collagen and collagen domain containing proteins as ligands. LAIR-1 is broadly expressed on immune cells and has a large availability of ligands in both circulation and tissues, implicating a need for tight regulation of this interaction. In the current study, we sought to examine the regulation and function of LAIR-1 on monocyte, dendritic cell (DC) and macrophage subtypes, using differentin vitromodels. We found that LAIR-1 is highly expressed on intermediate monocytes as well as on plasmacytoid DCs. LAIR-1 is also expressed on skin immune cells, mainly on tissue CD14(+)cells, macrophages and CD1c(+)DCs.In vitro, monocyte and type-2 conventional DC stimulation leads to LAIR-1 upregulation, which may reflect the importance of LAIR-1 as negative regulator under inflammatory conditions. Indeed, we demonstrate that LAIR-1 ligation on monocytes inhibits toll like receptor (TLR)4 and Interferon (IFN)-alpha- induced signals. Furthermore, LAIR-1 is downregulated on GM-CSF and IFN-gamma monocyte-derived macrophages and monocyte-derived DCs. In addition, LAIR-1 triggering during monocyte derived-DC differentiation results in significant phenotypic changes, as well as a different response to TLR4 and IFN-alpha stimulation. This indicates a role for LAIR-1 in skewing DC function, which impacts the cytokine expression profile of these cells. In conclusion, we demonstrate that LAIR-1 is consistently upregulated on monocytes and DC during the inflammatory phase of the immune response and tends to restore its expression during the resolution phase. Under inflammatory conditions, LAIR-1 has an inhibitory function, pointing toward to a potential intervention opportunity targeting LAIR-1 in inflammatory conditions.

Aetiology of the establishment of Leishmania donovani infection in its host is still not well understood. Host immune system plays a key role during pathogen entry, survival and propagation of the parasite. Toll-like receptors and its signalling pathways are the hallmarks of the innate immune system and Toll interacting protein (Tollip) is a key regulatory protein of this pathway. Genetic polymorphisms of Tollip gene are known to be associated with a wide range of bacterial and protozoan diseases. However, its role in Visceral Leishmaniasis (VL) as a risk factor is not known. Therefore, we carried out a case-control study to evaluate the role of Tollip gene polymorphism with VL in an endemic population of Assam, India. A total of 206 participants (70 cases and 136 healthy controls) were enrolled in this study. The two Tollip gene polymorphisms rs3750920 and rs5743899 were genotyped by the PCR-RFLP method. The findings show no evidence of deviation from Hardy-Weinberg equilibrium in either of the kala-azar cases or healthy controls. In Tollip variants the rs3750920 &rs5743899 genotype frequency was found within acceptable HWE limits (p-value > 0.05). Genetic association of the genotypes of rs3750920 did not show any association with VL. In case of rs5743899, the risk of VL due to allele G was found to be 1.859 times (p-value < 0.05) by the recessive model as well as the additive model OR: 1.728 (p-value < 0.05). But, the allele G of rs5743899 was indicative of protection against kala-azar in the males as per the multiplicative, co-dominant heterogeneous, recessive as well as the additive model with OR < 1 and p-value < 0.05. However, in the males, the allele A of rs5743899 increased the risk factor for kala-azar > 2-fold with an OR of 2.228 (p-value < 0.05) that is also supported by the additive model OR = 2.07 with a p-value < 0.05. The results of this study indicate that the presence of rs5743899 polymorphism may be a risk factor for developing VL even though other alleles confer some degree of protection against VL especially among the male population in this study.