Anti-TREML4 Polyclonal Antibody

Genome wide association studies have identified an association between Alzheimer's disease (AD) and common polymorphisms in the MS4A and TREM loci (each containing a cluster of homologous genes) and should be thoroughly investigated for the presence of potentially functional variations. We conducted a mutation analysis by next generation sequencing of 15 genes within the MS4A and TREM gene clusters; and catalogued rare coding variants detected in a North American data set of 210 cases and 233 controls. Investigation of the 5 homologues genes in the TREM locus revealed potentially damaging rare variants in TREM2, TREML1, TREML2, and TREML4. In agreement with a previous report, we observed a significant enrichment of TREM2-damaging missense substitutions in cases (N = 9; 4.2%) compared with controls (N = 2; 0.9%; p = 0.010; after Yates' correction p = 0.022). Among known AD-associated TREM2 substitutions, we detected p.R47H, p.D87N, and p.H157Y affecting both TREM2 isoforms (NM_018965 and NM_001271821). In addition, we identified 2 cases with novel TREM2 variants (p.L205P and p.G219C), which mapped only to the isoform NM_001271821 at the C-terminus. Investigation of the MS4A gene cluster revealed that potentially damaging missense substitutions and loss-of-function variants were twice as frequent in controls (N = 19; 8.2%) than cases (N = 9; 4.3%), generating a nominally significant result (p = 0.047; after Yates' correction p = 0.07). Validation of our observation in large data sets might address the question whether such variants could contribute to the protective effect of the minor alleles of Genome wide association study-significant single nucleotide polymorphisms at the MS4A locus. (C) 2016 Elsevier Inc. All rights reserved.

Members of the triggering expressed on myeloid cells (Trem) receptor family fine-tune inflammatory responses. We previously identified one of these receptors, called Treml4, expressed mainly in the spleen, as well as at high levels by CD8 alpha(+) dendritic cells and macrophages. Like other Trem family members, Treml4 has an Ig-like extracellular domain and a short cytoplasmic tail that associates with the adaptor DAP12. To follow up on our initial results that Treml4-Fc fusion proteins bind necrotic cells, we generated a knockout mouse to assess the role of Treml4 in the uptake and presentation of dying cells in vivo. Loss of Treml4 expression did not impair uptake of dying cells by CD8 alpha(+) dendritic cells or cross-presentation of cell-associated Ag to CD8(+) T cells, suggesting overlapping function between Treml4 and other receptors in vivo. To further investigate Treml4 function, we took advantage of a newly generated mAb against Treml4 and engineered its H chain to express three different Ags (i.e., OVA, HIV GAGp24, and the extracellular domain of the breast cancer protein HER2). OVA directed to Treml4 was efficiently presented to CD8(+) and CD4(+) T cells in vivo. Anti-Treml4-GAGp24 mAbs, given along with a maturation stimulus, induced Th1 Ag-specific responses that were not observed in Treml4 knockout mice. Also, HER2 targeting using anti-Treml4 mAbs elicited combined CD4(+) and CD8(+) T cell immunity, and both T cells participated in resistance to a transplantable tumor. Therefore, Treml4 participates in Ag presentation in vivo, and targeting Ags with anti-Treml4 Abs enhances immunization of otherwise naive mice. The Journal of Immunology, 2012, 188: 1147-1155.