Abstract
LILRA3 is the sole soluble member of the LILR family. Previous studies from our group had shown that a 6.7 kb genetic deletion of LILRA3 is associated with MS and Sjögren’s syndrome. An impairment of the immune response leads to a predisposition for B-NHL, so we wanted to study whether the deletion of LILRA3 is also a risk factor for B-NHL, as well as the function of LILRA3. We discovered that the frequency of the homozygous LILRA3 deletion was significantly higher in B-NHL (6%) than in blood donors (3%) (P = 0.03). We detected binding of fluorochrome-conjugated recombinant LILRA3 to monocytes and B-cells. Incubation of PBMCs with recombinant LILRA3 induced proliferation of CD8+ T-cells and NK cells, as determined by CFSE staining. Using a transwell system, we demonstrated that LILRA3-stimulated lymphocyte proliferation was mediated by monocytes and required both cell contact and soluble factors. Secretion of IL-6, IL-8, IL-1β and IL-10 in the cell supernatant was stimulated by LILRA3. We conclude that LILRA3 is an immunostimulatory molecule, whose deficiency is associated with higher frequency of B-NHL.
Highlights
The leukocyte-immunoglobulin (Ig)-like-receptors (LILRs) are a family of receptors located within the leukocyte receptor cluster on chromosome 19q13.4, in the vicinity of the killer cell inhibitory receptors and the leukocyte associated inhibitory receptors [1,2,3]
When Peripheral Blood Mononuclear Cells (PBMCs) were pre-incubated with an excess of unconjugated LILRA3 for competitive assays, the binding of the labelled LILRA3 was reduced to background levels, indicating that the binding and detection were specific
Control experiments with labelled glutamate decarboxylase-65 (GAD-65) did not show any specific binding to PBMCs which could be reduced in the presence of unlabelled GAD-65. 1 mg/mL of human intraveneous immunoglobulin and 100 mg/ mL pan-HLA class I antibody W6/32 did not neutralize the staining of LILRA3 (Figure S2)
Summary
The leukocyte-immunoglobulin (Ig)-like-receptors (LILRs) are a family of receptors located within the leukocyte receptor cluster on chromosome 19q13.4, in the vicinity of the killer cell inhibitory receptors and the leukocyte associated inhibitory receptors [1,2,3]. LILRA3 (CD85e; ILT6) corresponds to a less characterized member of the family, lacking transmembrane or cytoplasmic regions, and existing solely as a soluble protein [5,9,10]. The incidence of B-NHL is 70 times higher in patients infected by human immunodeficiency virus than in the general population [17]. B-NHL is recognized nowadays as an AIDSdefining disease among human immunodeficiency virus infected patients [18]. Single nucleotide polymorphisms in IL-10 and TNF have been demonstrated to be associated with NHL, in particular diffuse large B-cell lymphoma [19,20]
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