LAIR1, an ITIM-Containing Receptor Involved in Immune Disorders and in Hematological Neoplasms

Abstract

Leukocyte-associated immunoglobulin (Ig)-like receptor 1 (LAIR1, CD305) belongs to the family of immune-inhibitory receptors and is widely expressed on hematopoietic mature cells, particularly on immune cells. Four different types of ligands of LAIR1 have been described, including collagens, suggesting a potential immune-regulatory function on the extracellular matrix. By modulating cytokine secretion and cellular functions, LAIR1 displays distinct patterns of expression among NK cell and T/B lymphocyte subsets during their differentiation and cellular activation and plays a major negative immunoregulatory role. Beyond its implications in physiology, the activity of LAIR1 can be inappropriately involved in various autoimmune or inflammatory disorders and has been implicated in cancer physiopathology, including hematological neoplasms. Its action as an inhibitory receptor can result in the dysregulation of immune cellular responses and in immune escape within the tumor microenvironment. Furthermore, when expressed by tumor cells, LAIR1 can modulate their proliferation or invasion properties, with contradictory pro- or anti-tumoral effects depending on tumor type. In this review, we will focus on its role in normal physiological conditions, as well as during pathological situations, including hematological malignancies. We will also discuss potential therapeutic strategies targeting LAIR1 for the treatment of various autoimmune diseases and cancer settings.

Keywords: LAIR1; autoimmunity; collagen; hematological neoplasms; immunoregulatory; inflammation; inhibitory receptor.

Figure 2

LAIR1 expression in normal white blood cells. LAIR1 expression was evaluated by flow cytometry (FCM) in a total of 10 samples obtained from healthy adult subjects (n = 10 blood samples, median age: 31 (range: 21–63); gender (male/female): 3/7) after red blood cell lysis by Versalyse© Beckman Coulter. For technical procedures, see [14]. Age (median): 31 (range: 21–63); gender (male/female): 3/7. Monocytes and granulocytes were selected based on their well-known CD45/side scatter (SSC) profile. In the “lymphocyte gate” determined on the graph CD45/SSC, T lymphocytes, NK cells, and B lymphocytes were selected according to the respective criteria of expression of CD3, absence of expression of CD3 and CD19 and expression of CD56, and expression of CD19 and CD20. The results obtained for the mean fluorescence intensity (MFI) of LAIR1 are presented. The dotted line represents the positivity threshold for this marker.

Figure 1

Summary of LAIR1 expression and functions in normal leucocytes, plasmacytoid dendritic (pDCs) cells, and tumor cells.

Figure 3

LAIR1 expression in B cell lymphoma and comparison with normal B cells. LAIR1 expression was evaluated by flow cytometry (FCM) in a total of 163 samples obtained from patients with B cell chronic lymphoproliferative diseases at diagnosis, including n = 6 samples from patients with Burkitt Lymphoma (BL), n = 6 samples from patients with High-Grade B Cell Lymphoma (HGBCL), n = 21 samples from patients with Diffuse Large B Cell Lymphoma (DLBCL), n = 14 samples from patients with Follicular Lymphoma (FL), n = 25 samples from patients with Chronic Lymphocytic Leukemia (CLL), n = 11 samples from patients with Mantle Cell Lymphoma (MCL), n = 19 samples from patients with Hairy Cell Leukemia (HCL), n = 18 samples from patients with Waldenström Macroglobulinemia (WM), n = 36 samples from patients with Splenic Marginal Zone Lymphoma (SMZL), n = 4 samples from patients with Nodal Marginal Zone Lymphoma (NMZL), and n = 3 samples from patients with Splenic Diffuse Red Pulp Lymphoma (SDRPL). Median age: 70 and range: 8–93; gender (male/female): 102/61 (n = 99 blood samples, n = 50 bone marrow aspiration, n = 6 lymph node/splenic biopsies/cerebral biopsies, n = 8 serous liquid). In parallel, the level of expression of LAIR1 by normal B cells was evaluated by FCM in a total of 10 samples obtained from healthy adult subjects as described in Figure 2. Boxplots illustrate the mean fluorescence intensity (MFI) of LAIR1 on a logarithmic scale. The dotted line represents the positivity threshold for this marker. For technical procedures, see [14]. Statistical differences were determined between MFI of normal B cells and MFI of each type of B lymphoma using Prism 9© (unpaired t-test). Only significant results are presented (****, ***, or **).

Figure 4

Prognostic value of LAIR1 expression in patients with DLBCL. (A) Cytogenetically normal AML patients from the GSE12417 cohort (n = 78) were ranked according to increased LAIR1 expression (Affymetrix U133P microarrays), and the maximum difference in OS was obtained by splitting patients into high-risk and low-risk groups. (B,C) High LAIR1 expression also had prognostic value in DLBCL, including the Lenz CHOP cohort (n = 181) and Lenz R-CHOP cohort (n = 233) (Affymetrix U133P microarrays). (D) LAIR1 expression was also significantly associated with a poor outcome in MM (n = 345, Affymetrix U133P microarrays). Blue: low expression of LAIR1; red: high expression of LAIR1.