Understanding the Role of LFA-1 in Leukocyte Adhesion Deficiency Type I (LAD I): Moving towards Inflammation?

Abstract

LFA-1 (Lymphocyte function-associated antigen-1) is a heterodimeric integrin (CD11a/CD18) present on the surface of all leukocytes; it is essential for leukocyte recruitment to the site of tissue inflammation, but also for other immunological processes such as T cell activation and formation of the immunological synapse. Absent or dysfunctional expression of LFA-1, caused by mutations in the ITGB2 (integrin subunit beta 2) gene, results in a rare immunodeficiency syndrome known as Leukocyte adhesion deficiency type I (LAD I). Patients suffering from severe LAD I present with recurrent infections of the skin and mucosa, as well as inflammatory symptoms complicating the clinical course of the disease before and after allogeneic hematopoietic stem cell transplantation (alloHSCT); alloHSCT is currently the only established curative treatment option. With this review, we aim to provide an overview of the intrinsic role of inflammation in LAD I.

Keywords: hematopoietic stem cell transplantation; inborn errors of immunity; inflammation.

Figure 1

The leukocyte adhesion cascade. Inflammation leads to an activation of the endothelium by endogenous and exogenous stimuli. Selectins, expressed on the surface of activated endothelial cells, mediate rolling of the leukocytes on the luminal surface of the blood vessel. Interactions of the β2-integrin LFA-1 (lymphocyte function-associated antigen 1) and ICAM-1 and ICAM-2 (intercellular adhesion molecule 1 and 2) enable leukocytes to adhere to the inflamed endothelium. Paracellular and transcellular migration of the leukocytes through the vessel walls is then triggered by ligation of JAM-A (junctional adhesion molecule A), ICAM-1, and ICAM-2. In LAD I, absent or defective expression of β2-integrins results in an impaired transmigration of leukocytes.

Figure 2

Clinical signs. Lesions of the skin and mucosa without pus formation in a patient with severe LAD I.

Figure 3

Conformational states of LFA-1 (adapted from Walling et al. [33]). LFA-1 exists in three different conformational states: The low-affinity state (bent-closed) with the headpiece close to the plasma membrane, the intermediate affinity state (extended-closed) with straightened legs, and a closed headpiece and the high-affinity state (extended-open) with extended legs and an open headpiece.

Figure 4

Protein structure of CD18 (graphics performed with AlphaFold [37] and ChimeraX-1.3 [38]).

Figure 5

Inflammatory aspects of LAD I (adapted from Hajishengallis et al. [75]) Impaired migration of CD18-deficient neutrophils to the tissue leads to a disruption of neutrophil homeostasis in LAD I. This triggers the overproduction of IL-23 by macrophages and dendritic cells and downstream IL-17 produced by Th17-cells. IL-17 induces the production of G-CSF by fibroblasts, which results in excessive production and release of neutrophils from the bone marrow to the peripheral blood. The use of pharmacological inducers of neutrophil homeostasis regulators (LXRα/LXRβ and PPAR β/δ) and IL12/IL23 via Ustekinumab succeeded to cut off this inflammatory cascade.