Molecular mechanism of the recognition of bacterially cleaved immunoglobulin by the immune regulatory receptor LILRA2

Abstract

<jats:p>Human leukocyte immunoglobulin-like receptors (LILRs) typically regulate immune activation by binding to the human leukocyte antigen class I molecules. LILRA2, a member of the LILR family, was recently reported to bind to other unique ligands, the bacterially degraded Igs (N-truncated Igs), for the activation of immune cells. Therefore, LILRA2 is currently attracting significant attention as a novel innate immune receptor. However, the detailed recognition mechanisms required for this interaction remain unclear. In this study, using several biophysical techniques, we uncovered the molecular mechanism of N-truncated Ig recognition by LILRA2. Surface plasmon resonance analysis disclosed that LILRA2 specifically binds to N-truncated Ig with weak affinity (<jats:italic>K<jats:sub>d</jats:sub></jats:italic> = 4.8 μ<jats:sc>m</jats:sc>) and fast kinetics. However, immobilized LILRA2 exhibited a significantly enhanced interaction with N-truncated Ig due to avidity effects. This suggests that cell surface-bound LILRA2 rapidly monitors and identifies bi- or multivalent abnormal N-truncated Igs through specific cross-linking to induce immune activation. Van't Hoff analysis revealed that this interaction is enthalpy-driven, with a small entropy loss, and results from differential scanning calorimetry indicated the instability of the putative LILRA2-binding site, the Fab region of the N-truncated Ig. Atomic force microscopy revealed that N truncation does not cause significant structural changes in Ig. Furthermore, mutagenesis analysis identified the hydrophobic region of LILRA2 domain 2 as the N-truncated Ig-binding site, representing a novel ligand-binding site for the LILR family. These results provide detailed insights into the molecular regulation of LILR-mediated immune responses targeting ligands that have been modified by bacteria.</jats:p>

The mycoplasma surface proteins MIB and MIP promote the dissociation of the antibody-antigen interaction

“…Some mammalian species appear to have evolved a dedicated counter strategy. In human myeloid cells, for example, the leukocyte immunoglobulin-like receptor A2 (LILRA2) is able to specifically detect immunoglobulins that have lost their V H domain ( 33 , 34 ). Activation of LILRA2 results in the activation of monocytes and neutrophils and leads to the production of antimicrobial products such as reactive oxygen species and cytokines to help contain and clear the infection.…”

Leukocyte Immunoglobulin-Like Receptors in Regulating the Immune Response in Infectious Diseases: A Window of Opportunity to Pathogen Persistence and a Sound Target in Therapeutics

“…Yamazaki et al. provided recent insights into the molecular mechanism of LILRA2 recognizing the cleaved Ig that would occur via hydrophobic interaction of the LILRA2 D2 domain and exposed hydrophobic surface of N-truncated Ig ( 92 ). These findings highlight the molecular mechanisms of LILRA2-mediated inflammation to counteract the altered immune response induced by pathogens.…”

“…However, LILRA2 can promote neutrophil and monocyte activation to inhibit bacterial growth. Indeed, LILRA2 can recognize degraded antibodies generated by bacterial and fungal proteases including Mycoplasma hyorhinis , Legionella pneumophila , Streptococcus pneumonia and Candida albicans ( 55 , 92 ). The engagement of LILRA2 by cleaved Igs stimulates ROS production by neutrophils and inhibits bacterial multiplication in monocytes ( 55 ).…”

Beware of Mycoplasma Anti-immunoglobulin Strategies

“…Second, proteolytic degradation of immunoglobulins by MIB-MIP could be highly relevant to the question of mycoplasmas pathogenesis. Indeed, the hydrolyzed antibodies resulting from the processing by MIB-MIP are likely to be detected by the innate immunity activator leukocyte immunoglobulin-like receptor 2 (LILRA2) ( 82 , 83 ). This protein is part of the LILR superfamily of paired receptors, expressed at the surface of human myeloid cells and regulating the immune system ( 84 ).…”