title: Microbially cleaved immunoglobulins are sensed by the innate immune receptor LILRA2.
abstract: Microbial proteases degrade a variety of host proteins(1-3). However, it has remained largely unknown why microorganisms have evolved to acquire such proteases and how the host responds to microbially degraded products. Here, we have found that immunoglobulins disrupted by microbial pathogens are specifically detected by leukocyte immunoglobulin-like receptor A2 (LILRA2), an orphan activating receptor expressed on human myeloid cells. Proteases from Mycoplasma hyorhinis, Legionella pneumophila, Streptococcus pneumonia and Candida albicans cleaved the N-terminus of immunoglobulins. Identification of the immunoglobulin-cleaving protease from L. pneumophila revealed that the protease is conserved across some bacteria including Vibrio spp. and Pseudomonas aeruginosa. These microbially cleaved immunoglobulins but not normal immunoglobulins stimulated human neutrophils via LILRA2. In addition, stimulation of primary monocytes via LILRA2 inhibited the growth of L. pneumophila. When mice were infected with L. pneumophila, immunoglobulins were cleaved and recognized by LILRA2. More importantly, cleaved immunoglobulins were detected in patients with bacterial infections and stimulated LILRA2-expressing cells. Our findings demonstrate that LILRA2 is a type of innate immune receptor in the host immune system that detects immunoglobulin abnormalities caused by microbial pathogens.
authors: Laboratory of Immunochemistry, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Kouyuki
authors: K
authors: Hirayasu
authors: Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Fumiji
authors: F
authors: Saito
authors: Laboratory of Immunochemistry, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Tadahiro
authors: T
authors: Suenaga
authors: Laboratory of Immunochemistry, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Kyoko
authors: K
authors: Shida
authors: Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.|Department of Dermatology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Noriko
authors: N
authors: Arase
authors: Department of Otolaryngology, Tenshi Hospital, Sapporo, Japan.
authors: Keita
authors: K
authors: Oikawa
authors: Department of Dermatology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Toshifumi
authors: T
authors: Yamaoka
authors: Department of Dermatology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Hiroyuki
authors: H
authors: Murota
authors: Medical Mycology Research Center, Chiba University, Chuo-ku, Chiba 260-8673, Japan.
authors: Hiroji
authors: H
authors: Chibana
authors: Department of Microbiology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
authors: Ichiro
authors: I
authors: Nakagawa
authors: Laboratory of Combined Research on Microbiology and Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Tomoko
authors: T
authors: Kubori
authors: Laboratory of Combined Research on Microbiology and Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Hiroki
authors: H
authors: Nagai
authors: Department of Otolaryngology-Head and Neck Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan.
authors: Yuji
authors: Y
authors: Nakamaru
authors: Department of Dermatology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Ichiro
authors: I
authors: Katayama
authors: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors: Marco
authors: M
authors: Colonna
authors: Laboratory of Immunochemistry, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.|Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Hisashi
authors: 0000-0002-1153-3166
authors: H
authors: Arase
mesh_terms: D000818:Animals; D001419:Bacteria / Q000201:enzymology* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D007136:Immunoglobulins / Q000378:metabolism* / Q000494:pharmacology; D016952:Legionella pneumophila / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development / Q000276:immunology; D007877:Legionnaires' Disease; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000382:microbiology; D045790:Mycoplasma hyorhinis / Q000201:enzymology; D009504:Neutrophils / Q000187:drug effects; D010447:Peptide Hydrolases / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000276:immunology* / Q000378:metabolism; D013296:Streptococcus pneumoniae / Q000201:enzymology
chemical_list: D016207:Cytokines; D007136:Immunoglobulins; C105298:LILRA2 protein, human; D011971:Receptors, Immunologic; D010447:Peptide Hydrolases