title: Innate and humoral recognition of the products of cell death: differential antigenicity and immunogenicity in lupus.
abstract: While apoptotic debris is believed to constitute the original antigenic insult in lupus (which is characterized by a time-dependent diversification of autoreactivity), whether such debris and autoantibodies specifically recognizing its constituents mediate differential effects on innate and humoral responses in lupus-prone mice is currently unknown. Apoptotic blebs (as opposed to cellular lysate) enhanced preferentially the maturation of dendritic cells (DCs) from bone marrow precursors drawn from lupus-prone mice. Murine, somatically mutated, apoptotic cell-reactive immunoglobulin (Ig)G monoclonal antibodies demonstrated enhanced recognition of DCs and also displayed a prominent lupus strain-specific bias in mediating DC maturation. Further, immunization of such antibodies specifically in lupus-prone mice resulted in widespread humoral autoreactivity; hypergammaglobulinaemia (a hallmark of systemic autoimmunity) was observed, accompanied by enhanced antibody titres to cellular moieties. Induced antibodies recognized antigens distinct from those recognized by the antibodies employed for immunization; in particular, nephritis-associated anti-double stranded (ds) DNA antibodies and neonatal lupus-associated anti-Ro60 antibodies were elicited by a non-dsDNA, non-Ro60 reactive antibody, and Sm was a favoured target. Further, only in lupus-prone mice did such immunization enhance the kinetics of humoral anti-self responses, resulting in the advanced onset of glomerulosclerosis. These studies reveal that preferential innate and humoral recognition of the products of cell death in a lupus milieu influence the indices associated with autoimmune pathology.
authors: National Institute of Immunology, New Delhi, India.
authors: P
authors: P
authors: Arora
authors: Department of Microbiology, University College of Medical Sciences and Guru Teg Bahadur Hospital, Delhi, India.
authors: M
authors: M
authors: Malik
authors: National Institute of Immunology, New Delhi, India.
authors: R
authors: R
authors: Sachdeva
authors: National Institute of Immunology, New Delhi, India.|Department of Respiratory Virology, V.P. Chest Institute, University of Delhi, Delhi, India.
authors: L
authors: L
authors: Saxena
authors: National Institute of Immunology, New Delhi, India.|Dr Reddy's Laboratories, Biologics Development Center, Bachupalli, Hyderabad, Andhra Pradesh, India.
authors: J
authors: J
authors: Das
authors: Department of Microbiology, University College of Medical Sciences and Guru Teg Bahadur Hospital, Delhi, India.
authors: V G
authors: VG
authors: Ramachandran
authors: National Institute of Immunology, New Delhi, India.
authors: R
authors: R
authors: Pal
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D000917:Antibody Formation / Q000276:immunology*; D000918:Antibody Specificity / Q000276:immunology; D000941:Antigens / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D016923:Cell Death / Q000276:immunology*; D004247:DNA / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology*; D007114:Immunization / Q000379:methods; D007074:Immunoglobulin G / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008181:Lupus Nephritis / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008814:Mice, Inbred NZB
chemical_list: D000974:Antibodies, Antinuclear; D000941:Antigens; D001323:Autoantibodies; D007074:Immunoglobulin G; D004247:DNA
keywords: aberrant apoptosis; antigen spreading; apoptosis; immune pathology; systemic autoreactivity; systemic lupus erthythematosus