Systemic exposure to irradiated apoptotic cells induces autoantibody production - PubMed (original) (raw)

Systemic exposure to irradiated apoptotic cells induces autoantibody production

D Mevorach et al. J Exp Med. 1998.

Abstract

During apoptotic cell death, cell surface ligands initiate phagocytosis of the dying cell. Clearance of these apoptotic cells is thought to occur without an immune response. Since a number of autoantigens are located at the cell surface or within apoptotic blebs, we examined whether exposure of mice to syngeneic apoptotic cells by the intravenous route could induce autoantibody production. Normal mice injected with syngeneic apoptotic thymocytes developed antinuclear autoantibodies and anticardiolipin and anti-ssDNA antibodies. The autoantibody levels were generally lower than those observed in MRL/Faslpr mice and were transient. Surprisingly, six out of six immunized mice demonstrated immunoglobulin G deposition in the glomeruli several months after immunization. These findings indicate that systemic exposure to apoptotic cells can induce an immune response in normal mice, and may help to explain antigen selection and initiation of the immune response in diseases characterized by increased rates of apoptosis such as AIDS and, possibly, systemic lupus erythematosus.

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Figures

Figure 1

Figure 1

Injection of apoptotic cells induces ANAs. Serum obtained from normal C3H mice either uninjected (A) or injected with syngeneic apoptotic cells (B–D) were tested for ANAs by indirect immunofluorescence at a 1:50 dilution, 4–6 wk after the first injection. The cell lines used for ANA detection were the T cell lines, AE.7 (A and B) or HEP-2 (C and D). These figures are representative of the results summarized in Table 1.

Figure 2

Figure 2

Mice injected with apoptotic thymocytes produce anti- ssDNA and AcL autoantibodies. C3H mice (open circles) were immunized with saline (Nil), irradiated thymocytes (Irr-T), nonirradiated splenocytes (SPL), or a lysate from irradiated thymocytes (Lys-T). Sera obtained 2–6 wk after initial injection were tested for anti-ssDNA and AcL autoantibodies by ELISA as described in Materials and Methods. The results of IgM anti-ssDNA (A), IgG anti-ssDNA (B), IgM AcL (C), and IgG AcL (D) are shown. Results greater than the mean + 3 SD (horizontal line) obtained from age-matched controls were regarded as positive. Anti-ssDNA and AcL levels of 5–6-mo-old MRL/lpr mice (closed circles) are shown for comparison. The kinetics of IgG AcL antibody production are shown in E. Six C3H mice were immunized weekly with irradiated thymocytes (time 0 [_left arrow_] to wk 4). Starting at wk 12 (right arrow), three of these mice (closed triangles) were reimmunized weekly and three mice (open triangles) were used as controls. Serum was collected at the times shown and tested for AcL binding as described in Materials and Methods.

Figure 3

Figure 3

Immunization with apoptotic thymocytes results in IgG deposition in renal glomeruli. Kidneys obtained from normal C3H mice immunized with apoptotic thymocytes (A and B), were tested for IgG deposition by immunofluorescence. Nonimmunized, age-matched C3H and MRL/lpr mice were used as a negative (C) and positive (D) controls.

References

    1. Vaishnaw AK, McNally JD, Elkon KB. Apoptosis in the rheumatic diseases. Arthritis Rheum. 1997;40:1917–1927. - PubMed
    1. Mohan C, Adams S, Stanik V, Datta SK. Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus. J Exp Med. 1993;177:1367–1381. - PMC - PubMed
    1. Casciola-Rosen LA, Anhalt G, Rosen A. Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J Exp Med. 1994;179:1317–1330. - PMC - PubMed
    1. Rauch J, Janoff AS. Antibodies against phospholipids other than cardiolipin: potential roles for both phospholipid and protein. Lupus. 1996;5:498–502. - PubMed
    1. Verhoven B, Schlegel RA, Williamson P. Mechanisms of phosphatidylserine exposure, a phagocyte recognition signal, on apoptotic T lymphocytes. J Exp Med. 1995;182:1597–1601. - PMC - PubMed

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