J Clin Invest 112(11): 1639-1641

Complement system on the attack in autoimmunity

Washington University School of Medicine, St. Louis, Missouri, USA

Abstract

The antiphospholipid syndrome is characterized clinically by fetal loss and thrombosis and serologically by the presence of autoantibodies to lipid-binding proteins. In a model of this procoagulant condition in which these antibodies are injected into pregnant mice, fetal loss was prevented by blocking of complement activation. Specifically, interaction of complement component 5a (C5a) with its receptor is necessary for thrombosis of placental vasculature (see the related article beginning on page 1644). Inhibition of complement activation may have a therapeutic role in this disease.

Abstract

In the first autoimmune condition that was recognized as such over a century ago, antibody and complement were shown to lyse human red blood cells in a rare form of hemolytic anemia known as paroxysmal cold hemoglobinuria (1). Impressively, these same two factors had been found to mediate lysis of bacterial pathogens just three years earlier in 1892. While lysis was the end point in those early studies because it was both pathologically meaningful and easy to monitor, we now realize that it is the phlogistic and opsonic activities of complement that account for much of its physiologic and pathologic importance. The antiphospholipid syndrome (APS) is an autoimmune disease in which autoantibodies are synthesized to lipids and lipid-binding proteins. These antibodies bind to antigens expressed by endothelial cells and produce a clinical syndrome featuring thrombosis. Fetal wastage is caused by placental infarction. In this issue of the JCI, Girardi et al. report that activation of the complement cascade by the immune complexes is required for disease development in a mouse model of APS (2).

Footnotes

See the related article beginning on page 1644.

Conflict of interest: The author has declared that no conflict of interest exists.

Nonstandard abbreviations used: antiphospholipid syndrome (APS); alternative pathway (AP); complement component 5a (C5a); rheumatoid arthritis (RA).

Footnotes

References

1. Silverstein, A.M1989. A history of immunology. Academic Press Inc. San Diego, California, USA. 422 pp.
2. Girardi G, et al Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J. Clin. Invest.2003; 112:1644–1654. doi:10.1172/JCI200318817.
3. Matsumoto I, Staub A, Benoist C, Mathis DArthritis provoked by linked T and B cell recognition of a glycolytic enzyme. Science.1999; 286:1732–1735.[PubMed]
4. Matsumoto I, et al How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint-specific autoimmune disease. Nat. Immunol.2002; 3:360–365.[PubMed]
5. Ji H, et al Arthritis critically dependent on innate immune system players. Immunity.2002; 16:157–168.[PubMed]
6. Ratnoff WD, Fearon DT, Austen KFThe role of antibody in the activation of the alternative complement pathway. Springer Semin. Immunopathol.1983; 6:361–371.[PubMed]
7. Wipke BT, Allen PMEssential role of neutrophils in the initiation and progression of a murine model of rheumatoid arthritis. J. Immunol.2001; 167:1601–1608.[PubMed]
8. Branch DW, et al Immunoglobulin G fractions from patients with antiphospholipid antibodies cause fetal death in BALB/c mice: a model for autoimmune fetal loss. Am. J. Obstet. Gynecol.1990; 163:210–216.[PubMed]
9. Blank M, Cohen J, Toder V, Shoenfeld YInduction of antiphospholipid syndrome in naive mice with mouse lupus monoclonal and human polyclonal antibodies. Proc. Natl. Acad. Sci. U. S. A.1991; 88:3069–3073.
10. Piona A, et al Placental thrombosis and fetal loss after passive transfer of mouse lupus monoclonal or human polyclonal anti-cardiolipin antibodies in pregnant naive BALB/c mice. Scand. J. Immunol.1995; 41:427–432.[PubMed]
11. Ikematsu W, et al Human anticardiolipin monoclonal autoantibodies cause placental necrosis and fetal loss in BALB/c mice. Arthritis Rheum.1998; 41:1026–1039.[PubMed]
12. Rand JH, et al Pregnancy loss in the antiphospholipid-antibody syndrome: a possible thrombogenic mechanism. N. Engl. J. Med.1997; 337:154–160.[PubMed]
13. Pierangeli SS, et al Antiphospholipid antibodies from antiphospholipid syndrome patients activate endothelial cells in vitro and in vivo. Circulation.1999; 99:1997–2002.[PubMed]
14. Simantov R, et al Activation of cultured vascular endothelium by antiphospholipid antibodies. J. Clin. Invest.1995; 96:2211–2219.
15. Laudes IJ, et al Expression and function of C5a receptor in mouse microvascular endothelial cells. J. Immunol.2002; 169:5962–5970.[PubMed]
16. Barilla-LaBarca ML, Liszewski MK, Lambris JD, Hourcade D, Atkinson JPRole of membrane cofactor protein (CD46) in regulation of C4b and C3b deposited on cells. J. Immunol.2002; 168:6298–6304.[PubMed]
17. Manuelian T, et al Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome. J. Clin. Invest.2003; 111:1181–1190. doi:10.1172/JCI200316651.
18. Atkinson, J.P., and Bessler, M. 2000. Paroxysmal nocturnal hemoglobinuria. In The molecular basis of blood disease. W.B. Saunders Co. Philadelphia, Pennsylvania, USA. 564–577.
19. Richards A, et al Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome. Proc. Natl. Acad. Sci. U. S. A.2003; 100:12966–12971.
20. Tesser J, et al Safety and efficacy of the humanized anti-C5 antibody h5G1.1 in patients with rheumatoid arthritis. Arthritis Rheum.2001; 44(Suppl.):S274. (Abstr.) [PubMed]
21. Petri MEvidence-based management of thrombosis in the antiphospholipid antibody syndrome. Curr. Rheumatol. Rep.2003; 5:370–373.[PubMed]