Immune complexes as therapy for autoimmunity

For several decades, intravenous Ig has been used as treatment for a variety of immune-related diseases, including immune thrombocytopenic purpura (ITP), autoimmune neuropathies, systemic lupus erythematosus, myasthenia gravis, Guillain-Barré syndrome, skin blistering syndromes, and Kawasaki disease. Despite years of use, its mechanism of immunomodulation is still unclear. Recent studies using mouse models of ITP and arthritis, including one reported in this issue of the JCI, now provide some insights into this mechanism and the rationale for the development of Fcγ receptor–targeted therapeutics.

Intravenous Ig (IVIg) is remarkably effective in the treatment of immune thrombocytopenic purpura (ITP), with improved platelet counts seen in 80% of treated patients. ITP occurs in patients as the result of the generation of autoantibodies that bind to platelet surface antigens. These opsonized platelets are phagocytosed by Fc receptor–bearing splenic and hepatic macrophages (1). In the mouse, macrophage-mediated clearance occurs via activating Fc receptors, with complement-mediated uptake playing little or no role (2, 3). Thus, blockade of activating Fcγ receptors (FcγRs) would be predicted to be an effective therapy in ITP. Indeed, this has proven to be a valid approach; antibodies that block FcγRIII have been shown to be effective in murine studies (2, 4) as well as in pilot clinical studies (5).

Although activating Fc receptor blockade is an appealing mechanism, a second, unexpected FcγR-related pathway is clearly relevant to the therapeutic action of IVIg. It was recently shown (4) that the protective effect of IVIg is associated with upregulation of the inhibitory receptor FcγRIIB on splenic macrophages and is abrogated in mice lacking FcγRIIB. Curiously, this effect is independent of SHIP and SHP-1 (6), the 2 downstream inhibitory phosphatases previously assumed to be responsible for the inhibitory signaling pathway. Redundant functions of SHIP and SHP-1 or other phosphatases downstream of FcγRIIB may be responsible (7), but as yet the FcγRIIB-mediated signal is unclear. Adding further to the mystery is the observation that 2 distinct macrophage populations are involved; IVIg protection requires CSF-1–dependent macrophages, whereas the macrophage responsible for FcγRIII-mediated platelet clearance is CSF-1 independent (8). Thus, while other targets may prove effective in the treatment of immune complex–related (IC-related) autoimmunity (9, 10), at least 2 distinct FcγR therapeutic approaches are tenable: direct blockade of the phagocytic Fc receptors and IVIg-triggered, FcγRIIB-mediated inhibition (Figure 1).

Figure 1

Inhibition of phagocytosis in vivo can be accomplished via IC-mediated inhibition of FcγR functional activity. These complexes, varying in size and valency, operate through distinct mechanistic pathways. IVIg leads to the formation of variably sized ICs, including small monomeric and dimeric complexes. The small ICs (Ig dimers or soluble antigen/donor Ig complexes) require CSF-1–dependent macrophages and FcγRII expression to mediate their as-yet-undefined anti-inflammatory effect. Intravenous anti-D generates large particulate ICs, namely opsonized rbcs. These large ICs induce a phagocytic block in vivo in a manner independent of FcγRII expression. Perhaps mimicking the situation directly, antibodies that specifically engage either the inhibitory FcγRII (4) or the activating FcγRIII (4, 5) can also induce platelet count recovery.

A related therapeutic, intravenous anti-D, has also been highly effective in ITP, but only in Rh⁺ patients. The active component is clearly anti-D antibodies that generate large particulate ICs, namely opsonized rbcs, in Rh⁺ patients. In contrast, the active components in IVIg, a product obtained from sera pooled from thousands of donors, could conceivably include a variety of Fc receptor–binding ligands. In addition to the dominant species of monomeric IgG (which would bind FcRn and the high-affinity FcγRI), multiple types of ICs, which bind all Fc receptors, are likely to form in vivo after the administration of IVIg. These complexes of varying valencies include cell-associated and soluble host antigens bound by donor natural antibodies as well as dimers and aggregated Igs formed in the IVIg product itself. Using mimetic modeling studies, Siragam et al. (11) suggest that the 2 therapeutics IVIg and anti-D have distinct mechanisms of action, either via small, soluble ICs or via large, particulate ICs.

The protective capacity of small ICs was found to be FcγRIIB dependent, which recapitulated results seen previously with the IVIg effect (4). This suggests that in contrast to anti-D, small ICs likely mediate IVIg protection. In contrast, as reported elsewhere (12), opsonized rbcs (anti-OVA/OVA-coupled rbcs) were capable of protecting against platelet clearance in both normal and FcγRIIB-deficient mice, which suggests that they interfere directly with activating FcγR–mediated phagocytosis. The FcγRIIB-independent anti-inflammatory mechanism of opsonized particulates might be assumed to be the straightforward result of activating FcγR blockade by antibody-coated rbcs. However, the fact that large increases in platelet counts are achieved with anti-D with little concomitant induction of anemia (13) suggests that there are other contributing mechanisms, including induction of cytokines and downregulation of activating FcγRIII (Figure 1) (12, 14–17).

The implication is that IVIg is far from an optimized therapeutic. Thus, in addition to theoretical and practical concerns regarding safety, cost, and availability of this biologic, a better understanding of how the small IC component within IVIg exerts its therapeutic impact will drive development of an improved pharmaceutical product. Targeting FcγRIIB directly by cross-linking FcγRIIB-specific antibodies has been shown to be beneficial in the mouse model of ITP, and injection of small, preformed ICs is also protective (18). The current work provides another potential solution, namely injection of antibodies with specificities for serum proteins including albumin and transferrin, which provide FcγRII-dependent protection (11). Monoclonal antibodies recognizing a single epitope form monomeric ICs, implying that clustering of FcγRs by these small ICs is not required for their therapeutic effect. Even with polyclonal α-albumin or α-transferrin antibodies, the resultant ICs formed in vivo are still likely to be quite small, since the serum target proteins are present in such large molar excess. While this is an intriguing approach, an obvious concern is the potential for untoward IC-triggered hypersensitivity responses, which might complicate its clinical use.

Siragam et al. extend their observations beyond antibody-mediated thrombocytopenia in showing that both IVIg and its mimetic anti-murine albumin antibodies protect in the K/BxN serum–induced arthritis model (11). The clinical benefit of IVIg has been spotty in autoimmune conditions, such as rheumatoid arthritis (19–24), in which autoaggressive T cells are believed to be the culprits. Recent attention in these T cell–mediated diseases, however, has been redirected toward the role of humoral immunity in the activation of T cells (25). Further, deficiency of activating FcγRs has been shown to be protective in classical T cell–mediated diseases, including arthritis (20–24) and experimental autoimmune encephalomyelitis (26–29), which suggests that FcγR-based therapeutics might have as-yet-undiscovered clinical activity in T cell–mediated autoimmune conditions through regulatory effects on FcγR-bearing antigen-presenting cells. Identifying the critical FcγR mechanistic pathways hinted at by studies of IVIg may prove helpful in generating more effective pharmacologic agents and could widen the circle of patients possibly benefiting from FcγR-targeted therapeutics. Thus, other autoantibody-driven diseases, beyond ITP, may prove treatable with a little of what ails you.

See the related article beginning on page 155.

Nonstandard abbreviations used: FcγR, Fcγ receptor; IC, immune complex; ITP, immune thrombocytopenic purpura; IVIg, intravenous Ig.

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

1. Alves-Rosa, F, et al. Treatment with liposome-encapsulated clodronate as a new strategic approach in the management of immune thrombocytopenic purpura in a mouse model. Blood. 2000. 96:2834-2840.
   View this article via: PubMed Google Scholar
2. Clynes, R, Ravetch, JV. Cytotoxic antibodies trigger inflammation through Fc receptors. Immunity. 1995. 3:21-26.
   View this article via: PubMed CrossRef Google Scholar
3. Sylvestre, D, et al. Immunoglobulin G-me-diated inflammatory responses develop normal-ly in complement-deficient mice. J. Exp. Med. 1996. 184:2385-2392.
   View this article via: PubMed CrossRef Google Scholar
4. Samuelsson, A, Towers, TL, Ravetch, JV. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science. 2001. 291:484-486.
   View this article via: PubMed CrossRef Google Scholar
5. Clarkson, SB, et al. Treatment of refractory immune thrombocytopenic purpura with an anti-Fc gamma-receptor antibody. N. Engl. J. Med. 1986. 314:1236-1239.
   View this article via: PubMed Google Scholar
6. Crow, AR, et al. IVIg-mediated amelioration of murine ITP via FcgammaRIIB is independent of SHIP1, SHP-1, and Btk activity. Blood. 2003. 102:558-560.
   View this article via: PubMed CrossRef Google Scholar
7. van Mirre, E, van Royen, A, Hack, CE. IVIg-mediated amelioration of murine ITP via FcgammaRIIb is not necessarily independent of SHIP-1 and SHP-1 activity. Blood. 2004. 103:1973-1974.
   View this article via: PubMed CrossRef Google Scholar
8. Bruhns, P, et al. Colony-stimulating factor-1-dependent macrophages are responsible for IVIG protection in antibody-induced autoimmune disease. Immunity. 2003. 18:573-581.
   View this article via: PubMed CrossRef Google Scholar
9. Akilesh, S, et al. The MHC class I–like Fc receptor promotes humorally mediated autoimmune disease. J. Clin. Invest. 2004. 113:1328-1333. doi:10.1172/JCI200418838.
   View this article via: JCI PubMed Google Scholar
10. Hansen, RJ, Balthasar, JP. Intravenous immunoglobulin mediates an increase in anti-platelet antibody clearance via the FcRn receptor. Thromb. Haemost. 2002. 88:898-899.
    View this article via: PubMed Google Scholar
11. Siragam, V, et al. Can antibodies with specificity for soluble antigens mimic the therapeutic effects of intravenous IgG in the treatment of autoimmune disease? J. Clin. Invest. 2005. 115:155-160. doi:10.1172/JCI200522753.
    View this article via: JCI PubMed Google Scholar
12. Song, S, et al. Monoclonal IgG can ameliorate immune thrombocytopenia in a murine model of ITP: an alternative to IVIG. Blood. 2003. 101:3708-3713.
    View this article via: PubMed CrossRef Google Scholar
13. Scaradavou, A, Bussel, JB. Clinical experience with anti-D in the treatment of idiopathic thrombocytopenic purpura. Semin. Hematol. 1998. 35(Suppl. 1):52-57.
    View this article via: PubMed Google Scholar
14. Sutterwala, FS, et al. Selective suppression of interleukin-12 induction after macrophage receptor ligation. J. Exp. Med. 1997. 185:1977-1985.
    View this article via: PubMed CrossRef Google Scholar
15. Sutterwala, FS, et al. Reversal of pro-inflammatory responses by ligating the macrophage Fcgamma receptor type I. J. Exp. Med. 1998. 188:217-222.
    View this article via: PubMed CrossRef Google Scholar
16. Cooper, N, et al. Intravenous (IV) anti-D and IV immunoglobulin achieve acute platelet increases by different mechanisms: modulation of cytokine and platelet responses to IV anti-D by FcgammaRIIa and FcgammaRIIIa polymorphisms. Br. J. Haematol. 2004. 124:511-518.
    View this article via: PubMed CrossRef Google Scholar
17. Coopamah, MD, Freedman, J, Semple, JW. Anti-D initially stimulates an Fc-dependent leukocyte oxidative burst and subsequently suppresses erythrophagocytosis via interleukin-1 receptor antagonist. Blood. 2003. 102:2862-2867.
    View this article via: PubMed CrossRef Google Scholar
18. Bazin, R, Lemieux, R, Tremblay, T, St. Amour, I. Tetramolecular immune complexes are more efficient than IVIg to prevent antibody-dependent in vitro and in vivo phagocytosis of blood cells. Br. J. Haematol. 2004. 127:90-96.
    View this article via: PubMed CrossRef Google Scholar
19. Maeda, H, et al. Successful treatment of “malignant rheumatoid arthritis” in Japan with pooled intravenous immunoglobulin. Rheumatology. 2001. 40:955-956.
    View this article via: PubMed CrossRef Google Scholar
20. Diaz de Stahl, T, et al. Expression of FcgammaRIII is required for development of collagen-induced arthritis. Eur. J. Immunol. 2002. 32:2915-2922.
    View this article via: PubMed CrossRef Google Scholar
21. Ioan-Facsinay, A, et al. FcgammaRI (CD64) contributes substantially to severity of arthritis, hypersensitivity responses, and protection from bacterial infection. Immunity. 2002. 16:391-402.
    View this article via: PubMed CrossRef Google Scholar
22. Ji, H, et al. Arthritis critically dependent on innate immune system players. Immunity. 2002. 16:157-168.
    View this article via: PubMed CrossRef Google Scholar
23. Kaplan, CD, et al. Development of inflammation in proteoglycan-induced arthritis is dependent on Fc gamma R regulation of the cytokine/chemokine environment. J. Immunol. 2002. 169:5851-5859.
    View this article via: PubMed Google Scholar
24. Kleinau, S, Martinsson, P, Heyman, B. Induction and suppression of collagen-induced arthritis is dependent on distinct fcgamma receptors. J. Exp. Med. 2000. 191:1611-1616.
    View this article via: PubMed CrossRef Google Scholar
25. Looney, RJ, Anolik, J, Sanz, I. B cells as therapeutic targets for rheumatic diseases. Curr. Opin. Rheumatol. 2004. 16:180-185.
    View this article via: PubMed CrossRef Google Scholar
26. Abdul-Majid, KB, et al. Fc receptors are critical for autoimmune inflammatory damage to the central nervous system in experimental autoimmune encephalomyelitis. Scand. J. Immunol. 2002. 55:70-81.
    View this article via: PubMed CrossRef Google Scholar
27. Lock, C, et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat. Med. 2002. 8:500-508.
    View this article via: PubMed CrossRef Google Scholar
28. Pedotti, R, et al. Multiple elements of the allergic arm of the immune response modulate autoimmune demyelination. Proc. Natl. Acad. Sci. U. S. A. 2003. 100:1867-1872.
    View this article via: PubMed CrossRef Google Scholar
29. Robbie-Ryan, M, et al. Cutting edge: both activating and inhibitory Fc receptors expressed on mast cells regulate experimental allergic encephalomyelitis disease severity. J. Immunol. 2003. 170:1630-1634.
    View this article via: PubMed Google Scholar