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Department of Medicine and Microbiology, Columbia University, New York, New York, USA.
Abstract
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 Fc receptor–targeted therapeutics.
See the related article beginning on page 155
Fc receptors in the pathogenesis and treatment of ITP
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 Fc receptors (FcRs) would be predicted to be an effective therapy in ITP. Indeed, this has proven to be a valid approach; antibodies that block FcRIII 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 FcR-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 FcRIIB on splenic macrophages and is abrogated in mice lacking FcRIIB. 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 FcRIIB may be responsible (7), but as yet the FcRIIB-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 FcRIII-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 FcR therapeutic approaches are tenable: direct blockade of the phagocytic Fc receptors and IVIg-triggered, FcRIIB-mediated inhibition (Figure 1).
Figure 1
Inhibition of phagocytosis in vivo can be accomplished via IC-mediated inhibition of FcR 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 FcRII 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 FcRII expression. Perhaps mimicking the situation directly, antibodies that specifically engage either the inhibitory FcRII (4) or the activating FcRIII (4, 5) can also induce platelet count recovery.
What is the active component of IVIg and intravenous anti-D?
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 FcRI), 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 FcRIIB 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 FcRIIB-deficient mice, which suggests that they interfere directly with activating FcR–mediated phagocytosis. The FcRIIB-independent anti-inflammatory mechanism of opsonized particulates might be assumed to be the straightforward result of activating FcR 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 FcRIII (Figure 1) (12, 14-17).
New approaches to Fc receptor therapeutics
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 FcRIIB directly by cross-linking FcRIIB-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 FcRII-dependent protection (11). Monoclonal antibodies recognizing a single epitope form monomeric ICs, implying that clustering of FcRs by these small ICs is not required for their therapeutic effect. Even with polyclonal -albumin or -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.
Implications for other autoimmune states
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 FcRs 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 FcR-based therapeutics might have as-yet-undiscovered clinical activity in T cell–mediated autoimmune conditions through regulatory effects on FcR-bearing antigen-presenting cells. Identifying the critical FcR 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 FcR-targeted therapeutics. Thus, other autoantibody-driven diseases, beyond ITP, may prove treatable with a little of what ails you.
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