As much as knights and the Holy Grail are central elements in the King Arthur saga, the Arthus reaction is a central readout for inflammation, one of the most heavily studied topics in immunology. Abs of the IgG isotype are well known for their potent ability to trigger inflammation via activation of the complement pathway and/or via binding to cellular Fcγ receptors (FcγRs), which are broadly expressed on innate immune effector cells (1, 2). Clinically, this proinflammatory activity of IgG becomes evident in a variety of autoantibody-driven autoimmune diseases, in which IgG Abs recognize circulating autoantigens, resulting in the generation and deposition of immune complexes, ultimately initiating a cascade leading to tissue inflammation (also referred to as type III hypersensitivity) (3). Paradigm diseases for type III hypersensitivity are systemic lupus erythematosus, skin-blistering diseases, and rheumatoid arthritis, in which IgG immune complexes play a major role in organ inflammation. Of note, diseases such as rheumatoid arthritis may affect up to 1% of the population, underscoring the need to understand the Ab-dependent inflammatory cascades, which will drive the development of novel therapeutic interventions.
In this Pillars of Immunology commentary, we highlight the achievements of Diana L. Sylvestre and Jeffrey V. Ravetch, who identified the key role of FcγRs in initiating IgG-dependent inflammation in the Arthus reaction and—as we will briefly describe—in virtually all IgG-dependent inflammatory diseases (4). Since its description by Maurice Arthus in 1903 (5), the Arthus reaction became the paradigm in vivo model system to study key events in the process of inflammation, such as edema formation, hemorrhage, and recruitment of neutrophils. By injecting horse serum into the skin of rabbits repetitively, Arthus realized that when sensitized rabbits were challenged with the same Ag repeatedly in the skin, they developed all of the signs of inflammation (5). Later, a variant of the Arthus reaction, the so-called passive reverse Arthus reaction, became widely used, in which Abs specific for a model Ag (OVA or TNP, for example) are injected into the skin, followed by i.v. injection of the respective Ag into the animal. Once the Ag diffuses from the blood into tissues, immune complexes generated at the site of Ab injection will induce vasculature permeability, resulting in hemorrhage and edema formation.
In the 1960s, elegant studies performed in mice lacking the complement component C5 or using cobra venom factor to inactivate the complement cascade led to the widely accepted notion that triggering of the classical complement pathway was the dominant pathway responsible for initiating the inflammatory cascade via deposited IgG molecules (6–8). This dogma persisted for at least two decades. However, it was also clear that certain experimental conditions, such as low Ab doses and an interval of at least 3 h between Ab and Ag injection, favored a contribution of the complement system to the resulting tissue inflammation (6).
In contrast to complement, an assessment of the role played by FcγRs in the inflammatory cascade did not become possible until much later. Cloning and characterization of the first FcγRs, aided by the availability of FcγR-specific Abs, began only in the early 1980s and continued until the last mouse activating FcγR was identified in 2005 (9–11). Another breakthrough came with the advent of knockout mouse technology in the late 1980s, allowing the generation of an Fcer1g knockout mouse in 1994 (12). The Fcer1g gene encodes the common signaling adaptor molecule, the common FcRγ-chain, which is essential for signal transduction of all mouse activating FcγRs. Together, these innovations enabled an assessment of FcγR function in inflammation using a single knockout mouse (13).
Thus, the groundwork was laid for the seminal study by Sylvestre and Ravetch (4), which is remarkable for several reasons. First, they clearly demonstrated that the reverse passive cutaneous Arthus reaction is severely impaired in FcRγ-chain knockout mice, establishing a major role for FcγRs in the inflammatory cascade for the first time. Importantly, IgG-dependent inflammation also was impaired at those time points, in which mice lacking the complement component C5 were not protected against edema formation and hemorrhage. Moreover, the study used different hapten-specific mouse IgG subclasses and haptenized Ag to trigger the Arthus reaction in addition to the widely used rabbit-derived antisera. The importance of using homotypic Abs can only be appreciated retrospectively, now knowing that heterotypic IgG molecules (derived from a different species) may differ in their capacity to trigger complement and FcγR pathway activation. Furthermore, whereas both IgG2a and IgG3 are able to activate the complement system, only IgG2a could bind to all activating FcγRs and induce an inflammatory response via the Arthus reaction, which suggested that FcγRs, and not the complement pathway, were initiating the inflammatory cascade in mice (1). Finally, cobra venom factor injection showed only a mild reduction in inflammation, firmly establishing that activating FcγRs played a critical role in initiating the inflammatory sequelae of the Arthus reaction (4).
Two years later, Sylvestre et al. (14) and Sylvestre and Ravetch (15) extended these results by demonstrating that mouse strains deficient for the complement components C3 and C4 developed a normal Arthus reaction and that FcγRs expressed on mast cells played an essential role in initiating the inflammatory cascade. Since then, the critical role of FcγRs in initiating autoantibody dependent inflammatory sequelae has been confirmed and extended in different disease models of autoantibody-triggered inflammation. For example, work by Mathis and colleagues (3, 16–19) in a passive model of inflammatory arthritis and more recent studies in passive models of epidermolysis bullosa acquisita have both fully confirmed the critical role of FcγRs in initiating inflammation in the skin and joints. With respect to the contribution of the complement system, several studies have highlighted that it is not the classical or lectin pathways, but rather the alternative complement pathway that plays a critical role in the inflammatory cascade and that C5 and the C5a-receptor are key drivers of inflammation (8, 20, 21).
In summary, the pivotal study by Sylvestre and Ravetch (4) unraveled a key part of the Arthus mystery and paved the way for a better understanding of the holy grail of immunology: inflammation.
Max D. Cooper is a Distinguished Fellow of AAI.
This work was supported by Deutsche Forschungsgemeinschaft Grant DFG CRC1181-A07 (to F.N.).
The authors have no financial conflicts of interest.