No abstract

Immunoglobulin G (IgG) antibodies confer protection against pathogenic microorganisms, serve as therapeutics in tumor therapy, and are involved in destruction of healthy tissues during autoimmune diseases. Understanding the molecular pathways and effector cell types involved in antibody-mediated effector functions is a prerequisite to modulate these activities. In this study we used two independent model systems to identify innate immune effector cells required for IgG activity in vivo. We first defined the precise repertoire of receptors for the IgG Fc fragment (FcγR) on innate immune effector cells in the blood and on tissue-resident macrophage populations. Despite expression of relevant activating FcγRs on various phagocyte populations, our data indicate that the majority of these cell types are dispensable for IgG activity in vivo. In contrast, IgG-dependent effector functions were selectively impaired in animals lacking the CX(3)CR1(hi)Ly6C(lo)CD11c(int) monocyte subset, which expressed the full set of FcγRs required for IgG activity.

SummaryImmunoglobulin G (IgG) molecules can have two completely opposite functions. On one hand, they induce proinflammatory responses and recruit innate immune effector cells during infection with pathogenic microorganisms or autoimmune disease. On the other hand, intravenous infusion of high doses of pooled IgG molecules from thousands of donors [intravenous IG (IVIG) therapy] represents an efficient anti-inflammatory treatment for many autoimmune diseases. Whereas our understanding of the mechanism of the proinflammatory activity of IgG is quite advanced, we are only at the very beginning to comprehend how the anti-inflammatory activity comes about and what cellular and molecular players are involved in this activity. This review will summarize our current knowledge and focus upon the two major models of either IVIG-mediated competition for IgG-triggered effector functions or IVIG-mediated adjustment of cellular activation thresholds used to explain the mechanism of the anti-inflammatory activity.

Impaired regulatory T-cell function results in a severe chronic autoimmune disease affecting multiple organs in Scurfy mice and humans with the immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Previous studies have shown that T helper cells but not cytotoxic T cells are critical for the disease pathology. Whether this T-cell subset is responsible directly for tissue inflammation or rather indirectly via the interaction with B cells or myeloid cells is largely unknown. To study this and to identify potential therapeutic targets for this lethal disease we investigated the contribution of B cells to this complex autoimmune phenotype. We show that B cells and the production of autoantibodies plays a major role for skin, liver, lung, and kidney inflammation and therapeutic depletion of B cells resulted in reduced tissue pathology and in prolonged survival. In contrast, the absence of B cells did not impact systemic T-cell activation and hyperreactivity, indicating that autoantibody production by B cells may be a major factor for the autoimmune pathology in mice deficient for regulatory T cells.

Immunoglobulin G (IgG) molecules are a family of glycoproteins essential for defending the body against invading pathogens. The antibody constant domain is very potent in initiating proinflammatory pathways such as the activation of innate immune effector cells via cellular receptors specific for the antibody constant region (Fc receptors) and the activation of the complement pathway. During autoimmune disease the normally protective antimicrobial function of these molecules is targeted to healthy tissues often with disastrous consequences. Interestingly, one successful anti-inflammatory therapy for many autoimmune diseases is the infusion of high doses of IgG molecules, the so-called intravenous IgG therapy. How one class of molecules can have such opposing functions will be the major focus of this review.