A crucial role for macrophages in the pathology of K/B × N serum‐induced arthritis

Abstract

Autoantibodies in the form of immune complexes are known to be crucial mediators in initiating inflammation in a variety of autoimmune diseases. This has been well documented in the anti-collagen II antibody-induced arthritis animal model for a long time now. Recently, in the K/B Â N mouse model (the F1 of the TCR-transgenic KRN and the diabetic NOD mice), anti-glucose-6-phosphate isomerase (GPI) autoantibodies have been shown to induce arthritis. Experimental work in the K/B Â N model demonstrated key roles of autoantigenic immune complexes activating the alternative pathway of complement, the subsequent association with C5aR and FccRIII-mediated cell activation and production of the inflammatory cytokines IL-1 and TNF-a, finally leading to joint destruction. The presence of high amounts of inflammatory cytokines and matrix-degrading proteases at sites of inflammation obviously put the cytokineproducing macrophages as the next target for investigation in this model. Here, we show that mice depleted of macrophages by clodronate liposome treatment are completely resistant to K/B Â N serum-induced arthritis. Reconstituting clodronate liposometreated mice with macrophages from naive animals could reverse this resistance. Also, we found that deficiencies in the Wiskott-Aldrich syndrome protein and CD40, which are both implicated in macrophage activation, chemotaxis and phagocytosis, are not essential in serum-induced arthritis. Mast cell degranulation was seen in arthritogenic serum-treated mice even in the absence of macrophages, possibly suggesting that mast cell degranulation/activation acts hierarchically before macrophages in the inflammatory cascade of anti-GPI antibody-induced arthritis.

Cutting Edge: The Murine High-Affinity IgG Receptor FcγRIV Is Sufficient for Autoantibody-Induced Arthritis

“…FcgRIV is therefore sufficient for K/BxN-PA. FcgRIV-dependent arthritis was abolished when monocytes/macrophages or neutrophils were depleted in 5KO mice (Fig. 1C), as reported for wt mice (9,10). A recent report demonstrating that K/BxN-PA could be restored in neutrophil-deficient mice by transferring wt or FcgRIIIA 2/2 bone marrow, but not by transferring FcRg 2/2 bone marrow (11), supports the role of FcgRIV on neutrophils in K/BxN-PA.…”

Loss of CD34 Leads To Exacerbated Autoimmune Arthritis through Increased Vascular Permeability

“…These immune complexes lead to FcR cross-linking on local, resident mast cells, triggering them to degranulate and release vascular permeability factors and inflammatory mediators, which initiate the inflammatory phase of the disease. This phenomenon has been proposed to be hierarchically situated before activation of other inflammatory cells (such as macrophages) (20) and to induce chronic inflammation in this model and, again, would be consistent with a model in which resident mast cells would be sufficient for the initiation of disease.…”

JNK1 controls mast cell degranulation and IL-1β production in inflammatory arthritis

“…MCs coordinate with neutrophils to amplify joint swelling and disease penetrance in serum transfer arthritis (22,25,26). Although activation of MCs is likely to be the initiating event, neutrophils and macrophages also are involved in disease development (26,27).…”