Particularities of the vasculature can promote the organ specificity of autoimmune attack

Abstract

How certain autoimmune diseases target specific organs remains obscure. In the 'K/BxN' arthritis model, autoantibodies to a ubiquitous antigen elicit joint-restricted pathology. Here we have used intravital imaging to demonstrate that transfer of arthritogenic antibodies caused macromolecular vasopermeability localized to sites destined to develop arthritis, augmenting its severity. Vasopermeability depended on mast cells, neutrophils and FcgammaRIII but not complement, tumor necrosis factor or interleukin 1. Unexpectedly, radioresistant FcRgamma-expressing cells in an organ distant from the joint were required. Histamine and serotonin were critical, and systemic administration of these vasoactive amines recapitulated the joint localization of immune complex-triggered vasopermeability. We propose that regionally distinct vascular properties 'interface' with immune effector pathways to foster organ-specific autoimmune damage, perhaps explaining why arthritis accompanies many human infectious and autoimmune disorders.

Regulation of systemic and local myeloid cell subpopulations by bone marrow cell–derived granulocyte–macrophage colony‐stimulating factor in experimental inflammatory arthritis

“…This finding of a normal early, predominantly neutrophil, response but a later defective macrophage response in K/BxN serum-transfer arthritis induced in GM-CSF Ϫ/Ϫ mice is similar to what we observed in the methylated bovine serum albumin-induced peritonitis model in these mice (22). It has been suggested that macrophages are most likely important after the initiation of K/BxN serum-transfer arthritis, being a major source of proinflammatory cytokines (45), whereas neutrophils are required in the early stage involving the vascular permeability that precedes disease onset (46).…”

Video-rate two-photon imaging of mouse footpad – a promising model for studying leukocyte recruitment dynamics during inflammation

“…Because surgery in itself causes tissue damage and inflammation, this might adversely affect leukocyte behavior [10] and essentially precludes obtaining a physiological base line level of homing, which is an important control parameter. Recently, several groups have used non-invasive single-photon techniques such as confocal and near IR imaging to study leukocyte homing [17,18,20]. While these studies represent significant technological advances in their own right, 2P imaging has the advantages of decreased phototoxicity [21] and superior imaging depth that should make it possible to follow cells longer and deeper into tissues.…”

Targeted mast cell silencing protects against joint destruction and angiogenesis in experimental arthritis in mice

“…To separate the effects of mast cells on joint destruction and angiogenesis from the effects of T cell-produced IL-17, we used GPI antibody-induced arthritis that is entirely independent of B cell and T cell activation, because it can be induced even in Rag-2 Ϫ/Ϫ mice (3,11,12). Importantly, injection of GPI antibodies induces arthritis more rapidly than T cells differentiate into distinct functional phenotypes.…”

“…Importantly, some diseases such as GPI antibody-induced arthritis are entirely independent of T cells and B cells and thus are especially suitable for selective analysis of mast cell function in vivo (3,11,12). Thus, injection of K/BxN mouse serum containing anti-GPI antibodies into wild-type Kit ϩ /Kit ϩ mice led to severe arthritis within 6 days, characterized by severe edema and functional impairment of the paws 1808 KNEILLING ET AL ( Figure 1A Figures 1C and D), with a mean Ϯ SEM increase in ankle thickness of 480 Ϯ 264 m, 6 days after K/BxN mouse serum transfer.…”

“…To address these questions, we used a disease model of RA induced in mice by anti-glucose-6-phosphate isomerase (GPI) antibodies, because this RA model is entirely independent of T cells and B cells but is strictly dependent on mast cells (3,11,12).…”