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 FcγRIII but not complement, tumor necrosis factor or interleukin 1. Unexpectedly, radioresistant FcRγ-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.
* Note: In the version of this article initially published online, the end of the third sentence of the second subsection of Results is incorrect. The sentence should read “Intravenous administration of preaggregated normal mouse IgG elicited an increase in joint-localized vasopermeability very similar to that induced by the administration of arthritogenic serum (Fig. 2b and data not shown).” Also, the final acknowledgement is incorrect; it should read “… and by the National Institute of Diabetes and Digestive and Kidney Diseases–supported Diabetes and Endocrinology Research Center cores of the Joslin Diabetes Center.” The errors have been corrected for the HTML and print versions of the article.
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Change history
07 February 2006
In the version of this article initially published online, the end of the third sentence of the second subsection of Results is incorrect. The sentence should read “Intravenous administration of preaggregated normal mouse IgG elicited an increase in joint-localized vasopermeability very similar to that induced by the administration of arthritogenic serum (Fig. 2b and data not shown).” Also, the final acknowledgement is incorrect; it should read “… and by the National Institute of Diabetes and Digestive and Kidney Diseases–supported Diabetes and Endocrinology Research Center cores of the Joslin Diabetes Center.” The errors have been corrected for the HTML and print versions of the article.
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Acknowledgements
We thank V. Tran for assistance with serum collection; R. Melamed for software programming; N. Mathis for assistance with some of the experiments; L. Kozinn for assistance with manuscript preparation; and G. King for comments about the manuscript. Supported by the National Institutes of Health (PO1 AI54904 to C.B., D.M., R.W. and U.M.; RO1 AR046580 to D.M. and C.B.; and P50 CA86355, R24 CA92782 and R33 CA91007to R.W.), a Pfizer Postdoctoral Fellowship in Rheumatology/Immunology (B.B.) and by the National Institute of Diabetes and Digestive and Kidney Diseases–supported Diabetes and Endocrinology Research Center cores of the Joslin Diabetes Center.
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U.M. is a consultant for and owns stock in VisEn Medical; R.W. is a cofounder of and owns stock in VisEn Medical.
Supplementary information
Supplementary Fig. 1
Calculation of maximum rate of leak and duration at half-maximum. (PDF 302 kb)
Supplementary Fig. 2
IgG subtype-specificity of immune complex triggered vasopermeability. (PDF 265 kb)
Supplementary Fig. 3
Effect of portal ligation on plasma histamine concentrations. (PDF 160 kb)
Supplementary Fig. 4
Proposed Model. (PDF 219 kb)
Supplementary Video 1
Vascular leak in the hindpaws following administration of K/BxN serum. Angiosense 680 was injected iv into a B6 mouse. Confocal micrographs of a hindpaw taken every 3 s for 10 min following injection of 200 μl of K/BxN arthritogenic serum were compressed into a video to demonstrate the dynamic nature of the vascular response. (MOV 1985 kb)
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Binstadt, B., Patel, P., Alencar, H. et al. Particularities of the vasculature can promote the organ specificity of autoimmune attack. Nat Immunol 7, 284–292 (2006). https://doi.org/10.1038/ni1306
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DOI: https://doi.org/10.1038/ni1306
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