1. Genetic dissection of a major haplotype associated with arthritis reveal FcγR2b and FcγR3 to act additively
- Author
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Dorota Klaczkowska, Liselotte Bäckdahl, Rikard Holmdahl, Daniëlle Vaartjes, Kutty Selva Nandakumar, and Mark S. Cragg
- Subjects
0301 basic medicine ,Fc gamma receptor ,Immunology ,collagen‐induced arthritis ,Congenic ,Arthritis ,Biology ,Autoimmune Diseases ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Mice, Inbred NOD ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Immunology and Allergy ,Genetic Predisposition to Disease ,Basic ,Allele ,Gene ,Alleles ,Cells, Cultured ,Research Articles ,Cia9 locus ,Mice, Knockout ,Polymorphism, Genetic ,Innate immune system ,Receptors, IgG ,Haplotype ,medicine.disease ,Arthritis, Experimental ,FcγR3 ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Haplotypes ,Immunodeficiencies and autoimmunity ,FcγR2b ,Research Article|Basic ,Cell activation ,030215 immunology - Abstract
A haplotype with tightly linked Fc gamma receptor (FcγR) genes is known as a major locus controlling immune responses and autoimmune diseases, including arthritis. Here, we split a congenic fragment derived from the NOD mouse (Cia9) to study its effect on immune response and arthritis in mice. We found that arthritis susceptibility was indeed controlled by the FcγR gene cluster and a recombination between the FcγR2b and FcγR3 loci gave us the opportunity to separately study their impact. We identified the NOD‐derived FcγR2b and FcγR3 alleles as disease‐promoting for arthritis development without impact on antibody secretion. We further found that macrophage‐mediated phagocytosis was directly correlated to FcγR3 expression in the congenic mice. In conclusion, we positioned FcγR2b and FcγR3 alleles as disease regulatory and showed that their genetic polymorphisms independently and additively control innate immune cell activation and arthritis., The closely linked polymorphic Fcgr2b and Fcgr3 NOD alleles promote the development of arthritis and enhance the inflammatory response capacity.
- Published
- 2020