Background/Purpose: Arthritis and endocarditis co-exist in several human rheumatic diseases, including systemic lupus erythematosus, rheumatic fever, and rheumatoid arthritis.  K/BxN TCR transgenic mice, well known for their inflammatory arthritis, also develop spontaneous endocarditis.  FcRγ, the cytoplasmic signaling molecule shared by the three activating Fcγ receptors in the mouse (FcγRI, III, and IV), is required for endocarditis in K/BxN mice. Here we addressed two main questions: first, which of the three activating Fcγ receptors is required for endocarditis in this model and second, what FcRγ-expressing cell type drives endocarditis.

Methods:  Knockout alleles of each of the activating Fcγ receptors (FcγRI-/-, FcγRIII-/-, and FcγRIV-/-) were bred into the K/BxN system.  In addition, we utilized a reciprocal bone marrow transplantation approach to determine if endocarditis depended on FcRγ expression by bone marrow-derived cells or by radio-resistant host cells.  We assessed hearts for the presence of endocarditis via standard hematoxylin and eosin staining.  Additionally, we used immunohistochemistry to examine the expression of the three activating Fcγ receptors in the cardiac valves as well as the isotypes of antibodies bound to the inflamed cardiac valves. 

Results: Although IgG1 is the predominant autoantibody isotype in K/BxN mice, we found that IgG1, IgG2b, and IgG2c were all bound to their inflamed cardiac valves.  We also detected expression of each of the activating Fcγ receptors in the cardiac valves. K/BxN mice lacking expression of FcγRI, FcγRIII, or FcγRIV developed endocarditis with equivalent severity to control mice.  The bone marrow transplant experiments revealed that recipient mice lacking FcRγ were protected from endocarditis.  Surprisingly, the presence or absence of FcRγ on bone marrow-derived donor cells did not influence the severity of endocarditis.

Conclusion: Our results indicate that no single activating Fcγ receptor is solely required for the development of endocarditis in K/BxN mice.  The simplest explanation for these findings is that there is redundancy among the activating Fcγ receptors in driving endocarditis.  This interpretation is consistent with our data showing that multiple immunoglobulin isotypes are bound to the inflamed valves and that that each of the activating Fcγ receptors can be detected in the valves.  A less likely explanation is that an FcRγ-utilizing receptor type other than the activating Fcγ receptors is at play.  We also conclude that FcRγ chain expression by radio-resistant host cells rather than by radiosensitive, bone-marrow derived cells is required for the development of endocarditis.  Candidate cell types include cardiac stromal cells and/or radio-resistant dendritic cells.  Our findings provide new insight into the pathogenesis of cardiovascular inflammation in the setting of autoantibody-associated diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/fc-receptor-gamma-dependent-autoimmune-endocarditis-in-kbxn-mice/