Abstract
The K/BxN serum-transfer arthritis (STA) model is a murine model in which the immunological mechanisms occurring in rheumatoid arthritis (RA) and other arthritides can be studied. To induce K/BxN STA, serum from arthritic transgenic K/BxN mice is transferred to naive mice and manifestations of arthritis occur a few days later. The inflammatory response in the model is driven by autoantibodies against the ubiquitously expressed self-antigen, glucose-6-phosphate isomerase (G6PI), leading to the formation of immune complexes that drive the activation of different innate immune cells such as neutrophils, macrophages, and possibly mast cells. The pathogenesis further involves a range of immune mediators including cytokines, chemokines, complement factors, Toll-like receptors, Fc receptors, and integrins, as well as factors involved in pain and bone erosion. Hence, even though the K/BxN STA model mimics only the effector phase of RA, it still involves a wide range of relevant disease mediators. Additionally, as a murine model for arthritis, the K/BxN STA model has some obvious advantages. First, it has a rapid and robust onset of arthritis with 100% incidence in genetically identical animals. Second, it can be induced in a wide range of strain backgrounds and can therefore also be induced in gene-deficient strains to study the specific importance of disease mediators. Even though G6PI might not be an essential autoantigen, for example, in RA, the K/BxN STA model is a useful tool to understand how autoantibodies, in general, drive the progression of arthritis by interacting with downstream components of the innate immune system. Finally, the model has also proven useful as a model wherein arthritic pain can be studied. Taken together, these features make the K/BxN STA model a relevant one for RA, and it is a potentially valuable tool, especially for the preclinical screening of new therapeutic targets for RA and perhaps other forms of inflammatory arthritis. Here, we describe the molecular and cellular pathways in the development of K/BxN STA focusing on the recent advances in the understanding of the important mechanisms. Additionally, this review provides a comparison of the K/BxN STA model to some other arthritis models.
Highlights
Research into the pathogenesis of rheumatoid arthritis (RA) has benefited enormously from a vast number of animal models, wherein mechanisms governing arthritis can be studied
We have recently shown that granulocyte colony-stimulating factor (G-CSF), possibly produced from interleukin 1β (IL-1β) activation of a resident cell population, is a pivotal driver of the disease progression in the K/BxN serum-transfer arthritis (STA) model and possibly acts, in part, by regulating neutrophil numbers in the circulation (39) (Figure 2)
These results indicate that glucose-6-phosphate isomerase (G6PI) might be one of the several autoantigens able to serve as a target for autoantibodies in RA, but their pathogenic and diagnostic relevance is currently not clear
Summary
Research into the pathogenesis of rheumatoid arthritis (RA) has benefited enormously from a vast number of animal models, wherein mechanisms governing arthritis can be studied. In 1996, the K/BxN model of arthritis was reported for the first time by the Mathis/Benoist laboratory (1) This model was discovered by crossing T-cell receptor (TCR) transgenic KRN mice on a C57BL/6 background (transgenic for a TCR) recognizing a bovine ribonuclease peptide (RNase 43–56) presented by I-Ak major histocompatibility complex (MHC) class II molecule with autoimmune-prone non-obese diabetic (NOD) mice. Arthritis progression in the K/BxN mice is driven by activation of T cells expressing the KRN TCR that recognizes a self-peptide bound to the NOD-derived I-Ag7 molecule on MHC class II antigen-presenting cells (APCs). The main features of what we have termed for convenience, albeit somewhat arbitrary, the “initiation phase” of the K/BxN STA model, are depicted in the literature-based schematic in Figure 1 and summarized below
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