Editorial: Of Mice and Mice: Understanding Conflicting Murine Experimental Data

Mouse models can have a major impact on how we think about disease pathogenesis. One example of this impact relates to the role of microbiota—the microorganisms that colonize our gut, skin, and other locations—as modulators of immune function. Multiple studies over the last few years have demonstrated, using murine models, that commensal bacteria critically regulate the maturation of the immune system and thereby susceptibility to a variety of autoimmune diseases (1). These controlled animal experiments provide key support for human observational studies implicating colonization with specific types of bacteria in the pathogenesis of diseases such as rheumatoid arthritis (RA) (2) and lend credibility to the hypothesis that manipulation of the human microbiome could ultimately provide a new approach to the treatment of rheumatic diseases. However, mouse studies sometimes yield conflicting results that fuel negative sentiments toward the validity and relevance of mouse models of human disease. For example, an influential study by Wu et al published in 2010 (3) demonstrated that the generation of arthritogenic antibodies in the K/BxN mouse model of arthritis was mediated by Th17 cells, and that these cells were in turn dependent on colonization with segmented filamentous bacteria (SFB), a commensal inhabitant of the mouse terminal ileum. In contrast, in this issue of Arthritis & Rheumatology, Auger et al (4) report that interleukin-17A (IL-17A) is not required for the formation of arthritogenic antibodies in this model, and neither are SFB. Similar findings showing that IL-17A was “dispensable” for K/BxN mouse arthritis were reported by other investigators (5). The K/BxN mouse model of arthritis was developed in the laboratory of Diane Mathis and Christophe Benoist, who had set out to study thymic T cell development by crossing mice transgenic for a T cell receptor (TCR) called KRN, which recognizes a bovine pancreatic ribonuclease peptide in the context of the major histocompatibility complex (MHC) class II allele I-A, with mice with a variety of different MHC haplotypes. Unexpectedly, offspring from the cross between KRN-transgenic C57BL/6 mice (K/B) and diabetes-prone NOD mice (N) expressing the MHC class II allele I-A developed spontaneous arthritis. In an elegant series of studies, the Mathis/Benoist laboratory showed that arthritis in these K/BxN mice was mediated by an autoimmune response against the glycolytic enzyme glucose-6-phosphate isomerase (GPI), an enzyme that is ubiquitously expressed but when released free into the circulation tends to deposit on the cartilage surface in synovial joints. Although anti-GPI immune responses do not appear to play a role in the pathogenesis of RA, the K/BxN mouse model of arthritis, together with the discovery of anti– citrullinated protein antibodies at approximately the same time, contributed to the renewed interest in the role of autoantibodies in RA. The study by Wu et al demonstrated that the K/BxN mouse model of arthritis critically depends on the microbial environment. The authors showed that germ-free K/BxN mice did not develop arthritis but that disease was readily induced when germ-free K/BxN mice were colonized with feces from mice housed under standard conditions. This appeared to depend on a Th17 immune response, because disease development could be blocked by administration of neutralizing anti–IL-17A antibodies. Given the previous description by Ivanov et al (the Dan Littman group) of the role of SFB in Th17 immune responses in mice (6), Wu et al found that SFB played a key role in driving arthritis in their K/BxN mice. Together with studies by other investigators that demonstrated effects of clostridia and bacteroides species on regulatory T cells, this study helped to establish the paradigm that distinct members of intestinal microbiota may shape immune responses beyond the intestine, thereby contributing to the development of extraintestinal disease. Joerg Ermann, MD: Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. Address correspondence to Joerg Ermann, MD, Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Smith Building, Room 614, 1 Jimmy Fund Way, Boston, MA 02115. E-mail: jermann@bwh.harvard. edu. Submitted for publication March 28, 2016; accepted in revised form March 31, 2016.