Spontaneous inflammatory arthritis in HLA-B27 transgenic mice lacking beta 2-microglobulin: a model of human spondyloarthropathies.

Abstract

Human class I major histocompatibility complex allele HLA-B27 is associated with a group of human diseases called "spondyloarthropathies." Studies on transgenic rats expressing HLA-B27 and human beta 2-microglobulin have confirmed the role of HLA-B27 in disease pathogenesis. Here we report spontaneous inflammatory arthritis in HLA-B27 transgenic mice lacking beta 2-microglobulin (B27+ beta 2m-/-). In the absence of beta 2-microglobulin, B27+ beta 2m-/- animals do not express the HLA-B27 transgene on the cell surface and have a very low level of CD8+ T cells. Most of the B27+ beta 2m-/- male mice showed nail changes, hair loss, and swelling in paws, which leads to ankylosis. The symptoms occur only after the B27+ beta 2m-/- mice are transferred from the specific pathogen-free mouse colony. These results suggest that aberrant assembly, transport, and expression of the HLA-B27 molecule may predispose an individual for development of the disease when exposed to an appropriate environmental trigger.

Recognition of chlamydial antigen by HLA‐B27‐restricted cytotoxic T cells in HLA‐B*2705 transgenic CBA (H‐2k) mice

“…In our B27 transgenic mouse model as well as in transgenic mouse models described by other investigators (26,(52)(53)(54)(55)(56), but unlike the findings in the B27 transgenic rat model (4)(5)(6), the transgenic mouse model studied by Weinreich et a1 (57), or the recently described model of HLA-B27 transgenic mice lacking P2m (58), no spontaneous or induced manifestation of disease occurs. It nevertheless provides a model suitable for defining a bacteria-specific CD8 immune response.…”

Lymphoblastoid cells express HLA‐B27 homodimers both intracellularly and at the cell surface following endosomal recycling

“…One possible hypothesis is that arthritogenic peptides are presented by B27 heterodimers to auto-reactive T cells [6]. Alternatively, a direct pathogenic role for class I heavy chains has been suggested by a mouse model of spondyloarthritis that requires expression of B27 in the absence of g 2 m [7]. Moreover, disease onset is delayed and severity reduced by treatment with the heavy chainspecific mAb HC-10 but not by an mAb detecting intact g 2 m-associated B27 molecules (ME-1) [8,9].…”

The role of MHC class I heterodimer expression in mouse ankylosing enthesopathy

“…Khare and co-workers have recently described a spontaneous inflammatory arthritis (SIA), which, in marked contrast to ANKENT, is found only in HLA-B27 transgenic, β2m ko mice with no class I heterodimer expression (Khare et al 1995). The ANKENT and SIA models have been described using different B27 transgenes (B*2702 and B*2705, respectively (Krimpenfort et al 1987;Nickerson et al 1990), as well as independently produced ko founders (Zijlstra et al 1989;Koller and Smithies 1989, respectively).…”

“…The ANKENT and SIA models have been described using different B27 transgenes (B*2702 and B*2705, respectively (Krimpenfort et al 1987;Nickerson et al 1990), as well as independently produced ko founders (Zijlstra et al 1989;Koller and Smithies 1989, respectively). Moreover, ANKENT and SIA have distinct pathological characteristics: nail changes, synovial inflammation, and phalangeal joint involvement are present in SIA (Khare et al 1995) but absent in ANKENT (Weinreich et al 1995a). SIA occurred only when mice were moved from a specific-pathogen-free to a conventional unit, suggesting that an environmental trigger, in addition to abnormal transport or expression of B27 heavy chain, is involved (Khare et al 1995).…”

“…Moreover, ANKENT and SIA have distinct pathological characteristics: nail changes, synovial inflammation, and phalangeal joint involvement are present in SIA (Khare et al 1995) but absent in ANKENT (Weinreich et al 1995a). SIA occurred only when mice were moved from a specific-pathogen-free to a conventional unit, suggesting that an environmental trigger, in addition to abnormal transport or expression of B27 heavy chain, is involved (Khare et al 1995). Once this environmental trigger is defined, its effect in the ANKENT model can be examined.…”