RESUMO
Ankylosing enthesopathy (ANKENT) is a spontaneous mouse joint disease with strikingly similar pathology to human HLA-B27-associated enthesopathies such as ankylosing spondylitis. In C57Bl/10 mice, transgenic HLA-B*2702 as well as H2 genes have been shown to be relative risk factors for ANKENT. To investigate the role of major histocompatibility complex (MHC) class I expression in disease pathogenesis, ANKENT occurrence was compared among beta2-microglobulin (beta2m) knockout littermates with or without transgenes for HLA-B*2702 and human beta2m. In the knockout phenotype lacking beta2m, ANKENT occurrence is significantly reduced (P = 0.016). In the absence of beta2m, B*2702 is not detected on the cell membrane, nor does it increase the risk for ANKENT. This means that the previous finding that HLA-B*2702 increases susceptibility to ANKENT in C57Bl/10 mice cannot be ascribed to a transgene insertion effect. Rather, in order to increase disease susceptibility, B*2702 must be coexpressed with mouse beta2m (mo-beta2m). In contrast, when HLA-B*2702 is expressed with beta2m of human origin, disease susceptibility is not affected. Thus, both H2(b)-derived class I heterodimers and HLA-B*2702/mo-beta2m heterodimers contribute to ANKENT susceptibility.
Assuntos
Anquilose/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/fisiologia , Animais , Anquilose/tratamento farmacológico , Anquilose/epidemiologia , Anquilose/genética , Dimerização , Genótipo , Antígenos H-2/biossíntese , Antígenos H-2/genética , Antígenos H-2/fisiologia , Antígeno HLA-B27/genética , Antígenos de Histocompatibilidade Classe I/biossíntese , Humanos , Imunofenotipagem , Incidência , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Transgenes , Microglobulina beta-2/genética , Microglobulina beta-2/uso terapêuticoRESUMO
OBJECTIVE: To evaluate the number of males per cage as a possible risk factor for murine ankylosing enthesopathy (ANKENT)--a spontaneous joint disease with parallels to human seronegative spondylarthropathies--since ANKENT shows incomplete penetrance of genetic susceptibility factors among individuals living in a stable environment. METHODS: Frequency of ANKENT was compared among males housed with females, with other males, or alone. RESULTS: In three independent cohorts, a trend was observed that males housed with females rarely develop the disease, in contrast to males housed with other males (P < 0.25, P < 0.05, and P < 0.01). Furthermore, no males caged alone developed ANKENT, whereas disease did occur in males grouped together (P < 0.01). When healthy males (retired breeders) were recaged either alone or with other males, ANKENT developed among the grouped males only (P < 0.005). CONCLUSIONS: Caging males together is a relative risk factor for ANKENT. Grouped caging may perturb the immune system through endocrine pathways or modify microbiological load through behaviour (for example, infection due to biting).
Assuntos
Meio Social , Espondilite Anquilosante/etiologia , Animais , Cruzamento , Suscetibilidade a Doenças , Masculino , Camundongos , Camundongos Transgênicos , Fatores de Risco , Espondilite Anquilosante/genéticaRESUMO
Murine ankylosing enthesopathy (ANKENT) is a spontaneous joint disease with numerous parallels to the human seronegative spondylarthropathies at the level of disease distribution, genetics and pathology. Although several genetic susceptibility factors have been identified previously, there is variation in disease susceptibility among genetically identical individuals, living in a stable environment. Preliminary observations indicate that males housed together with females rarely develop the disease, in contrast to males housed with other males (p < 0.25, p < 0.05, and p < 0.01). Furthermore, males caged under solitary conditions developed no ANKENT, whereas the disease did develop among individuals housed in groups of 4 (p < 0.01). The mechanism through which grouped caging induces a risk for ANKENT requires further study.
Assuntos
Criação de Animais Domésticos , Anquilose , Doenças Reumáticas/genética , Animais , Anquilose/genética , Anquilose/fisiopatologia , Distribuição de Qui-Quadrado , Masculino , Camundongos , Camundongos Transgênicos , Fatores SexuaisRESUMO
HLA-B27 is a risk factor for several human diseases through a mechanism that is not yet understood. This article describes a naturally occurring joint disease in laboratory mice, ANKENT. ANKENT begins with mild inflammation and culminates in irreversible stiffening of the ankle and/or tarsal joints in one or both hind paws. The macroscopic and histologic features of ANKENT, its relationship to age, gender, and environment, and some immunologic aspects are considered. With respect to genetics, it is demonstrated that an HLA-B27 transgene is a relative risk factor for ANKENT. Its impact depends on the H-2 haplotype, reaching a relative risk value of 9.4 for C57Bl/10, H-2b males (p < 0.025). Several features of ANKENT are reminiscent of human AS: joint pathology, age and gender distribution, the presence of non-MHC as well as MHC risk factors (including HLA-B27), and the suspicion that environmental factors are involved.
