BXSB/MpJ-Yaa mouse model of systemic autoimmune disease shows increased apoptotic germ cells in stage XII of the seminiferous epithelial cycle

Abstract

In mammals, the reproductive system and autoimmunity regulate mutual functions. Importantly, systemic autoimmune diseases are thought to cause male infertility, but the underlying pathological mechanism remains unclear. In this study, the morpho-function of the testes in BXSB/MpJ-Yaa mice were analyzed as a representative mouse model for systemic autoimmune diseases to investigate the effect of excessive autoimmunity on spermatogenesis. At 12 and 24 weeks of age, BXSB/MpJ-Yaa mice showed splenomegaly and increased levels of serum autoantibodies, whereas no controls showed similar autoimmune condition. In histological analysis, the enlarged lumen of the seminiferous tubules accompanied with scarce spermatozoa in the epididymal ducts were observed in some of the BXSB/MpJ-Yaa and BXSB/MpJ mice, but not in C57BL/6N mice. Histoplanimetrical analysis revealed significantly increased residual bodies and apoptotic germ cells in the seminiferous tubules in BXSB/MpJ-Yaa testes without apparent inflammation. Notably, in stage XII of the seminiferous epithelial cycles, the apoptotic germ cell number was remarkably increased, showing a significant correlation with the indices of systemic autoimmune disease in BXSB/MpJ-Yaa mice. Furthermore, the Sertoli cell number was reduced at the early disease stage, which likely caused subsequent morphological changes in BXSB/MpJ-Yaa testes. Thus, our histological study revealed the altered morphologies of BXSB/MpJ-Yaa testes, which were not observed in controls, and statistical analysis suggested the effects of an autoimmune condition on this phenotype, particularly the apoptosis of meiotic germ cells. BXSB/MpJ-Yaa mice were shown to be an efficient model to study the relationship between systemic autoimmune disease and the local reproductive system.

Tertiary lymphoid structures as local perpetuators of organ-specific immune injury: implication for lupus nephritis

“…Furthermore, the presence of TLS in human kidney biopsies correlated with increased B cell hyperactivity and serum levels of CXCL13 (70). Subsequently, transcriptomic studies of LN kidneys in MRL/lpr and BXSB models showed increased cxcl13/cxcr5 along with upregulated expression signature associated with TLS formation (63), suggesting a role of CXCL13/CXCR5 in TLS formation in LN. In animal studies, BAFF, TLR7 signaling, and Fli-1 have also been suggested to play a role in TLS formation (54, 65,71).…”

“…These animals had a higher ex vivo FDG accumulation in the kidney of anti-dsDNA antibody positive group compared to antibody-negative mice, which is consistent with the presence of large population of metabolic active or activated immune cells (35). Thus, TLS may contribute to LN in multiple ways (Table 5), such as by being a local source of activated immune cells (35), local IFN-I production (61), maintaining systemic autoantibody production (66, 78), site for intermolecular epitope spreading (80, 81) to local autoantigens such as to locally overexpressed vimentin (79), and facilitating tubulointerstitial inflammation (63,68).…”

“…Post-translational modifications of antibodies (83) Intrarenal B cell clonal expansion and ongoing somatic hypermutation (68,63) Antigen presentation (63,67) Epitope spreading to local autoantigens (79) There is some evidence to suggest that certain infections and immune inflammatory states favor the GC or the extrafollicular response (92). It has been suggested that the extrafollicular response may occur in the context of severe infections with high pathogen burden (92).…”

Morphological Features of the Testis among Autoimmune Mouse Model and Healthy Strains

“…Among these models, the BXSB/MpJ-Yaa in which there is a Y chromosome-linked autoimmune acceleration gene accelerates the systemic autoimmune disease in males (Henry & Mohan, 2005). Recently, our team showed some histopathological abnormalities in the testis of the BXSB/MpJ-Yaa mice including an increased number of both residual bodies and apoptotic germ cells in stage XII, and decreased numbers of Sertoli cells, and concluded that these testicular lesions could play a role in the pathogenesis of reproductive dysfunction in this autoimmune disease mouse model (Otani et al, 2020). The MRL/MpJ mice are the control strain of MRL/MpJ-Fas lpr (MRL/lpr) mice and show mild autoimmune disease in older ages (Heydemann, 2012).…”

“…The knowledge of how systemic autoimmune disease histologically alters the testis is limited (Otani et al, 2020). However, the morphological testicular alterations in the testes of MRL/lpr mice have not studied yet.…”