SUMMARYExperimental autoimmune orchitis (EAO) was produced in C3H/He mice with as high as 100% incidence by two or ihrce s,c. injections of I x 10' viable syngeneic lesticular germ ceils (TC) without resorting lo adjuvants. Bordetella pertu.\si.s vaccine, or other immunological manipukuions. On day 40 after the lirst injection ofTC. the lesions induced were characterized by interstitial infiltration ol' inflammatory cells and severe hypospermatogenesis in the testis with resulting whole organ atrophy and. in contrast, by a complete lack ofepididymitis. Immunological studies revealed thai ihis form of immunization caused both delayed-typc hypersensitivity and humoral antihody responses to syngeneic TC. We compared the susceptibilities lo the induction of this lype of EAO among six different strains ofinbred mice comprising A'J.AKR. BALB/c. C3H/Hc.C57BL/6 and DBA/2 mice. All strains except for DBA/2 mice developed lesions of EAO to a greater or lesser extent, and severe disease was induced with high frequency in two strains, C3H/'He and A'J. As this murine model of EAO can be induced withoui the use of Freund's complete adjuvant and B. pertus.u.t vaccine, it is simply "autoimmune* in nature and may provide new ways for further investigation into the immunological mechanisms which regulate deleterious autoimmune reactions to germ cell antigens leading to the male infertility.
To determine whether the regulation of apoptosis in the testes of patients with varicocele testes was abnormal, affecting germ-cell differentiation and sperm production, we studied apoptosis in the testes of normal men and infertile men with varicocele. In all, 56 testicular biopsy specimens were collected from 28 varicocele patients. The specimens from the testes of five normal volunteers with informed consent were used as controls. In situ end-labeled cells were counted with a CAS 200 image analyzer, and an apoptotic index (AI) was calculated by division of the number of labeled cells by the total number of spermatocytes and spermatogonia in over 20 seminiferous tubules. The apoptosis was also examined by electron microscope. The mean AI was 9.67 +/- 0.93% in normal testes (n = 5). In contrast, the mean AIs determined in the right and left testes of varicocele patients (n = 28) were 3.90 +/- 2.28% and 3.78 +/- 2.87%, respectively. The AIs recorded for the testes of varicocele patients were significantly lower than those noted for normal men (P < 0.05). In varicocele patients the AI obtained in the right testis was not statistically significantly different from that found in the left testis. The numbers of apoptotic cells per Sertoli cell also decreased in the testes of varicocele patients as compared with normal men (P < 0.01). Evaluation of all specimens, including the normal controls, revealed no significant correlation either between the AI and the sperm concentration on the seminogram or between the AI and Johnsen's mean score. There was also no relationship between the AI and the serum level of follicle-stimulating hormone, lutenizing hormone, testosterone, or estradiol. In conclusion, apoptosis is decreased in germ cells in the testes of infertile men with varicocele as compared with normal men.
SUMMARY:Recognition and uptake of apoptotic cells by neighboring phagocytes is essential for the clearance of dying cells without accompanying inflammation or tissue damage. In the thymus, many apoptotic cells are generated in the process of negative selection, and both thymic macrophages (professional phagocytes) and nursing thymic epithelial cells (nursing TEC; nonprofessional phagocytes) recognize and ingest them. However the receptors responsible for this recognition and uptake have not been identified. In the present study, we have established a human nursing TEC line and examined the expression of several genes of the scavenger receptor family considered to be potential receptors for apoptotic cells. Human scavenger receptor-B1 (hSR-B1)/CLA-1, previously shown to recognize apoptotic cells, was strongly expressed in nursing TEC, whereas there was little or no expression of the other scavenger receptors tested: scavenger receptor class A, CD36, or CD68. Suppression of hSR-B1/CLA-1 expression using antisense oligonucleotides decreased the binding of apoptotic thymocytes to nursing TEC by more than 40%. These results indicate that hSR-B1/CLA-1 may play a major role in the clearance of apoptotic cells in the thymus, mediating the recognition and ingestion of apoptotic thymocytes by nursing TEC. (Lab Invest 2000, 80:263-270).
Previous studies demonstrated that experimental autoimmune orchitis (EAO) was produced in C3H/He mice with very high incidence by two or three subcutaneous injections of viable syngeneic testicular germ cells, without the use of any adjuvants or immunopotentiators and that the disease induced was characterized by a complete lack of epididymitis despite a definite orchitis with hypospermatogenesis. In this report, immunohistochemical characterization of immune cells in the fully-developed orchitic lesion was carried out using monoclonal antibodies and immunoperoxidase staining. Thy-1.2+ cells, Mac-1+ cells, B220+ cells and cytoplasmic Ig-bearing cells in the lesion were estimated to be approximately 30, 15, 20 and 30% of all inflammatory cells, respectively. Major phenotype of T cells in the lesion was CD4+ (approximately 85%) with the remainder (approximately 15%) being CD8+. The percentages of cytoplasmic IgG-, IgA- and IgM-bearing cells were estimated as approximately 35, 60 and 5% of all cytoplasmic Ig-bearing cells, respectively. Deposits of immunoglobulins and third component of complement were identified on the basement membrane of the seminiferous tubules, interstitium between the tubules, vessel endothelium and degenerated germ cells in the lesion. Circulating antibodies directed against the acrosomal portion of germ cells were detected in IgG and IgM classes but not in IgA class. Inflammatory cells (including macrophages, B cells and, probably, activated T cells) in the lesion were Ia+, but Leydig cells, Sertoli cells and germ cells did not stain for Ia at all.
SUMMARYThe laminin a2-chain is a component of merosin, a member of the laminin family molecules, which is mainly expressed in the basement membranes of striated muscle. It is known that laminin a2 gene (lama2) null mutant mice (dy 3k /dy 3k ) exhibit congenital muscular dystrophy (CMD). Because the laminin a2-chain is also expressed in the thymus, the role of merosin in the thymus was examined. In association with the onset of muscular dystrophy, CD4+ CD8 + double-positive (DP) thymocytes disappear by apoptotic cell death, while CD4 + CD8 ± or CD4 ± CD8 + thymocytes remain. In order to study the mechanisms leading to the selective death of DP cells in the absence of merosin, the role of the interaction between very late activation antigen-6 (VLA-6), a candidate merosin ligand in the thymus, and merosin was examined. The in vitro survival of thymocytes from normal mice was maintained by the addition of either anti-VLA-6 monoclonal antibodies (mAbs) or merosin. Furthermore, when the normal thymocytes were cultured on thymic epithelial cell lines, viable DP cell recoveries on wild-type epithelial cells were better than on cells from null mutant mice. The results suggest that DP cells are more sensitive to an uncharacterized apoptotic death signal, and that survival is supported by the interaction between VLA-6 and merosin.
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