Early expression in (NZB × DBA/2)F₁ hybrids of thymus dysfunction and abnormal antibody production inherited from the NZB parent

Abstract

NZB mice, DBA/2 mice and reciprocal F1 hybrids between both strains were studied from birth to two months of age for the secretion of a serum thymic factor, thymulin (formerly named Facteur Thymique Sérique) and for spontaneous and antigen-induced immune responses: spontaneous splenic anti-2,4,6-trinitrophenyl (TNP) plaque-forming cells (PFC), spontaneous IgM serum levels, immune direct anti-sheep red blood cells (SRBC) PFC and immune serum antibody production to human gamma globulin (HGG) as well as susceptibility to tolerance induction by deaggregated HGG. An early decline of thymulin serum level was detected from two weeks of age both in NZB mice and F1 hybrids, the latter maintaining a level intermediate between that of both parental strains. Such a fall of circulating thymulin was associated to a decreased number of thymulin-secreting cells. F1 hybrids and NZB mice exhibited at two and three weeks of age spontaneous anti-TNP PFC in the spleen, and increased IgM serum levels as compared to DBA/2 mice. When immunized at birth with SRBC or at two weeks of age with HGG, NZB mice and F1 mice similarly exhibited a higher anti-SRBC antibody response, as measured 5 days later by PFC numbers, and a higher anti-HGG serum antibody production 2 weeks post-immunization, than age-matched DBA/2 mice. F1 hybrids tended to develop with age spontaneous and immune antibody responses lower than NZB mice but still much higher than DBA/2 mice. Conversely, after tolerization at birth with deaggregated HGG NZB mice but not the F1 hybrids produced higher titers of anti-HGG antibodies upon challenge than similarly tolerized DBA/2 mice. DBA/2 mothered and NZB mothered F1 hybrids did not differ for any parameter tested and no influence of the sex could be detected.

Reduced Thymic Aire Expression and Abnormal NF-κB2 Signaling in a Model of Systemic Autoimmunity

“…It has been hypothesized that NZB thymic defects occur as a result of premature thymic involution (55,56). Although we show that TEC defects are present before puberty, since low levels of sex steroids circulate early in life (57), mice were castrated to determine whether hypersensitivity to sex steroids causes the defect, and whether sex steroid ablation could be beneficial in normalizing the NZB thymic defect.…”