Background
Mutations of the thyroid hormone receptor α (THRA) gene cause resistance to thyroid hormone (RTHα). RTHα patients exhibit very mild abnormal thyroid function test
Conclusions
Analysis of lymphopoiesis in a mouse model of RTHα showed that B cell lymphopoiesis was suppressed by TRα1 mutations. The suppressed development of B cells was, at least in part, via inhibition of the expression of key regulators, Ebf1, Tcf3, and Pax5, by TRα1 mutations. These findings suggest that the mutations of the THRA gene in patients could lead to B cell deficiency.
Methods
We assessed lymphocyte abundance in the peripheral circulation and in the lymphoid organs of Thra1PV/+ mice. We evaluated the effect of thyroid hormone on B cell development in the bone and spleen of these mice. We identified key transcription factors that are directly regulated by TRα1 in the regulation of B cell development.
Results
Compared with wild-type mice, a significant reduction in B cells, but not in T cells, was detected in the peripheral circulation, bone marrow, and spleen of Thra1PV/+ mice. The expression of key transcription regulators of B cell development, such as Ebf1, Tcf3, and Pax5, was significantly decreased in the bone marrow and spleen of Thra1PV/+ mice. We further elucidated that the Ebf1 gene, essential for lineage specification in the early B cell development, was directly regulated by TRα1. Thus, mutations of TRα1 could impair B cell development in the bone marrow via suppression of key regulators of B lymphopoiesis. Conclusions: Analysis of lymphopoiesis in a mouse model of RTHα showed that B cell lymphopoiesis was suppressed by TRα1 mutations. The suppressed development of B cells was, at least in part, via inhibition of the expression of key regulators, Ebf1, Tcf3, and Pax5, by TRα1 mutations. These findings suggest that the mutations of the THRA gene in patients could lead to B cell deficiency.