in the Human Thymus Differentiation and Hassall Body Formation Corticosteroids Regulate Epithelial Cell

The presence of characteristic epithelial swirls called Hassall bodies within the human thymic medulla has been used as an indicator of ongoing or recent thymopoiesis. We present a case where Hassall bodies were present in the absence of current or past thymopoiesis. The patient had been treated with corticosteroids for presumed asthma before his diagnosis of X-linked SCID. Two other cases of nonimmunodeﬁcient patients treated with high-dose corticosteroids had markedly increased numbers of thymic Hassall bodies. To determine whether corticosteroid treatment induces thymic epithelial (TE) differentiation to form Hassall bodies, mAbs reactive with speciﬁc cytokeratins (CKs), ﬁlaggrin, and involucrin were used to deﬁne distinct stages of TE cell differentiation. Treatment of primary TE monolayers with hydrocortisone in vitro induced expression of involucrin and high-molecular-mass CKs that are characteristic of TE differentiation. Treatment of thymic organ cultures with hydrocortisone induced both medullary and subcapsular cortical TE cells to express CK6, a differentiation marker that is normally expressed only by Hassall bodies in vivo. These experimental studies combined with the case observations indicate that exogenous corticosteroids can regulate terminal differentiation of TE cells both in vitro and in vivo. Thus, the presence of Hassall bodies in thymus from corticosteroid-treated patients cannot be taken as an absolute indication of previous thymopoiesis. Because corticosteroids are also made within the thymus under normal physiologic conditions, these studies support the hypothesis that endogenous corticosteroids may play a role in normal TE differentiation and Hassall body formation in vivo. The Journal of Immunology, 2004, 172: 617–624. SCID (X-SCID) and primary failure of thymopoiesis. This patient had been treated with corticosteroids for presumed asthma before his diagnosis of immunodeﬁciency. We identiﬁed two other cases of nonimmunodeﬁcient patients treated with high-dose corticosteroids who also had markedly increased numbers of thymic Hassall bodies. These case observations led us to hypoth-esize that corticosteroids may regulate the differentiation of TE cells to form Hassall bodies. We identiﬁed a panel of mAbs reactive with speciﬁc CKs, ﬁlaggrin, and involucrin that deﬁne distinct phenotypically recognizable stages of TE cell differentiation to form Hassall bodies. Treatment of primary TE cell monolayers and thymic organ cultures with hydrocortisone in vitro altered the expression of involucrin and CKs that are characteristically expressed by Hassall bodies and terminally differentiated epidermal keratinocytes in vivo. Taken together, these studies indicate that exogenous corticosteroids can regulate terminal differentiation of TE cells in vitro and drive Hassall body formation in vivo. Because corticosteroids are also made within the thymus under normal physiologic conditions (17–20), these studies raise the possibility that endogenous corticosteroids may play a role in normal TE differentiation and Hassall body formation.