Immunodeficiency: primary or acquired
Chromosome 22q11.2 deletion syndrome (22q11.2 DS) is the most frequent chromosomal microdeletion disorder reported (1/4000). Individuals with this deletion often present with multi-system disorders including a thymic hypoplasia, cardiac anomalies, hypoparathyroidism, and/or dysmorphic facial features. Over 90% of individuals have a deletion of 2.4 Mb, which comprises 90 genes, 50% protein coding and the remainder microRNAs, long noncoding RNAs and pseudogenes. The principal cause of the development defects is a haploinsufficiency of T-box 1 transcription factor (Tbx1). Between 40-60% of patients have some degree of thymic hypoplasia, resulting in their peripheral T cell lymphopenia. Defects in the thymic stromal tissue is the underlying cause of the hypoplasia. We analyzed the thymic tissue in a mouse models of 22q11.2 deletion syndrome, termed the Df1/+ line. Comparative transcriptome analyses of hypoplastic and normal-sized lobes from matched Df1/+ embryos revealed a signature mRNA expression pattern unique to hypoplastic tissue. Ingenuity pathway analysis uncovered selective pathways compromised in these lobes. Immunohistochemistry and fetal thymic organ culture assays are currently being used to characterize the molecular defects of the thymic stroma at the onset of thymic tissue specification in embryos. Inflammatory conditions are being introduced in pregnant Df1/+ mice to determine if the penetrance and severity of clinical phenotypes associated with 22q11.2 DS is affected by stress in utero. Findings from our studies may lead to better strategies for improving human thymopoiesis, particularly for patients with 22q11.2 and 10p deletion syndromes, as well as those undergoing chemo ablative treatments that impact the thymus.
UT Southwestern Medical Ctr
UT Southwestern Medical Center