Morphologic analysis of ocular defects in transgenic mice expressing allo-MHC in the lens

Purpose. In previous work, we have shown that transgenic mice expressing high copy numbers of the H-2D^d alloantigen under the control of the α A-crystallin promoter in the lens exhibit ocular defects including cataracts and microphthalmia. To better understand the nature of these abnormalities, we have evaluated the embryological development of the lens and other ocular structures in this transgenic model. Methods. Ocular morphology was studied by light and electron microscopy in heterozygous mice from our D^d. 14 line, which have phenotypic ocular abnormalities. Eyes were assessed from day 8 to day 20 of gestation, and at different stages from birth to 4 months. The findings were compared with C57B1/6 controls. Results. The first histologic abnormalities were noted at day 13 of gestation, with lens fiber cell death associated with apoptotic nuclei. Progressive lens fiber cell disruption was noted through day 20, with the development of a central cataract extending from the anterior to posterior capsule and relative preservation of the lens cells in the equatorial region. The eyes were microphthalmic at day 16-20, with retinal infolding and detachment in some specimens. Lens capsule rupture with lens material accumulating in the vitreous cavity was first noted at four weeks post-partum with associated vitreous inflammation. Evolution of cataract formation and resolution of the inflammatory response occurred at age 2 to 4 months. Conclusions. Lens defects occur early during embryological development and coincide with the onset of α-A crystallin synthesis, suggesting that D^d protein expression disrupts normal cellular development soon after it is expressed. The characteristics of the cataracts suggest the abnormal protein has the greatest effect on secondary lens fibers as they migrate and elongate.