RAG2-/-, I kappa B-alpha-/- chimeras display a psoriasiform skin disease

Nuclear factor-kappaB, a ubiquitous transcription factor involved in inflam matory and immune responses, is inappropriately activated in several immune -related diseases, such as allograft rejection, or bronchial asthma. As nuc lear factor-kappaB activity is regulated by inhibitor of kappaB (I kappaB), the gene encoding I kappaB-alpha was disrupted in mice to observe the in v ivo effects of hyperactivation of nuclear factor-kappaB. I kappaB-alpha-/- mice have constitutive nuclear factor-kappaB activity, severe skin disease, and neonatal lethality. To determine the role of I kappaB-alpha deficient immunocytes in the pathogenesis of the skin disease in adult mice, we utili zed the RAG2-deficient blastocyst complementation system to generate RAG2-/ -, I kappaB-alpha-/- chimeras. These animals display a psoriasiform dermati tis characterized by hyperplastic epidermal keratinocytes and dermal infilt ration of immunocytes, including lymphocytes. Skin grafts transferred from diseased chimeras to recipient nude mice produce hyperproliferative psorias iform epidermal keratinocytes in response to stimulation. Furthermore, adop tive transfer of lymph node cells from diseased chimeras to RAG2-/- recipie nt mice recapitulates the disease. Taken together, these characterizations provide evidence to suggest that constitutive activation of nuclear factor- kappaB, due to deficiency in I kappaB-alpha, can invoke severe psoriasiform dermatitis in adult mice.