Neonatal cholestasis is a common presenting feature of liver disease in infancy. Most cases can be attributed to idiopathic neonatal hepatitis (INH) or extahapatic biliary atresia (EHBA), which each occur in 1 of 10,000 live births. Two distinct types of EHBA exist - an embryonic form associated with other on genital anomalies, and the more common acquired form, with cholestasis occurring after an initial noncholestatic period. The acquired form h as been postulated to be related etiologically to INH. Although INH and EHBA are well recognized, definable causes of neonatal cholestasis, their etiologies have remained obscure. One definable cause of neonatal cholestaic liver disease is neonatal lupus erythematosus (NLE), an autoimmune disease associated with maternal anti-Ro autoantibodies. Babies with this condition have one or more of the following: complete heart block, cardiomyopathy, cutaneous lupus lesions, thrombocytopenia, and liver disease. In virtually all cases reported of NLE with liver disease, heart or skin disease has been present in addition to liver disease. However, babies with cholestatic liver disease without other signs of NLE are not routinely screened for NLE autoantibodies. We propose that NLE liver disease can occur as an isolated finding, and may be a common cause of INH and EHBA. The goals of this project are as follows: (1) to establish whether INH and EHBa, or subsets thereof, are autoimmune in origin Maternal sera from cases of INH and EHBA will be examined for the presence of NLE-associated autoantibodies. (2) to determine why the liver is targeted for injury These studies will examine the hypothesis that it is the epitome binding to the Ro autoantigen that determines whether or not the liver will be effected. (3) develop models of autoimmune neonatal liver disease Female rabbits will be immunized with Ro or with peptides representing liver disease-associated epitomes, and they and their offspring will be examined for the development of liver disease. The toxic effects of the liver disease-associated autoantibodies on cultured liver cells will be examined. The ultimate goals are more specific therapy of INH and EHBA, and a greater understanding of the mechanisms of tissue injury in neonatal autoimmune liver disease.
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