Objective: To characterize Alexander disease (AxD) phenotypes and determine correlations with age at onset (AAO) and genetic mutation. AxD is an astrogliopathy usually characterized on MRI by leukodystrophy and caused by glial fibrillary acidic protein (GFAP) mutations. Methods:We present 30 new cases of AxD and reviewed 185 previously reported cases. We conducted Wilcoxon rank sum tests to identify variables scaling with AAO, survival analysis to identify predictors of mortality, and 2 tests to assess the effects of common GFAP mutations.Finally, we performed latent class analysis (LCA) to statistically define AxD subtypes.Results: LCA identified 2 classes of AxD. Type I is characterized by early onset, seizures, macrocephaly, motor delay, encephalopathy, failure to thrive, paroxysmal deterioration, and typical MRI features. Type II is characterized by later onset, autonomic dysfunction, ocular movement abnormalities, bulbar symptoms, and atypical MRI features. Survival analysis predicted a nearly 2-fold increase in mortality among patients with type I AxD relative to those with type II. R79 and R239 GFAP mutations were most common (16.6% and 20.3% of all cases, respectively). These common mutations predicted distinct clinical outcomes, with R239 predicting the most aggressive course.

Recently, we identified a child born with a genetic deficiency of IL-2 receptor ␣ (IL-2R␣, CD25) expression who had several clinical manifestations of primary biliary cirrhosis (PBC). In addition, there has been suggestive evidence in both patients with PBC and their first-degree relatives that a deficiency of regulatory T cells (Tregs) is an integral component for susceptibility to PBC. Based on these observations, we generated IL-2R␣/CD25 deficient (IL-2R␣ ؊/؊ ) mice and wildtype littermate controls and followed them longitudinally for the natural history of liver immunopathology and appearance of antimitochondrial antibodies (AMAs). The analyses included immunohistochemical staining of liver and portal tract infiltrates as well as FACS profiles of lymphoid subpopulations in liver and spleen. In addition, serum cytokine profiles were quantitated. Importantly, IL-2R␣ ؊/؊ , but not littermate controls, develop portal inflammation and biliary ductular damage similar to human patients with PBC. CD4 ؉ and CD8 ؉ T cells predominate among portal cell infiltrates and sera reflect a Th1 cytokine bias with increased levels of IFN-␥, TNF-␣, IL-2 and IL-12p40. Of importance is the finding that the IL-2R␣ ؊/؊ mice not only develop significantly increased serum levels of IgG and IgA, but they also develop AMAs with specificity for PDC-E2, which maps to the inner lipoyl domain of the autoantigen, all characteristics which are hallmarks of human PBC. In conclusion, the IL-2R␣ ؊/؊ mice should facilitate studies of the early events in PBC and especially the tantalizing connection between Treg deficiency and autoimmunity specifically directed to mitochondrially located PDC-E2 and subsequent biliary ductular cell damage. (HEPATOLOGY 2006;44:1240-1249.) P rimary biliary cirrhosis (PBC) is a chronic autoimmune liver disease primarily affecting smaller intrahepatic bile ducts and characterized by autoantibodies to the mitochondrially located E2 subunits of pyruvate dehydrogenase and related enzymes (PDC-E2), traditionally known as antimitochondrial antibodies (AMA). 1 A better understanding of the initial pathologic events will lead to better understanding for this eventually morbid and often fatal human disease. In particular, the early immunologic events in PBC have remained obscure, partly because of the long asymptomatic period. Clearly animal models of human PBC would greatly facilitate studies of the etiology of this disease and specially facilitate the identification of the early events that lead to this disease. Two murine models have recently been described that provide data which suggest that indeed this goal may be achieved. The first is the presence of AMA and severe biliary disease in a congenic strain of NOD mice, coined NOD.c3c4. 2,3 The second model is the appearance of autoimmune cholangitis and AMAs in TGF-␤ receptor II dominant-negative mice. 4 We have also seen a PBC-like disease in a child with homozygous IL-2R␣ (CD25) deficiency. 5 This latter finding is of interest since our laboratory has previously documente...

There have been important advances in defining effector mechanisms for several human autoimmune diseases. However, for most human autoimmune diseases, the induction stage is less well defined and there are very few clues on etiology. Our laboratory has focused on defining the molecular basis of autoantibody recognition and epitope modification in primary biliary cirrhosis (PBC). Our work has demonstrated that antibodies to mitochondria (AMA), the hallmark of disease, are directed against a very conserved site of pyruvate dehydrogenase (PDCE2). We have also demonstrated that several chemical xenobiotics, chosen based on quantitative structural activity relationship analysis and rigorous epitope analysis, when coupled to the lysine residue that normally binds the lipoic acid co-factor of PDC-E2, reacts as well or better to PBC sera than native autoantigen. In the present studies, we immunized C57BL/6 mice with one such xenobiotic, 2-octynoic acid (2OA), coupled to bovine serum albumin (BSA) and followed mice for 24 weeks. Animals were studied for appearance of histologic lesions as well as appearance of antibodies to PDC-E2, serum levels of TNF-α and IFN-γ and splenic and liver lymphoid phenotyping by flow cytometry. Mice immunized with 2OA manifest autoimmune cholangitis, typical mitochondrial autoantibodies, increased liver lymphoid cell numbers, an increase in CD8+ liver infiltrating cells, particularly CD8+ T cells that co-express CD44, and finally an elevation of serum TNF-α and IFN-γ. In conclusion, these data provide a persuasive argument in favor of an environmental origin for human PBC.

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