AMAs are now known to appear for several years longer before the onset of clinical disease or diagnosis. The presence of IgM reactivity to SAc throughout all stages of PBC is consistent with data that the onset of clinical disease occurs several years or longer after the first appearance of autoantibodies. In fact, elevated IgM throughout all stages of PBC is well known to occur in patients with PBC.50 This indeed appears to be the case for other autoimmune diseases, but given the frequency of PBC,

this becomes a formidable task. PF-2341066 It is interesting to note that among the 50 early-stage and the 50 late-stage PBC sera studied, seven of the early-stage and seven of the late-stage sera were AMA-negative and SAc-negative. Of interest, IgM reactivity to SAc-BSA in 6/43 of the PDC-E2-positive early-stage PBC sera were higher than IgM reactivity to PDC-E2; this pattern was not noted in the late-stage group. The significance of this can only be extrapolated. We do not propose that there will be any specific clinical significance to the IgM

reactivity other than the importance that it reflects a potential footprint of the earliest events that may lead to breach of tolerance. Indeed, all the data herein supports the concept that molecular mimicry between SAc and the lipoyl moiety of PDC-E2 is an important mechanism in induction of autoantibodies to PDC-E2. Finally, we should emphasize that we believe that multiple agents may be capable of similar modification

of PDC-E2 through either their electrophilic properties and the creation Alectinib nmr of neoantigens or perhaps 上海皓元 direct molecular mimicry. We propose the following hypothetical etiology of PBC. Initial exposure to chemicals such as xenobiotic-modified PDC-E2 leads to a primary IgM-specific immune response against the antigen, e.g., SAc. Subsequently, the similarity between the lipoyl domain of PDC-E2 and the xenobiotic-modified lipoyl domain of PDC-E2 (SAc-moiety) generates crossreactive immune responses against the self-antigen, leading to the self-tolerance breakdown to the lipoyl domain of mitochondrial PDC-E2. Later, through the process of affinity maturation and isotype switching, the secondary immune response produces IgGs that are highly specific for mitochondrial PDC-E2. Once self-tolerance to PDC-E2 is broken, the immune destruction is restricted to biliary epithelial cells (BECs) due to their unique physiology and exacerbated by the retention of PDC-E2 in apoptotic blebs from the apoptosis of BECs.51, 52 “
“Cancer stem cells (CSC) have been identified in a growing number of human malignancies. CSC are functionally defined by their ability to self-renew and recapitulate tumors in the ectopic setting, and a growing number of studies have shown that they display other functional characteristics, such as invasion and drug resistance.