Antimitochondrial antibody heterogeneity and the xenobiotic etiology of primary biliary cirrhosis.

UNLABELLED: Antimitochondrial antibodies (AMAs) directed against the lipoyl domain of the E2 subunit of pyruvate dehydrogenase (PDC-E2) are detected in 95% of patients with primary biliary cirrhosis (PBC) and are present before the onset of clinical disease. The recent demonstration that AMAs recognize xenobiotic modified PDC-E2 with higher titers than native PDC-E2 raises the possibility that the earliest events involved in loss of tolerance are related to xenobiotic modification. We hypothesized that reactivity to such xenobiotics would be predominantly immunoglobulin M (IgM) and using sera from a large cohort of PBC patients and controls (n = 516), we examined in detail sera reactivity against either 6,8-bis(acetylthio) octanoic acid (SAc)-conjugated bovine serum albumin (BSA), recombinant PDC-E2 (rPDC-E2) or BSA alone. Further, we also defined the relative specificity to the SAc moiety using inhibition enzyme-linked immunosorbent assay (ELISA); SAc conjugate and rPDC-E2-specific affinity-purified antibodies were also examined for antigen specificity, isotype, and crossreactivity. Reactivity to SAc conjugates is predominantly IgM; such reactivity reflects a footprint of previous xenobiotic exposure. Indeed, this observation is supported by both direct binding, crossreactivity, and inhibition studies. In both early and late-stage PBC, the predominant Ig isotype to SAc is IgM, with titers higher with advanced stage disease. We also note that there was a higher level of IgM reactivity to SAc than to rPDC-E2 in early-stage versus late-stage PBC. Interestingly, this finding is particularly significant in light of the structural similarity between SAc and the reduced form of lipoic acid, a step which is similar to the normal physiological oxidation of lipoic acid. CONCLUSION: Specific modifications of the disulfide bond within the lipoic-acid-conjugated PDC-E2 moiety, i.e., by an electrophilic agent renders PDC-E2 immunogenic in a genetically susceptible host.

Women remain underrepresented in leadership positions in academic gastroenterology throughout the United States.

BACKGROUND: Publication history is a key factor in securing academic promotion, but historical underrepresentation of women in gastroenterology may be an ongoing obstacle to achieving gender parity in leadership positions. METHODS: We carried out a cross-sectional study of gastroenterology programs in the United States, with data including faculty and trainee names, leadership positions, Hirsch indices, and year of first gastroenterology certification gathered from 1 February 2020 to 1 March 2020. Our outcomes of interest were: 1) sex representation in various leadership positions in academic gastroenterology departments; and 2) mean difference in Hirsch indices between men and women, for which we used univariate and multivariate regression models. RESULTS: Our cohort included 3655 faculty members and trainees across 163 academic gastroenterology programs in the United States. Women comprised 28.7% (1049/3655) of the cohort, including 713/2657 (26.8%) of faculty and 56/289 (19.4%) of all fellowship program directors and divisional/departmental chairs and chiefs. Male faculty had higher mean Hirsch indices compared to women (11.4 vs. 5.5, P<0.001), and when adjusted for year of first gastroenterology certification, men had a larger Hirsch index by 2.8 (95% confidence interval 1.3-4.1, P<0.001). Women were also underrepresented in various subspecialties of gastroenterology, particularly advanced endoscopy. CONCLUSIONS: Women in academic gastroenterology remain underrepresented in leadership positions and have lower Hirsch indices than men. Our findings may stem not only from differences in mentorship and career goals, but also from underlying structural factors that disadvantage women.