Mucosal Immunity and Primary Biliary Cirrhosis: Presence of Antimitochondrial Antibodies in Urine

Abstract

We have shown that IgA-class antimitochondrial autoantibodies (AMA) can be detected in the bile and saliva of patients with PBC, suggesting that AMA are secreted into the luminal fluid across bile ducts and salivary glands. These data prompted us to determine whether AMA of the IgA isotype may be transported across other epithelial mucosa. Therefore, we tested for the presence of AMA in the urine specimens of 83 patients with PBC and 58 non-PBC controls including healthy individuals and patients with other liver diseases. Patients enrolled in this study had no history of renal disease, and we confirmed there was less than 50 g/mL of protein in each of the urine specimens. Interestingly, we found that AMA were present in the urine of 71/83 (86%) of all patients with PBC and in 71/78 (91%) of patients with PBC that were serum AMA positive. In contrast, AMA were not detected in any of the 58 control urine specimens. Of particular interest, AMA of the IgA isotype was present in 57/83 (69%) of patients with PBC, and in 52 of these 57, we found secretory-type IgA. In a nested random subgroup of urine samples, the prevalence of the IgA2 AMA was 6/18 (33%), significantly lower than in matched serum samples, 13/16 (81%, P ‫؍‬ .007). These data show that AMA of the IgA isotype is secreted into urine from the uroepithelium of patients with PBC, and support the thesis that PBC originated from either a mucosal challenge or a loss of mucosal tolerance. (HEPATOLOGY 2000;32: 910-915.)

Caspase induction by IgA antimitochondrial antibody: IgA-mediated biliary injury in primary biliary cirrhosis

“…It is possible that these differences reflect a much higher titer of autoantibodies to PDC-E2 compared to OGDC-E2 or BCOADC-E2 not only in the sera, but also in the secretions in PBC. 7,8,42,43 It would be interesting to prospectively study patients ranked on their capacity to induce caspase activation in this system and determine whether this predicts their progression of disease. Fig.…”

Genes and (auto)immunity in primary biliary cirrhosis

“…BECs, similar to other epithelial cells, secrete IgA and AMA-IgA have been detected in bile and other body fluids (including urine and saliva) from patients with PBC to react with PDC-E2. 169,170 More recently, our group demonstrated the colocalization of AMA-IgA and PDC-E2, or a mimicking molecule, on the apical surface and in the cytoplasm of PBC-BECs. 171 To assess the direct pathogenicity of AMAIgA to BECs, Matsumura et al 172 incubated highly purified AMA-IgAs with canine kidney cells transfected with the human polymeric Ig receptor, inducing caspase upregulation and thus providing evidence of the direct proapoptotic effect.…”

“…111 Further, the PDC-E2 amino acids E, D, and K are essential for the recognition of the epitope by HLA-restricted T-cell clones, similar to that observed for AMA. PDC-E2 [163][164][165][166][167][168][169][170][171][172][173][174][175][176] -specific CD4 þ Tcell clones also react with other AMA-specific mitochondrial autoantigens, including the E2 subunits of OGDC and BCOADC, as well as E3BP. 112,113 In all these molecules, interestingly, the epitopes include a lipoylated domain.…”

“…The study of TCR b gene rearrangements of cell clones obtained from PBC liver biopsies demonstrated different degrees of oligoclonality of the infiltrating T cells. 114,115 The use of TCR Vb or Jb genes by PDC-E2 [163][164][165][166][167][168][169][170][171][172][173][174][175][176] -reactive T-cell clones is also highly diverse with GXG or GXS motifs found within the complementaritydetermining region 3 (CDR3) of all T-cell clones. 116 When autoreactive T-cell frequencies are compared among different tissues of patients with PBC, PDC-E2 163-176 -reactive precursor T cells are 100-150-fold more represented in the hilar lymph nodes and the liver compared to the peripheral blood, possibly with changes in different disease stages.…”

The Role of Pathogenic Autoantibodies in Autoimmunity

“…Thus, the tissue specificity of the damage may be related to IgA anti-PDC-E2 transcytosed for secretion through the biliary epithelium that could carry PDC-E2 to the cell surface in the process. IgA antibodies have been described in in bile, saliva and urine in primary biliary cirrhosis [269][270][271][272] and the presence of IgA anti-PDC-E2 in serum and in saliva, has been linked to the histological progression of PBC [273].…”