Researchers have identified laminin 511 as a novel antigen in autoimmune pancreatitis (AIP). A truncated form of the antigen was found in about half of human patients, but fewer than 2% of controls, and mice that were immunized with the antigen responded with induced antibodies and suffered pancreatic injury.
Laminin 511 plays a key role in cell–extracellular matrix (ECM) adhesion in pancreatic tissue. The results, published in Science Translational Medicine, could improve the biologic understanding of AIP and could potentially be a useful diagnostic marker for the disease.
Some autoantibodies are known to be associated with AIP, but the seropositive frequency is low among patients.
The researchers previously demonstrated that injecting IgG from AIP patients into neonatal mice led to pancreatic injury. The IgG was bound to the basement membrane of the pancreatic acini, suggesting the presence of autoantibodies that recognize an antigen in the ECM.
The researchers then screened previously known proteins from the pancreatic ECM against sera from AIP patients, performing Western blot analyses and immunosorbent column chromatography with human and mouse pancreas extracts, and AIP patient IgG. But this approach yielded no results.
The team then conducted an enzyme-linked immunosorbent assay using known pancreatic ECM proteins, which included the laminin subunits 511-FL, 521-FL, 511-E8, 521-E8, 111-EI, 211-E8, and 332-E8. The E8 designates a truncated protein produced by pancreatic elastase that contains the integrin-binding site.
That experiment revealed that 511-E8 is a consistent autoantigen, and a survey of AIP patients found that 26 of 51 (51.0%) had autoantibodies against 511-E8, compared with just 2 of 122 (1.6%) of controls (P less than .001). Further immunohistochemistry studies confirmed that patient IgG binds to laminin in pancreatic tissue.
When the researchers injected 511-E8, 511-FL, 521-FL, or ovalbumin into 8-week-old mice, and then again after 28 days and 56 days, only those who received 511-E8 showed evidence of pancreatic injury 28 days after the final immunization. The mice generated autoantibodies to 511-E8 but not ovalbumin.
The findings may have clinical significance. Patients with antibodies to laminin 511-E8 had a lower frequency of malignancies (0% vs. 32%; P =.0017) and allergic diseases (12% vs. 48%; P =.0043) than patients with no laminin 511-E8 antibodies.
The study was funded by the Japan Society for the Promotion of Science; the Japanese Ministry of Health, Labour, and Welfare; the Practical Research Project for Rare/Intractable Diseases Grant,; the Agency for Medical Research and Development; and the Takeda Science Foundation. One of the authors has filed a patent related to the study results.
SOURCE: Shiokawa M et al. Sci. Transl. Med. 2018 Aug 8. doi: 10.1126/scitranslmed.aaq0997.
