IAPP and type 1 diabetes: implications for immunity, metabolism and islet transplants
- 1Department of Surgery, BC Children’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada
- 2Department of Pathology and Laboratory Medicine, BC Children’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada
- Correspondence should be addressed to C B Verchere: bverchere{at}bcchr.ca
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Figure 1
ProIAPP processing in humans and mice. Schematic of proIAPP processing in humans (A) and mice (B). The initially translated IAPP prepropeptide contains a signal peptide (orange residues) linked to a proIAPP precursor containing the final IAPP peptide (green residues), flanked by N and C terminal flanking regions (blue residues); the N and C terminal flanking regions are also termed IAPP1 and IAPP2, respectively, by some groups. Epitopes are indicated in solid lines. Broken lines indicate residues within the peptide that form epitopes following additional modifications. The signal peptide is cleaved from preproIAPP to produce the proIAPP peptide (hproIAPP1–67 in humans; mproIAPP1–70 in mice). The proIAPP precursor is subsequently cleaved by PC1/3 to release the C-terminal-flanking region and an N-terminally extended proIAPP intermediate (hproIAPP1–48 in humans; mproIAPP1–51 in mice). These are likely cleaved by PC2 to release the N-terminal-flanking region and mature IAPP (hIAPP1–37 in humans; mIAPP1–37 in mice). CPE removes the basic residues (grey) after each PC cleavage. The glycine residue (dark grey) is removed and C-terminal tyrosine amidated by the enzyme peptidylglycine alpha-amidating monooxygenase (PAM).
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Figure 2
IAPP epitopes in type 1 diabetes. Primary structures of mouse and human proIAPP peptides are shown. Colours denote N- and C-terminal flanking regions (blue), mature peptide (green), and residues removed by CPE and PAM during processing (grey). Epitopes are indicated in solid lines. Broken lines indicate residues within the peptide that form autoantigens following additional modifications. (A) The primary structure of NOD and Balb/c mproIAPP1–70: epitope mIAPP1–20, originally termed KS20, is present in the pro and mature peptide forms; an additional autoantigen is formed in NOD mice by fusion between the mproIAPP55–59 sequence within the C-terminal-flanking region, and a C-peptide cleavage product (purple). Balb/c mice form a non-antigenic hybrid peptide due to a single amino acid substitution in the C-terminal-flanking region of mproIAPP. (B) The primary structure of the hpreproIAPP signal peptide (orange) and hproIAPP1–67: epitopes hpreproIAPP5–13 and hpreproIAPP9–17 are present in the signal peptide; two autoantigens are formed by hybrid peptides derived from the N- and C-terminal flanking regions of hproIAPP1–67 fused with a C-peptide cleavage product (purple); hproIAPP42–62 forms an additional epitope following citrullination of R51 and R59 (red asterisks). This epitope has also been termed IAPP65–84(73-Cit,81-Cit) based on its position in the hpreproIAPP peptide.
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Figure 3
Macrophage activation by IAPP. Prefibrillar IAPP aggregates may signal through toll-like receptor (TLR) 2 or a TLR2/6 heterodimer to activate NFkB signalling and provide signal 1 (indicated) for proIL1B synthesis. IAPP aggregates are also taken up through phagocytosis and accumulate in the phagolysosomal pathway where they may seed to form fibrils, possibly mediated via the scavenger receptor CD36. Accumulation of IAPP aggregates and/or fibrils results in lysosomal disruption and the release of cathepsin B, providing signal 2 (indicated) for NLRP3 activation and inflammasome assembly. The NLRP3 inflammasome processes proIL1B to mature IL1B, which is subsequently secreted. Large extracellular deposits of mature IAPP fibrils and/or amyloid plaques may also induce frustrated phagocytosis resulting in further inflammation.
- © 2018 Society for Endocrinology
