Human islets and dendritic cells generate post-translationally modified islet autoantigens

Area of Science:

• Immunology
• Endocrinology
• Molecular Biology

Background:

• Type 1 diabetes (T1D) initiation involves a breakdown of peripheral tolerance.
• Post-translational modification, specifically deamidation of islet autoantigens, is implicated in T1D pathogenesis.
• Deamidated autoantigens exhibit increased binding to high-risk human leucocyte antigen (HLA) haplotypes, promoting T cell activation.

Purpose of the Study:

• To investigate human pancreatic islets and dendritic cells (DCs) as sources of deamidated islet autoantigens.
• To examine the role of inflammation in altering deamidation processes.
• To identify the enzyme responsible for deamidation and its activity in different cellular contexts.

Main Methods:

• Analysis of tissue transglutaminase presence and activity in human islets, dendritic cells (DCs), and tolerogenic DCs (tolDCs).
• Treatment of islets with inflammatory cytokines to assess deamidation of insulin C-peptide.
• Pulsing DCs with native islet autoantigens and assessing presentation of deamidated neoepitopes in HLA-DQ2/8 homozygous and heterozygous contexts.

Main Results:

• Tissue transglutaminase was found in islets, DCs, and tolDCs, with increased activity after inflammatory insult.
• Inflammatory cytokines induced deamidation of insulin C-peptide in human islets.
• Dendritic cells heterozygous for HLA-DQ2/8 presented naturally processed deamidated neoepitopes from islet autoantigens, unlike homozygous DCs.

Conclusions:

• Human islets and dendritic cells are identified as sources of deamidated islet autoantigens.
• Inflammatory activation of tissue transglutaminase is implicated as a mechanism for deamidation in both islets and DCs.
• Deamidated neoepitopes presented by DCs may contribute to T cell activation in type 1 diabetes.