Antibody Response to Serpin B13 Induces Adaptive Changes in Mouse Pancreatic Islets and Slows Down the Decline in the Residual Beta Cell Function in Children With Recent Onset of Type 1 Diabetes Mellitus

J Biol Chem. 2016 Jan 1;291(1):266-78. doi: 10.1074/jbc.M115.687848. Epub 2015 Nov 17.

Abstract

Type 1 diabetes mellitus (T1D) is characterized by a heightened antibody (Ab) response to pancreatic islet self-antigens, which is a biomarker of progressive islet pathology. We recently identified a novel antibody to clade B serpin that reduces islet-associated T cell accumulation and is linked to the delayed onset of T1D. As natural immunity to clade B arises early in life, we hypothesized that it may influence islet development during that time. To test this possibility healthy young Balb/c male mice were injected with serpin B13 mAb or IgG control and examined for the number and cellularity of pancreatic islets by immunofluorescence and FACS. Beta cell proliferation was assessed by measuring nucleotide analog 5-ethynyl-2'-deoxyuridine (5-EdU) incorporation into the DNA and islet Reg gene expression was measured by real time PCR. Human studies involved measuring anti-serpin B13 autoantibodies by Luminex. We found that injecting anti-serpin B13 monoclonal Ab enhanced beta cell proliferation and Reg gene expression, induced the generation of ∼80 pancreatic islets per animal, and ultimately led to increase in the beta cell mass. These findings are relevant to human T1D because our analysis of subjects just diagnosed with T1D revealed an association between baseline anti-serpin activity and slower residual beta cell function decline in the first year after the onset of diabetes. Our findings reveal a new role for the anti-serpin immunological response in promoting adaptive changes in the endocrine pancreas and suggests that enhancement of this response could potentially help impede the progression of T1D in humans.

Keywords: Type 1 diabetes; antibody; beta cell (B-cell); pancreatic islet; serpin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology
  • Antibody Formation / drug effects
  • Antibody Formation / immunology*
  • Blood Glucose / metabolism
  • C-Peptide / immunology
  • Cell Proliferation / drug effects
  • Child
  • Deoxyuridine / analogs & derivatives
  • Deoxyuridine / metabolism
  • Diabetes Mellitus, Experimental / blood
  • Diabetes Mellitus, Experimental / immunology
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / pathology*
  • Female
  • Humans
  • Immunization, Passive
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / immunology*
  • Insulin-Secreting Cells / pathology*
  • Linear Models
  • Male
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Serpins / immunology*
  • Up-Regulation / drug effects

Substances

  • Antibodies, Monoclonal
  • Blood Glucose
  • C-Peptide
  • SERPINB13 protein, human
  • Serpinb13 protein, mouse
  • Serpins
  • 5-ethynyl-2'-deoxyuridine
  • Deoxyuridine