Screening for Insulitis in Adult Autoantibody-Positive Organ Donors

Abstract

Antibodies against islet cell antigens are used as predictive markers of type 1 diabetes, but it is unknown whether they reflect an ongoing autoimmune process in islet tissue. We investigated whether organs from adult donors that are positive for autoantibodies (aAbs) against islet cell antigens exhibit insulitis and/or a reduced ␤-cell mass. Serum from 1,507 organ donors (age 25-60 years) was analyzed for islet cell antibodies (ICAs), glutamate decarboxylase aAbs (GADAs), insulinoma-associated protein 2 aAbs (IA2As), and insulin aAbs. T ype 1 diabetes results from a specific and major loss of insulin-producing ␤-cells presumably through a T-cell-mediated process (1-5). At clinical onset, patients present circulating autoantibodies (aAbs) against islet cell antigens, which can appear many years before hyperglycemia is established and which are therefore used for prediction of the disease. In firstdegree relatives of type 1 diabetic patients, the risk for developing the disease is higher when multiple positivity is present for aAbs against the islet cell cytoplasm (islet cell antibodies [ICA]), insulin (insulin aAbs [IAA]), the 65,000 M r isoform of glutamate decarboxylase (glutamate decarboxylase aAbs [GADA]), or the insulinoma-associated protein 2 tyrosine phosphatase (insulinoma-associated protein 2 aAbs [IA-2A]) (6 -12). Antibody positivity is therefore used for patient recruitment in prevention trials, but it is still unknown whether it corresponds to an insulitis process in the pancreas and, if so, for which combination. There are only few studies available on the histopathology of the pancreas in antibody ϩ nondiabetic individuals (13,14). In the four reported cases, no leukocytic islet infiltrate or signs of ␤-cell damage were noticed; three of them were GADA ϩ patients with polyendocrinopathy, and one was an IA-2A ϩ organ donor. In the present study we investigated the pancreas in 62 aAb ϩ organ donors. This larger series allowed us to identify two cases with insulitis, one of whom presenting signs of ␤-cell proliferation, and to correlate these histopathological findings to the small subgroup of patients with three or four aAbs and a high-risk genotype. RESEARCH DESIGN AND METHODSCollection of pancreatic tissue. Pancreas biopsies were obtained from the Beta Cell Bank, which operates for a clinical trial on islet cell transplantation in Belgium (15,16). They were taken as part of a quality control procedure that was approved by the ethics committees of the Belgian Diabetes Registry and participating hospitals. Tissue (ϳ0.5 cm 3 ) was excised from the body region of cold-preserved (UW flushed) donor organs that were provided by Eurotransplant Foundation (Leiden, The Netherlands). It was fixed in 4% (vol/vol) phosphate-buffered formaldehyde, pH 7.4, or Bouin's fixative; embedded in paraffin; and then histologically analyzed. Between 1989 and 2004, a total of 1,507 biopsies were collected from patients aged 25-60 years for whom serum or plasma was also available for islet cell antibody assays. For none of t...

New Insight on Human Type 1 Diabetes Biology: nPOD and nPOD-Transplantation

“…To date, insulitis has been demonstrated in two of three non-diabetic donors with multiple autoantibodies but not in any of the 18 donors with a single autoantibody. Although such donors likely did not have a relative with T1D and rarely were found to carry high-risk HLA types for T1D, these findings are in agreement with the analysis of tissue blocks from pancreata that were processed for islet isolation in Europe [49] and with the well-established low risk of T1D demonstrated by prospective follow-up of patients’ relatives with a single autoantibody [50]. However, a number of studies are discovering evidence for abnormalities affecting the pancreas of donors with autoantibodies, perhaps pointing at some initial stages in the disease pathogenesis that may or may not necessarily progress to overt disease but could be important co-factors in their own right or if more sustained autoimmunity was triggered.…”

“…Major findings emerging from these studies are summarized below:A key question posed when nPOD was established was whether individuals with autoantibody (single or multiple) would have insulitis in the pancreas [26, 48, 49]. To date, insulitis has been demonstrated in two of three non-diabetic donors with multiple autoantibodies but not in any of the 18 donors with a single autoantibody.…”

The Diabetes Susceptibility Gene Clec16a Regulates Mitophagy

“…Amongst the earliest signs of T1DM in non-diabetic high-risk patients is the loss of first phase insulin release (FPIR), an early indicator of β-cell impairment (Chase et al, 2001; Defronzo, 2009), with only rare instances of insulitis (In't Veld et al, 2007), suggesting that β-cell dysfunction predates insulitis. Similarly, animal models of T1DM display loss of FPIR and β-cell ER stress prior to immune infiltration (Ize-Ludlow et al, 2011; Marhfour et al, 2012).…”

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“…In donors >15 years of age, insulitis was only found in 29% of those with acute-onset diabetes [21, 22]. In autoantibody-positive donors, the numbers were far lower: only two out of 62 autoantibody-positive, non-diabetic organ donors showed insulitis [23]. Furthermore, insulitis seems to follow a lobular pattern rather than affecting all islets in a given pancreas [14, 24].…”