TY - JOUR
T1 - Hyaluronan deposition in islets may precede and direct the location of islet immune cell infiltrates
AU - Bogdani, M.
AU - Speake, C.
AU - Dufort, M.J.
AU - Johnson, P.Y.
AU - Larmore, M.J.
AU - Day, Anthony
AU - Wight, T.N.
AU - Lernmark, A.
AU - Greenbaum, C.J.
PY - 2020/1/6
Y1 - 2020/1/6
N2 - Aims/hypothesis Substantial deposition of the extracellular matrix component hyaluronan (HA) is characteristic of insulitis in overt type 1 diabetes. We investigated whether HA accumulation is detectable in islets early in disease pathogenesis and how this affects the development of insulitis and the beta cell
mass.
Methods Pancreas tissues from 15 non-diabetic organ donors positive for islet autoantibodies (aAbs) and from 14 age-matched aAb-negative controls were examined for the amount of islet HA staining and the presence of insulitis. The kinetics of HA deposition in islets along with the onset and progression of
insulitis, and changes in beta cell mass were investigated in BioBreeding DRlyp/lyp rats (a model of spontaneous autoimmune diabetes) from 40 days of age until diabetes onset.
Results Abundant islet HA deposits were observed in pancreas tissues from 3 single and 4 double aAb+ donors (aAb+HAhigh). In these 7 tissues, the islet HA-stained areas measured 1000±650 µm2 and were 4 fold larger than those from aAb- controls. The aAb+HAhigh tissues also showed a greater prevalence of
islets highly rich in HA (17% of the islets contained largest HA-stained areas of >2000 μm2 vs. less than 1% in the controls). The amount of islet HA staining was associated with the number of aAbs but not with the Human Leukocyte Antigen (HLA) genotype or changes in beta cell mass. Among the 7 aAb+HAhigh
tissues, 3 from single and one from double aAb+ donors did not show any islet immune cell infiltrates, indicating that HA accumulates in aAb+ donors independently of insulitis. The 3 aAb+HAhigh tissues exhibiting insulitis had the largest HA-stained areas, and the islet infiltrating immune cells co-localized
with the most prominent HA deposits (>2000 µm2). Accumulation of HA in islets was evident prior to insulitis in 7-8-week-old pre-symptomatic DRlyp/lyp rats, in which islet HA-stained areas measured 370±170 µm2 and were 3-fold larger than in 6-week-old rats. This initial islet HA deposition was not concurrent with beta cell loss. Insulitis was first detected in 9-10-week-old rats in which the HA-stained areas were 4980±500 µm2. At this age, the rats also exhibited a 40% reduction in beta cell mass. Further enlargement of the HA-positive areas, measuring 7220±1300 µm2, was associated with invasive insulitis. HA deposits remained abundant in islets of rats with destructive insulitis, which had lost 85% of their beta cells.
Conclusions/interpretation This study indicates that HA deposition in islets occurs early in type 1 diabetes and prior to insulitis, and points to a potential role of HA in triggering islet immune cell infiltration and promotion of insulitis.
AB - Aims/hypothesis Substantial deposition of the extracellular matrix component hyaluronan (HA) is characteristic of insulitis in overt type 1 diabetes. We investigated whether HA accumulation is detectable in islets early in disease pathogenesis and how this affects the development of insulitis and the beta cell
mass.
Methods Pancreas tissues from 15 non-diabetic organ donors positive for islet autoantibodies (aAbs) and from 14 age-matched aAb-negative controls were examined for the amount of islet HA staining and the presence of insulitis. The kinetics of HA deposition in islets along with the onset and progression of
insulitis, and changes in beta cell mass were investigated in BioBreeding DRlyp/lyp rats (a model of spontaneous autoimmune diabetes) from 40 days of age until diabetes onset.
Results Abundant islet HA deposits were observed in pancreas tissues from 3 single and 4 double aAb+ donors (aAb+HAhigh). In these 7 tissues, the islet HA-stained areas measured 1000±650 µm2 and were 4 fold larger than those from aAb- controls. The aAb+HAhigh tissues also showed a greater prevalence of
islets highly rich in HA (17% of the islets contained largest HA-stained areas of >2000 μm2 vs. less than 1% in the controls). The amount of islet HA staining was associated with the number of aAbs but not with the Human Leukocyte Antigen (HLA) genotype or changes in beta cell mass. Among the 7 aAb+HAhigh
tissues, 3 from single and one from double aAb+ donors did not show any islet immune cell infiltrates, indicating that HA accumulates in aAb+ donors independently of insulitis. The 3 aAb+HAhigh tissues exhibiting insulitis had the largest HA-stained areas, and the islet infiltrating immune cells co-localized
with the most prominent HA deposits (>2000 µm2). Accumulation of HA in islets was evident prior to insulitis in 7-8-week-old pre-symptomatic DRlyp/lyp rats, in which islet HA-stained areas measured 370±170 µm2 and were 3-fold larger than in 6-week-old rats. This initial islet HA deposition was not concurrent with beta cell loss. Insulitis was first detected in 9-10-week-old rats in which the HA-stained areas were 4980±500 µm2. At this age, the rats also exhibited a 40% reduction in beta cell mass. Further enlargement of the HA-positive areas, measuring 7220±1300 µm2, was associated with invasive insulitis. HA deposits remained abundant in islets of rats with destructive insulitis, which had lost 85% of their beta cells.
Conclusions/interpretation This study indicates that HA deposition in islets occurs early in type 1 diabetes and prior to insulitis, and points to a potential role of HA in triggering islet immune cell infiltration and promotion of insulitis.
U2 - 10.1007/s00125-019-05066-7
DO - 10.1007/s00125-019-05066-7
M3 - Article
SN - 0012-186X
JO - Diabetologia
JF - Diabetologia
ER -
