Extracellular matrix and the maintenance and loss of peripheral immune tolerance in autoimmune insulitis

Abstract

There is a growing appreciation that the extracellular matrix (ECM) contributes to both the maintenance of immune tolerance in healthy tissues and to its loss at sites of autoimmunity. Here, we review recent literature on the role of ECM and particularly the glycosaminoglycans hyaluronan and heparan sulfate in the development of autoimmune, type 1 diabetes (T1D). Data from transplant models suggest that healthy islets are embedded within an intact ECM that supports beta-cell homeostasis and provides physical and immunoregulatory barriers against immune infiltration. However, studies of human insulitis as well as the non-obese diabetic (NOD) and DORmO mouse models of T1D indicate that autoimmune insulitis is associated with the degradation of basement membrane structures, the catabolism of the islet interstitium, and the accumulation of a hyaluronan-rich, pro-inflammatory ECM. Moreover, in these models of autoimmune diabetes, either the pharmacologic inhibition of heparan sulfate catabolism, the reduction of hyaluronan synthesis, or the targeting of the pathways that sense these ECM changes can all prevent beta-cell destruction. Together these data support an emerging paradigm that in healthy islets the local ECM contributes to both immune tolerance and beta-cell homeostasis while in chronic inflammation the islet ECM is permissive to immune infiltration and beta-cell destruction. Therapies that support ECM-mediated 'barrier tolerance' may have potential as adjunctive agents in combination regimens designed to prevent or treat autoimmunity.

Figure 1:. Autoimmune insulitis in the DORmO mouse model of T1D is associated with the progressive, sequential loss of local tissue barriers against autoimmunity.

H&E staining of islets from DORmO mice at various ages and stages of progressive insulitis: (A) no infiltration (3–4 weeks of age), (B) peri-insulitis (4–5 weeks), (C) insulitis (8 weeks), and (D) islet destruction (12 weeks).

Figure 2:. Autoimmune insulitis is associated with the degradation of islet basement membranes, the catabolism of the interstitial matrix and the deposition of a pro-inflammatory matrix dominated by hyaluronan.

Histologic staining of the islet ECM molecules in healthy BalbC mice and in the DORmO mouse model of T1D. In DORmO mice, basement membrane integrity is lost, as evidenced by the break-down in perlecan staining (left). Interstitial matrix likewise undergoes catabolism, as evidenced by the loss of heparan sulfate structures (center). Finally, there occurs the deposition of a pro-inflammatory matrix dominated by hyaluronan (right).

Figure 3:. A schematic of the sequential loss of ECM barriers against in autoimmune insulitis.

In healthy islets, the ECM provides physical and immunoregulatory barriers against immune infiltration. However, in autoimmune diabetes, effector T cells evade central and peripheral tolerance and accumulate around islets (top). These auto-reactive cells require a break in the laminin rich basement membrane for entry (right). Degradation of islet HS leads to beta cell death (bottom). Deposition of HA allows for further infiltration, effector cell activation, and inhibition of Treg expansion (left). Along with effects on infiltrating leukocytes, this remodeling of the islet ECM also adversely impacts β-cell health.

Figure 4:. Peripheral and barrier tolerance mechanisms.

(A) Peripheral tolerance of autoreactive effector T cells is maintained via inhibition by thymic Tregs, induction of anergy, antigenic ignorance, or differentiation to inducible Tregs. (B) The intact islet ECM provides physical and immunologic barriers (“barrier tolerance”) that contribute to immune tolerance. These include a basement membrane that prevents immune infiltration, protective barriers against reactive oxygen species as with HS, and immunomodulatory barriers like the stabilization and sequestration of HA that limit immune activation.