NATURE MEDICINE • VOLUME 9 • NUMBER 2 • FEBRUARY 2003 161

NEWS & VIEWS

Type 1 diabetes (T1D) results from a T-cell-mediated autoimmune process thatdestroys the insulin-producing β-cells ofthe pancreas1. The β-cells, along withother types of cells,are contained insmall islands of en-docrine cells calledthe pancreatic islets.T1D begins with along asymptomaticstage characterizedby insulitis, an in-flammatory infiltra-tion of the islets thatselectively destroysthe β-cells whileleaving other celltypes in the isletlargely intact. Theautoimmune processcan be detected yearsbefore the onset ofdisease by the pres-ence of β-cell-reac-tive T cells andautoantibodies inthe blood, allowingthe identification ofprediabetic individu-als and possible ther-apeutic intervention.

Recent studieshave noted thatmice prone to β-cellautoimmunity are also susceptible todeveloping autoreactivity to neuronaltissues2,3. On the basis of those find-ings, Winer et al. examined the ner-vous system tissue surrounding theislet cells during the development ofT1D in diabetes-prone non-obese dia-betic (NOD) mice4.

The islets are surrounded by a looseweb of nerve fibers and a non-myeli-nating type of Schwann cell, Schwanncells being the glial cells of the periph-eral nervous system5,6. Before invadingthe islets, immune cells accumulateoutside the islet in close associationwith the Schwann cell network.Previous studies have shown that au-toimmune, but not chemically in-

duced, β-cell damage disrupts this net-work5. The authors extended thesestudies, taking advantage of the factthat Schwann cells can be imaged im-munohistologically by their expressionof glial fibrillary acidic protein (GFAP)in Schwann cells. They showed thatwhen immune cells initially invade theislet, they do not move directly towardsthe β-cells in the islet interior. Rather,the immune cells first accumulatearound the Schwann cells from the in-terior as well as the exterior of the islet.This early immunological focus onSchwann cells leads to the progressiveloss of GFAP staining around the islets,often well before there is any detectableloss of β-cell insulin staining. Thus,

Schwann cells seem to be an unex-pected early casualty of the T1D

autoimmune diseaseprocess. However, itis important to bearin mind that β-celldestruction may actu-ally begin soon afterthe onset of insulitisbut may be maskedby compensatory β-cell proliferative re-sponses7.

At the onset of insuli-tis, the authors detectedautoreactive T-cell re-sponses to GFAP. Theyalso detected responsesto two proteins ex-pressed by both periph-eral Schwann cells andβ-cells , S100β and glu-tamic acid decarboxy-lase (GAD). Furthermore,autoantibodies againstGFAP were present inmost young NOD mice.Next, the authors testedfor autoimmune re-sponses to these antigensin humans. Peripheralblood cells from new-onset T1D patients and individuals withprobable prediabetesdisplayed proliferativeresponses to GFAP

or S100β as well as to β-cell antigens. Moreover, sera frommost new-onset and at-risk patients con-tained autoantibodies against GFAP.Thus, autoreactivity to Schwann cellantigens may provide additional mark-ers of impending T1D.

All this prompts the obvious ques-tion: is loss of tolerance to Schwanncells a crucial step in the developmentof T1D? In NOD mice, β-cell autoim-munity is thought to be initiated by β-cell apoptosis, followed by the uptakeof β-cell antigens by islet antigen-pre-senting cells. These cells then migrateto the pancreatic lymph nodes and ac-tivate β-cell-reactive T cells8 (Fig. 1).This initial autoimmune response may

Murder mysteries in type 1 diabetesNervous system cells surrounding insulin-producing cells in the pancreas are destroyed early

in the development type 1 diabetes, reveals a new study. The findings broaden our ideas of thedisease process and may lead to new prediagnostic markers and therapies (pages 198-205).

DANIEL L. KAUFMAN

ββ

β

Peri-insulitis

Invasive insulitis

Schwann cell

β cell antigenβ cell specificT cell

Antigen-presenting cell

α, δ, PP cellsβ β

β

ββ

β

Pancreatic lymph node

Islet

Schwann cell-specific T cell Schwann cell antigen

Schwann cell/β cell shared antigen

Schwann cell/β-cell specific T-cell

a

b

c

Fig. 1 Models of the initiation and progression of type 1 diabetes. a, Apoptosis of β-cells, pe-ripheral Schwann cells or both leads to antigen uptake by antigen-presenting cells and activa-tion of cognate T cells in the pancreatic lymph nodes. b, Immune cells accumulate aroundislets in close association with Schwann cells (peri-insulitis). This first wave of autoimmune re-sponse may be directed against Schwann cell antigens (yellow; for example, GFAP), β-cell anti-gens (blue; for example, insulin) or both. Because β-cells and Schwann cells express some ofthe same proteins (red; for example, GAD, S100β), the autoimmune response against one celltype may damage the other cell type. Schwann cells might also be indirectly damaged by by-stander effects, leading to the spreading of autoimmunity to Schwann cell antigens. The con-verse, where Schwann cell autoimmunity evolves into β-cell autoimmunity, could also occur. c, Immune cells invade the islet and autoimmunity to β-cell antigens continues to spread (in-vasive insulitis).

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162 NATURE MEDICINE • VOLUME 9 • NUMBER 2 • FEBRUARY 2003

NEWS & VIEWS

recognize some antigens common toboth β-cells and Schwann cells, such asGAD, a known early target of high-avidity T cells in young NOD mice9.Alternatively, autoimmunity mayspread to Schwann cells. In this casethe early peri-islet infiltrate causes by-stander damage to Schwann cells andthe release of Schwann cell antigens. Inthe context of ‘danger signals’, thisleads to the spreading of autoreactivityto Schwann cell antigens.

It is also possible that Schwann cellautoimmunity evolves into β-cell au-toimmunity. However, T-cell clonesspecific for β-cell antigens can mediateT1D when transfused into immune-in-competent NOD.scid mice10, and Tcells that recognize a transgene prod-uct specifically expressed in the β-cellscan mediate T1D in transgenic NODmice11. Thus, Schwann cell autoreactiv-ity is not essential for T1D pathogene-sis. Moreover, T cells from NOD micewhose β-cells were ablated at an earlyage cannot transfer disease12. And theearly deletion of T cells reactive toGAD13 or pro-insulin14 circumvents thedevelopment of autoimmunity in NODmice.

To begin to dissect the role ofSchwann cell autoreactivity in T1Dpathogenesis, the authors generatedGFAP-reactive T-cell lines from NODmice. When transfused into NOD.scidmice, these T cells quickly formed aperi-insulitis that progressively dam-aged the Schwann cells. However,there was no apparent β-cell loss, indi-cating that T1D pathogenesis requiresautoimmunity to other (β-cell) anti-gens. The authors then showed thatimmunization with GFAP or S100βcould inhibit the transfer of T1D.Evidently, β-cells can be protected byimmunization with autoantigensfrom nearby damaged cells by by-stander effects, although in otherstudies, antigens from neighboring α-cells did not protect β-cells. Thesefindings suggest that Schwann cell au-toantigens may be useful therapeuti-cally, but do not provide informationon disease etiology.

Next, the authors examinedSchwann cell autoimmunity in two dif-ferent T1D transgenic mouse models.In the first model, the transgenic miceexpress a viral protein in their β-cells,as well as a T-cell receptor specific forthat viral protein on most of theirCD8+ T cells. After infection with the

virus and activation of CD8+ T cells,islet infiltration, β-cell death and T1Drapidly ensue. Despite massive β-celldeath, the Schwann cell network re-mained largely intact. Thus, when thetarget antigen is expressed only in β-cells, there is little or no Schwann celldamage, suggesting that shared autore-activity with β-cells is necessary forSchwann cell destruction. These obser-vations also show that Schwann cellsare not just a physical barrier that isdisrupted by invasive insulitis, andthat these cells do not necessarily suc-cumb to bystander damage. In the sec-ond T1D model, the majority of T cellsexpress a T-cell receptor that is fre-quently found on islet-infiltratingCD8+ T cells. In these mice, bothSchwann cells and β-cells were de-stroyed. It is unknown whether the β-cell antigen that is targeted by theseCD8+ T cells is also expressed bySchwann cells.

In a previous report, GAD-contain-ing neurons near the islet also becameundetectable in NOD mice well beforea marked reduction in β-cells15.Together, these reports show that twodifferent nervous system cell typesnear the islets suffer major damageearly in the T1D disease process. Theresults of Winer et al. suggest thatthese losses are not due to the by-stander effects of insulitis.Interestingly, developing neurons un-dergo a ‘remodeling’ process involvingapoptosis to eliminate inactive neu-rons or synaptic connections. Just as β-cell apoptosis is thought to provideantigens that initiate β-cell autoimmu-nity8, so might neuronal tissue remod-eling provide antigens that can primeautoimmunity. The outcome of expo-sure to these antigens may depend crit-ically on the immunological milieu.Indeed, when NOD mice are deficientin the co-stimulatory molecule B7-2,their immune system shifts to overtlyattacking peripheral nerves and only aslight peri-insulitis develops2. Notably,NOD mice also develop salivary glandautoreactivity, whose etiology is inde-pendent of β-cell autoimmunity.

Diabetes sleuths are thus presentedwith several murder mysteries and im-munological puzzles. Are the deaths ofSchwann cells and GAD-containingneurons due to bystander effects, theirshared expression of β-cell autoanti-gens, an independent autoimmuneprocess, or a general propensity for β-

cell and neuronal tissue autoimmu-nity? Why are other cell types withinthe islet spared from major damage?

The observations of Winer et al. donot, as yet, call for a re-working of thecurrent paradigms of how β-cell au-toimmunity is initiated. However, theyraise many fundamental questionsconcerning the T1D disease processand may provide new clinical ap-proaches to pre-diagnosing and pre-venting T1D.

1. Tisch, R. & McDevitt, H. Insulin-dependent dia-betes mellitus. Cell 85, 291–297 (1996).

2. Salomon, B. et al. Development of spontaneousautoimmune peripheral polyneuropathy in B7-2-deficient NOD mice. J. Exp. Med. 194, 677–684(2001).

3. Winer, S. et al. Type I diabetes and multiple scle-rosis patients target islet plus central nervoussystem autoantigens; nonimmunized nonobesediabetic mice can develop autoimmune en-cephalitis. J. Immunol. 166, 2831–2841 (2001).

4. Winer, S. et al. Autoimmune islet destruction inspontaneous type 1 diabetes is not β-cell exclu-sive. Nat. Med. 9, 198–205 (2003).

5. Teitelman, G., Guz, Y., Ivkovic, S. & Ehrlich, M.Islet injury induces neurotrophin expression inpancreatic cells and reactive gliosis of peri-isletSchwann cells. J. Neurobiol. 34, 304–318 (1998).

6. Sunami, E. et al. Morphological characteristics ofSchwann cells in the islets of Langerhans of themurine pancreas. Arch. Histol. Cytol. 64, 191–201(2001).

7. Sreenan, S. et al. Increased β-cell proliferationand reduced mass before diabetes onset in thenonobese diabetic mouse. Diabetes 48, 989–996(1999).

8. Mathis, D., Vence, L. & Benoist, C. β-Cell deathduring progression to diabetes. Nature 414,792–798 (2001).

9. Tian, J., Gregori, S., Adorini, L. & Kaufman, D.L.The frequency of high avidity T cells determinesthe hierarchy of determinant spreading. J. Immunol. 166, 7144–7150 (2001).

10. Haskins, K. & Wegmann, D. Diabetogenic T-cellclones. Diabetes 45, 1299–1305 (1996).

11. von Herrath, M.G. Regulation of virally inducedautoimmunity and immunopathology: contribu-tion of LCMV transgenic models to understand-ing autoimmune insulin-dependent diabetesmellitus. Curr. Top. Microbiol. Immunol. 263,145–175 (2002).

12. Larger, E., Becourt, C., Bach, J.F. & Boitard, C.Pancreatic islet β-cells drive T cell-immune re-sponses in the nonobese diabetic mouse model.J. Exp. Med. 181, 1635–1642 (1995).

13. Kaufman, D.L. et al. Spontaneous loss of T-celltolerance to glutamic acid decarboxylase inmurine insulin-dependent diabetes. Nature 366,69–72 (1993).

14. French, M.B. et al. Transgenic expression ofmouse proinsulin II prevents diabetes innonobese diabetic mice. Diabetes 46, 34–39(1997).

15. Saravia-Fernandez, F. et al. Localization of γ-aminobutyric acid and glutamic acid decar-boxylase in the pancreas of the nonobese dia-betic mouse. Endocrinology 137, 3497–3506(1996).

Department of Molecular and Medical PharmacologyUCLA School of MedicineUniversity of California, Los AngelesLos Angeles, California, USAEmail: dkaufman@mednet.ucla.edu

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