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International Congress of Immunology 2016

Abstract Book

Autoimmunity

1906

Insulin-degrading enzyme deficiency protects from type 1

diabetes by regulating autoantigenicity and proliferation of

pancreatic beta cells

Bessard, M.-A.

1

, Moser, A.

1

, Waeckel-Enée, E.

1

, Chhuon, C.

2

, Lipecka,

J.

2

, Kim, J.

1

, Guenette, S.

3

, Santamaria, P.

4

, Wong, F.S.

5

, Diana, J.

1

,

Guerrera, C.

2

, Unanue, E.

6

, van Endert, P.

1

1

INSERM U 1151, Paris, France,

2

INSERM US 24, Paris, France,

3

Massachusetts General Institute for Neurodegenerative Diseases,

Charlestown, United States,

4

University of Calgary, Julia McFarlane

Diabetes Research Centre, Calgary, Canada,

5

University of Cardiff,

Cardiff, United Kingdom,

6

Washington University School of

Medicine, Division of Immunobiology, Saint Louis, United States

Type 1 diabetes is the result of the destruction of pancreatic

beta cells by autoreactive T cells. Proinsulin as an autoantigen

with beta cell-restricted expression triggers and sustains

the autoimmune CD4+ and CD8+ T cell response and islet

inflammation. We hypothesized that insulin-degrading enzyme

(IDE), a protease genetically associated with type 2 diabetes

possessing very high insulin affinity, might be involved in

proinsulin processing and presentation. We find high expression

of IDE and an increased number of autoantigenic insulin

B chain fragments in IDE-deficient beta cells of non-obese

diabetic (NOD) mice, and normal to increased stimulation of

insulin-specific CD8 and CD4 T cells by IDE-deficient islets. This

suggests that IDE physiologically degrades (pro)insulin in beta

cells. However, surprisingly, IDE-deficient NOD mice are more

resistant to diabetes transfer by T cells specific for insulin but

not for another key autoantigen, harbor fewer diabetogenic

splenocytes and display strongly reduced diabetes incidence.

Moreover, IDE-deficient islet grafts are more resistant to

autoimmune rejection. Seeking to explain the apparent

paradox between normal to increased insulin presentation

and resistance to the diabetogenic action of insulin-specific

T cells, we find that IDE deficiency results in upregulated beta

cell regeneration in response to autoimmune inflammation.

Diabetes protection in IDE-deficient mice most likely result from

moderately increased beta cell stress recently shown to induce

beta cell proliferation. Thus IDE acts both in processing of the

key autoantigen in murine type 1 diabetes and as a regulator

of beta cell stress, ultimately enhancing autoimmune pathology

and diabetes.

Redemption or Revolt of Forbidden Clones: Mutations,

Autoantibodies and CTLA4-Ig Therapy

Goodnow, C.

1

, Reed, J.

1

, Burnett, D.

1

, Brink, R.

1

, Christ, D.

1

, Schofield,

P.

1

, Perotti, S.

2

, Enders, A.

2

, Ziegler, J.

3

, Wainstein, B.

3

, Roscioli, T.

1,3

,

Gray, P.

3

1

Garvan Institute of Medical Research, Darlinghurst NSW,

2

John

Curtin School of Medical Research, Canberra ACT,

3

Sydney

Children’s Hospital, Randwick, NSW

Many B cells in the pre-immune repertoire carry antibodies that

bind to self-antigens. Some are deleted before these antibodies

can be tested for binding foreign antigens, but others are

carried on anergic B cells. Tolerance by B cell clonal anergy is

enigmatic since the B cells exist in a potentially reversible

state, balanced between activation and apoptosis, posing

the risk of autoimmunity. Here I will describe a clinical case

of LRBA deficiency resulting in life-threatening autoimmune

cytopenias that rapidly resolved by treatment with CTLA4-Ig

(Abatacept) following diagnosis by whole genome sequencing.

By producing a mouse avatar of the case, we confirm that LRBA-

deficiency leads selectively to low CTLA4 on Tregs and other T

cells. Autoantibody secretion in LRBA or CTLA4 deficiency may

be explained by our earlier findings that failure to dampen

CD86 expression on anergic B cells allows them to escape FasL-

mediated killing by helper T cells and be reactivated to form

huge numbers of plasma cells. I will present evidence that

physiological reactivation of anergic cells in humans and mice

yields precursors for germinal centre cells that hypermutate

their antibody variable segments away from self-reactivity. This

represents a mechanism for actively acquired tolerance that has

been hypothesised in the past but not taken seriously. IgD, which

is the main antigen receptor displayed on anergic B cells before

any reactivation, helps to keep anergic cells alive in the pre-

immunerepertoirebyattenuatingtheirresponsetoself-antigens.