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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.