Heat shock proteins
protect stressed cells from apoptosis.
We reasoned that an environmental stressor inducing HSP70 expression may
be
associated with greater secretion by melanocytes. Extracellular stress
proteins
can bind dendritic cells and induce immune response to peptides bound to
these
molecular chaperones. Meanwhile, intracellular colocalization with
melanosomal
proteins explains the immunogenic cargo that leads to vitiligo
development.
We showed that HSP70i is central to disease development in mouse models;
knockout mice do not depigment in response to antigenic challenge,
whereas HSP70i alone is sufficient to induce disease in a transgenic
mouse
model of spontaneous depigmentation. Thus, we hypothesized that
targeting
HSP70i in autoimmune vitiligo is suited to halt depigmentation. We
confirmed that dendritic cell profiles in human patients mimic those
observed
in response to HSP70i in mice. The c-terminus and a peptide within it
proved
crucial to depigmentation. A single amino acid modification
introduced by site directed mutagenesis was sufficient to prevent human
dendritic cell activation and inhibit depigmentation in mice. Mutant
HSP70i
drove expansion of a regulatory subset of APC, in contrast to the
inflammatory
DC subset observed in response to wildtype HSP70i. Treatment was
associated
with reduced T cell influx to the skin, and circulating T cells
maintained a
memory profile not observed in response to the wildtype molecule. Mutant
HSP70i
likewise affected profiles of immune cells collected from cultured
human
skin explants. Taken together, our data support the remarkable treatment
potential of mutant HSP70i for vitiligo.