Tesis Doctorado
Modulatión of dendritic cell functión by ho-1 and mr: implicatións on autoimmune and cardióvascular disease
Autor
Herrada-Hidalgo, Andrés Alonso
Institución
Resumen
The adaptive immune response consists of a highly specialized system of cells and
molecules that are able to recognize and destroy specific invading pathogens without
affecting the host's own tissues. However, in sorne situations adaptive immune response is
directed against self-tissues, such as joints, nervous system, or pancreas, generating
arthritis, multiple sclerosis or diabetes, respectively. The initiation of an adaptive immune
response depends on the specific interaction between nai"ve CD4+ T cells and antigenpresenting
cells (APC). Among all APCs, dendritic cells (DCs) have the unique capacity to
efficiently prime and modulate nai"ve CD4+ and CD8+ T cells during an adaptive immune
response. In view of the key importance of DC function in T cell activation and adaptive
immune response induction, it is important to investigate different pathways involved in the
modulation of DC function, in order to prevent self damage in autoimmune disease. Thus,
we evaluated the role of externa! signals, such as aldosterone hormone, or interna! proteins,
such as hemoxigenase-1 (H0-1) in the modulation of DC function. Excessive production of
aldosterone leads to the development of hypertension and cardiovascular disease by
generating an inflammatory state that can be promoted by T cell immunity. Our results
show that this hormone augmented the activation of CD8+ T cells in a DC-dependent
fashion. Consistently, DCs express mineralocorticoid receptor (MR), secreting IL-6 and
TGF-{3 in response to aldosterone. Aldosterone also increases CD4+ T cell activation,
imposing a T helper 17 (Th17) phenotype, which has recently been associated to the
promotion of inflarnmatory and autoimmune diseases. Accordingly, we observed that
aldosterone enhances the progression of experimental autoimmune encephalomyelitis (EAE), an autoirnmune disease promoted by Th17 cells. Our data suggest that modulation
of DC function by aldosterone enhances CD8+ T cell activation and promotes Th17-
polarized irnmune responses, which might contribute to the inflarnmatory damage leading
to hypertension and cardiovascular disease. Accordingly, in primary aldosteronism patients,
who have increased serum levels of aldosterone, there is an imbalance in pro- and antiinflarnmatory
cytokine levels, compared with essential hypertensive patients or healthy
controls. On the other hand the enzyme H0-1, which catalyzes the degradation of Heme
group to biliverdin, carbon monoxide, and Fe+, has been associated with
irnmunosuppressive and anti-inflarnmatory functions on DCs. In order to evaluate the role
ofH0-1 on DC function, we evaluated the expression levels ofthis enzyme in FcyRIIb -/-
mice, which developed spontaneous lupus-like disease, and monocytes/DCs from Systemic
Lupus Erythematosus (SLE) patients and controls. Our results show that H0-1 levels in
monocytes but not in DCs or CD4+ T cells were reduced in SLE patients compared with
controls. Similar results were obtained from DCs of SLE mice at advanced ages, when
autoirnmune disease appears, as corroborated by ANAS and proteinuria positive. Thus, we
found a decrease of H0-1 expression on monocytes from SLE patients, suggesting that this
imbalance in monocyte function could be in part explained by a decrease of H0-1 activity,
leading to activation of autoreactive T cells and the development of autoirnmunity. These
findings support the hypothesis that regulating DC function modulates adaptive irnmune
response, and highlights new targets in the regulation of DC function. PFCHA-Becas Doctor en Ciencias Biológicas Mención en Genética Molecular y Microbiología 201p. PFCHA-Becas TERMINADA