Biology Reference
In-Depth Information
lism that can produce hyperlipidaemia. Indeed, TNF-a inhibits the intake of
free fatty acids by adipocytes via the inhibition of lipoprotein lipase, leading
to fat wasting, but also increases lipogenesis via the stimulation of the hepatic
triglyceride synthetase, leading to hyperlipidaemia (Grunfeld et al., 1990). In
addition, TNF-a promotes insulin resistance via both the increase in circulat-
ing free fatty acids and a direct action on the insulin receptor. Interestingly, the
T-cell polarization to TNF-a synthesis that we observed in HAART-treated
patients seems to favor the development of the lipodystrophy syndrome by
contributing to alteration in lipid metabolism. Indeed, we found signi®cant
positive correlations between the absolute number of TNF-a CD8 T-cell pre-
cursors and lipid parameters usually altered in lipodystrophy including choles-
terol, triglycerides, and the atherogenic ratio apolipoprotein B(Apo B)/Apo
A1 ( Ledru et al., 2000). Thus, new potent multitherapies can induce metabolic
complications, which are related to hormonal and cytokine dysfunctions. In
addition, recent studies have reported unusual clinical in¯ammatory syndromes
after initiation of HAART, such as immune recovery vitritis ( IRV ) in cytome-
galovirus retinitis patients or focal mycobacterial lymphadenitis. Our observa-
tions suggest that, through the dysregulation of TNF-a T-cell homeostasis,
HAART creates a proin¯ammatory environment that might contribute to the
development of these immune restoration in¯ammatory diseases.
CONCLUSION
The main role of apoptosis in speci®c immunity is to limit the antigen-speci®c
clonal expansion, thus contributing to the termination of the response and pre-
vention of autoimmunity. Premature lymphocyte apoptosis in the context of
HIV infection is the consequence of continuous production of viral proteins,
leading to an unbalanced immune activation and to the triggering of apoptotic
programs in all lymphocyte subsets, and turning nonprofessional T cells into
cytotoxic cells able to kill healthy noninfected cells through the CD95 pathway.
Premature apoptosis is also responsible for the disappearance of T-helper cells
primed for type-1 cytokine synthesis, thus contributing to the lack of cytokines/
survival factors essential to the maintenance of HIV-speci®c immune response.
Under potent antiretroviral therapies, a signi®cant decrease in spontaneous or
TCR- or CD95-induced lymphocyte apoptosis is observed, concomitant with a
partial quantitative and qualitative restoration of the immune system in treated
patients. However, owing to the suppression of physiological apoptosis, possi-
bly because of antiapoptotic e¨ects of some of the anti-HIV drugs, potent
therapies are associated with alteration of TNF-a T-cell homeostasis, leading to
an accumulation in the blood of T cells primed for TNF-a synthesis, and con-
tributing to the development of metabolic complications such as hyperlipidemia
and insulin resistance, associated with peripheral loss of fatty tissue charac-
teristic of the lipodystrophy syndrome, as recently identi®ed in patients with
HAART.
