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https://www.arca.fiocruz.br/handle/icict/49825
DYNAMICS OF T-LYMPHOCYTE ACTIVATION RELATED TO PARADOXICAL TUBERCULOSIS-ASSOCIATED IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME IN PERSONS WITH ADVANCED HIV
IRIS pathogenesis,
Coinfection
Inflammation
T cell activation
Autor(es)
Tibúrcio, Rafael V.
Duarte, Beatriz Barreto
Naredren, Gopolan
Queiroz, Artur Trancoso Lopo de
Anbalagan, Selvaraj
Nayak, Kaustuv
Ravichandran, Narayanan
Subramani, Rajasekaran
Antonelli, Lis R. V.
Satagopan, Kumar
Anbalagan, Komathi
Porter, Brian O.
Sher, Alan
Swaminathan, Soumya
Sereti, Irini
Andrade, Bruno Bezerril de
Duarte, Beatriz Barreto
Naredren, Gopolan
Queiroz, Artur Trancoso Lopo de
Anbalagan, Selvaraj
Nayak, Kaustuv
Ravichandran, Narayanan
Subramani, Rajasekaran
Antonelli, Lis R. V.
Satagopan, Kumar
Anbalagan, Komathi
Porter, Brian O.
Sher, Alan
Swaminathan, Soumya
Sereti, Irini
Andrade, Bruno Bezerril de
Afiliação
"Múltipla ver em Notas"
Resumo em Inglês
Most persons living with HIV (PLWH) experience a significant restoration of their immunity
associated with successful inhibition of viral replication after antiretroviral therapy (ART)
initiation. Nevertheless, with the robust quantitative and qualitative restoration of CD4+ Tlymphocytes,
a fraction of patients co-infected with tuberculosis develop immune
reconstitution inflammatory syndrome (TB-IRIS), a dysregulated inflammatory response
that can be associated with significant tissue damage. Several studies underscored the
role of adaptive immune cells in IRIS pathogenesis, but to what degree T lymphocyte
activation contributes to TB-IRIS development remains largely elusive. Here, we sought to
dissect the phenotypic landscape of T lymphocyte activation in PLWH coinfected with TB
inititating ART, focusing on characterization of the profiles linked to development of TBIRIS.
We confirmed previous observations demonstrating that TB-IRIS individuals display
pronounced CD4+ lymphopenia prior to ART initiation. Additionally, we found an ARTinduced
increase in T lymphocyte activation, proliferation and cytotoxicity among TB-IRIS patients. Importantly, we demonstrate that TB-IRIS subjects display higher frequencies of
cytotoxic CD8+ T lymphocytes which is not affected by ART. Moreover, These patients
exhibit higher levels of activated (HLA-DR+) and profilerative (Ki-67+) CD4+ T cells after
ART commencenment than their Non-IRIS counterparts. Our network analysis reveal
significant negative correlations between Total CD4+ T cells counts and the frequencies of
Cytotoxic CD8+ T cells in our study population which could suggest the existance of
compensatory mechanisms for Mtb-infected cells elimination in the face of severe CD4+ T
cell lymphopenia. We also investigated the correlation between T lymphocyte activation
profiles and the abundance of several inflammatory molecules in plasma. We applied
unsupervised machine learning techniques to predict and diagnose TB-IRIS before and
during ART. Our analyses suggest that CD4+ T cell activation markers are good TB-IRIS
predictors, whereas the combination of CD4+ and CD8+ T cells markers are better at
diagnosing TB-IRIS patients during IRIS events Overall, our findings contribute to a more
refined understanding of immunological mechanisms in TB-IRIS pathogenesis that may
assist in new diagnostic tools and more targeted patient management.
Palavras-chave em inglês
T lymphocytes,IRIS pathogenesis,
Coinfection
Inflammation
T cell activation
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