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Aparna Srinivasan

Publications and source records attributed to Aparna Srinivasan.

8 recordsLinked to original sources
PubMed2026

Integrating genetic predictors into subsequent breast cancer risk prediction in survivors of childhood cancer.

PURPOSE: Female survivors of childhood cancer are at high risk for developing breast cancer. The contributions of most general population primary breast cancer genetic predictors to this risk have not been explored. METHODS: Analyses included females who survived &#x2265;5 years after their childhood cancer diagnosis with available array (N&#x2009;=&#x2009;2096, subsequent breast cancer [SBC]=218) or whole-genome sequencing (WGS; N&#x2009;=&#x2009;3292, SBC=101) data from the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort. We computed 99 externally-validated primary breast cancer polygenic risk scores (PRS). Using deep-coverage WGS, ClinVar-annotated pathogenic/likely pathogenic (P/LP) variants in breast cancer susceptibility genes were identified. Cox proportional hazards models assessed associations with SBC risk, adjusting for treatments and genetic ancestry. RESULTS: Among 5388 female survivors (genetic ancestry, European: N&#x2009;=&#x2009;4,752; African: N&#x2009;=&#x2009;444; East Asian: N&#x2009;=&#x2009;192), 319 developed SBC. Most (90.9%) PRSs were nominally associated with SBC risk (P&#x2009;<&#x2009;0.05), but effect sizes varied substantially. PRSs with superior discriminatory ability had greater genome-wide coverage (e.g., 6.4 million-variant PRS, HR per SD&#x2009;=&#x2009;1.71, 95% CI&#x2009;=&#x2009;1.43 to 2.05; P&#x2009;=&#x2009;4.2x10-9) and 7.7-fold higher odds (P&#x2009;=&#x2009;7.0x10-4) of including variants in multiple DNA damage repair pathways compared with PRSs with weaker risk associations. Among survivors with WGS, 1.6% carried P/LP variants in clinical testing panel genes, which was associated with a 7.4-fold greater risk (95% CI&#x2009;=&#x2009;3.16 to 17.19). Including genetic factors improved SBC risk prediction by age 40 (P&#x2009;<&#x2009;0.001) compared to treatment exposures alone. CONCLUSIONS: Externally-validated primary breast cancer genetic susceptibility predictors are relevant for SBC risk prediction and should be prioritized for risk stratification in survivors.

Journal Article↗
PubMed2006

Pivotal advance: exposure to LPS suppresses CD4+ T cell cytokine production in Salmonella-infected mice and exacerbates murine typhoid.

A number of studies have documented suppression of lymphocyte activation in mice infected with Salmonella. Here, we describe incomplete activation of CD4+ T cells following intravenous injection of specific peptide and LPS into Salmonella-infected mice. Although antigen-specific CD4+ T cells were activated by peptide/LPS to increase surface CD69 expression, they did not produce IL-2 or TNF-alpha. Suppression of cytokine production did not require prolonged exposure of the T cells to the Salmonella-infected environment, was not antigen specific, but was dependent upon the presence of LPS during stimulation. These data suggest that Salmonella-infected mice are exquisitely sensitive to the generation of a suppressive environment following innate immune stimulation with LPS. In agreement with this interpretation, repeated low-dose administration of LPS caused uncontrolled replication of attenuated Salmonella in vivo.

Adoptive Transfer↗
PubMed2006

Activation of Salmonella-specific immune responses in the intestinal mucosa.

The mammalian immune response to Salmonella has long been a subject of scientific study. Indeed, many of the general aspects of bacterial pathogenesis and host immune defense have been well described. However, a lack of clarity remains concerning important aspects of the host immune response to Salmonella, particularly with regard to the induction of an immune response in the intestinal mucosa. A major limitation has been the general lack of knowledge about specific antigenic targets that are recognized by both the innate and adaptive immune response in the intestine. Progress towards the identification of these targets is critical for the development of a detailed model of immunity to Salmonella and will lead to a better understanding of mucosal immune responses to other intracellular pathogens.

Animals↗
PubMed2006

CCR6-mediated dendritic cell activation of pathogen-specific T cells in Peyer's patches.

T cell activation by dendritic cells (DCs) is critical to the initiation of adaptive immune responses and protection against pathogens. Here, we demonstrate that a specialized DC subset in Peyer's patches (PPs) mediates the rapid activation of pathogen specific T cells. This DC subset is characterized by the expression of the chemokine receptor CCR6 and is found only in PPs. CCR6(+) DCs were recruited into the dome regions of PPs upon invasion of the follicle associated epithelium (FAE) by an enteric pathogen and were responsible for the rapid local activation of pathogen-specific T cells. CCR6-deficient DCs were unable to respond to bacterial invasion of PPs and failed to initiate T cell activation, resulting in reduced defense against oral infection. Thus, CCR6-dependent regulation of DCs is responsible for localized T cell dependent defense against entero-invasive pathogens.

Adoptive Transfer↗
PubMed2004

Low-dose Salmonella infection evades activation of flagellin-specific CD4 T cells.

Many pathogens can establish a lethal infection from relatively small inocula, yet the effect of infectious dose upon CD4 T cell activation is not clearly understood. This issue was examined by tracking Salmonella flagellin-specific SM1 T cells in vivo, after i.v. and oral challenge of mice with virulent Salmonella typhimurium. SM1 T cells rapidly expressed activation markers and expanded in response to high-dose infection but remained completely unresponsive in mice challenged with low doses of Salmonella. SM1 T cells, in these mice, remained unresponsive, despite massive bacterial replication in vivo. Naive SM1 T cells in low-dose Salmonella-infected mice were activated rapidly after the injection of flagellin peptide, demonstrating that these T cells were fully capable of responding, ruling out the possibility of a bacterial-induced suppressive environment. The inability of flagellin-specific SM1 T cells to respond to low-dose infection was not due to Ag down-regulation, because flagellin expression was detected using a functional assay. Together, these data suggest that low-dose Salmonella infection can evade flagellin-specific CD4 T cell activation in vivo.

Administration, Oral↗
PubMed2004

Massive number of antigen-specific CD4 T cells during vaccination with live attenuated Salmonella causes interclonal competition.

The clonal burst size of CD4 T cells is predicted to be less than that of CD8 T cells. In this study, we demonstrate that massive numbers of Ag-specific CD4 T cells respond during vaccination of mice with live attenuated Salmonella, reaching a peak frequency of approximately 50% of CD4 T cells. Salmonella-specific T cells persisted at high frequency for several weeks and could be detected in the memory population for months after infection. Surprisingly, the expansion of endogenous Salmonella-specific CD4 T cells prevented the persistence of adoptively transferred Salmonella-specific T cells in vivo, demonstrating interclonal competition for access to the memory compartment.

Adoptive Transfer↗
PubMed2004

Visualizing the immune response to pathogens.

Advances in immune visualization have enabled the physical tracking of immune responses in vivo. The adaptation of such technology to models of infectious disease holds the promise of a more detailed analysis of host-pathogen interactions in a natural setting. However, the visualization of pathogen-specific immune responses in vivo confronts challenges that are inherent to the study of infectious disease systems. Recent attempts to track pathogen-specific immune responses in vivo validate the usefulness and underline the complexity of this experimental strategy.

Animals↗