Lymph node fibrosis: a structural barrier to unleashing effective vaccine immunity
Boris Julg and Galit Alter
Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA. Infectious Disease Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
Address correspondence to: Galit Alter, Ragon Institute of MGH, MIT and Harvard, 400 Technology Square, Cambridge, Massachusetts 02139, USA. Phone: 617.724.0546; Email: galter@mgh.harvard.edu.
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Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA. Infectious Disease Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
Address correspondence to: Galit Alter, Ragon Institute of MGH, MIT and Harvard, 400 Technology Square, Cambridge, Massachusetts 02139, USA. Phone: 617.724.0546; Email: galter@mgh.harvard.edu.
Find articles by Alter, G. in: JCI | PubMed | Google Scholar
First published May 21, 2018 - More info
J Clin Invest. 2018;128(7):2743–2745. https://doi.org/10.1172/JCI121053.
Copyright © 2018, American Society for Clinical Investigation
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Abstract
Vaccine responses vary by geographic location. We have previously described how HIV-associated inflammation leads to fibrosis of secondary lymph nodes (LNs) and T cell depletion. We hypothesized that other infections may cause LN inflammation and fibrosis, in a process similar to that seen in HIV infection, which may lead to T cell depletion and affect vaccine responses. We studied LNs of individuals from Kampala, Uganda, before and after yellow fever vaccination (YFV) and found fibrosis in LNs that was similar to that seen in HIV infection. We found blunted antibody responses to YFV that correlated to the amount of LN fibrosis and loss of T cells, including T follicular helper cells. These data suggest that LN fibrosis is not limited to HIV infection and may be associated with impaired immunologic responses to vaccines. This may have an impact on vaccine development, especially for infectious diseases prevalent in the developing world.
Authors
Cissy Kityo, Krystelle Nganou Makamdop, Meghan Rothenberger, Jeffrey G. Chipman, Torfi Hoskuldsson, Gregory J. Beilman, Bartosz Grzywacz, Peter Mugyenyi, Francis Ssali, Rama S. Akondy, Jodi Anderson, Thomas E. Schmidt, Thomas Reimann, Samuel P. Callisto, Jordan Schoephoerster, Jared Schuster, Proscovia Muloma, Patrick Ssengendo, Eirini Moysi, Constantinos Petrovas, Ray Lanciotti, Lin Zhang, Maria T. Arévalo, Benigno Rodriguez, Ted M. Ross, Lydie Trautmann, Rafick-Pierre Sekaly, Michael M. Lederman, Richard A. Koup, Rafi Ahmed, Cavan Reilly, Daniel C. Douek, Timothy W. Schacker
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Structural effects on vaccine-induced immunity
In this issue, Kityo et al. (30) specifically explore the role of inflammation, tissue architecture, and fibrosis in modulating vaccine-induced immunity. In a tour de force, the study, which includes lymph node (LN) excisions and immune profiling, specifically aimed to define the linkage among LN inflammation, fibrosis, chronic immune activation, and vaccine-induced immunity. The authors hypothesized that similar to HIV-induced changes in lymphoid architecture (29), recurrent coinfections may contribute to the reduced vaccine responsiveness in low-income countries by altering immune activation–induced lymphoid architecture. Kityo and colleagues (30) recruited three different cohorts to address their hypothesis, specifically 30 HIV– Ugandans, a subset of which was subsequently given YFV; a group of HIV– participants from Atlanta, USA, who received YFV; and a group of 10 HIV– individuals from Minnesota, USA. LNs were collected from the Ugandans and the Minnesotans. Ugandans exhibited enhanced inflammatory cytokine responses, marked by elevated levels of TGF-β, IL-6, IL-4, IL-21, and MIP-1β, compared with subjects from the U.S., suggesting distinct inflammatory profiles across geographic regions of the globe. Additionally, collagen levels were markedly increased in the T cell zone (TZ) in LNs of Ugandans compared with those from U.S. controls, similar to what has been previously reported in HIV+ individuals (29). Furthermore, there was a significant inverse correlation between TZ collagen deposition and TZ CD4+ T cell frequencies, known to be essential drivers of effective vaccine-induced antibody responses, suggesting T cell depletion in the Ugandans, even in the absence of HIV infection. To further determine if the observed differences in lymphatic tissue anatomy were associated with vaccine responsiveness, Kityo and colleagues (30) examined draining LNs 10–14 days after YFV and measured plasma YFV antibody titers by plaque reduction assay. Interestingly, not only was there a relative lack of primary follicles with fewer secondary follicles (germinal centers [GCs]) prior to vaccination in the Ugandan cohort, but also the majority of these individuals did not have a detectable increase in primary or secondary follicle formation following vaccination. Moreover, these immunological defects were consistent with a poor antibody response in the Ugandan cohort and correlated with increased damage in the fibroblastic reticular cell network (FRCn), an anatomic correlate of poor vaccine response. Thus, these data provide a definitive link among chronic inflammation, damaged lymphoid architecture, and poor vaccine outcome (Figure 1).
Figure 1Factors driving lower vaccine responsiveness around the globe. The cartoon bar graph depicts the observed differences in vaccine responsiveness around the globe, and highlights factors that have been associated with vaccine immunogenicity. Factors listed in black have been previously published. Factors listed in red represent the findings in the manuscript by Kityo et al., which evaluated differences in vaccine response in subjects from the U.S. (Minnesota and Georgia, blue) and subjects from Uganda (red).
Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)