Chronic Viral Infection Promotes Efficient Germinal Center B Cell Responses

Abstract

Highlights d Chronic viral infection elicits potent and sustained germinal center (GC) responses d Chronic infection triggers prolonged plasma cell and memory B cell output from GCs d GC B cells hypermutate efficiently and are potently selected in chronic infection

Quantitative and Qualitative Analysis of Humoral Immunity Reveals Continued and Personalized Evolution in Chronic Viral Infection

“…Furthermore, longitudinal antibody repertoire sequencing revealed sustained increased clonal diversity in chronic compared acute infection, suggesting that the selective pressures favored the diversification of multiple distinct B cells within a given clonal lineage, opposed to few B cells continually outcompeting the remainder of the clonal lineage. These data are consistent with reports on antibody evolution in other infectious diseases, where development of neutralizing antibodies was not necessarily dependent on excessive SHM of a few selected B cell clones (Goodwin et al, 2018;Murugan et al, 2018) and are compatible with the findings by Fallet et al (2020), where comparable mutation levels were observed in chronically and acutely infected mice.…”

“…On the contrary, antibody responses in persistently infected mice were even more invigorated at 20 dpi; GCs, LCMV-specific PCs, LCMV-ELISA titers, and the amount of unique clonotypes found in blood reached their maximum ( Figures 1B, 1C, 1J, and 2F). These data are in agreement with Fallet et al (2020), reporting a sustained GC response with prolonged PC and memory B cell output. Furthermore, our EdU-tracing experiments showed that BM resident PCs in chronic infection were extensively cycling up to 3 weeks post-infection ( Figures 5F-5H).…”

“…Because high antibody titers were observed in both acute and chronic mice at 10 dpi, we concluded that they are likely the result of an extrafollicular differentiation of activated B cells into short-lived PBs, rather than solely a GC-derived response. This hypothesis was further supported by Fallet et al (2020; this issue of Cell Reports). Using an activation-induced cytidine deaminase (AID) reporter mouse model revealed GC B cell numbers that had activated AID 10 days after infection and persisted throughout day 60 in GCs were higher in chronic compared to acute infections.…”

Viral nucleoprotein antibodies activate TRIM21 and induce T cell immunity

“…In acute LCMV infection, anti‐N antibodies can be detected from as early as 4 days and remain higher in titre than anti‐GP antibodies throughout the response (Battegay et al , 1993; Eschli et al , 2007). Crucially, while LCMV is almost entirely cleared within a few weeks (Moskophidis et al , 1993), a neutralising titre is often only observed after several months and only when virus infection has become persistent (Fallet et al , 2020). This could be taken to suggest that antibodies are not important to resolve infection, but in mice with restricted antibody specificity (MD4; Straub et al , 2013) and T11μMT; Bergthaler et al , 2009), lacking functional B cells (JHT (Bergthaler et al , 2009)) or an ability to produce soluble antibodies (ΔIgMi Straub et al , 2013), viraemia persists for a month or more.…”

Physical ‘strength’ of the multi‐protein chain connecting immune cells: Does the weakest link limit antibody affinity maturation?

“…Recent studies have argued that chronic infections can result in more potent GC responses. [ 71,72 ] Yet, it is possible in some chronic infection settings that a larger fraction of selected GC B cells than in acute infections is terminally differentiated into plasma and memory cells, which may leave insufficient numbers of GC B cells to efficiently mutate and continue the GC reaction, [ 73 ] possibly contributing to the low ceiling. This hypothesis, however, cannot explain the scenarios where Abs with high affinities, close to the ceiling, arise soon after the onset of (an acute) infection due to random mutations in the Ab genes.…”