Organized B cell sites in cartilaginous fishes reveal the evolutionary foundation of germinal centers

Matz, Hanover; Taylor, Richard S.; Redmond, Anthony K.; Hill, Thomas M.; Daniels, Rose Ruiz; Beltrán, Mariana; Henderson, Neil C.; Macqueen, Daniel J.; Dooley, Helen

doi:10.1016/j.celrep.2023.112664

Cited by 16 publications

(10 citation statements)

References 63 publications

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“…In contrast, SHM arose approximately 450 million years ago in ectothermic cartilaginous fish, which can also generate MBCs and PCs 66–68 . In cartilaginous fish, SHM functions to diversify antibody responses and only modestly enhances affinity 69,70 . Efficient affinity maturation only developed with the advent of GCs.…”

Section: Discussionmentioning

confidence: 99%

BRWD1 establishes epigenetic states for germinal center initiation, maintenance, and function

Wright,

Kennedy,

et al. 2024

Preprint

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Germinal center (GC) B cells segregate into three subsets that compartmentalize the antagonistic molecular programs of selection, proliferation, and somatic hypermutation. In bone marrow, the epigenetic reader BRWD1 orchestrates and insulates the sequential stages of cell proliferation andIgkrecombination. We hypothesized BRWD1 might play similar insulative roles in the periphery. InBrwd1-/-follicular B cells, GC initiation and class switch recombination following immunization were inhibited. In contrast, inBrwd1-/-GC B cells there was admixing of chromatin accessibility across GC subsets and transcriptional dysregulation including induction of inflammatory pathways. This global molecular GC dysregulation was associated with specific defects in proliferation, affinity maturation, and tolerance. These data suggest that GC subset identity is required for some but not all GC-attributed functions. Furthermore, these data demonstrate a central role for BRWD1 in orchestrating epigenetic transitions at multiple steps along B cell developmental and activation pathways.

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Section: Discussionmentioning

confidence: 99%

BRWD1 establishes epigenetic states for germinal center initiation, maintenance, and function

Wright,

Kennedy,

et al. 2024

Preprint

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“…In contrast to teleosts, some cold-blooded species contain B cell follicles, and those regions could represent tissue areas where adaptive immune responses are induced. For instance, sharks have previously been shown to contain B cell follicles ( 3 ), and a recent study reported that nurse shark B cell follicles constitute organized B cell selection sites where immune responses appear to be induced ( 36 ). B cell follicles have also been described in the adult Xenopus spleen, and although they are not present in all amphibian species ( 3 ), they appear to contain most of the cellular and molecular machinery required for the induction of adaptive immune responses ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

Cold-blooded vertebrates evolved organized germinal center–like structures

Shibasaki,

Afanasyev,

Fernández-Montero

et al. 2023

Sci. Immunol.

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Germinal centers (GCs) or analogous secondary lymphoid microstructures (SLMs) are thought to have evolved in endothermic species. However, living representatives of their ectothermic ancestors can mount potent secondary antibody (Ab) responses upon infection or immunization, despite the apparent lack of SLMs in these cold-blooded vertebrates. How and where adaptive immune responses are induced in ectothermic species in the absence of GCs or analogous SLMs remains poorly understood. Here we infected a teleost fish (trout) with the parasite Ichthyophthirius multifiliis (Ich) and identified the formation of large aggregates of highly proliferating IgM + B cells and CD4 + T cells, contiguous to splenic melanomacrophage centers (MMCs). Most of these MMC-associated lymphoid aggregates (M-LAs) contained numerous antigen (Ag)-specific B cells. Analysis of the IgM heavy chain CDR3 repertoire of microdissected splenic M-LAs and non M-LA areas revealed that the most frequent B cell clones induced after Ich infection were highly shared only within the M-LAs of infected animals. These M-LAs represented highly polyclonal SLMs in which Ag-specific B cell clonal expansion occurred. M-LA-associated B cells expressed high levels of activation-induced cytidine deaminase and underwent significant apoptosis, and somatic hypermutation of Igμ genes occurred prevalently in these cells. Our findings demonstrate that ectotherms evolved organized SLMs with GC-like roles. Moreover, our results also point to primordially conserved mechanisms by which M-LAs and mammalian polyclonal GCs develop and function.

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“…Our laboratory recently provided the first evidence for how B cell selection may be orchestrated within the cartilaginous fish SLO. Fluorescence in situ hybridization experiments revealed that the splenic follicles of immunized nurse sharks contain Ig+/AICDA+/Ki-67+ cells around the circumference of the white pulp ( 127 ) ( Figure 2 ). CD3ϵ+ T cells were identified in aggregates associated with the borders of B cell follicles, as well as distributed within the follicles themselves ( 127 ).…”

Section: Cartilaginous Fishes: For B Cell Follicles Onlymentioning

confidence: 99%

“…Fluorescence in situ hybridization experiments revealed that the splenic follicles of immunized nurse sharks contain Ig+/AICDA+/Ki-67+ cells around the circumference of the white pulp ( 127 ) ( Figure 2 ). CD3ϵ+ T cells were identified in aggregates associated with the borders of B cell follicles, as well as distributed within the follicles themselves ( 127 ). Single nuclei sequencing of nurse shark spleen samples revealed B cells with centrocyte- and centroblast-like gene expression signatures ( 127 ).…”

Section: Cartilaginous Fishes: For B Cell Follicles Onlymentioning

confidence: 99%

450 million years in the making: mapping the evolutionary foundations of germinal centers

Matz

Dooley

2023

Front. Immunol.

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Germinal centers (GCs) are distinct microanatomical structures that form in the secondary lymphoid organs of endothermic vertebrates (i.e., mammals and some birds). Within GCs, B cells undergo a Darwinian selection process to identify clones which can respond to pathogen insult as well as affinity mature the B cell repertoire. The GC response ultimately generates memory B cells and bone marrow plasma cells which facilitate humoral immunological memory, the basis for successful vaccination programs. GCs have not been observed in the secondary lymphoid organs of ectothermic jawed vertebrates (i.e., fishes, reptiles, and amphibians). However, abundant research over the past decades has indicated these organisms can produce antigen specific B cell responses and some degree of affinity maturation. This review examines data demonstrating that the fundamentals of B cell selection may be more conserved across vertebrate phylogeny than previously anticipated. Further, research in both conventional mammalian model systems and comparative models raises the question of what evolutionary benefit GCs provide endotherms if they are seemingly unnecessary for generating the basic functional components of jawed vertebrate humoral adaptive immune responses.

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Organized B cell sites in cartilaginous fishes reveal the evolutionary foundation of germinal centers

Cited by 16 publications

References 63 publications

BRWD1 establishes epigenetic states for germinal center initiation, maintenance, and function

BRWD1 establishes epigenetic states for germinal center initiation, maintenance, and function

Cold-blooded vertebrates evolved organized germinal center–like structures

450 million years in the making: mapping the evolutionary foundations of germinal centers

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