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Unveiling the Secrets of Immune Response in Fish

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By Milthon Lujan

Intense IgM+ B cell proliferation occurs nearby splenic melanomacrophage centers (MMCs) upon infection. (A and B) Immunofluorescence analysis of EdU incorporation by cells of spleen from control (A) or infected fish (B). Spleen cryosections were stained for EdU (magenta) and IgM (green). Groups of dark cells in all images represent MMCs. White circles in (B) outline MMC-adjacent areas with high cell proliferation. Credit: Yasuhiro et al., Science Immunology (2023). DOI: 10.1126/sciimmunol.adf1627
Intense IgM+ B cell proliferation occurs nearby splenic melanomacrophage centers (MMCs) upon infection. (A and B) Immunofluorescence analysis of EdU incorporation by cells of spleen from control (A) or infected fish (B). Spleen cryosections were stained for EdU (magenta) and IgM (green). Groups of dark cells in all images represent MMCs. White circles in (B) outline MMC-adjacent areas with high cell proliferation. Credit: Yasuhiro et al., Science Immunology (2023). DOI: 10.1126/sciimmunol.adf1627

In the intricate world of immunology, the evolution of adaptive immune responses in ectothermic species has long puzzled scientists.

After infection or immunization, all jawed vertebrates generate proteins called antibodies that bind to pathogens, neutralizing them. Robust and lasting antibody responses in warm-blooded species, such as mammals, occur in secondary lymphoid microstructures (SLM), with germinal centers (GC) at their core.

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Once thought exclusive to endothermic species, an innovative study has uncovered highly organized analogous secondary lymphoid microstructures (SLM) in ectothermic vertebrates, such as fish, challenging the conventional understanding of this crucial immunological component.

In a compelling feat, an international team of scientists from the University of Pennsylvania’s School of Veterinary Medicine, Nihon University, I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, and the University of Santiago de Compostela infected trout with the Ichthyophthirius multifiliis parasite, triggering a robust secondary antibody response in bony fish occurring in SLM, akin to the functions of GCs in warm-blooded animals.

Absence of GCs in Cold-Blooded Animals

Despite the apparent absence of GCs or analogous SLMs in ectothermic species, the study reveals that living representatives of cold-blooded vertebrates can orchestrate robust adaptive immune responses upon infection or immunization. The key question arises: How and where are these responses induced in the absence of conventional immune structures?

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The Discovery: Melanomacrophage Centers (MMCs) and M-LAs

The researchers infected trout with Ich and observed a fascinating phenomenon: the formation of large aggregates of highly proliferating IgM+ B cells and CD4+ T cells. These aggregates, termed Melanomacrophage Center-associated Lymphoid Aggregates (M-LAs), were found contiguous to melanomacrophage centers (MMCs) in the spleen. Most importantly, these M-LAs contained numerous antigen-specific B cells, indicating a localized and organized immune response.

Highly Polyclonal SLMs in Ectotherms

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Analysis of the IgM heavy chain CDR3 repertoire within the splenic M-LAs revealed highly shared B cell clones induced specifically after Ich infection. These M-LAs represented highly polyclonal secondary lymphoid microstructures, analogous to GCs found in warm-blooded species. The findings suggest that ectotherms have evolved organized SLMs with GC-like roles, challenging the conventional understanding of immune responses in cold-blooded vertebrates.

Conserved Mechanisms and Evolutionary Insights

The revelations of the study go beyond the mere existence of SLMs in ectotherms. They point to primordially conserved mechanisms by which M-LAs in cold-blooded species and mammalian polyclonal GCs develop and function. The expression of activation-induced cytidine deaminase, significant apoptosis, and prevalent somatic hypermutation of Igμ genes in M-LA-associated B cells highlight parallels with warm-blooded immune responses.

“Our findings challenge the previous dogma that fish do not contain specific lymphoid microenvironments where immune responses are generated, while revealing a previously unknown type of SLM in jawed vertebrates,” said J. Oriol Sunyer, corresponding author of the study and professor of Immunology at Penn Vet.

Application in Aquaculture

From an applied perspective, these findings are fundamental for generating more effective, knowledge-based vaccines for fish. Disease management and health issues pose significant obstacles to the developing aquaculture industry in the U.S. and worldwide.

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Now that we know where and how antibody responses are induced in fish, the study of M-LA will identify correlates of activation and immune protection that will pave the way for the detection and development of more effective and safer vaccines and adjuvants for the aquaculture industry,” added Sunyer.

Conclusion

The discovery of organized SLMs in trout, with functions similar to GCs, challenges ingrained beliefs about the evolutionary trajectory of the adaptive immune system. It also provides tantalizing insights into the conservation of molecular mechanisms governing the development and function of GCs in both ectothermic and endothermic vertebrates.

Moreover, these findings underscore the remarkable adaptability of the immune system, capable of developing distinct yet effective strategies to combat pathogens across a wide range of species. The presence of GC-like SLMs in trout highlights the underlying unity of immunological principles, even amidst variable environmental conditions and physiological adaptations.

This groundbreaking study opens a new chapter in our understanding of the adaptive immune system, demonstrating that the capacity for organized immunological structures transcends the boundaries of endothermy. Further exploration of these ectothermic SLMs may unveil new insights into evolutionary foundations and molecular mechanisms governing adaptive immune responses in a broader spectrum of organisms.

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“This discovery has far-reaching implications for our understanding of the evolution of the immune system and its potential applications in various fields, from fish vaccination to human medicine,” concluded Sunyer.

The research was funded by the National Institutes of Health, U.S. Department of Agriculture, Japan Society for the Promotion of Science Overseas Research Fellowship, Japan Society for the Promotion of Science KAKENHI, and the National Natural Science Foundation of China.

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Reference (open access)
Yasuhiro Shibasaki et al., 2023. Cold-blooded vertebrates evolved organized germinal center–like structures. Sci. Immunol.8,eadf1627(2023). DOI:10.1126/sciimmunol.adf1627

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