Scientists navigate uncharted waters in fish immunology research

During infection or immunization, all species of jawed vertebrates generate proteins called antibodies that bind to and neutralize pathogens. Strong and long-lasting antibody responses in warm-blooded species such as mammals are produced in secondary lymphoid microstructures (SLMs), among which germinal centers (GCs) constitute the centerpiece.

Despite the apparent absence of GCs or similar SLMs in cold-blooded vertebrates (e.g. fish), these species can mount significant antibody responses that can persist for several months. Thus, for decades, the outstanding question has been how and where antibody responses are generated in species lacking GC or analogous SLM structures.

A new study presented on the cover of the journal Scientific immunology, reconsiders the understanding of immune responses in cold-blooded species. Researchers at the University of Pennsylvania School of Veterinary Medicine (Penn Vet) have discovered, contrary to previous belief, that the induction of antibody responses in bony fish occurs in primordially organized SLMs that play roles similar to those of GCs of warm-blooded animals.

Specifically, the study identifies the formation in the spleen of large aggregates of highly proliferating B cells (the cells that produce antibodies) and T cells (the cells that help B cells produce antibodies) during infection or immunization of fish. Areas of newly induced B and T cells form near melanomacrophage centers (MMCs), which are tissue areas containing groups of dark-colored melanomacrophages where antigen is retained during infection.

These recently discovered MMC-associated lymphoid aggregates (M-LAs) contain numerous antigen-specific B cells, highlighting their key role in the immune response. Furthermore, similar to what occurs in GCs, processes of B cell clonal expansion and somatic hypermutation occur within M-LAs.

“Our results challenge the old dogma that fish do not contain specific lymphoid microenvironments in which immune responses are generated, while revealing a type of SLM previously unknown in jawed vertebrates,” said J Oriol Sunyer, corresponding author of the study and professor of immunology at Penn. Veterinarian. “This discovery has far-reaching implications for our understanding of the evolution of the immune system and its potential applications in diverse areas, from fish vaccinology to human medicine.”

The research presents a new perspective on how immune responses can be induced in vertebrates, providing new opportunities to understand the primordially conserved principles by which M-LAs and GCs function.

“For example, fish M-LAs are highly polyclonal structures, thus resembling newly identified mammalian GCs that function in polyclonal contexts,” Sunyer said. “Therefore, studying fish M-LAs is likely to shed light on the mechanisms by which polyclonal GCs and M-LAs are formed.”

From an applied perspective, these results are essential for the generation of more effective knowledge-based vaccines for fish. Disease and health management issues are one of the major obstacles to the development of the aquaculture industry in the United States and around the world.

While vaccines administered to fish have contributed enormously to the near eradication of several fish diseases, many vaccines against a number of ancient and emerging fish pathogens are ineffective due to our lack of knowledge of how immune responses are generated in these species.

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