From seabed to sickbed: lessons gained from allorecognition in marine invertebrates

Abstract

Despite decades of progress, long-term outcomes in human organ transplantation remain challenging. Functional decline in transplanted organs has stagnated over the past two decades, with most patients requiring lifelong immunosuppression, therapies that overlook the principles of self/non-self recognition and natural transplantation events in humans. To address these discrepancies, this perspective proposes that immunity evolved not as pathogen-driven but as a mechanism to preserve individuality by preventing invasion from parasitic conspecific cells. It further reveals that the concept of "self/non-self" recognition encompasses multiple theories with complex and often ambiguous terminology, lacking precise definitions. In comparisons, natural historecognition reactions in sessile marine invertebrates are regulated by a wide spectrum of precise and specific allorecognition systems, with transitive and non-transitive hierarchies. Using the coral Stylophora pistillata and the ascidian Botryllus schlosseri as models, it is evident these organisms distinguish 'self' from 'non-self' with remarkable accuracy across various allogeneic combinations, identifying each non-self entity while simultaneously recognizing selfhood through transitive allogeneic hierarchies. Their allorecognition offers an improved explanation for post-transplant outcomes by accounting for the natural dynamic, spatiotemporal evolution of selfhood. To bridge natural (in invertebrates and humans alike) and clinical transplantation phenomena, the 'allorecognition landscape' (AL) metaphor is proposed. This unified framework conceptualizes self/non-self recognition as shaped by two dynamic continuums of 'self' and 'non-self' nature. Throughout the patient lifespan, the AL represents diverse and transient arrays of specific 'self' and 'non-self' states (including reciprocal states) that shift over time in either recognition direction, requiring adaptable clinical strategies to address their evolving nature.

Keywords: allorecognition landscape; chimerism; corals; fusion; marine invertebrates; organ transplantation; self/non-self recognition; tunicates.

Figure 1

A cartoon depicting the simplest transitive (linear) and non-transitive (circular) allorecognition relationships among three conspecifics (the various colors) of the hermatypic coral Stylophora pistillata ( Figure 2a ). The colored arrows depict directionality and hierarchy of rejection outcomes.

Figure 2

The two representative marine invertebrates: (a) a colony of the branching coral Stylophora pistillata growing in the field; (b) a colony of the tunicate Botryllus schlosseri growing in the laboratory on a glass slide. Zooids (zo, each 2 mm long) form star-shaped clusters (system, st), each with a centered shared atrial siphon. The zooids are embedded in a transparent tunic(tu) containing vessels and terminal ampullae (am) of the colonial circulatory system. Buds (bd) are partially covered by adult zooids.

Figure 3

A schematic illustration showcasing the remarkable diversity and precise specificity of historecognition in the Cnidaria (represented by Stylophora pistillata; left panel) and in the Tunicata (represented by Botryllus schlosseri; right panel). Colonies of these marine invertebrates are naturally encountered in various allogeneic responses (arrowheads reveal hierarchies for the effector arms). A single invertebrate genotype is not restricted to a single mode of interaction during allogeneic encounters, thus its extensive repertoire of effector mechanisms allows for precise and specific responses to an unlimited range of 'nonself' attributes. At the bottom: shared key allogeneic properties. The S. pistillata green allogeneic interactions- suggested, not yet approved.

Figure 4

Botryllus schlosseri allorecognition. (a, b) Non-self recognition: (a) two PORs at contacting ampullae in the left colony tunic, marked by blue asterisks. (b) a close up of non-self recognition with 3 PORs at contacting ampullae in the left colony tunic, marked by white asterisks. (c, d) Resorption of the right partner in a chimera: (c) two weeks following chimera formation between two compatible young colonies. The left colony with 10 zooids, the right colony with 8 zooids. (d) several months thereafter. The right colony is completely resorbed, the left colony with two systems of functional zooids. am= ampullae.

Figure 5

A schematic illustration of the evolving ‘allorecognition landscape’ metaphor and the shifting ‘self/nonself’. The figure illustrates the dynamic nature of immunological "self/nonself" recognition (distinct from effector mechanisms) in humans with transplanted organs. This process is represented as a unified allorecognition landscape, shaped by two recognition planes or continuums (depicted in red and green). Throughout an individual's lifespan, these continuums reflect diverse arrays of specific allorecognition states, including reciprocal states of 75:25%, 50:50%, and 25:75%. These recognition states are transient and can shift over time in either direction, transitioning into various states and requiring tailored clinical considerations.