I recently had a conversation with a colleague whose research centers around animal health and immunology with a particular focus on transition dairy cows. She pointed me toward an interesting article discussing immune resilience in people (Nature Communications, 2023, 14:3286). Immune resilience (IR) is defined as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance (immunocompetence) and control inflammation in infectious diseases as well as other causes of inflammatory stress. Although the underlying reasons are poorly understood and undoubtedly complex for why some individuals remain healthier throughout life than others, this article hypothesizes that the advantage is attributable in part to optimal IR.
In some ways, this gets at the heart of last month’s newsletter article touching on immunity in transition cows. Even though the Nature Communications’ article is based on human research, it raises some interesting considerations for those of us who work with livestock. Why do individuals manifest such wide differences in lifespan, health status across age, and susceptibility to infectious disease? Given that infections are among the most impactful environmental factors shaping the genome, immune mechanisms may have evolved based on conferred resistance to the ancestral burden of inflammatory stress associated with infectious diseases. Resistance mechanisms could include higher immunocompetence and prevention of uncontrolled inflammation. For these reasons, IR is based upon three advantages:
- immunocompetence including the capacity to preserve and/or rapidly restore immune functions and control inflammation,
- a lower comorbidity burden, and
- resistance to infections.
IR is rooted in the principle that repeated inflammatory (antigenic) exposures are inevitable throughout life, necessitating allostatic processes that mediate adaptation, ideally returning immunocompetence and inflammation to optimal or pre-exposure levels. With this definition, optimal IR is linked to a conjoined high immunocompetence-low inflammation state.
The relevance of IR is built around the notion that in most individuals experiencing antigenic exposure, IR will transiently erode/degrade leading to a temporary low immunocompetence-high inflammation state. Some individuals may resist this degradation or rapidly reconstitute IR to pre-exposure levels. Consequently, there appear to be two IR phenotypes: 1) erosion-resistant signifying successful immune allostasis, and 2) erosion-susceptible signifying incomplete/unsuccessful allostasis.
This is probably a good time to revisit the word allostasis. Allostatic is derived from the Greek roots “allo-“ meaning “other” or “different” and “-stasis” meaning “standing still” or “stability”. So allostasis essentially means maintaining stability by being variable. Aside from its utility for describing IR phenotypes, I think that the concept of allostasis is a perfect fit for what we hope and expect for livestock. Their ability to adapt to changing environmental conditions, infectious pressures, and metabolic demands while remaining functionally stable is both necessary and incredible. However, not all individuals are as successful as others. This begs the question why do some individuals manifest attributes consistent with an immunosuppressive-proinflammatory state predisposing them to increased disease risks/severity and potentially premature mortality? Conversely, why do other individuals resist manifesting these attributes?
The sum of the Nature Communication’s findings suggests that optimal IR is an indicator of successful immune allostasis (adaptation) when experiencing inflammatory stressors, correlating with a distinctive immunocompetence-inflammation balance (high immunocompetence-low inflammation) that associates with superior immunity-dependent health outcomes, including longevity. However, the reality is that many individuals do not have the capacity to preserve optimal IR when experiencing common inflammatory insults such as symptomatic viral infections. Deviations from optimal IR are associated with an immunosuppressive-proinflammatory, mortality-associated gene expression profile. Those individuals with capacity to resist this deviation or who during the recovery phase rapidly reconstitute optimal IR manifest health and survival advantages. However, under the pressure of repeated inflammatory (antigenic) stressors experienced across their lifetime, the number of individuals that retain capacity to resist IR degradation declines. Individuals with residual deficits in IR (suboptimal/nonoptimal IR) have health and survival disadvantages.
Ultimately the question is how does any of this translate into applied research? I would like to believe that our ongoing research here at WSU under the FDIU umbrella will provide us with insight into something akin to dairy cow IR profiles. In fact, Lindsey Richmond is a 2nd year DVM student concurrently working on her PhD with a focus on peripheral leukocyte transcriptomic changes associated with both dairy calf respiratory disease and transition cow challenges such as metritis. Broadly speaking, the foundational principles underlying IR might prove useful for selective use of therapeutics, development of therapies to promote immune health, and targeted herd health programs. Undoubtedly, disease risks/severity and responses to therapies may differ according to IR status. Thus, early detection of individuals with IR degradation could prompt a work-up to identify the underlying inflammatory stressors. There is also the potential to develop strategies that, by targeting the IR erosion-susceptible phenotype, may improve vaccine responsiveness, healthspan, and lifespan. In fact, differences in the prevalence of IR metrics may help to explain the distributions of diseases such as viral and bacterial infections across subpopulations of animals and provide a means to gauge immune health regardless of age, sex, and underlying comorbidity. Hence, strategies for improving IR and lowering recurrent inflammatory stress may emerge as high priorities for incorporation into herd health practices. Regardless, we should never forget that individuals with suboptimal or nonoptimal IR can potentially regain optimal IR through reduction of exposure to infectious, environmental, behavioral, and other stressors.