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In biology and medicine, timing is everything. One small spark at the wrong moment can set off a chain reaction — or embed a lasting memory in tissues and cells, shaping future responses for years or even decades.
This memory can live on in the immune niche, through trained or maladaptive epigenetic changes in tissue-resident macrophages, or even in neurons through altered receptor expression and synaptic remodeling. Depending on the context, these changes can unfold over hours, days, or silently prime a system for years before revealing their true impact.
The “two-hit hypothesis” — originally proposed in cancer genetics (Knudson’s model for retinoblastoma) — has since become a versatile framework to explain complex disease processes far beyond oncology. It suggests that an initial “hit” or priming event creates a latent vulnerability, and a second “hit” later on triggers full-blown pathology.
While well established in cancer biology, its implications stretch much wider, particularly into immunology, neurobiology, and the intersections of the two.
In neurodegenerative diseases, an early inflammatory or toxic “priming” event can set the stage for later degeneration. Microglia, the brain’s resident macrophage-like immune cells, can enter a persistently reactive state after initial insults — such as systemic infections, traumatic brain injury, chronic stress, or exposure to neurotoxic proteins (like amyloid-β). Once primed, they respond more aggressively to subsequent challenges, sometimes exacerbating neuronal damage rather than protecting against it.
This “microglial priming” concept mirrors what we see in tissue-resident macrophages elsewhere — for example, in the lung, where interstitial macrophages can be epigenetically reprogrammed to adopt long-lived inflammatory or tolerogenic profiles depending on early life exposures.
Importantly, neurons themselves can also be “primed.” In sensory neurons, for instance, an early inflammatory hit can upregulate ion channels and receptors (such as TRPV1 or Nav1.7), leaving these neurons hypersensitive to future stimuli and contributing to chronic pain syndromes (Basbaum et al., 2009). Similarly, in the CNS, repeated “hits” can drive central sensitization via altered synaptic receptor expression and microglial modulation (Woolf, 2011; Salter & Stevens, 2017).
In our recent work (Kortmann et al., 2023), we identified TMC3 as a marker distinguishing lung-innervating sensory neurons. Interestingly, these neurons appear roughly equally divided into nociceptive and mechanoreceptive subtypes. One intriguing hypothesis is that early inflammatory or environmental “hits” could shift this balance — reducing mechanosensitivity (affecting normal airway reflexes) or amplifying nociceptive input, potentially priming the lung’s sensory-immune niche for hyperreactivity. While speculative, such changes in sensory neuron composition or receptor expression may represent another dimension of neuroimmune priming with long-term consequences for respiratory health.
In immunology, we see the two-hit framework in experimental inflammasome models: a priming step (such as LPS stimulation) is needed to induce expression of pro-IL-1β, followed by a second signal (like ATP) that triggers inflammasome assembly and inflammatory cytokine release.
Asthma offers a striking example from respiratory immunology: severe rhinovirus infections in infancy have been associated with higher asthma risk later in life. Early viral encounters appear to “train” the immune system toward a hyperreactive state, setting the stage for chronic airway inflammation when environmental exposures (pollutants, allergens) occur later.
Importantly, the “hits” can vary dramatically between individuals. Genetic background, ethnicity, and environmental context shape how these priming events unfold, highlighting the need for personalized approaches.
Severe systemic hyperinflammatory responses, such as cytokine release syndrome (CRS) or “cytokine storms,” illustrate another potential second hit. In these scenarios, an initial primed immune state may remain silent until a strong secondary challenge — for instance, viral infection, certain biologic therapies, or CAR-T cell infusions — unleashes a massive cytokine cascade. This “storm” can drive severe systemic symptoms, multi-organ dysfunction, and even fatal outcomes (Shimabukuro-Vornhagen et al., 2018; Fajgenbaum & June, 2020).
In patients with underlying chronic inflammation or prior tissue priming, these storms may further amplify susceptibility to complications, including neurotoxicity or organ dysfunction. Understanding and anticipating these interactions could inform strategies to modulate the immune response before it spirals into self-damage — and highlights the importance of personalized risk assessment in modern immunotherapies.
These examples illustrate a broader principle: disease risk and manifestation are not determined by single events but by sequences of experiences — each adding another layer to the immune and neural “memory.”
In personalized medicine, incorporating a patient’s immunological and environmental history — including early infections, chronic stress, or exposures to toxins — may soon become standard. We might map a person’s “priming timeline” to anticipate future vulnerabilities and design interventions that preempt disease rather than merely treat it.
Moreover, while we often think of priming as creating risk, it’s worth asking: Could we prime for resilience? The Hygiene Hypothesis suggests that early, diverse microbial exposures may protect against allergic and autoimmune conditions later in life. While encouraging kids to “get dirty” is one side, for urban settings with limited access to natural environments, future strategies might even involve “farm-like” microbial interventions to promote healthy immune maturation.
The two-hit hypothesis encourages us to move beyond static snapshots of health and disease and embrace dynamic, systems-level thinking.
By understanding the first “hit” — whether it’s an infection, trauma, or chronic stress — we gain crucial context for the second. We may begin to predict who is at higher risk for severe outcomes and develop strategies to disrupt or even reverse harmful priming before it culminates in disease.
Whether designing therapies, preventive approaches, or studying why some patients weather storms that devastate others, considering the priming history reveals hidden layers of vulnerability — and opportunity for intervention.
Exploring these questions will move us closer to true precision health — a model that doesn’t just react to disease but anticipates and reshapes its trajectory.
Let’s start thinking in sequences, not snapshots.
Published: July 10, 2025
— Jens