Evolution of Th2 Immunity: A Rapid Repair Response to Tissue Destructive Pathogens

Abstract

Throughout evolutionary history, animals have faced attack byfellow metazoans, often resulting in damage to tissues. This cantake the form of a worm migrating to find its reproductive niche oreating host tissue for food, or even the bite of an insect. A pro-inflammatory oxidative-type of immunological attack, typicallyutilized against intracellular microbes, can in some cases kill thesemulticellular parasites [1], but because worms and insects cannotbe contained within a single cell, the collateral tissue damage thatwill result from such an attack could seriously compromise hostfitness. During the course of evolution, the most cost-effectiveapproach to deal with very large foreign invaders may have beento tolerate them and quickly repair any tissue damage thatcompromised fitness [2,3]. In this scenario, Th1 immunitycharacterized by IFN-c production evolved to control our innateanti-microbial pathways, while the host defense system thatevolved to cope with metazoan parasites was the innate tissuerepair process, now controlled by Th2 cells. Th2 cells subsequentlyevolved additional mechanisms to contain or even expel theoffending element and produce cytokines such as IL-4, IL-5, IL-10, and IL-13 that promote alternative macrophage activation,eosinophil maturation and recruitment, and IgE production, toname just a few [4]. Many of these Th2 processes promote the‘‘walling off’’ of large bodies through granuloma formation andmatrix deposition, which would quite naturally follow frommechanisms evolved to close open wounds.Evolutionary hypotheses are difficult to prove, but murinestudies of helminth infection provide ‘‘modern’’ evidence thattissue repair orchestrated by Th2 cells is a primary host defenseagainst metazoa. As illustrated in Figure 1 for Schistosoma mansoni,metazoan invaders literally tear through important barriers, ofteninducing micro-hemorrhages and tissue damage in multiple organsas they complete their life cycle (Figure 1). Strikingly, S. mansoniinfection of IL-4Ra-deficient animals that lack most Th2 effectorresponses results in lethal sepsis once eggs produced in themesenteric blood vessels cross the intestinal wall [5]. This suggeststhat IL-4Ra-mediated pathways are critically needed to maintaingut integrity and prevent leakage of luminal dwelling bacteria intothe blood. A similar scenario plays out during infections with manygut nematodes, with broad-spectrum antibiotics providing at leastpartial protection from sepsis when IL-4Ra-driven barrierimmunity is impaired [6].The cardinal features of adaptive immunity are memory andantigen-specificity. Since Th2 cells are part of the adaptiveimmune system, this raises the question of why we need to‘‘remember’’ to repair the wounds that are induced by specificparasites. A hookworm causes bleeding as it migrates through thelung and then penetrates the gut wall to feed. A parasite-specificmemory Th2 cell might accelerate wound closure, significantlyreducing detrimental effects on secondary exposures. Indeed,adaptive immunity and memory may be equally important fortolerance mechanisms that minimize host damage as they are forresistance to the pathogen itself [3,7]. To date, no experimentshave directly addressed whether wounds repair faster on asecondary encounter with the same injuring agent. However,there is evidence to suggest that hemorrhaging is reduced onsecondary infection with lung-migrating nematodes (GrahamLeGros, personal communication).Helminths, the best-described inducers of Th2 cytokines,include parasites from animal phyla that diverged over a billionyears ago, and increasing evidence suggests that insect bites arealso Th2-inducers [8,9]. Thus, it appears that we are hard-wiredto mount Th2 responses to an attack by any metazoan pathogen.Tissue destruction is a common feature of these parasites, and weare proposing that Th2 immunity evolved as an adaptive tissuerepair mechanism that quickly heals the wounds they inflict. Theseevolutionary principles, if true, must apply beyond mammals.Infection of Atlantic salmon with sea lice causes gross skin lesionsthat must be rapidly healed, as any break can result in osmoticshock in the aqueous environment. Activated Th2 cells migrate tothe site of attachment and may mediate essential repair of thelesion but also expulsion of the ectoparasite [10]. Importantly, ananti-wounding response is not unique to vertebrates, but one of thefitness advantages provided by the adaptive immune system mayhave been the ability to accelerate this response as needed, tomediate parasite-specific tolerance [3].