Innate immunity: an overview

Abstract

Though sometimes portrayed as “new,” the science of innate immunity made its start more than 100 years ago. Recent progress has reflected the application of new methods to old problems. In particular, genetic dissection of innate immune pathways has been pursued with great success in model organisms. This has opened the way to an understanding of innate immune sensing. The effector arm of innate immunity has also been tackled, largely though the use of biochemical methods.

Introduction

Within this chapter, two aspects of innate immunity are discussed: the afferent (or sensing) arm, and the efferent (or effector) arm. The former field deals with how we (and all multicellular organisms) perceive infection; the latter field with how we eradicate infection. Each arm of innate immunity may further be divided into cellular and humoral components. All four topics will be discussed in turn, but to begin with, it is useful to consider afferent and efferent approaches, and their separate historical roots. Efferent and afferent systems were investigated independently, by workers who used entirely different tools.

As to the afferent arm, the modern field of innate immunity, with its intense concern over how microbes are sensed, is very much linked to the older field microbial pathogenesis. When Pasteur and Koch independently propounded the germ theory of disease, they declared that microbes caused all infections. The implicit corollary to this decree was the fact that however complex the observable events in an infection might be, they must ultimately be traceable to specific molecular components of microbes. It did not take long for investigators to focus their attention on the microbial “poisons” that gave infections their nefarious character. In the fullness of time, it became clear that the innate immune system itself is what makes microbes poisonous, for in its attempt to combat infection, the host may harm its own tissues and undermine its own survival.

Microbial poisons had been approached in the pre-microbial era. Von Haller and later Magendie (for reviews, see Rietschel and Westphal (1999), Beutler and Rietschel (2003)) had investigated the toxic properties of putrefied organic material (extracts of rotten meat or fish) in the hope of understanding why putrescence had such severe systemic effects when it occurred in vivo, as in a gangrenous limb. These earliest workers did not attempt to purify a toxin, but established its existence. Later, “sepsin,” (Von Bergmann, 1868, Von Bergmann, 1872) was isolated as a molecular derivative of the remnants of beer fermentation, and so may have been derived from yeast, bacteria, or plant residue. It was purportedly crystallized, and was found to be toxic both to dogs and frogs, causing intestinal hemorrhage and fever. Still later (Panum, 1874), the so called “putrid poison” was isolated from infected tissues: a substance that was alcohol insoluble, heat stable, and purified through a series of purification steps that would likely have retained what we now call “endotoxin,” or lipopolysaccharide (LPS).

Because of its stability, the ease with which it could be purified, and the potency of its biological effects, endotoxin offered an important inroad into the decipherment of innate immune sensing, as described below. It was Pfeiffer who gave endotoxin its name (Pfeiffer, 1892). Working in the post-microbial era, and starting with pure cultures of Vibrio cholerae, he noted that even animals immunized against the bacteria would succumb to its inoculation, though no viable organisms could be retrieved from their bodies afterward. He found that a heat-stable derivative of the microbes could induce fever and shock in guinea pigs, and this principle, he reasoned, was responsible for the symptoms observed during an authentic infection. Several decades were to pass before LPS was chemically characterized (Nikaido, 1962, Osborn, 1963, Raetz and Whitfield, 2002), and before it was realized that LPS was a surface component (Osborn et al., 1974, Nikaido et al., 1966) of virtually all Gram-negative (but not Gram-positive) bacteria.

The story of LPS was to some degree mirrored in the later determination that many other components of microbes were toxic to the host. Among these were peptidoglycan, lipoteichoic acid, DNA (which is unmethylated in microbes and therefore structurally distinguishable from host DNA), and dsRNA (produced in abundance by many viruses; even DNA viruses, which commonly produce bi-directional transcripts). Moreover, the toxicity of LPS was seen to be only one of its biological properties. In small doses, LPS exerted a “cross protective” effect, rendering animals resistant to subsequent challenge with virulent pathogens. LPS also had a strong adjuvant effect, and it had long been known that many microbes (most notably mycobacteria) would help to generate a strong response to a co-injected protein antigen (Condie et al., 1955b).

As to the effector arm of innate immunity, Hunter first recognized leukocytes at the site of inflammation in 1774 (Silverstein, 1979). However, the observations of Metchnikoff, who witnessed the engulfment of particulate dyes and fungal spores by “wandering cells” in invertebrates in 1882 and announced his cellular theory of immunity in 1884 (Metchnikov, 1884), must be taken as a starting point in the functional analysis of innate immune cells. By 1890, Massart and Bordet had shown that injured cells release chemical substances that attract phagocytes, and by 1917, time-lapse cinematography had given a more tangible reality to the phenomenon of chemotaxis.

As Metchnikoff made his observations, the science of adaptive immunity had begun to flourish independently, and there was initially much controversy between “cellularists” and “humoralists” as to which system of host defense was the most important in vertebrates, and particularly in humans. To some extent, the conflict was resolved in 1903 by the finding that antibodies fulfill an opsonizing function (Wright et al., 1903), and when Ehrlich and Metchnikoff shared the Nobel Prize in Physiology and Medicine in 1908, the cooperative interactions between innate and adaptive immunity were emphasized by the Royal Swedish Academy (Mörner, 1908). Nonetheless, for a time, the science of innate immunity was eclipsed by the science of adaptive immunity, in part because cell-based defenses were much harder to analyze. Only in 1966, with the demonstration (Holmes et al., 1966) that a discrete mutational defect of effector function could cause a severe immunodeficiency disease, was a genetic foothold gained for the study of innate immunity, and only with the development of modern genomic tools was it possible to understand the central sensing mechanism by which innate immune cells “see” the world.

All the while, there were those who felt that neither cellular nor humeral immune components per se were of prime importance to the inflammatory response. For example, the “rubor” of inflammation was ascribed to a primary vascular effect, promoting the leakage of humeral components into the tissue (Cohnheim, 1873). The idea has some justification, and in light of modern knowledge, it is clear that there is much interplay between leukocytes and the vascular wall. But all this merely begs the question as to just what innate immunity is: where it starts and where it ends.

All metazoan organisms have evolved complex immune defense systems, used to repel invasive microbes that would parasitize or kill them. These immune systems are remarkably effective insofar as severe or sustained infections are quite rare. They are imperfect in that serious infections sometimes do occur, and also, in that immune responses may sometimes injure the host. Innate immunity is the most universal, the most rapidly acting, and by some appraisals, the most important type of immunity. Most organisms survive through innate immune mechanisms alone; only in vertebrates have alternative systems for pathogen recognition and elimination, collectively called adaptive immunity, been evolved.

As a topic for investigation, innate immunity is enormously broad, and it is sometimes difficult to decide where the innate immune system ends and the rest of the host begins. In part, this is because innate immune mechanisms are dynamic on an evolutionary time scale. The host population is shaped by the selective pressures that microbes impose, and survives as best it can. On occasion, proteins that clearly evolved to fulfill a task unrelated to host defense are co-opted to kill pathogens. To cite one example of this, it is well known that a coding variant of the human β-globin chain gives rise to HbS (sickle hemoglobin). The mutation responsible for HbS has achieved a high frequency in some human populations because of the selective pressure imposed by Plasmodium falciparum: a virulent pathogen that began to infect humans only a few thousand years ago. HbS provides heterozygotes with dominant resistance to P. falciparum, because infected erythrocytes sickle and are removed by the spleen. Is hemoglobin, at least as it is modified by this mutation, a component of the innate immune system? Perhaps, but it is not a core element of the innate immune system, and not utilized for any immune purpose by most organisms.

The core elements of the innate immune system were, for the most part, fixed in the tree of life hundreds of millions (in some cases billions) of years ago, and hence, are broadly represented. While it is sometimes considered that innate immunity is “primitive” or “crude” compared to adaptive immunity, the opposite is true: in fact, the innate immune system has been refined for a longer period of time than the adaptive immune system, and is more perfect in almost every way.

It is widely considered that any “true” immune system, however advanced or primitive, must be capable of doing three things:

• Recognition of a diverse array of pathogens.

• Killing these pathogens once they are recognized.

• Sparing tissues of the host (i.e. there must be self-tolerance).

The innate immune system solved these problems long ago, and vestiges of the original innate immune “battle plan” may be seen in all advanced life forms today. The adaptive immune system, arising as it did in the context of a functioning innate immune system, managed to achieve the same ends, but did so in a very different way. The adaptive immune system was something of a luxury, since a high level of protection was already provided by the innate system that preceded it. The early events through which adaptive immunity became permanently engrafted within the vertebrate line, ultimately intermeshing with the innate immune system and complementing it, are among the greatest mysteries with which biology must contend.

The principal components of the innate immune system include cellular and humoral elements, each of which is endowed with afferent and efferent arms as discussed above (Fig. 1).