Review
Evolution of immune systems from self/not self to danger to artificial immune systems (AIS)

https://doi.org/10.1016/j.plrev.2009.12.001Get rights and content

Abstract

This review will examine the evolution of immune mechanisms by emphasizing information from animal groups exclusive of all vertebrates. There will be a focus on concepts that propelled the immune system into prominent discourse in the life sciences. The self/not self hypothesis was crucial and so was the concern for immunologic memory or anamnesia, development of cancer, autoimmunity, and clonal selection. Now we may be able to deconstruct clonal selection since it is not applicable in the sense that it is not applicable to invertebrate mechanisms. Clonal selection seems to be purely as all evidence indicates a vertebrate strategy and therefore irrelevant to invertebrates. Some views may insist that anthropocentric mammalian immunologists utilized a tool to propel: the universal innate immune system of ubiquitous and plentiful invertebrates as an essential system for vertebrates. This was advantageous for all immunology; moreover innate immunity acquired an extended raison d'être. Innate immunity should help if there would be a failure of the adaptive immune system. Still to be answered are questions concerning immunologic surveillance that includes clonal selection. We can then ask does immunologic surveillance play a role in the survival of invertebrates that most universally seem to not develop cancer of vertebrates especially mammals; invertebrates only develop benign tumor. A recent proposal concerns an alternative explanation that is all embracing. Danger hypothesis operates in striking contrast to the self/not self hypothesis. This view holds that the immune system is adapted to intervene not because self is threatened but because of the system's sense of danger. This perception occurs by means of signals other than recognition of microbial pattern recognition molecules characteristic of invertebrates. Response to danger may be another way of analyzing innate immunity that does not trigger the production of clones and therefore does not rely entirely on the self/not self model. The review will end with certain perspectives on artificial immune systems new on the scene and the product of computational immunologists. The tentative view is to question if the immune systems of invertebrates might be amenable to such an analysis? This would offer more credence to the innate system, often pushed aside thus favoring the adaptive responses.

Introduction

When we think about or hear the immune system, our first reaction in the minds of most people (immunologists; non-immunologists) is to think that the immune system only helps humans and protects them from infection that may include viruses, bacteria, fungi and parasites. This is only partially true for several reasons. First, our immune system rarely acts alone but functions in association with the other two linked regulating systems (the nervous and endocrine systems; not to be examined in this review). Second, when we examine the immune systems close up, there are several generalizations that emerge. The immune system is ubiquitous, found in all creatures including plants and is therefore not restricted to humans (Fig. 1) [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13]. Every living being possesses an immune system and this is not to exclude the ubiquitous viruses that also struggle for survival by a kind of protection akin to an immune system, functioning appropriately for their level of evolution. Third, beginning with single cells including the one-celled amoeba and at every animal “lower” levels of evolution, we can see mechanisms that ensure their survival: Moving further, the immune system, if carefully traced stepwise during evolution treating extremely limited fossil forms, reveals progressively more complex development after we critically examine various levels of plant and animal evolution.

This aspect of analyzing immune systems concerns a greater emphasis and preoccupation with the human immune system. As a result much of the fascination of sequential development is excluded. Thus only in rare instances as will be revealed in this section do a few comparative immunologists focus on certain representative animal groups. This approach reveals a myriad of intriguing adaptations that in the end help to clarify what may have happened as the human immune system developed during evolution. Simply stated, levels of biological evolution reveal concomitant tiers of immune complexity during evolution of immune responses. A prime example concerns the unicellular amoeba. Because of its essential structure, the nature of its form must combine, perforce, all functions essential for life into one structure, the single cell. The amoebas' act of phagocytosis is both a food getting apparatus and a unicellular immune response! So then what remains in higher animals, including humans? The human phagocytes of various kinds owe their phylogenesis and ontogenesis to the amoeba. Every available space in the body is guarded by a phagocyte whose location carries unique names, e.g. macrophages, neutrophils, antigen presenting cells, and even the microglia found in the brain; this ensures an enormous immuno-physiological network that serves as this ubiquitous linkage between the immune, nervous, and endocrine systems. The immune system is one example that reveals levels of organization and complexity. These systems mirror the organization, components and functionally diverse strategies that provide ubiquitous surveillance that ensures survival.

Perlovsky poses a pervasive and difficult question that challenges the utility of the immune system in relation to survival “Why deadly diseases exist from an evolutionary viewpoint? Some diseases, e.g. Influenza are clear; the disease agents are multiplying inside the host. But why cancer exists? The host dies and cancer agents (if they exist) die with the host. It may be a malfunction of the organism”? [14]. Here are possible responses. One of the prevailing views concerning the evolutionary pressures that gave rise to the immune system centers around immunologic surveillance as proposed by Burnet [15]. According to this view, host animals are exposed to pathogenic organisms from the exterior and the immune systems evolve to protect against these harmful intruders. Yet we all know that there are microorganisms that live within us and seem to play no role in spreading a particular disease or killing us. Then, according to the surveillance view, there are some other explanations for evolution of immune systems. According to surveillance, cancer poses an internal threat, in which cells no longer become recognizable as self (self/not self model) and therefore become cancerous and out of control. In this instance, the driving force for evolution of the immune system could be to effectively keep potentially cancerous cells in check, not allowing their uncontrolled metastases.

Still, we are faced with the monumental problem of understanding innate vs. adaptive immunity. Why? On the one hand, there are millions of invertebrate animals that are known to not develop cancer, but they are vulnerable to pathogens, and they have a highly effective innate immune system. By contrast, all vertebrates with a progressively well-developed adaptive immune systems all develop some form of cancer. We can therefore ask the question, “is it better for animal survival to have an innate system and be free from cancer OR possess the highly evolved adaptive system and fall vulnerable to cancer?” Here are several possible explanations derived exclusively from two diametrically diverse groups: mammals and flies that emphasize similarity in gene controlled responses to metabolic changes that are often associated with obesity, longevity and cancer, the current point. These points do lend credence to and may help clarify the question of Perlovsky.

According to Slattery and Fitzpatrick [16], “Colorectal cancer (CRC) is a multifactorial disease with several hypothesized etiologic factors including inflammatory processes; hormones such as estrogen, androgen, and insulin; and energy-related factors. They have integrated this evidence in a pathway which they refer to as the convergence of hormones, inflammation, and energy-related factors (CHIEF). First, given the physiology of the gut, substantial epidemiologic and molecular data support the hypothesis that activation of innate immunity in the normal gut mucosa by various environmental agents (commensal bacteria, dietary antigens, mucosal irritants, pathogens) and endogenous factors such as estrogen, androgens, and insulin levels provoke basal inflammation as an underlying factor for the association of insulin, estrogen, and energy-related factors with CRC. Second, critical genes involved in this pathway, e.g., phosphatase tensin homologue on chromosome 10 (PTEN) and serine threonine kinase 11 (STK11)/LKB1, are tumor suppressor genes often mutated in intestinal cancer or CRC. Third, results from laboratory experiments reveal that cellular PTEN and STK11/LKB1 tumor suppressor enzymes are vulnerable to inactivation by redox-active species, especially chemically reactive lipid mediators of inflammation and redox stress. Epidemiologic results add more support to the underlying proposal that CHIEF comprises important elements of CRC risk. They suggest that a similar CHIEF pathway, although focusing on CRC, may also play an important role in the etiology of other cancers.” This explanation pertains to vertebrates, especially humans.

Now to maintain a balance of possible explanations by inclusion of a well-known invertebrate model, Zhang et al. [17] agree that insulin/insulin-like growth factor signaling regulates homeostasis and growth in mammals and is implicated in diseases from diabetes to cancer. In the well-known fruit fly, Drosophila melanogaster, a mainstay model in all of biology, as perhaps in other invertebrates, multiple insulin-like peptides (Dilps) are encoded by a family of related genes. To assess Dilps' physiological roles, they generated small deficiencies that uncover single or multiple dilps, generating genetic loss-of-function mutations. Deletion of dilps1–5 generated homozygotes (homozygotic flies) that are small, severely growth-delayed, poorly viable and fertile. These flies display reduced metabolic activity, decreased triglyceride levels and prematurely activate autophagy, indicative of “starvation in the midst of plenty,” a hallmark of type-I diabetes. In addition circulating sugar levels are elevated in Df[dilp1–5] homozygotes during eating and fasting. In contrast, Df[dilp6] or Df[dilp7] flies showed no major metabolic defects. It is interesting to speculate on the physiological differences between mammals and insects that may explain the unexpected survival of lean, ‘diabetic’ flies. However, this is not so unlike the situation in mammals where diabetes caused by obesity may open a floodgate of metabolic diseases.

Once again, more information is derived from flies [18]. “In metazoans, [there are] factors associated with the insulin family [that] control growth, metabolism, longevity, and fertility in response to environmental cues. [As in the other system,] in Drosophila, a family of seven insulin-like peptides, called Dilps, activate a common insulin receptor. Some Dilp peptides carry both metabolic and growth functions, raising the possibility that various binding partners specify their functions. To test this assumption, they identified dALS, the fly ortholog of the vertebrate insulin-like growth factor (IGF)-binding protein acid-labile subunit (ALS), as a Dilp partner. It forms a circulating trimeric complex with one molecule of Dilp and one molecule of Imp-L2, an IgG-family molecule distantly related to mammalian IGF-binding proteins (IGFBPs). In addition, that also found that dALS antagonizes Dilp function to control animal growth as well as carbohydrate and fat metabolism. These interesting results inspired by Arquier et al., to propose an evolutionary explanation or pathway. Briefly this view proposes that ALS function appeared prior to the separation between metabolic and growth effects that are associated with vertebrate insulin and IGFs.”

Section snippets

Biology the earliest ancestor

Biology is a vast discipline that has a long history punctuated by important changes in thought, approaches and applications. The history of biology can be traced to analyses of the living world from ancient to modern times [19], [20]. Although the concept of biology as a single coherent field arose in the 19th century, the biological sciences emerged from traditions of medicine and natural history reaching back to the ancient Egyptians. However, the greatest opening after centuries of change

Self vs. non-self

“In the beginning”…“Once upon a time”… . Self, not self became and remained the unchallenged dictum that guided the searches of 20th century experimental immunologists especially those interested in evolution. Now in the 21st century we have moved in other directions and are guided by newer and perhaps prescient flashes of imagination and maybe even genius. Perhaps that was and is only natural since the essence of the first split giving us the cellular component of the two armed immune systems

Animal kingdom: relevance of species in immunological research

A brief description of the animal world is instructive for this review since advances in current understanding; the mechanisms usually focus on mammals, mice and humans with no particular emphasis on what happens in other vertebrates (fish, amphibians, reptiles, birds). Certain invertebrates have played critical roles and contributed enormously to deciphering the intricacies of the immune system including those that are important such as earthworms [animals where there is first evidence of

Acquired immunity in prokaryotes: the ultimate in evolutionary precursors?

It is appropriate to offer another definition crucial for understanding origins of self/not self, memory and the concepts of clonal selection, tolerance, etc. CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) are direct repeats found in the DNA of many bacteria and archaea. These repeats range in size from 24 to 48 base pairs. They usually show some dyad symmetry but are not truly palindromic. The repeats are separated by spacers of similar length. Spacers are usually unique in

Unicellular colonial protozoans

How multicellular animals evolved from a protozoan ancestor is relevant to immunity and clearly a central question in animal evolution [33]. In order to answer this question, there are two possibilities: the first approach to animal origins is to determine which developmental proteins may have predated them and may have been subsequently co-opted for their development. Second, another strategy to explore involves competitive genomics a technique that can identify the minimal set of intact genes

Protostomes and deuterostomes: increased immune complexity

“Among higher animals, there are two basic divisions, the protostomes and the deuterostomes. Early in the development of these animals, they undergo a process called gastrulation. Originally a ball of cells one layer thick, the embryo develops a second layer by making an indentation that goes deep enough to form a tube right through the embryo. This tube later forms the digestive tract. The hole that forms first from the gastrulation is called the blastopore. What makes the protostomes and the

Danger? Going against the grain?

For essentially all of its 20th century life, immunology has grown and been propelled by a single penetrating explanatory force: self/not self. Recently, immunologists have argued that self/not self is irrelevant and that it actually detects “danger” or “strangers.” Both of these viewpoints present problems. Since the immune system has been pieced together throughout evolution and utilizes a vast compendium of innate and adaptive defense mechanisms, it is now possible to define immunity more

Innate immunity in a moth Galleria mellonella

Here is an insect system where experimental results support the danger theory. Altincicek et al. [68] have worked with thermolysin-like metalloproteinases such as aureolysin, pseudolysin, and bacillolysin that represent virulence factors of diverse bacterial pathogens. Injection of thermolysin into larvae of the greater wax moth, Galleria mellonella, mediated strong innate immune responses. Thermolysin-mediated proteolysis of hemolymph proteins yielded a variety of small-sized (<3 kDa) protein

An exemplary model of granulocyte reactions that support danger

Now we explore a model where adaptive immunity is the rule. Moving now to a human system, eosinophilic granulocytes occur in tissues found at interfaces with the external environment, e.g. the gastrointestinal, genitourinary and respiratory tracts [70]. According to Stenfeldt and Wennerȧs, the second most numerous of human leucocytes is often associated with tissue damage in various diseases. In a simple but elegant experiment, these investigators evaluated whether necrotic epithelial cells can

Advantages of danger

Agreeing with Vance [52], there is compelling evidence that adaptive and innate systems do blur. For comparison, it is well to begin with the adaptive in order to dispel or even diffuse partiality so the problem does not focus overwhelmingly on the innate. Vance explained: “The underlying delusion is that immune responses obey a small set of laws like the movements of the planets obey the law of gravity. The danger theory even proposes to encompass immunity in just three “Laws of Lymphotics.”

Recombinatorial rearrangement gives rise to antigen receptor genes

According to Cooper and Alder [93], a clonally diverse anticipatory repertoire in which each lymphocyte bears a unique antigen receptor is the central feature of the adaptive immune system that evolved in our vertebrate ancestors. The survival advantage gained through adding this type of adaptive immune system to pre-existing innate immune systems led to the evolution of alternative ways for lymphocytes to generate diverse antigen receptors for use in recognizing and repelling pathogenic

The quagmire of definitions, innate vs. adaptive immunity, that is the question

Despite these just reviewed, more conciliatory assertions of comparative immunologists who work with vertebrates, there are by contrast strong cautionary assertions from invertebrate immunologists Hauton and Smith [95]. Recently claims have been made for radical new insights in the field of invertebrate immunology that involve memory, specificity and/or maternal transfer of immunocompetence, all hallmarks of vertebrate type adaptive immunity. For evidence these claims rely on phenomena, such as

Narrowing the gap

Pham et al. [99] present new interpretations with respect to specificity and memory. Drosophila melanogaster, like other invertebrates, relies solely on its innate immune response to fight invading microbes; by definition, innate immunity lacks adaptive characteristics. However, they reveal that priming Drosophila with a sub-lethal dose of Streptococcus pneumoniae protects against an otherwise-lethal second challenge of S. pneumoniae. This protective effect exhibits coarse specificity for S.

Negative selection, clonal selection and immune networks

It is not often that ideas such as artificial immune systems are treated at least superficially for now along with evolution of immune systems where there still reigns an impenetrable strict demarcation between innate and adaptive immunity that is not artificial. The essential reason for AIS recognizes experts in the discipline who are farsighted with respect to novel ideas that may fit alongside evolution and therefore the implication for interdisciplinary research is more biologically

What is the quantal theory of immunity?

Finally, the question, exactly how the immune system discriminates between all environmental antigens to which it reacts vs. all self-antigens to which it does not, is a principal unanswered question in immunology [107]. Because of advances in understanding the immune system that have occurred in the last 50 years, for the first time it is possible to formulate yet a new theory only superseded by the danger theory, termed the “Quantal Theory of Immunity,” which reduces the problem from the

Will the danger model accommodate invertebrate and vertebrate immunity?

According to Noble, recognition of specific protein antigens leads to immunological memory of antigen, whereas recognition of danger signals by the innate immune system determines the size, nature and longevity of a response [110]. Recent data indicate that recognition of danger might have long-lasting effects on CD8 memory T-cell populations, specifically enhancing early cytokine release and thus altering the nature of subsequent immune responses. Here, a modified model of immune regulation is

Perspectives

Has this been an appropriate tribute to Metchnikoff whose work inspired a 20th century group of comparative and invertebrate immunologists? And now we can add another view. The danger model will do much to broaden and enrich horizons without sacrificing established “sacred tenets” such as self/not self, clonal selection. These were essential to a fledging discipline that began its fluorescence in the early 1960s [111], [112], [113], [114], [115], [116] propelled immunologists this far. There is

Acknowledgements

I express appreciation to Jesus Heredia and Lok-Hin Law for assistance in preparing this manuscript. Expressions of gratitude are due to my friends and colleagues at the University of Pecs who contributed immeasurably to the formulation of Fig. 1, Fig. 2, Fig. 3.

Glossary

Adaptive immune system
highly specialized, systemic cells and processes that eliminate or prevent pathogenic challenges. Thought to have arisen in the first jawed vertebrates, the adaptive or “specific” immune system is activated by the “non-specific” and evolutionarily older innate immune system (which is the major system of host defense against pathogens in nearly all other living things). The adaptive immune response provides the vertebrate immune system with the ability to recognize and

References (119)

  • H. Liu et al.

    Antiviral immunity in crustaceans

    Fish Shellfish Immunol

    (2009)
  • I. Söderhäll et al.

    A novel protein acts as a negative regulator of prophenoloxidase activation and melanization in the freshwater crayfish Pacifastacus leniusculus

    J Biol Chem

    (2009)
  • M. Larkin et al.

    Immunology's dangerous thinker

    Lancet

    (1997)
  • M.F. Flajnik et al.

    Evolution of innate and adaptive immunity: Can we draw a line?

    Trends Immunol

    (2004)
  • G.W. Litman et al.

    New insights into alternative mechanisms of immune receptor diversification

    Adv Immunol

    (2005)
  • N.C. Franc et al.

    Croquemort, a novel Drosophila hemocyte/macrophage receptor that recognizes apoptotic cells

    Immunity

    (1996)
  • S.-M. Zhang et al.

    The FREP gene family in the snail Biomphalaria glabrata additional members, and evidence consistent with alternative splicing and FREP retrosequences

    Dev Comp Immunol

    (2003)
  • M.F. Flajnik et al.

    Evolution of innate and adaptive immunity: Can we draw a line?

    Trends Immunol

    (2004)
  • P. Engelmann et al.

    Earthworm leukocytes react with different mammalian antigen-specific monoclonal antibodies

    Zoology (Jena)

    (2002)
  • P. Engelmann et al.

    Anticipating innate immunity without a Toll

    Mol Immunol

    (2005)
  • P. Engelmann et al.

    Monoclonal antibodies identify four distinct annelid leukocyte markers

    Dev Comp Immunol

    (2005)
  • P. Engelmann et al.

    Earthworm leukocytes kill HeLa, HEp-2, PC-12 and PA317 cells in vitro

    J Biochem Biophys Methods

    (2004)
  • S. Koenig et al.

    Mass spectrometric analyses of CL39, CL41 and H1, H2, H3 confirm identity with fetidin and lysenin produced by earthworm leukocytes

    Dev Comp Immunol

    (2003)
  • C.R. Davidson et al.

    Toll-like receptor genes (TLRs) from Capitella capitata and Helobdella robusta (Annelida)

    Dev Comp Immunol

    (2008)
  • M.D. Cooper et al.

    The evolution of adaptive immune systems

    Cell

    (2006)
  • J. Kurtz

    Specific memory within innate immune systems

    Trends Immunol

    (2005)
  • T. Tanji et al.

    Regulators of the Toll and Imd pathways in the Drosophila innate immune response

    Trends Immunol

    (2005)
  • E.L. Cooper
  • K. Kvell et al.

    Blurring borders: Innate immunity with adaptive features

    Clin Dev Immunol

    (2007)
  • E.L. Cooper

    From Darwin and Metchnikoff to Burnet and beyond

    Contrib Microbiol

    (2008)
  • E.L. Cooper

    Comparative immunology

    (1976)
  • E.L. Cooper

    Immunity in invertebrates

    CRC Crit Rev Immunol

    (1981)
  • E.L. Cooper
  • E.L. Cooper
  • E.L. Cooper
  • M.H. Mansour et al.
  • E.L. Cooper
  • E.L. Cooper

    L'evolution de l'immunite

    La Recherche

    (1979)
  • E.L. Cooper et al.

    Invertebrate immunity: Another viewpoint

    Scand J Immunol

    (1992)
  • Perlovsky L. Personal...
  • F.M. Burnet

    Immunological surveillance

    (1970)
  • M.L. Slattery et al.

    Convergence of hormones, inflammation, and energy-related factors: A novel pathway of cancer etiology

    Canc Prev Res

    (2009)
  • H. Zhang et al.

    Deletion of Drosophila insulin-like peptides causes growth defects and metabolic abnormalities

    Proc Natl Acad Sci USA

    (2009)
  • J. Needham

    A history of embryology

    (1959)
  • E. Mayr

    Evolution and the diversity of life

    (1976)
  • S.J. Gould

    Ontogeny and phylogeny

    (1977)
  • E.L. Cooper et al.

    Digging for innate immunity since Darwin and Metchnikoff

    Bioessays

    (2002)
  • Ribatti D. Sir Frank Macfarlane Burnet and the clonal selection theory of antibody formation, Clin Exp Med (2009) [Epub...
  • A.M. Silverstein

    A history of immunology

    (1989)
  • A.I. Tauber et al.

    Metchnikoff and the origins of immunology: From metaphor to theory

    (1991)
  • Cited by (0)

    View full text