Scand. J. Immunol.

50, 456460, 1999

REVIEW

Invertebrates versus Vertebrates Innate Immunity: In the Light of

Evolution
(Nothing in biology makes sense except in the light of evolution T. Dobzhansky, Amer Biol Teacher 1973;35:1259)

B. RINKEVICH
National Institute of Oceanography, Tel Shikmona, P.O. Box 8030, Haifa, Israel

(Received 20 April 1999; Accepted in revised form 10 July 1999)

Rinkevich B. Invertebrates versus Vertebrates Innate Immunity: In the Light of Evolution. Scand J Immunol
1999;50:456460
Invertebrates use a nonadaptive, innate immunity, the expression of germline encoded receptors, to identify
the allogeneic and xenogeneic attributes. Vertebrates also have the capacity to express ontogenically related
adaptive immunity which is a somatically selected gene rearrangement process. Several commonly accepted
generalizations are utilized to explain the enigmatic lack of the adaptive immunity in invertebrates. All point
to the primitive nature of the innate immunity and the primitive organization of the body plan and the life
history patterns of invertebrates. Seven of the most common generalizations are reviewed and confuted by
virtue of a biased literature presentation. Subsequently, three evolutionary puzzles are raised and the accepted
paradigm that the vertebrate immunity is pathogenically directed is further challenged. This leads to an
alternative idea suggesting that preserving the individuality against the threat of invading conspecific cells
might have been the original function of the immune system. This ancient system has been co-opted later on to
serve as a defence mechanism against pathogens. The secondary role arose in the form of a multiplicity of
newly developed phenomena, one of them being the vertebrate adaptive immunity. This proposal is supported
by the fact that vertebrates still exhibit two distinct but common types of naturally occurring transplantation
events (natural chimerism) and by a variety of recent studies, providing evidence for the crucial role of the
vertebrates innate immunity in signalling and triggering the acquired effector mechanisms.
Dr B. Rinkevich, National Institute of Oceanography, Tel Shikmona, P.O. Box 8030, Haifa 31080, Israel

INTRODUCTION
In recent review essays [19] newly emerged features for the
vertebrate innate immunity have been discussed followed by
comparisons [46] of several aspects of vertebrates and the
invertebrates immunity. All essays further affirmed the paradigm which states that the most striking characterization and the
essence of the innate immunity (or as it is often called, nonadaptive or nonspecific immunity) is the deployment of germline
encoded receptors to identify noxious elements. In contrast, the
somatically selected acquired immunity is based on the gene
rearrangement processes. Both types of immune responses,
however, are involved with a multiplicity of phenomena.
Recent studies on the vertebrate immunity provide ample support
for the crucial role of the innate immunity in signalling
acquired effector mechanisms with information for the nature
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of alien antigens and for the induction and direction of

adaptive immune responses (reviewed in 2, 3, 69), contrary
to previous ideas. With these new results, the evolution of
immunity has been revisited in a manner advocating that the
innate immunity should not be envisioned anymore as an
evolutionary rudiment whose only function is to contain the
infection until the real, or adaptive immune response can be
induced [3, 6]. The simplistic notion that the innate immunity
is of importance to invertebrates but almost an irrelevance in
complex vertebrates, is therefore no longer tenable [10].
Further, this new tenet legitimately raises the old question of
why invertebrates did not develop an adaptive immunity. I will
critically examine several generalizations commonly accepted
for vertebratess versus invertebrate immune responses and
ponder over an alternative evolutionary route for the vertebrate
immunity.

Evolution of Innate Immunity

ENIGMATIC ASPECTS AND COMMONLY
ACCEPTED, BUT FLAWED, GENERALIZATIONS
From the very beginning of the study on immune responses
throughout this reductionist era, it is commonly accepted that the
evolution of immunity is pathogen directed. In other words, the
immune recognition and the related effector mechanisms were
evolutionarily selected specifically to combat infectious organisms. The contemporary fact that the immune systems are the
efficient effector arms to fight pathogenic agents makes this
assumption appear logical. There are however, in vivo and in
vitro results that differ from this line of thought. For example,
several studies surprisingly show a number of significant
findings. MHC-class I deficient mice may effectively handle
infections by intracellular the pathogens (reviewed in 11), MHCheterozygote organisms are no more resistant to the infectious
diseases than the homozygotes [11], and non-MHC antigens
(parasites, viral glycoproteins, bacteria, etc.) may stimulate an
alloreactivity at least 100-fold lower than T-cell responses to
stimulator cells which express foreign MHC antigens of allogeneic origin (reviewed in 12). Furthermore, these studies show
that infectious tolerance is a common phenomenon that can be
induced in many ways and does not require a thymus or clonal
deletion. It can spread through many generations of secondary
recipients [13]. Support from other perspectives focuses the
outcome for a variety of viral strategies of immune evasion
and the fact that more than 50 different virus genes have already
been identified as vertebrate immune modulators [14]. Additionally, there is the recent finding that we probably owe the
repertoire of our immune system to one transposon insertion
event (that carried the forerunners of the recombinase activating
genes, RAG-1 and RAG-2) which occurred in an ancestor of the
jawed vertebrates about 450 million years ago [15].
There is, in addition, another enigmatic aspect: there is no
dispute that in contemporary vertebrates the immune systems
execute cellular and humoral functions that are essential to fight
pathogens. Yet, all vertebrates also express an allorecognition,
using the same immune systems and efficiently reject the allografts, a phenomenon that seemingly never occurs in nature, and
hence, may be regarded as an evolutionary paradox. Allorecognition has been experimentally documented in a variety of
invertebrate taxa [12] and is naturally displayed in various sessile,
colonial invertebrates (reviewed in 16). Commonly accepted
generalizations produced by comparing the innate invertebrate
alloimmunity with a vertebrate acquired immunity have led to
the prediction of a number of evolutionary expectations which
attempt to interpret the enigmatic observation that invertebrates
lack somatic-selected immunity. Seven of the most popular
arguments are summarized in Table 1, revealing a biased consideration by mainstream immunologists. For example, many
invertebrate taxa are larger than small vertebrates (such as the
mouse), they live longer, are morphologically complex, possess
highly specific immunity reflecting maturation and memory
components, exhibit an innate immunity that is associated with
a variety of life history traits (similar to the vertebrate MHC;

457

reviewed in 11) is involved in allo-and xenogeneic responses

rather than treating the infectious organisms, and in some cases
also reveal a proliferation of cellular components.
It is evident therefore that innate invertebrate immunity cannot
be regarded anymore as a sort of brute-force system that
unleashes blunt, nonspecific weapons at any and every invader
[6]. Do more primitive functions/systems acquire new roles in
the adaptive world [7] or have evolutionary forces shaped
immune responses in a different way? We may therefore redefine
three evolutionary puzzles as follows. First, the enigmatic lack
of invertebrate-acquired immunity (based on receptors that
are generated through a somatic mechanism during individual
ontogeny) [3]. Second, the puzzling expression of alloreactivity
following vertebrate transplantations (in addition to the MHC,
we may also consider minor histocompatibility antigens which
are extremely numerous up to 720 in mice. They have also
been regarded as the immunogenetic nightmare in transplantation) [28]. Third, the development of both the antiself and the
antinonself repertoires during B- and T-cell generations that are
associated with an expression of additional mechanisms aiming
to eliminate the antiself specificities (in other words, why is there
an antiself attributing generation in the pathogenic selected
immune system?).
THE PARADIGM: GUARANTEEING
INDIVIDUALITY FIRST
To answer the above tangled riddles, let us consider three alternative ideas, all standing in opposition to the accepted paradigm
holding that the vertebrate immunity is pathogenically directed.
First, the vertebrate innate immunity may have had another function in the ancestral groups and this system may have survived to
present as a relic [29] or vestige of ancient systems that have been
made redundant by the evolution of acquired immunity [2].
Second, the vertebrate adaptive immunity took advantage on
an ancient polymorphic gene family encoding cell surface interaction molecules [30]. For example, molecules featuring multiple
Ig-like domains appeared early in the eukaryotic evolution and
are also presented in the yeast a-agglutinin cell wall protein [31],
and third preserving the individuality (from littering the soma
and the germline by conspecific alien cells) might have been the
original function of the immune system. Defence against the
pathogens appeared later, revealing the multiplicity of newly
developed phenomena. I favour the latter argument.
The consideration of any one of the above three ideas requires
the demonstration of the intimate linkage between the innate and
the adaptive immunities in vertebrates. In other words, the innate
immunity is not a pot-pourri of mechanisms that most likely
arose independently of one another and must therefore be treated
individually [22]. Taking into consideration the third theory of
guaranteeing individuality first, further requires the contemporary existence of naturally occurring transplantation events in the
vertebrates, namely, that the conventional wisdom for treating
vertebrate allograft reactions essentially as a man-made artifact,
is incorrect.

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458 B. Rinkevich
Table 1. Commonly accepted generalizations for the possible reasons why invertebrates lack acquired immunity (selected citations)

The arguments

The literature reveals that

Invertebrates are morphologically less complex,

smaller than vertebrates with limited numbers of
cells, and short lived. They can not sustain the
development of acquired immunity [17].

Many invertebrates (molluscs, tunicates, crustaceans, echinoderms,

etc) are morphologically complex, significantly larger than many
mammals. Other, such as corals, may live for hundreds of
years, exceeding the life of expectancies of all contemporary
vertebrates.

Invertebrate transplant rejection is not specific [1, 2, 18].

Innate immunity targets only invariant molecular
constituents of infectious agents [3].

Colonial marine invertebrates are able to diversify their responses

specifically to different allogeneic and xenogeneic challenges
[reviewed in 12, 19]. Humoral antimicrobial responses in Drosophila
discriminate between various classes of microorganisms [6, 20].
Invertebrate immunocytes specifically respond differently to various
molecular structures [21].

No immunological memory [3, 17, 22] or

maturation, hallmark components of acquired
immunity, are found in invertebrate alloresponses.

Both components of immunity are documented in a variety of marine

organisms [reviewed in 12, 16, 23].

No evidence for proliferation of circulating blood

borne cells [1, 3, 17].

Circulating hemocyte proliferation has been recorded in shrimp after

mitogenic or infectious stimulations [24] and in vitro in tunicates [25].

The essence of innate immunity is the detection

of molecules unique to infectious organisms [2, 4].

Innate immunity in invertebrates has been repeatedly documented in

allo- and xenogeneic responses [12, 16, 19].

Invertebrates are r-selected, vertebrates are

K-selected [3].

The r-K selection predictions best envisage life history parameter

comparisons between individuals of the same population or related
species rather than between different phyla. An example is the r-k
selection comparison between 72 primate species [26].

Invertebrates possess receptors that together recognize

a limited number of epitopes, frequently those shared
by groups of parasites [22].

There is to date no single study supporting this argument on the

molecular level. On the other hand, sponges upregulate Ig-like
receptors during autograft self-recognition challenges [27].

Over the years, studies have revealed ample support for the
two premises above. With respect to the first premise, several
recent reviews discussed key phenomena demonstrating how
innate and adaptive immunities in vertebrates are functionally
intermingled. This includes: first the participation of the mannose
receptor in antigen processing [32], second the role of Toll
protein in providing a link between the adaptive and the innate
immune systems [3, 4, 6, 33], 3. the regulation of natural IgM
repertoire by complement and the finding that the humoral
immune response and the formation of memory B cells are greatly
enhanced by coupling the complement to the antigen [34], 4. the
roles of stress proteins in innate and adaptive immunity [7], 5.
the evolution of self-tolerance in an eye for links between
both types of immunity, 6. immune responses in the absence of
costimulation [8], and more. Additionally, there is an increased
knowledge about the important role of macrophages in both the
innate and adaptive immunities [2, 3, 810]. With respect to the
second premise, contrary to the general belief, vertebrates do
exhibit two distinct but common types of the naturally occurring

transplantation events; the phenomena associated with (1)

bone marrow transplantation, in dizygotic twins and (2) fetal
implantation including human cases of whole body chimerism
(spontaneous early fusion of dizygotic twins into one body),
germ cell chimerism, proliferations of the fetal cells in the
maternal blood system decades after parturition and more
(reviewed in 35, 36).
The fact that even modern vertebrates form natural chimeras
may indicate that the allorecognition to avoid the state of
chimerism is shaped through evolutionary selection pressures,
especially when the chimerism is associated with detrimental
aspects. Based on the above, I suggest that preserving the
individual homogeneity was the original function of the immune
system. Littering individuality may arise from the proliferation
of somatic variants (such as cancer cells) or allogeneic cells
threatening to parasitize both the soma- and the germline. According to this tenet, the immunity developed to survey against allogeneic changes and only later on took on the role of surveying
against xenogeneic parameters (including parasites, bacteria and

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Evolution of Innate Immunity

viruses). Does the allorecognition still play this primitive role in
the biology of contemporary multicellular organisms?
GENETICALLY NONHOMOGENEOUS ENTITIES
IN NATURE
Somatic variants and chimeras between the genetically distinct
conspecifics are the cause for nonhomogeneous entities. Surprisingly enough, naturally occurring chimeras have been recorded
in over nine phyla, crossing all the systematic boundaries in
protists, plants and animals [37]. The consequences and the
evolutionary significance for the state of the chimerism, by
considering several fitness costs and benefits, have been discussed
in several studies (reviewed in 16, 37). While the benefits have
been recorded for primitive organisms only (such as slime molds
and algae; 16, 37), the chimerism of the higher organisms is not
advantageous because it involves a variety of costs including
somatic and germ cell parasitism [38]. Even in humans, the natural
chimerism may lead to a variety of disorders such as death
and stillborns [23]. Furthermore, in many colonial marine
invertebrates (including members of the phylum Chordata)
allorecognition may be essential for the survival and is subjected
to the selection pressures [16]. For some species, highly polymorphic gene systems have been found to control allorecognition,
reminiscent of the polymorphic MHC of the vertebrates [39].
The general idea that immunity did not arise in evolution to
fight infection is not new. Stewart [40] has already contended
that the immunoglobulins may be relatively late evolutionary
developments owing to the redeployment of a system established
for other reasons. By developing two mathematical models and
by ignoring the idea of a pathogen-directed immunity, De Boer
[41] concluded that somatic compatibility systems, the mechanisms that deter genotypes from being contaminated by maladapted
alien genotypes, might be the origin for immunity whereas the
defence against parasites was only acquired much later in evolution. Following the argument raised above, and if, preservation of
the individual identity was the original function of the immune
system and the defence against pathogens occurred only afterwards, we may expect to find not only intimate linkages between
the innate and the adaptive immunity in the vertebrates [19] but
also different defence types against pathogens. These recently
developed mechanisms probably evolved independently in different taxa expressing nonhomologous properties. One such example
is the use of ancient components of a transposable element in the
generation of gene rearrangements (V(D)J recombination) in the
vertebrates: a single transposon insertion which probably occurred
some 450 million years ago soon after the divergence of the
jawed and the jawless vertebrates [15]. Therefore, instead of the
usual comparison of the invertebrates versus the vertebrates
immune systems along the line of innate versus adaptive responses
against parasites [3, 4], more consideration should be given to
allorecognition, the possible common background system on
which the diverse immunity has been developed. The avoidance
of a state of nonhomogeneous entity on the basis of polymorphic
compatibility molecules, was probably the evolutionary driving

459

force for all innate and adaptive immune systems. Another facet
of this idea, not discussed here but deserving of consideration,
is the survey for the oncogenesis, probably as primitive and
fundamental as the chimerism.

ACKNOWLEDGMENTS
This study is part of the work carried out at the Minerva
Center for Marine Invertebrates Immunology and Developmental Biology and was supported by grants from the US-Israel
Binational Science Foundation and the International Human
Frontier Science Program.
REFERENCES
1 Thompson CB. New insights into V(D)J recombination and its role
in the evolution of the immune system. Immunity 1995;3:5319.
2 Fearon DT, Locksley RM. The instructive role of innate immunity in
the acquired immune response. Science 1996;272:504.
3 Medzhitov R, Janeway CA. Innate immunity: the virtues of a
nonclonal system of recognition. Cell 1997;91:2958.
4 Medzhitov R, Janeway CA. Self-defense: the fruit fly style. Proc Natl
Acad Sci USA 1998;95:42930.
5 Plytycz B, Seljelid R. MHC molecules and lymphocytes: Evolutionary perspective. Arch Immunol Ther Exp 1998;46:13742.
6 Vogel G. Fly development genes lead to immune find. Science
1998;281:19424.
7 Srivastava PK, Menoret A, Basu S, Binder RJ, McQuade KL. Heat
shock proteins come of age: Primitive functions acquire new roles in
an adaptive world. Immunity 1998;8:65765.
8 Bachmann MF, Zinkernagel RM, Oxenius A. Immune responses in
the absence of costimulation: Viruses know the trick. J Immunol
1998;161:57914.
9 Fazekas de St Groth B. The evolution of self-tolerance: a new cell
arises to meet the challenge of self-reactivity. Immunol Today
1998;19:44854.
10 Turner MW. 90 years on: a therapy to stimulate the phagocytes?
Scand J Immunol 1998;48:1246.
11 Apanius V, Dustin P, Slev PR, Ruff LR, Potts WK. The nature
of selection on the major histocompatibility complex. Crit Rev
Immunol 1997;17:179224.
12 Cooper EL, Rinkevich B, Uhlenbruck G, Valembois P. Invertebrate
immunity: another viewpoint. Scand J Immunol 1992;35:24766.
13 Cobbold S, Waldmann H. Infectious tolerance. Curr Opin Immunol
1998;10:51824.
14 Ploegh HL. Viral strategies of immune evasion. Science 1998;280:
24853.
15 Agrawal A, Eastman QM, Schatz DG. Transposition mediated
by RAG1 and RAG2 and its implications for the evolution of the
immune system. Nature 1998;394:74451.
16 Rinkevich B. Immune responsiveness in marine invertebrates
revisited: the concourse of puzzles. In: Soderhall K, Vasta G,
Iwanaga S, eds. New Directions in Invertebrate Immunology. Fair
Haven, NJ: SOS Publications, 1996a:5590.
17 Klein J. Are invertebrates capable of anticipatory immune
responses? Scand J Immunol 1989;29:499505.
18 Silverstein AM, Rose NR. On the mystique of the immunological
self. Immunol Rev 1997;159:197206.

q 1999 Blackwell Science Ltd, Scandinavian Journal of Immunology, 50, 456460

460 B. Rinkevich
19 Rinkevich B. Links between alloimmune and their genetic background in colonial urochordates and cnidarians: Evidence for the
recognition of nonself as opposed to self. In: Stolen JS, et al. eds.
Modulators of Immune Responses: the Evolutionary Trail. Fair
Haven, NJ: SOS Publications, 1996b:113.
20 Lemaitre B, Reichhart J-M, Hoffmann JA. Drosophila host defense:
differential induction of antimicrobial peptide genes after infection
by various classes of microorganisms. Proc Natl Acad Sci USA
1997;94:146149.
21 Stefano GB, Smith EM, Cadet P, Hughes TK Jr. HIV gp120
alternation of DAMA and IL-1a induced chemotaxic responses in
human and invertebrate immunocytes. J Neuroimmunol 1993;43:
17784.
22 Klein J. Homology between immune responses in vertebrates and
invertebrates: does it exist? Scand J Immunol 1997;46:55864.
23 Frank U, Oren U, Loya Y, Rinkevich B. Alloimmune maturation in
the coral Stylophora pistillata is achieved through three distinctive
stages, four months post metamorphosis. Proc R Soc Lond B
1997;264:99104.
24 Sequeira T, Tavares D, Arala-Chaves M. Evidence for circulating
hemocyte proliferation in the shrimp Penaeus japonicus. Dev Comp
Immunol 1996;20:97104.
25 Peddie CM, Smith VJ. Lymphocyte-like cells in ascidians: precursors for vertebrate lymphocytes? Fish Shellfish Immunol
1995;5:61329.
26 Ross C. Environmental correlates of the intrinsic rate of natural
increase in primates. Oecologia 1992;90:38390.
27 Blumbach B, Diehl-Seifert B, Seack J, Steffen RM, Muller IM,
Muller WEG. Cloning and expression of new receptors belonging of
the immunoglobulin superfamily from the marine sponge Geodia
cydonium. Immunogenetics 1999;49:751763.
28 Perreault C, Roy DC, Fortin C. Immunodominant minor histocompatibility antigens: the major ones. Immunol Today 1998;19:6974.

29 Buss LW, Green DR. Histoincompatibility in vertebrates: the relict

hypothesis. Dev Comp Immunol 1985;9:191201.
30 Weissman IL. Was the MHC made for the immune system, or did
immunity take advantage of an ancient polymorphic gene family
encoding cell surface interaction molecules? A speculative assay.
Intern Rev Immunol 1988;3:397416.
31 Chen MH, Shen ZM, Robin S, Kahn PC, Lipke PN. Structure of
Saccharomyces cerevisia a-agglutinin: Evidence for a yeast cell wall
protein with multiple immunoglobulin-like domains with atypical
disulfides. J Biol Chem 1995;270:2616877.
32 Stahl PD, Ezekowitz RAB. The mannose receptor is a pattern
recognition receptor involved in host defense. Curr Opin Immunol
1998;10:505.
33 Hoffman JA, Kafatos FC, Janeway CA, Ezekowitz RAB. Phylogenetic perspectives in innate immunity. Science 1999;284:13138.
34 Carroll MC, Prodeus AP. Linkages of innate and adaptive immunity.
Curr Opin Immunol 1998;10:3640.
35 Benirschke K, Kaufmann P. Pathology of the Human Placenta. New
York: Springer-Verlag 1990.
36 Rinkevich B. Immunology of human implantation. From the invertebrate point of view. Human Reprod 1998;13:1015.
37 Buss LW. Somatic cell parasitism and the evolution of somatic tissue
compatibility. Proc Natl Acad Sci USA 1982;79:533741.
38 Pancer Z, Gershon H, Rinkevich B. Coexistence and possible
parasitism of somatic and germ cell lines in chimeras of the colonial
urochordate Botryllus schlosseri. Biol Bull 1995;189:10612.
39 Scofield VL, Schlumpberger JM, West LA, Weissman IL. Protochordate allorecognition is controlled by an MHC-like gene system.
Nature 1982;295:499502.
40 Stewart J. Immunoglobulins did not arise in evolution to fight
infection. Immunol Today 1992;13:3969.
41 De Boer RT. The evolution of polymorphic compatibility molecules.
Mol Biol Evol 1995;12:494502.

q 1999 Blackwell Science Ltd, Scandinavian Journal of Immunology, 50, 456460