A comparison of the immune strategy of vertebrates and invertebrates

DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY Printed in the United States

Vol. 2, pp. 243-252, 1978 Pergamon Press, Inc.

A COMPARISON OF THE IMMUNE STRATEGY OF VERTEBRATES AND INVERTEBRATES

A. J. Cunningham Ontario Cancer Institute and Dept. of Medical Biophysics University of Toronto 500 Sherbourne Street Toronto, Ontario Canada M4X IK9

ABSTRACT

Invertebrates display immunity, in that they often produce macromoleucles or develop cellular reactions which protect them against foreign substances in their environment. However, it seems probable that most species rely on conventional e~olutionary strategy when faced with entirely new antigens, such as mutant pathogenic microorganisms: the species varies randomly, and resistant individuals are selected. By contrast, vertebrates have a more elaborate mechanism which enables the individual to learn, during its own life time, to react against a great variety of novel antigenic stimuli. This involves exploiting the evolutionary potential of an internal population of lymphocytes. These cells proliferate, rather like a bacterial or protozoan population, and variants appear amongst them. Useful variants are selected by antigens. The overall principle of adaptation to a changing antigenic e n v i r o n m e n t i s the same in both vertebrates and invertebrates, but the "unit" which lives or dies according to its immune capability is the whole individual for most invertebrate species, while in the vertebrates it is the lymphocyte.

INTRODUCTION Whether most invertebrates make "true" immune responses debated question.

There is no doubt that many invertebrate

protect themselves

against pathogens

is a widely species can

and exclude foreign substances by

making macromolecules

or cellular reactions which have some protective

value

Equally,

(reviews 1-7).

it is clear that the vertebrate

system must have evolved from some more "primitive" just as the vertebrates

0145-305~7~0401-0243/$02.0~0 Copyright©1978 Pe~amon Pmss

themselves

immune

recognition system,

evolved from invertebrates.

The impor-

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IMMUNE STRATEGY

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tant and unresolved issue is the degree of relationship between vertebrate and invertebrate immune mechanisms..

Opinions fall into two main groups.

The first school, which seems to include most people actually working with invertebrates, feels that there has been a gradual and progressive refinement during evolution of mechanisms for reacting against foreign substances (e.g., ref. 8).

Vertebrate immunity is seen as a more sophisticated form

of a basically similar mechanism existing in invertebrates.

The second

school, among which immunologists studying "conventional" immune reactions in higher animals are more likely to be found, considers that the vertebrate system is a radically new mechanism which has arisen relatively recently in evolution.

The following article supports the latter view, but

attempts to bring the two schools together by stressing that the basic Darwinian strategy of random variation and selection is used in both kinds of immunity. i.

Comparison of the proper£ies of vertebrate and invertebrate immune systems

(table i)

"Vertebrates" are a relatively homogeneous group, while "invertebrates" comprise some twenty distinct phyla.

It is clear that the different in-

vertebrate phyla may have evolved very diverse defence mechanisms, and that some of the higher invertebrates may, in fact, have the beginnings of a vertebrate-type immune system (discussed below).

For the purposes of this

discussion, however we will compare immune strategies of vertebrates with those of the majority of invertebrate species. Effector molecules Any system with discriminatory powers is likely to use an array of different "receptor" macromolecules.

Several invertebrate classes have

been shown to possess such antigen-reactive substances

(1-7).

The mole-

cules are diverse (different antigens do not absorb all of them) in some cases (9-12), but have very little specificity of action in other cases (1,2,7).

They are often protective

(5,13), and may act like vertebrate

antibodies to opsonise foreign particles for phagocytosis

(9,12,14).

The

structure of invertebrate agglutinins appears very different from that of antibody from higher vertebrates

(7,10,15,16), but this does not necessarily

imply a profound difference in activity.

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IMMUNE STRATEGY

245

TABLE I Comparison of Invertebrate and Vertebrate Immune Mechanisms

Invertebrate* A.

Effector molecules Diversity Power to discriminate between different antigens

very high

usually low

high

Specific cells Clonally individuated (lymphocytes) Expansion and suppression of clones

C.

low

very different

Structure

B.

Vertebrate

-

+

-

+

Adaptive functions Memo ry (rarely +) Acquired tolerance

D.

E.

Response to "unexpected" stimuli

probably none

+

Number of V genes

?

few?

Somatic variation

-

+

Allelic exclusion

-

+

Possible genetic mechanisms

*"-" means not yet demonstrated.

Effector cells Vertebrate immune responses are carried out by lymphocytes and related cells.

As Burnet predicted

(17), the diversity of antibodies reflects a

parallel diversity in the lymphocytes which make them. amplification of specific lymphocytes,

Memory depends on

and tolerance on their suppression

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or deletion..

Vol. 2, No. 2

There is not, as far as I know, any conclusive evidence for

clonal diversity of the cells taking part in invertebrate immune responses, although such evidence could perhaps be sought with modern techniques of specific cell fractionation.

There is however, some recent evidence for

adaptive graft rejection among higher invertebrates, the annelids and echinoderms, which may herald the first phylogenetic emergence of true immune reactions

(18,19).

Annelids, for example, accept autografts but re-

ject skin from other genera (18).

The rejection is associated with an

accumulation of coelomocytes around the graft.

A second graft from the

same donor is rejected more quickly and to the accompaniment of a more rapid congregation of coelomocytes,

l~:would be extremely interesting to

have information on the diversity of these coelomocytes; if they are acting like vertebrate lymphocytes they should show clonal differences. Adaptive functions The vertebrate immune system is, above all, a learnin$ system. be said to learn in positive and negative ways.

It can

The positive side of im-

munological learning results in memory, a state of enhanced responsiveness to antigens previously encountered.

An immense repertoire of different

antibody specificities is built up by the individual vertebrate during its ontogeny.

There is evidence that environmental antigens help to create

this repertoire by stimulating clones which throw off variants

(20-22).

Different individuals, even when virtually identical genetically, usually make a unique range of antibodies against the same antigen (23), indicating a major role of chance in determining what particular antibody repertoire will be expressed.

The negative side of immunological learning is, of

course, acquired tolerance.

Vertebrates develop tolerance to self antigens

(24) and to foreign substances, the efficiency of learning being usually highest when the antigens are present early in life. Contrast this with invertebrate immunity.

While some examples are

known where specific protective functions are induced or enhanced by antigen (6,25), the norm seems to be production of a similar level of "natural" antigen-reactive substances by most members of a species, independent of their antigenic history (1,5,7,11).

There are examples of

specific memory (18,19), but in the majority of cases studied, memory, in the sense of persistent, heightened responsiveness, does not seem to follow antigenic stimulation (1,26,27). has often been discussed.

This lack of positive adaptiveness

The other side of the immunological coin, tol-

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247

erance, has been very little studied in the lower animals. evidence that specific clearance mechanisms of foreign material in molluscs

can be saturated by high doses

(28), or in crustaceans

to be little evidence as yet for acquired tolerance to induce specific tolerance

Apart from some

(29), there seems

in invertebrates.

Attempts

in the higher invertebrates would be extremely

interesting. Parallels have been drawn

(8,30-33) between the mutual incompatibility

reactions of certain invertebrate actions of vertebrates.

animals or plants and the homograft re-

The comparison derives some piquancy

norance of the reasons for vertebrate histocompatibility

from our ig-

polymorphism.

The

resemblance between these two systems seems likely to be superficial, ever.

Vertebrate alloreactivity

is confined to lymphocytes and related cells,

and only a small proportion of lymphocytes alloantigens.

The anomalous

can react against any one set of

features of allogeneic reactions

plained in terms of well-known vertebrate-type 35).

Tolerance and memory to particular

of these features vertebrate

how-

can be ex-

immunological mechanisms

alloantigens

(34,

can be acquired.

is known to apply to the incompatibility

None

reactions of in-

and plants, which have probably evolved to promote diversity with-

in species. Response to "unexpected" Adaptivity

stimuli

alone does not imply the existence of an immune system.

Even individual bacteria can adapt, for example, by more rapidly synthesizing an enzyme in response to a substrate. vertebrate

There is, however,

a property of the

immune system, pointed out by Cohn (36), which is even more fund-

amental than memory and tolerance. expected" stimuli, never previously

This is its ability to respond to "un-

i.e., to react against antigens which the species has

encountered.

any foreign macromolecular

Vertebrates

substances.

can learn to respond to almost

Invertebrates,

while able to react

against a large variety ~f foreign substances normally present in their environment,

seem more liable to have "blind spots" in their repertorie,

is, to be quite unable to react against occasional "new" antigens How then do they protect themselves

(2,26,37).

against the rapidly evolving populations

of potentially pathogenic micro-organisms

with which all animals are faced?

I suggest that the central difference between immune mechanisms vertebrates

that

and the lower invertebrates

is as follows.

in

Invertebrates possess

genes coding for useful and protective macromolecules.

When a new pathogen

or other harmful molecule appears in their environment,

most members of the

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IMMUNE STRATEGY

species may die and a few variants This is, of course,

form the basis of a new, resistant strain.

classical Darwinian evolution,

including vertebrates, dividual does not.

Vol. 2, No. 2

and to all genes.

applicable

to all species

The population adapts,

"Learning" is genetic.

By contrast,

the in-

vertebrates

also developed an internal population of semi-autonomous

have

lymphocytes,

which

behave in may ways like an evolving protozoan or bacterial population. Variants

appear in the population

for the present discussion), with which they react.

and are selected by those environmental

In a metaphorical

contains a "symbiont" population unfolds within their "host". can adapt to new antigens,

sense,

using classical

(17).

Immunological

geny of a stimulated

lymphocyte,

logical context,

level.

by exploiting

"learning"

history

this population,

evolutionary mechanisms,

as was

is inherited by the pro-

but is not passed on by the "host" to its

That is, learning is'"genetic"

typic" at the vertebrate

antigens

the individual vertebrate

of cells whose entire evolutionary

A vertebrate,

recognized by Burnet

offspring.

(the exact genetic mechanism is not crucial

at the lymphocyte

Vertebrate

offspring

level, but "pheno-

inherit,

in an immuno-

only the capacity to acquire their own lymphocyte

repertoire.

Genetic basis of immunity The view that each generation of vertebrates lymphocyte population genes are inherited,

relies on a freshly evolving

fits best with the idea that relatively and that variants

appear somatically.

new specificities within a clone of lymphocytes

few antibody V-

The evolution of

can be very rapid

There may have been, at about the period of vertebrate

emergence,

(21,22). an evolu-

tionary event which made available at the same time three novel but related genetic mechanisms:

a translocation mechanism

different C genes), allelic exclusion lymphocytes

by antigen

diversification 2.

(for attaching V genes to

(which facilitates

selection of variant

(24), and a hypervariation mechanism to speed up the

of lymphocytes.

Self-not self discrimination There is an assumption in some of the literature

which seems illogical.

on invertebrate

i~m~unity

It can be expressed as a syllogism.

Major premise:

all animals distinguish

self from not self.

Minor premise:

the immune system distinguishes

Conclusion:

all animals have an immune system.

self from not self.

The logical fallacy is to assume that self-not self discrimination clusively a property of immune systems.

is ex-

In fact, it is a feature of all

living cells, as was pointed out years ago by Boyden

(38).

For example,

cells

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IMMUNE STRATEGY

249

cells of the same tissue recognise one another and distinguish between themselves and other tissues within the-same animal many invertebrates

have phagocytic

(39).

it is not solely responsible 3.

The immune system is

and highly specialised kind of recognition

order to function efficiently,

it has to distinguish

for maintaining

How do many invertebrates

system.

In

self from not self, but

this distinction.

manage without an immune system?

Why is it that vertebrates

have found it necessary

tain such an elaborate and specialised

to develop and re-

immune system, while many invertebrate

species seem to survive using only the normal evolutionary ulation variation and selection? denominator between vertebrates

strategy of pop-

Any attempt to define a relevant common on the one hand and invertebrates

other is bound to be frustrated by the existence either kind.

and

cells which are capable of some discrimin-

atory activity in the absence of specific antibody. only one particular

Both vertebrates

However, vertebrates

of exceptional

on the

species of

have several broad properties which Would

seem to make an adaptive immune system much more vital to their survival. Firstly,

they generally

has correspondingly

more chance of encountering

their long generation vertebrates

live longer than invertebrates.

times, vertebrate

a pathogenic

organism.

With

species are much less able than in-

to counter, by genetic variation of their own, the rapid evolution

of microorganism

populations.

Secondly,

have many more progeny than vertebrates. majority in any generation, dividuals

Thus the individual

unfortunate

usually

(not always)

This allows death of the vast

without jeopardising

the species.

Those in-

enough to meet a pathogenic microorganism may simply

die, unless they are themselves have too few members

invertebrates

resistant variants.

Most vertebrate

species

to rely on this kind of mechanism.

A number of other reasons can be suggested for the development

of an

adaptive immune system by vertebrates,

although it is difficult to know how

important

For example, vertebrates

these rationalisations

highly complex,

are.

and are perhaps more liable to be incapacitated

from reproducing) invading parasites

by even relatively

(prevented

slight structural damage inflicted by

(but complexity has its compensations:

dividual to support a "police force" of lymphocytes~). ability brought about by vertebrate

are usually

it allows an in-

The increased ~ d a p t -

evolution also induced species to leave

the sea and move about on land, where they probably envountered a more varied antigenic environment, the development

a fact of life which would also have encouraged

of an immune system.

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CONCLUSIONS We are left with the conclusion that most invertebrate species do not have a "true" immune system of the vertebrate kind.

However, there is no

doubt that a study of invertebrate immunity is an important area of biological research.

Many of the recognition mechanisms used by invertebrates must be

of fundamental importance throughout the animal kingdom, while vertebrate immunity is probably a late evolutionary "frill".

But is seems that in-

appropriate comparisons are sometimes made between invertebrate and vertebrate immune reactions.

The opinion expressed here is that more useful

parallels could be drawn between the response of a population on invertebrates and that of the lymphocyte population within a single vertebrate individual. ACKNOWLEDGEMENTS I am particularly indebted to Drs. K.J. Lafferty and C. Jenkin for many valuable discussions.

Drs. P.A. Bretscher, E. Steele and M.M.

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