Comparative Immunology1

Abstract

Comparative immunology, derived from zoology and immunology, examines immune systems during evolution. We now know that invertebrates have molecules that share homology with some of those in vertebrates. Acquired immunity first appeared in the vertebrates, but before then innate immune systems had been successfully defending invertebrates and plants against microbial infections for hundreds of millions of years. The germline-encoded receptors of innate systems are relatively limited in diversity and unable to make fine distinctions between closely related structures. Nevertheless, they can recognize certain chemical features shared by groups of microorganisms (e.g., pattern recognition receptors) but not by the host, such as lipopolysaccharide of Gram-negative bacterial cell walls. This capability enables innate immunity to detect the presence of an infection, if not the precise cause—it is thus a biological rather than a structural distinction. Because of its evolutionary success, innate immunity is no longer considered primarily a stopgap measure, a temporary expedient for host defense. It no longer seems to matter that there is an absence of genetic-recombination mechanisms to generate neither specificity nor ‘memory’, because first and second exposures to a microbial substance elicit similar responses. Comparative immunology has enriched the parent field of immunology.

This society wide symposium on Comparative Immunology assembled experts concerned with the evolution of immune systems though not the first time (Cooper, 1975; Gershwin and Cooper, 1978; Cooper and Wright, 1984). Comparative Immunology is now an established field, around since Metchnikoff but officially since about 1977, with a journal (Developmental and Comparative Immunology) (DCI) and an International Society of Developmental and Comparative Immunology (ISDCI). Both DCI and ISDCI were founded almost simultaneously (1977). DCI has published nearly 30 volumes with a steadily rising impact factor. ISDCI has held 8 triennial congresses (Aberdeen, Scotland, Los Angeles, California, Reims, France, Nottingham, England, Portland, Oregon, Wageningen, The Netherlands, Williamsburg, Virginia, Cairns, Australia, [2000]) and many workshops and smaller meetings in notably Mexico, Wales, and Italy. During this short but vigorous history several national, adherent societies have been organized in Japan, Italy and Germany. Loosely structured groups also meet sporadically in France, England in the U.S. (Mid Atlantic and Florida) and in Egypt and Latin America. Among the many scientific associations in the USA, there is no formal, organized group of comparative immunologists [although there was an official Division of Comparative Immunology established before the name change from ASZ to SICB. Each year, the ISDCI convenes an invited symposium within the organized structure of the American Association of Immunologists (AAI). Although excellent for visibility, especially with the more mammalian and human oriented AAI, this falls under the aegis of the international society that is not national.

Comparative immunology, derived from zoology and immunology, examines immune systems during evolution. (Cooper, 1976, 1985, 1990; Wright and Cooper, 1976; Gershwin and Cooper, 1978; Cooper et al., 1992; Beck et al., 1994, 2001). Invertebrate immunology, a branch begins analyses even with protozoans, capable of phagocytosis! (Cooper, 1974, 1996a, b; Bibel, 1988; Smith and Davidson, 1992; Travis, 1993; Humphreys and Reinherz, 1994; Flajnik, 1994). Now we know that they possess molecules with conserved sequences found in multicellular species (lysins in amoebas and interleukins in ciliates) (Cooper et al., 2002; Boman, 1995, 1998; Hoffmann et al., 1999). Phagocytosis in invertebrates paved the way for reconciling controversy between humoral immunity vs. cellular immunity. Immunologists discovered antibodies in vertebrates and different but equally efficient molecules that mediate humoral immunity in invertebrates (e.g., lysins, agglutinins, and opsonins). Cellular immunity, e.g., graft rejection, seems to share similar characteristics in both animal groups. The immune system is divided into two major groups: adaptive (induced, specific, clonal, anticipatory) and innate (natural, non-specific, non-clonal, non-anticipatory (Hultmark, 1994; Medzhitov and Janeway, 1998; Medzhitov et al., 1997). Invertebrates possess cellular and humoral responses that are mostly innate, whereas both the innate and the adaptive are associated with vertebrates. Comparative immunology promises the unification of interrelated mechanisms and concepts based upon firm molecular information, (e.g., signal transduction; homology vs. analogy; convergent vs. divergent evolution) (Janeway, 1998); unification of the three regulatory systems, immune, nervous, and endocrine; understanding of immunity in models of economic importance (e.g., pests, parasites, disease vectors, and food) that will be useful as inexpensive, non-controversial sources of information; analyses of relation between biospheric inhabitants, environment and seasons (Cooper and Parrinello, 1996a, b); the development of “new wave antibiotics” and therapeutic components based upon naturally occurring antimicrobial molecules (Cooper et al., 2002).

Werner Müller and Isabell Müller (University of Mainz; Germany), showed that during the evolutionary transition to metazoan organization, cell-cell- as well as cell-matrix recognition molecules developed leading to establishment of an immune system. Sponges [Porifera] represent the oldest still extant metazoan phylum that reveals major features of a common metazoan ancestor, the Urmetazoa. It seems that successful evolutionary transition to sponges and the subsequent rapid radiation into other metazoan phyla, became possible due to acquisition of modular molecules involved in cell adhesion and then immuno-defense.

Christopher Bayne (Oregon State University) asked the question: Is adaptive immunity absolutely dependent on innate immunity? This reflects the phenomenal recent growth in appreciation for the innate arms of immune systems, and the realization that adaptive immunity is an evolutionary neophyte, acquired by metazoans contemporaneously with RAG genes and jaws in Silurian times, some 440 (perhaps 475) million years ago (mybp). He focused on immuno-competence in molluscan species, and in so doing presented the variety of internal defense mechanisms that had evolved in this phylum well before the end of the Precambrian some 550 mybp. Bayne distinguished immuno-competence at this intermediate level of phylogeny from immuno-competence in modern mammals.

Innate immunity is of extreme importance to immunology both in the historical context and conceptually as well. According to Tomas Ganz (UCLA School of Medicine) the production of antimicrobial peptides and proteins is an important means of host defense in eukaryotes. Small antimicrobial peptides act largely by disrupting the structure or function of microbial cell membranes. Antimicrobial peptides are numerous, found in epithelial layers, phagocytic cells and body fluids of multicellular animals, from mollusks and annelids to humans (Vetvicka et al., 1993; Cooper et al., 2002).

Hemocyte encapsulation responses, an extension of phagocytosis by the freshwater snail Biomphalaria glabrata, represent the primary effector mechanism against larval stages of the blood fluke Schistosoma mansoni. Timothy Yoshino and his colleagues at the University of Wisconsin have devoted enormous efforts to the immune capabilities of mollusks, (from the classical protostome line of evolution) but with a broad application to parasitism. Although cellular adhesion and spreading are critical components, two areas require intense investigation: a) analysis of receptors involved in parasite recognition; b) cell signaling pathways that communicate hemocyte behaviors upon receiving appropriate stimulation.

On the classical deuterostome line, antimicrobial molecules, as expressions of the humoral immune response have been examined extensively in tunicates by Robert Lehrer and his colleagues at UCLA School of Medicine, Scripps Institute of Oceanography, La Jolla, and the Institute for Experimental Medicine, St. Petersburg, Russia. The aim has been to understand their immune capabilities as natural peptide antibiotics but with the view toward their potential uses. Tunicates rely on hemocyte-mediated innate immunity for protection against microbial and eukaroytic invaders.

The evolutionary position occupied by the protochordates, bridging invertebrates and vertebrates, suggests that these organisms may express extant examples of the most advanced defense mechanisms that preceded the advent of immunoglobulins. Gerardo Vasta and his colleagues at the University of Maryland, extend an analysis of aspects of innate immunity with protochordates and to some extent fish. According to their current hypothesis the lectin-mediated pathway for complement activation may have preceded the immunoglobulin-mediated pathway. With respect to fish, the search for homologous fucose-binding C-type lectin in liver and plasma of teleost fish resulted in the identification of a novel lectin family.

Gary Litman (University of Florida) has provided new and crucial information concerning novel immune-type receptor genes and origins of adaptive and innate immune recognition extending the work on fish. Prototypic forms of novel immune-type receptors (NITRs) encode a variable (V) region, a unique V/C2 domain, a transmembrane region and a cytoplasmic tail containing immunoreceptor tyrosine-based inhibition motifs (ITIMs). NITRs exhibit properties of adaptive and innate immune receptors that encode diversified V regions but do not undergo somatic rearrangement. Taken together, these studies indicate that leukocyte regulatory receptors, such as those mediating natural killer function, emerged early in vertebrate evolution. In addition, newly discovered genes in protochordates may represent significant links between innate and adaptive immunity.

Terminal Deoxynucleotidyl Transferase (TdT) that belongs to the DNA polymerase beta gene family is a nuclear enzyme that adds nontemplated nucleotides to free 3′-hydroxyl ends of DNA fragments. Simona Bartl (Moss Landing Marine Laboratories) California, has focused her research on cartilaginous fishes and their terminal deoxynucleotidyl transferase (TdT) genes. In mammals, the only documented function for TdT is to add nucleotides at gene element (V, D, and J) junctions during immunoglobulin (Ig) and T cell receptor (TCR) gene rearrangement. Thus it diversifies the receptor repertoire. In this context, other genes of immunological importance occur in sharks and rays, especially Ig, TCR, Major Histocompatibility Complex genes (required for antigen recognition by T cells) and recombination activating genes (essential for gene rearrangement).

The capacity of cells to respond to environmental challenges such as oxidative damage is an ancient evolutionary development that persisted through vertebrate development as innate immunity. John Marchalonis and Samuel Schluter (University of Arizona) have focused on analyzing the rapid evolutionary emergence of the combinatorial recognition repertoire. Adaptive immunity, by contrast is the characteristic immune response of vertebrates, is a relatively recent evolutionary development and is present only in jawed vertebrates. The vertebrate “combinatorial” response is defined by the: 1) presence of lymphocytes as specific antigen recognition cells; 2) complete panel of antibodies, T cell receptors, and major histocompatibility complex molecules.

Stem cells, their sources, biology, transplantation and evolution have recently become high-profile topics according to Irving Weissman (Stanford University) Although sources are known in invertebrates, their origins and suitability for clinical situations is a contentious point with respect to humans. Prospective hematopoietic stem cells (HSC) isolation from mice and humans reveals increased information about their characteristics after transplantation. Turning to evolutionary precursors, in a colonial protochordate, somatic and germ line stem cells enter shared blood vessels of natural allogeneic chimeras where they participate in generating somatic organs and the germ line. As has occurred during the history of biology, what we learn from more primitive species will with encouragement and support, provide clues to physiology in mammals especially humans.

The Society of Integrative and Comparative Biology (SICB), through its adherent divisions, integrates several branches of the biological sciences including two that are devoted to regulation of organismal activity: the nervous and endocrine systems. Multicellular organisms also possess a third component the immune system. SICB could recognize this triumvirate by re-establishing a Division of Comparative Immunology designed to expand the scientific foundation of SICB by bringing in new groups of researchers and to identify unique approaches that enhance the scientific programs within and between divisions. This symposium presented new “growth” areas for the society; emphasizing integration between divisions, (developmental biology; endocrinology; physiology and biochemistry). In serving to rejuvenate, integrate and diversify, SICB would fulfill its role, i.e., devotion and commitment to integrative and comparative biology.

1

From the Symposium Comparative Immunology presented at the Annual Meeting of the Society for Integrative and Comparative Biology, 2–6 January 2002, at Anaheim, California.