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PL.1 The evolution of the immune response
The Scientific and Social Program of the V1*hISDCI Congress
$31
SCIENTIFIC CONTRIBUTIONS
PL.1 THE EVOLUTION
OF THE IMMUNE
RESPONSE
L. Du Pasquier Basel Institute for Immunology, Grenzacherstrasse 487, 4005 Basel, Switzerland With respect to the origin and development of the vertebrate immune system, the recent finding seems to have accentuated the differences between vertebrates and invertebrate phyla: 1) rearrangement has not been found outside vertebrates, 2) clonal expansion of receptors bearing lymphoid-like cells have not been found in invertebrates, and 3) specific immune memory has not been documented enough and doubts remain about its existence in most non vertebrate phyla. Phagocytosis, inflammatory reaction, complement-like substances and interleukin-like molecules can, however, be found and stem probably from origins independent of the specific nonself recognition system of vertebrates. When looking at elements of the immune system, molecules related to MHC, Ig and TCR are identifiable in non vertebrate phyla, but are not necessarily engaged in immune functions, nor necessarily engaged in cell-cell interaction. When they are, they obey different functional principles. The recent advances in the molecular analysis of the components of the immune system in vertebrates have clarified several points and shown that if the fundamental elements of MHC class I or class II related genes and Ig, TCR superfamilies characterized by rearrangement of the vertebrate immune system were conserved, except in cyclostomes, their multiplicity, gene organization and their usage could differ significantly among vertebrate classes. This can be very misleading in evolutionary terms. Coevolution of gene organization cannot be considered as a rule. MHC class I and class II molecules seem to be conserved in all classes of gnathostomes, and the features of these molecules in several classes indicate that among vertebrates, they have been under the same selection pressures, i.e. that their function is identical. More puzzling is the case of the non classical MHC class I genes that segregate independently of the MHC in the amphibian Xenopus. Evolution of MHC can be approached in almost an experimental way by comparing natural and laboratory made polyploid animals where various forms of duplication have taken place. There is a pressure to express a limited number of MHC class I genes (1 pair of alleles) and a larger number of class II genes (e.g. 6 class II B/individual). Several cases of MHC gene duplications, especially in the non classical genes, seem to have taken place after the speciation events. In lg gene organization, there is also no example of strict coevolution of the organization of the
$32
The Scientific and Social Program of the W h ISDCI Congress
various loci. All the possibilities (cluster type organization or multiple V elements with a unique C element in common) seem to have been used both for H and L loci in various classes. With respect to antibody responses, the somatic generation of Ig genes by rearrangement has been found in all vertebrates, but cyclostomes and the further somatic generation of diversity via somatic mutations (or gene conversion?) is also present in cold-blooded vertebrates. The reason for big differences in antibody responses between mammals and most other vertebrates seems to be due to lack of optimal selection of variants in cold-blooded vertebrates lacking typical germinal centers. Very likely, at the time of generation of the first vertebrates, from precursors homologous to these actual invertebrate non rearranging genes, major gene shuffling has generated molecules involved in the vertebrate immune system, and at the same time the mechanism of rearrangement offered the possibility of somatically creating clones of cells specialized in recognition, a feature selected by all vertebrate immune systems. Improvement in the selection of such clones and their mutants is one of the rare features of the immune system, together with isotype diversification, that seems to follow the somehow accepted phylogenetic tress of vertebrates, and accounts for most of the variations seen in the antibody responses of vertebrates. Data are beginning to appear about the TCR evolution which should, in the next year, allow a better understanding of the evolutionary aspects of the T-cell function.
PL.2 PSYCHONEUROIMMUNOLOGY IMMUNE RESPONSES
~:
BEHAVIORAL
REGULATION
OF
Nicholas Cohen, Robert Ader, Jonathan D. Karp, Jan A. Moynihan University of Rochester Medical Center, Center for Psychoneuroimmunology Research, Departments of Microbiology and Immunology and of Psychiatry, Rochester, NY 14642, USA For many years, immunologists considered an immune response to be a direct consequence of, and solely determined by, the administration of antigen to an autonomous immune system. In the past decade, however, we have come to realize that immune responses are regulated by the central nervous system (CNS), through products of the hypothalmo-pituitary adrenal (HPA) axis, central and peripheral neurotransmitters, and other neuropeptides and hormones. This realization that the CNS has immunomodulatory potential is based on data derived from many different lines of research. For example: (1) lymphoid tissues are innervated by noradrenergic and peptidergic nerve fibers, and abrogation of this sympathetic innervation can alter expression of natural and acquired immunity; (2) lymphocytes and macrophages express cell surface receptors for a diversity of hormones and neuropeptides; (3) cytokines produced both by ceils of the central nervous system (CNS) and the immune system are important mediators of neural-immune interactions; (4) antigenand mitogen-stimulated lymphocytes can produce an army of hormones; (5) natural and experimental manipulation of hormone- or neurotransmitter-immunocyte receptor interactions evoke alterations in immunologicaUy relevant events in fish, amphibians, and mammals; (6) at least some antecedents of neural-immune system interactions can be identified in invertebrates; and (7) an animal's behavior can regulate its immune responses and immune responses can modify an animal's behavior2. This presentation will review recent data from our laboratory dealing with behavioral regulation of immunity. Specifically, I will discuss novel examples in which classical (Pavlovian) conditioning and "stress" evoke immunomodulatory signals in mice3. Conditioning Studies: One of the most dramatic examples of CNS-immune system communication stems from a series of reports revealing that learning processes, as exemplified by classical
$31
SCIENTIFIC CONTRIBUTIONS
PL.1 THE EVOLUTION
OF THE IMMUNE
RESPONSE
L. Du Pasquier Basel Institute for Immunology, Grenzacherstrasse 487, 4005 Basel, Switzerland With respect to the origin and development of the vertebrate immune system, the recent finding seems to have accentuated the differences between vertebrates and invertebrate phyla: 1) rearrangement has not been found outside vertebrates, 2) clonal expansion of receptors bearing lymphoid-like cells have not been found in invertebrates, and 3) specific immune memory has not been documented enough and doubts remain about its existence in most non vertebrate phyla. Phagocytosis, inflammatory reaction, complement-like substances and interleukin-like molecules can, however, be found and stem probably from origins independent of the specific nonself recognition system of vertebrates. When looking at elements of the immune system, molecules related to MHC, Ig and TCR are identifiable in non vertebrate phyla, but are not necessarily engaged in immune functions, nor necessarily engaged in cell-cell interaction. When they are, they obey different functional principles. The recent advances in the molecular analysis of the components of the immune system in vertebrates have clarified several points and shown that if the fundamental elements of MHC class I or class II related genes and Ig, TCR superfamilies characterized by rearrangement of the vertebrate immune system were conserved, except in cyclostomes, their multiplicity, gene organization and their usage could differ significantly among vertebrate classes. This can be very misleading in evolutionary terms. Coevolution of gene organization cannot be considered as a rule. MHC class I and class II molecules seem to be conserved in all classes of gnathostomes, and the features of these molecules in several classes indicate that among vertebrates, they have been under the same selection pressures, i.e. that their function is identical. More puzzling is the case of the non classical MHC class I genes that segregate independently of the MHC in the amphibian Xenopus. Evolution of MHC can be approached in almost an experimental way by comparing natural and laboratory made polyploid animals where various forms of duplication have taken place. There is a pressure to express a limited number of MHC class I genes (1 pair of alleles) and a larger number of class II genes (e.g. 6 class II B/individual). Several cases of MHC gene duplications, especially in the non classical genes, seem to have taken place after the speciation events. In lg gene organization, there is also no example of strict coevolution of the organization of the
$32
The Scientific and Social Program of the W h ISDCI Congress
various loci. All the possibilities (cluster type organization or multiple V elements with a unique C element in common) seem to have been used both for H and L loci in various classes. With respect to antibody responses, the somatic generation of Ig genes by rearrangement has been found in all vertebrates, but cyclostomes and the further somatic generation of diversity via somatic mutations (or gene conversion?) is also present in cold-blooded vertebrates. The reason for big differences in antibody responses between mammals and most other vertebrates seems to be due to lack of optimal selection of variants in cold-blooded vertebrates lacking typical germinal centers. Very likely, at the time of generation of the first vertebrates, from precursors homologous to these actual invertebrate non rearranging genes, major gene shuffling has generated molecules involved in the vertebrate immune system, and at the same time the mechanism of rearrangement offered the possibility of somatically creating clones of cells specialized in recognition, a feature selected by all vertebrate immune systems. Improvement in the selection of such clones and their mutants is one of the rare features of the immune system, together with isotype diversification, that seems to follow the somehow accepted phylogenetic tress of vertebrates, and accounts for most of the variations seen in the antibody responses of vertebrates. Data are beginning to appear about the TCR evolution which should, in the next year, allow a better understanding of the evolutionary aspects of the T-cell function.
PL.2 PSYCHONEUROIMMUNOLOGY IMMUNE RESPONSES
~:
BEHAVIORAL
REGULATION
OF
Nicholas Cohen, Robert Ader, Jonathan D. Karp, Jan A. Moynihan University of Rochester Medical Center, Center for Psychoneuroimmunology Research, Departments of Microbiology and Immunology and of Psychiatry, Rochester, NY 14642, USA For many years, immunologists considered an immune response to be a direct consequence of, and solely determined by, the administration of antigen to an autonomous immune system. In the past decade, however, we have come to realize that immune responses are regulated by the central nervous system (CNS), through products of the hypothalmo-pituitary adrenal (HPA) axis, central and peripheral neurotransmitters, and other neuropeptides and hormones. This realization that the CNS has immunomodulatory potential is based on data derived from many different lines of research. For example: (1) lymphoid tissues are innervated by noradrenergic and peptidergic nerve fibers, and abrogation of this sympathetic innervation can alter expression of natural and acquired immunity; (2) lymphocytes and macrophages express cell surface receptors for a diversity of hormones and neuropeptides; (3) cytokines produced both by ceils of the central nervous system (CNS) and the immune system are important mediators of neural-immune interactions; (4) antigenand mitogen-stimulated lymphocytes can produce an army of hormones; (5) natural and experimental manipulation of hormone- or neurotransmitter-immunocyte receptor interactions evoke alterations in immunologicaUy relevant events in fish, amphibians, and mammals; (6) at least some antecedents of neural-immune system interactions can be identified in invertebrates; and (7) an animal's behavior can regulate its immune responses and immune responses can modify an animal's behavior2. This presentation will review recent data from our laboratory dealing with behavioral regulation of immunity. Specifically, I will discuss novel examples in which classical (Pavlovian) conditioning and "stress" evoke immunomodulatory signals in mice3. Conditioning Studies: One of the most dramatic examples of CNS-immune system communication stems from a series of reports revealing that learning processes, as exemplified by classical