Begell House Inc.
Critical Reviews™ in Immunology
CRI
1040-8401
37
2-6
2017
The Nature of Selection on the Major Histocompatibility Complex
75-125
10.1615/CritRevImmunol.v37.i2-6.10
Victor
Apanius
Institute of Parasitology, McGill University-Macdonald College, 21,111 Lakeshore Rd., Ste-Anne-de-Bellevue, Quebec, Canada,Department of Biological Sciences, Florida International University, University Park, Miami, FL 33199
Dustin
Penn
Department of Zoology, University of Florida, Gainesville, FL 32611; Department of Biology, University of Utah, Salt Lake City, UT 84112
Patricia R.
Slev
Department of Pathology and Laboratory Medicine, University of Florida, Gainesville, FL 32610
L. Ramelle
Ruff
Department of Pathology and Laboratory Medicine, University of Florida, Gainesville, FL 32610
Wayne K.
Potts
Department of Biology, University of Utah, Salt Lake City, UT 84112; Department of Pathology and Laboratory Medicine, University of Florida, Gainesville, FL 32610
host-parasite coevolution
immunogenetics
sexual selection
kin recognition
odor
life history
Only natural selection can account for the extreme genetic diversity of genes of the major histocompatibility complex (MHC). Although the structure and function of classic MHC genes is well understood at the molecular and cellular levels, there is controversy about how MHC diversity is selectively maintained. The diversifying selection can be driven by pathogen interactions and inbreeding avoidance mechanisms. Pathogen-driven selection can maintain MHC polymorphism based on heterozygote advantage or frequency-dependent selection due to pathogen evasion of MHC-dependent immune recognition. Empirical evidence demonstrates that specific MHC haplotypes are resistant to certain infectious agents, while susceptible to others. These data are consistent with both heterozygote advantage and frequency-dependent models. Additional research is needed to discriminate between these mechanisms. Infectious agents can precipitate autoimmunity and can potentially contribute to MHC diversity through molecular mimicry and by favoring immunodominance. MHC-dependent abortion and mate choice, based on olfaction, can also maintain MHC diversity and probably functions both to avoid genome-wide inbreeding and produce MHC-heterozygous offspring with increased immune responsiveness. Although this diverse set of hypotheses are often treated as competing alternatives, we believe that they all fit into a coherent, internally consistent thesis. It is likely that at least in some species, all of these mechanisms operate, leading to the extreme diversification found in MHC genes.
Regulatory Functions of Phospholipase A2
127-195
10.1615/CritRevImmunol.v37.i2-6.20
Makoto
Murakami
Department of Health Chemistry, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142, Japan
Yoshihito
Nakatani
Department of Health Chemistry, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142, Japan
Gen-ichi
Atsumi
Department of Health Chemistry, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142, Japan
Keizo
Inoue
Department of Health Chemistry, Faculty of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan
Ichiro
Kudo
Department of Health Chemistry, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142, Japan
secretory phospholipase A2
cytosolic phospholipase A2
Ca2+-independent phospholipase A2
prostaglandin
leukotriene
cyclooxygenase
Phospholipase A2 (PLA2) plays crucial roles in diverse cellular responses, including phospholipid digestion and metabolism, host defense and signal transduction. PLA2 provides precursors for generation of eicosanoids, such as prostaglandins (PGs) and leukotrienes (LTs), when the cleaved fatty acid is arachidonic acid, platelet-activating factor (PAF) when the sn-1 position of the phosphatidylcholine contains an alkyl ether linkage and some bioactive lysophospholipids, such as lysophosphatidic acid (lysoPA). As overproduction of these lipid mediators causes inflammation and tissue disorders, it is extremely important to understand the mechanisms regulating the expression and functions of PLA2. Recent advances in molecular and cellular biology have enabled us to understand the molecular nature, possible function, and regulation of a variety of PLA2 isozymes. Mammalian tissues and cells generally contain more than one enzyme, each of which is regulated independently and exerts distinct functions. Here we classify mammalian PLA2s into three large groups, namely, secretory (sPLA2), cytosolic (cPLA2), and Ca2+-independent PLA2s, on the basis of their enzymatic properties and structures and focus on the general undestanding of the possible regulatory functions of each PLA2 isozyme. In particular, the roles of type II sPLA2 and cPLA2 in lipid mediator generation are discussed.
Functions of IL-4 and Control of Its Expression
197-229
10.1615/CritRevImmunol.v37.i2-6.30
Melissa A.
Brown
Department of Experimental Pathology and Graduate Program in Immunology and Molecular Pathogenesis, Emory University School of Medicine, Atlanta, GA 30322
John
Hural
Department of Experimental Pathology and Graduate Program in Immunology and Molecular Pathogenesis, Emory University School of Medicine, Atlanta, GA 30322
IL-4
T cells
mast cells
basophils
transcriptional regulation
TCR- and FceRI-mediated signaling mechanisms
NF-AT
IL-4 has been called the "prototypic immunoregulatory cytokine." Like many cytokines, it can affect a variety of target cells in multiple ways. IL-4 has an important role in regulating antibody production, hematopoiesis and inflammation, and the development of effector T-cell responses. It is produced only by a subset of activated hematopoietic cells, including T cells and FcεRl+ mast cells and basophils. Based on the different tissue distribution and access to distinct target cells, IL-4 derived from T and FcεRl+ cells may have quite different effects on these immunological processes. In view of this, as well as the clear correlation of aberrant expression with disease, it is of interest to understand the signals that regulate IL-4 expression in a cell-specific manner. Recently, progress has been made in defining the T-cell- and FcεRl-receptor-mediated signals that stimulate IL-4 gene expression. These studies have demonstrated that there are common and cell-specific signaling pathways that regulate production of this cytokine. In this review, we summarize the activities of IL-4 defined both in vitro and in vivo and compare the signals leading to IL-4 expression in cells of both T- and mast-cell lineage.
Opioid and Opiate Immunoregulatory Processes
231-270
10.1615/CritRevImmunol.v37.i2-6.40
George B.
Stefano
Neuroscience Research Institute, State University of New York at Old Westbury, Old Westbury, New York ,Cardiothoracic Division, Department of Surgery, State University of New York at Stony Brook, Stony Brook, New York,Division of Psychiatry,
Berta
Scharrer
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, New York
Eric M.
Smith
Departments of Psychiatry, University of Texas Medical Branch at Galveston, Galveston, Texas
Thomas K.
Hughes Jr.
Departments of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, Texas
Harold I.
Magazine
Department of Biology, Queens College and Graduate School of the City University of New York, 65-30 Kissena Blvd., Flushing, New York
Thomas V.
Bilfinger
Cardiothoracic Division, Department of Surgery, State University of New York at Stony Brook, Stony Brook, New York
Alan R.
Hartman
Cardiothoracic Division, Department of Surgery, State University of New York at Stony Brook, Stony Brook, New York
Gregory L.
Fricchione
Division of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
Yu
Liu
Neuroscience Research Institute, State University of New York at Old Westbury, Old Westbury, New York
Maynard H.
Makman
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York
opioid peptides
morphine
opiate receptors
invertebrates
human immunocytes
The discovery of the ability of the nervous system to communicate through "public" circuits with other systems of the body is attributed to Ernst and Berta Scharrer, who described the neurosecretory process in 1928. Indeed, the immune system has been identified as another important neuroendocrine target tissue. Opioid peptides are involved in this communication (i.e., neuroimmune) and with that of autoimmunoregulation (communication between immunocytes). The significance of opioid neuropeptide involvement with the immune system is ascertained from the presence of novel δ, μ., and κ receptors on inflammatory cells that result in modulation of cellular activity after activation, as well as the presence of specific enzymatic degradation and regulation processes. In contrast to the relatively uniform antinociceptive action of opiate and opioid signal molecules in neural tissues, the presence of naturally occurring morphine in plasma and a novel μ3 opiate-specific receptor on inflammatory cells adds to the growing knowledge that opioid and opiate signal molecules may have antagonistic actions in select tissues. In examining various disorders (e.g., human immunodeficiency virus, substance abuse, parasitism, and the diffuse inflammatory response associated with surgery) evidence has also been found for the involvement of opiate/opioid signaling in prominent mechanisms. In addition, the presence of similar mechanisms in man and organisms 500 million years divergent in evolution bespeaks the importance of this family of signal molecules. The present review provides an overview of recent advances in the field of opiate and opioid immunoregulatory processes and speculates as to their significance in diverse biological systems.
Tumor Necrosis Factor: Function, Release and Clearance
271-283
10.1615/CritRevImmunol.v37.i2-6.50
M. H. A.
Bemelmans
Department of Surgery, University Hospital Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands
L. J. H.
van Tits
Department of Surgery, University Hospital Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands
W. A.
Buurman
Department of Surgery, University Hospital Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands
soluble TNF receptors
cytokine
kidney
Tumor Necrosis Factor (TNF) is a multifunctional cytokine. It plays an important role in the pathophysiology of several diseases. Recently, it has been discovered that TNF is circulating in two different forms, a bioactive form and an immunologically detectable form. These two forms of TNF show different clearance kinetics. The immunological form is supposed to be an inactivated TNF protein. For this inactivation, proteolytic degradation or TNF binding by inactivating proteins is necessary. In this review we have focused on TNF inactivation by TNF binding proteins. Recent data show that there are soluble TNF receptors circulating which can bind and inactivate TNF. These receptors are membrane-bound TNF receptors which have been proteolytically cleaved from the cell membrane. Two TNF receptors are circulating, the soluble TNF receptor of 55 kDa (P55) and the receptor of 75 kDa (P75). The receptors are held responsible not only for inactivation of the TNF, but also for the clearance of TNF. Recent data show that the kidney is the most important organ for TNF clearance, followed by the liver. All other organs are of less importance. In this review, function, release, and clearance of TNF are discussed.
Accessory Molecule and Costimulation Requirements for CD4 T Cell Response
285-313
10.1615/CritRevImmunol.v37.i2-6.60
Michael
Croft
Department of Biology and the Cancer Center, University of California San Diego, La Jolla, CA 92093
Caroline
Dubey
Department of Biology and the Cancer Center, University of California San Diego, La Jolla, CA 92093
TCR signals
co-signals
T cell activation
accessory molecules
costimulation
naive
memory
effectors
T cell activation is brought about by recognition of peptide/MHC complexes on an antigen-presenting cell (APC) by the T cell receptor (TCR). However, in general this appears to be insufficient for the full development of T cell responses and therefore additional signals are required, provided by ligation of counter-receptors on the T cell by APC accessory molecules. Although many studies have suggested that B7 molecules (CD80/CD86) binding to CD28 induce this second signal, it is now evident that any one of a number of molecules may provide accessory function and that efficient response is only generated following multiple interactions. It has also become clear that T cells exist in varying states of activation or differentiation, and that requirements for accessory molecules and costimuli are not always equivalent. This review covers much of the recent data regarding accessory molecule regulation of T cell responses. A modified version of the two signal model is presented, suggesting that the major function of accessory molecules during the initial stages of activation is to augment the ability to signal through the TCR, and that the primary role of costimulatory signals is to allow IL-2 secretion and growth. The requirement for multiple accessory molecule interactions is discussed in relation to activation of naive T cells and how such interactions are less critical at the memory and effector stages. Finally, this new information is related to how T cells interact with varying APC and how these interactions may modulate T cell response.
Microbial Products and Cytokines in Sleep and Fever Regulation
315-339
10.1615/CritRevImmunol.v37.i2-6.70
James M.
Krueger
Department of Physiology and Biophysics, University of Tennessee, Memphis, 894 Union Avenue, Memphis, TN 38163
Jeannine A.
Majde
Office of Naval Research, Arlington, VA 22217
bacteria
viruses
fungi
fever
slow-wave sleep
REM sleep
EEG
interferon
interleukin-1
TNF
brain
Excessive sleepiness and fever are constitutional symptoms associated with systemic infection. Although fevers have been investigated for many years, sleep responses to infectious challenge have only recently been investigated. Inoculation of animals with bacterial, viral, protozoan and fungal organisms result in complex sleep responses dependent upon the microbial agent and route of administration. The general pattern is characterized by an initial robust increase in non-rapid eye movement sleep (NREMS) followed by a period of NREMS inhibition. REMS is inhibited after infectious challenge. The sleep responses are accompanied by fever but the two responses are, in part, independent from each other. Sleep responses, like fevers, may be beneficial to host defense although this area is relatively uninvestigated. Microbial products likely responsible for sleep and fever responses include bacterial muramyl peptides and endotoxin, and viral double stranded RNA. These microbial products induce sleep and fever responses in animal models. The exact mechanism of how these structurally diverse microbial products elicit sleep and fever remain unknown; however these substances share the ability to induce cytokine production. Cytokines such as interleukin-1 (IL-1), tumor necrosis factor, acidic fibroblast growth factor (FGF), and interferon-α (IFN-α) are somnogenic whether given directly into brain or intravenously. Other cytokines lack somnogenic activity, e.g., IL-2, IL-6, IFNβ and basic FGF. The somnogenic actions of cytokines probably involve growth hormone-releasing hormone (GHRH) and nitric oxide. Anti-GHRH or inhibition of NO production inhibits normal sleep and inhibits IL-1-induced sleep. In conclusion, cytokines are likely key mediators of fever and sleep responses to infection. The microbial-cytokine altered sleep likely results from an amplification of physiological sleep mechanisms which include cytokines, several neuropeptides and neurotransmitters such as nitric oxide.
HLA Class I Chromosomal Region, Genes, and Products: Facts and Questions
341-379
10.1615/CritRevImmunol.v37.i2-6.80
Philippe
Le Bouteiller
Unite INSERM 395, CHU Purpan, BP 3028, 31024 Toulouse, France
human MHC
classical/nonclassical class I genes
molecular organization
polymorphism
regulation
Among the various areas of recent investigation in the field of human MHC class I antigens, the following have been selected for discussion in this review: (1) classical HLA class I genes: are they ubiquitously expressed?, what are the special features of their polymorphism?, are HLA-C molecules functional?, (2) non-classical HLA class I gene products: how restricted is their tissue distribution?, do they exhibit a little polymorphism?, what is their function, if any? (3) non-HLA genes recently detected in the HLA class I chromosomal region: are some of them involved in immunological function and development?, (4) other novel coding sequences present, or possibly present, in the region: the hemochromatosis gene, grc region and associated tumor suppressor genes, housekeeping genes, human equivalent of the murine H-2M region and Ped gene; (5) transcriptional regulation: are there cis-regulatory elements, including locus control region(s). located elsewhere than in the promoters? are CpG methylation, gene imprinting, chromatin structure, DNA rearrangement also implicated? what are the transcription factors involved and how do they interact with each other? is there HLA class I locus-, allele-, or isoform-specific regulation? is class I gene expression dysregulated in human tumors? The answers to these questions are crucial for the development of the future directions for research.
Macrophage Migration Inhibitory Factor (MIF): A Glucocorticoid Counter-Regulator within the Immune System
381-391
10.1615/CritRevImmunol.v37.i2-6.90
Thierry
Calandra
The Picower Institute for Medical Research, Laboratory of Medical Biochemistry, 350 Community Drive, Manhasset, NY 11030
Richard
Bucala
The Picower Institute for Medical Research, Laboratory of Medical Biochemistry, 350 Community Drive, Manhasset, NY 11030
MIF
glucocorticoids
macrophage
T cell
cytokine
septic shock
pituitary
Originally described as a T lymphocyte-derived factor that inhibited the random migration of macrophages, the protein known as macrophage migration inhibitory factor (MIF) was an enigmatic cytokine for almost 3 decades. In recent years, the discovery of MIF as a product of the anterior pituitary gland and the cloning and expression of bioactive, recombinant MIF protein have led to the definition of its critical biological role in vivo. MIF has the unique property of being released from macrophages and T lymphocytes that have been stimulated by glucocorticoids. Once released, MIF overcomes the inhibitory effects of glucocorticoids on TNFα, IL-1β, IL-6, and IL-8 production by LPS-stimulated monocytes in vitro and suppresses the protective effects of steroids against lethal endotoxemia in vivo. MIF also antagonizes glucocorticoid inhibition of T-cell proliferation in vitro by restoring IL-2 and IFN-γ production. This observation has identified a pivotal role for MIF within the immune system and fills an important gap in our understanding of the control of inflammatory and immune responses. Glucocorticoids have long been considered to be an integral component of the stress response to infection or tissue invasion and serve to modulate inflammatory and immune responses. MIF is the first mediator to be identified that can counter-regulate the inhibitory effects of glucocorticoids and thus plays a critical role in the host control of inflammation and immunity.
Functions of CD40 and Its Ligand, gp39 (CD40L)
393-443
10.1615/CritRevImmunol.v37.i2-6.100
Jon D.
Laman
Division of Immunological and Infectious Diseases, TNO Prevention and Health (TNO-PG), P. O. Box 2215, 2301 CE Leiden, The Netherlands
Eric
Claassen
Division of Immunological and Infectious Diseases, TNO Prevention and Health (TNO-PG), P. O. Box 2215, 2301 CE Leiden, The Netherlands
Randolph J.
Noelle
Department of Microbiology, Dartmouth Medical School, One Medical Center Drive, Lebanon, NH 03756
CD40
CD40 Ligand
gp39
lymphocyte activation
signal transduction
tolerance
cognate T and B cell interaction
antibody
isotype switching
autoimmunity
immunotherapy
Initially, a role for the interaction between CD40, expressed on B cells, and gp39 (CD40L), expressed on activated T cells, has been defined in humoral immunity. CD40-CD40L interaction is an essential signal for B cell proliferation, expression of activation markers, immunoglobulin production, and isotype switching. CD40-CD40L interaction is also required for formation of B memory cells and germinal centers, and signaling through CD40 prevents apoptosis of germinal center B cells. Defective expression of CD40L in humans leads to an inability to produce isotypes other than IgM (hyper IgM syndrome), and to an absence of germinal centers.
More recent evidence indicates an expansion of the role of the CD40-CD40L axis in cellular interactions beyond antibody formation. Induced expression of CD40 on monocytes can lead to CD40L-activated monocyte effector mechanisms. In addition, CD40-CD40L interactions are crucially involved in development of autoimmune disease in a number of animal models. CD40-CD40L interactions also impact on growth regulation of certain carcinomas. Manipulation of CD40L has also been used to develop novel strategies for long-term antigen-specific tolerization of peripheral T cells. Finally, the CD40-CD40L axis is involved in thymic selection.
Following is a comprehensive overview of CD40L-CD40 interactions in physiological and pathogenic cellular responses and a discussion of the therapeutic ramifications of these interactions.
Cellular Mucins: Targets for Immunotherapy
445-461
10.1615/CritRevImmunol.v37.i2-6.110
Vasso
Apostolopoulos
The Austin Research Institiute, Studley Road, Heidelberg 3084, Victoria, Australia
Ian F. C.
McKenzie
The Austin Research Institiute, Studley Road, Heidelberg 3084, Victoria, Australia
mucins
immunotherapy
vaccine
tumor
antigen
peptides
Mucins are attracting great interest as potential targets for immunotherapy in the development of vaccines for cancers expressing Mucinl (MUC1) (e.g., breast, pancreas, ovary, and others) as there is (1) a 10-fold increase in the amount in adenocarcinomas; (2) an alteration in expression where they become ubiquitous, and (3) due to altered glycosylation, new epitopes appear on the cell surface that are absent in normal tissues. These new epitopes can be carbohydrate; others are peptide in nature. The cloning of the cDNAs from mucins, particularly MUC1, has led to rapid advances being made, and it is clear that a highly immunogenic peptide exists within the variable number of tandem repeats (VNTR) found in all mucins. This peptide is immunogenic in mice, giving rise to strong antibody production, and most monoclonal antibodies made to breast cancer, which react with the protein core, react with the peptide APDTR. It is now also clear that humans with breast cancer have, in their draining lymph nodes, precursors of cytotoxic T cells that can be stimulated in vitro to react against breast cancer and indeed against the APDTR or a closely related peptide − shown from antibody-blocking studies. These CTLs are unique in that they are non-MHC restricted. The identification of suitable targets, coupled with the known immunogenicity of both the peptide and neo-carbohydrate epitopes, has led to the development of several different programs to immunize humans against breast cancer using either synthetic carbohydrates or peptides conjugated with adjuvants, and clinical trials are now in progress to evaluate their immunogenicity and anti-cancer effects.
Lymphocyte Activation in Health and Disease
463-487
10.1615/CritRevImmunol.v37.i2-6.120
Michael J.
Berridge
The Babraham Institute Laboratory of Molecular Signalling, P. O. Box 158, Cambridge CB2 3ES, U.K.
proliferation
apoptosis
inositol trisphosphate
calcium
protein kinase C
ras
CD28
gene transcription
IL-2
Fas
ceramide
Lymphocytes employ a complex assembly of signaling elements that have been organized on a spatiotemporal map to define their role in stimulating both proliferation and apoptosis. The antigen/major histocompatibility complex (MHC) initiates the sequence by organizing the assembly of an active T-cell receptor (TCR) complex responsible for transmitting information down various signaling cassettes (e.g., the IP3/Ca2+, DAG/ PKC, ras/MAPK, and the PI 3-K pathways). It is proposed that CD28 may exert its costimulatory action by facilitating the assembly of an effective scaffold of signaling elements within the TCR complex. The absence of costimulation through CD28 seems to result in the assembly of a defective scaffold that reverses slowly and may thus account for the state of unresponsiveness responsible for peripheral T-cell tolerance. The signaling cassettes activated by the TCR and CD28 then engage cytosolic factors that transmit information into the nucleus to activate the genes that code for the IL-2 and Fas signaling pathways. The IL-2 and Fas receptors employ additional signaling cassettes (e.g., the JAK/STAT and the sphingomyelinase/ceramide pathways) to mediate their effects on proliferation and apoptosis, respectively. Information concerning these signaling systems is beginning to provide therapeutic strategies to manipulate the immune system to overcome human immunodeficiency virus (HIV) infection, autoimmune diseases, and graft rejection.
T Cell Activation Pathways: B7, LFA-3, and ICAM-1 Shape Unique T Cell Profiles
489-506
10.1615/CritRevImmunol.v37.i2-6.130
Anette Gjorloff
Wingren
The Wallenberg Laboratory, Department of Tumor Immunology, University of Lund, Box 7031, S-220 07, Lund, Sweden
Eduardo
Parra
The Wallenberg Laboratory, Department of Tumor Immunology, University of Lund, Box 7031, S-220 07, Lund, Sweden
Mikael
Varga
Pharmacia Immunology Oncology, Scheelevägen 22, S-223 63, Lund, Sweden
Terje
Kalland
The Wallenberg Laboratory, Department of Tumor Immunology, University of Lund, Box 7031, S-220 07; Pharmacia Immunology Oncology, Scheelevägen 22, S-223 63, Lund, Sweden
Hans-Olov
Sjogren
The Wallenberg Laboratory, Department of Tumor Immunology, University of Lund, Box 7031, S-220 07, Lund, Sweden
Gunnar
Hedlund
The Wallenberg Laboratory, Department of Tumor Immunology, University of Lund, Box 7031, S-220 07; Pharmacia Immunology Oncology, Scheelevägen 22, S-223 63, Lund, Sweden
Mikael
Dohlsten
The Wallenberg Laboratory, Department of Tumor Immunology, University of Lund, Box 7031, S-220 07; Pharmacia Immunology Oncology, Scheelevägen 22, S-223 63, Lund, Sweden
T lymphocytes
costimulation
B7
LFA-3
ICAM-1
superantigen
T helper cell subsets
Two signals are required for induction of cell proliferation and cytokine production in resting T cells. Occupancy of the T cell receptor by antigen/MHC complexes delivers the first signal to the T cell, while the second signal is provided by interaction with costimulatory ligands on APC. CD2, LFA-1, and CD28 are the major costimulatory and adhesive molecules on T cells and bind to the LFA-3, ICAM-1 and B7 ligands, respectively, on APC. LFA-3 plays a central role for naive and memory T helper cells during the early phase of an immune response. The LFA-3/CD2 pathway initiates strong antigen-independent cell adhesion, substantial expansion of naive T helper cells, and induction of large amounts of IFN-γ in memory cells.
The release of IFN-γ may upregulate expression of ICAM-1 and B7 on APC and allows multiple adhesion pathways to amplify the immune response. The LFA- 1/ICAM-l pathway stimulates adhesion and cell proliferation more efficiently in memory T helper cells than in naive cells. Further, the results suggest that naive T helper cells express functionally inactive LFA-1 molecules on the cell surface, which may have a physiological role in keeping these cells in a resting state. B7 costimulation superinduces IL-2 production in both naive and memory T helper cells and generates long-lasting cell proliferation. This permits transition from an autocrine to a paracrine immune response. Coexpression of B7/LFA-3 provides an optimal APC function and enables a vigorous T cell response to minute amounts of antigen. AP-1 and NF-κB transcription factors are involved in the induction of several cytokine gene promoters and play a central role in the regulation of IL-2 gene transcription. LFA-3 costimulation only moderately enhances AP-1 DNA-binding activity and does not influence the NF-κB activity induced by TCR engagement, whereas B7 costimulation induces large amounts of NF-κB and AP-1 activity in T helper cells. The costimulatory ligands represent a family of adhesion molecules with considerable redundancy. Interfamily redundancy of LFA-3, B7, and ICAM ligands offers an opportunity to regulate distinct T cell response profiles in various microenvironments at separate time points of an immune response.
DNA Vaccines – A Modern Gimmick or a Boon to Vaccinology?
507-521
10.1615/CritRevImmunol.v37.i2-6.140
Elanchezhiyan
Manickan
Department of Microbiology, University of Tennessee, Knoxville, TN 37996-0845
Kevin L.
Karem
Department of Microbiology, University of Tennessee, Knoxville, TN 37996-0845
Barry T.
Rouse
Department of Microbiology, University of Tennessee, Knoxville, TN 37996-0845
plasmids
infectious disease
gene therapy
mucosal delivery
cytokines
virus
CTLs and CD4+ T cells
The reports in 1993 that naked DNA encoding viral genes conferred protective immunity came as a surprise to most vaccinologists. This review analyses the expanding number of examples where plasmid DNA induces immune responses. Issues such as the type of immunity induced, mechanisms of immune protection, and how DNA vaccines compare with other approaches are emphasized. Additional issues discussed include the likely means by which DNA vaccines induce CTL, how the potency and type of immunity induced can be modified, and whether DNA vaccines represent a practical means of manipulating unwanted immune response occurring during immunoinflammatory diseases. It seems doubtful if DNA vaccines will replace currently effective vaccines, but they may prove useful for prophylactic use against some agents that at present lack an effective vaccine. DNA vaccines promise to be valuable to manipulate the immune response in situations where responses to agents are inappropriate or ineffective.
The Mucosal Adjuvant Activities of ADP-Ribosylating Bacterial Enterotoxins
523-554
10.1615/CritRevImmunol.v37.i2-6.150
Denis P.
Snider
Department of Pathology, HSC-3N26H, McMaster University, 1200 Main St. W., Hamilton, Ontario, Canada L8N 3Z5
cholera toxin
heat-labile toxin
mucosal immunity
cAMP
The bacterial enterotoxins, cholera toxin and the heat labile toxin of E. coli, are well known adjuvants for mucosal immune response. Their common A chain mediates the toxigenic mechanism by causing ADP ribosylation of G proteins and subsequent elevation of cAMP in target cells. A large IgA and IgG antibody response to admixed protein antigen (Ag) is the hallmark of these adjuvants and is clearly associated with the A chain activity. Expansion of Ag-specific B and T cells, alteration of T cell cytokine production, and changes in regulatory T cells have been reported as adjuvant mechanisms. The B chain derivatives of these toxins can also weakly enhance immune response, especially if covalently associated with Ag and used for nasophyrangeal immunization. Importantly, these toxins or their B chain derivatives can alter the normal immune regulation that produces oral tolerance. This indicates that they modulate mechanisms operative between the mucosal and systemic immune systems. There are some discrepancies between in vitro models of CT or LT activity and in vivo manifestations of their adjuvant activities. Interpretation of current data regarding in vivo mechanism is hampered by an incomplete understanding of how mucosal B and T cells can interact with systemic lymphoid tissue and vice versa. More important, there is no clear understanding of the early effects of the toxins on the local (and draining) mucosal lymphoid tissues. This is especially true in the critical areas of antigen presentation, T and B cell activation, and cytokine production.
lnterleukin-1 Receptor Antagonist
555-583
10.1615/CritRevImmunol.v37.i2-6.160
Andrew C.
Lennard
Yamanouchi Research Institute U.K., Littlemore Hospital, Oxford OX4 4XN, U.K.
cytokine
gene
promoter
regulation
inflammation
pharmacology
The interleukin-1 receptor antagonist (IL-lra) is unusual in that it is the only known naturally occurring, cytokine receptor antagonist with no apparent agonist function. Over the last 5 years, since the cloning of the IL-lra cDNA sequence, there has been intensive research on the genetics, regulation, and potential therapeutic value of this protein. The later discovery of a second form of IL-lra in 1991 has complicated the picture. Whereas the originally described IL-lra is predominantly glycosylated and secreted (sIL-lra), the alternative isoform is unglycosylated and intracellular (icIL-lra). Although the biological roles of the two forms are still open to question, IL-lra is likely to be of great importance in the pathogenesis of both acute and chronic inflammatory diseases. A large body of evidence for this conclusion has come from animal models of inflammatory disease that respond well to administration of exogenous IL-lra. A role for recombinant IL-lra in the management of human disease is still under investigation. The two forms of IL-lra are encoded by a single gene by alternative usage of two first exons. Expression of sIL-lra and icIl-lra is regulated by two promoters. In this review I explore the genetics of the gene encoding IL-lra (IL-1RN) and the mechanisms of IL-lra gene activation to produce sIL-lra and icIL-lra. Also, possible biological roles for these immunomodulators in health and disease are discussed.