Annual Review of Immunology - Volume 16, 1998

The interleukin-1 receptor antagonist (IL-1Ra) is a member of the IL-1 family that binds to IL-1 receptors but does not induce any intracellular response. Two structural variants of IL-1Ra have previously been described: a 17-kDa form that is secreted from monocytes, macrophages, neutrophils, and other cells (sIL-1Ra) and an 18-kDa form that remains in the cytoplasm of keratinocytes and other epithelial cells, monocytes, and fibroblasts (icIL-1Ra). An additional 16-kDa intracellular isoform of IL-1Ra has recently been described in neutrophils, monocytes, and hepatic cells. Both of the major isoforms of IL-1Ra are transcribed from the same gene through the use of alternative first exons. The two promoters regulating transcription of the secreted and intracellular forms have been cloned, and some of the functional cis-acting DNA regions have been characterized. The production of IL-1Ra is stimulated by many substances including adherent IgG, other cytokines, and bacterial or viral components. The tissue distribution of IL-1Ra in mice indicates that sIL-1Ra is found predominantly in peripheral blood cells, lungs, spleen, and liver, while icIL-1Ra is found in large amounts in skin. Studies in transgenic and knockout mice indicate that IL-1Ra is important in host defense against endotoxin-induced injury. IL-1Ra is produced by hepatic cells with the characteristics of an acute phase protein. Endogenous IL-1Ra is produced in numerous experimental animal models of disease as well as in human autoimmune and chronic inflammatory diseases. The use of neutralizing anti-IL-1Ra antibodies has demonstrated that endogenous IL-1Ra is an important natural antiinflammatory protein in arthritis, colitis, and granulomatous pulmonary disease. Treatment of human diseases with recombinant human IL-1Ra showed an absence of benefit in sepsis syndrome. However, patients with rheumatoid arthritis treated with IL-1Ra for six months exhibited improvements in clinical parameters and in radiographic evidence of joint damage.

In the past 10 years, our knowledge of the malaria parasite has increased enormously: identification and analysis of parasite antigens, demonstration of protection of monkeys and mice following immunization with these antigens, and better understanding of the mechanisms of immunity to malaria and the pathogenesis of disease in malaria. Powerful new adjuvants have been developed, some of which—it is hoped—will be suitable for human use. Recently, a successful human trial of a vaccine aimed at sporozoites (the stage inoculated by mosquitoes) was completed. However, it is the red blood cell stage of the parasite that causes disease, and it is against this stage—in which the parasite grows at an exponential rate—that it has proven very difficult to induce a protective immune response by vaccination. This review focuses on recent exciting developments toward a blood-stage vaccine. We analyze the major obstacles to vaccine development and outline a strategy involving public- and industry-funded research that should result in development of a vaccine.

CD81 (TAPA-1) is a widely expressed cell-surface protein involved in an astonishing variety of biologic responses. It has been cloned independently several times for different functional effects and is reported to influence adhesion, morphology, activation, proliferation, and differentiation of B, T, and other cells. On B cells CD81 is part of a complex with CD21, CD19, and Leu13. This complex reduces the threshold for B cell activation via the B cell receptor by bridging Ag specific recognition and CD21-mediated complement recognition. Similarly on T cells CD81 associates with CD4 and CD8 and provides a costimulatory signal with CD3. In fetal thymic organ culture, mAb to CD81 block maturation of CD4⁻CD8⁻ thymocytes, and expression of CD81 on CHO cells endows those cells with the ability to support T cell maturation. However, CD81-deficient mice express normal numbers and subsets of T cells. These mice do exhibit diminished antibody responses to protein antigens. CD81 is also physically and functionally associated with several integrins. Anti-CD81 can activate integrin α4β1(VLA-4) on B cells, facilitating their adhesion to tonsilar interfollicular stroma. Similarly, anti-CD81 can activate αLβ2 (LFA-1) on human thymocytes. CD81 can also affect cognate B-T cell interactions because anti-CD81 increases IL-4 synthesis by T cells responding to antigen presented by B cells but not by monocytes. The tetraspanin superfamily (or TM4SF) includes CD81, CD9, CD37, CD53, CD63, CD82, CD151, and an increasing number of additional proteins. Like CD81, several tetraspanins are involved in cell adhesion, motility, and metastasis, as well as cell activation and signal transduction.

CD40-CD154–mediated contact-dependent signals between B and T cells are required for the generation of thymus dependent (TD) humoral immune responses. CD40-CD154 interactions are however also important in many other cell systems. CD40 is expressed by a large variety of cell types other than B cells, and these include dendritic cells, follicular dendritic cells, monocytes, macrophages, mast cells, fibroblasts, and endothelial cells. CD40- and CD154-knockout mice and antibodies to CD40 and CD154 have helped to elucidate the role of the CD40-CD154 system in immune responses. Recently published studies indicate that CD40-CD154 interactions can influence T cell priming and T cell–mediated effector functions; they can also upregulate costimulatory molecules and activate macrophages, NK cells, and endothelia as well as participate in organ-specific autoimmune disease, graft rejection, and even atherosclerosis. This review focuses on the role of the CD40-CD154 system in the regulation of many newly discovered functions important in inflammation and cell-mediated immunity.

The transforming growth factor β (TGF-β) family of proteins are a set of pleiotropic secreted signaling molecules with unique and potent immunoregulatory properties. TGF-β1 is produced by every leukocyte lineage, including lymphocytes, macrophages, and dendritic cells, and its expression serves in both autocrine and paracrine modes to control the differentiation, proliferation, and state of activation of these immune cells. TGF-β can modulate expression of adhesion molecules, provide a chemotactic gradient for leukocytes and other cells participating in an inflammatory response, and inhibit them once they have become activated. Increased production and activation of latent TGF-β have been linked to immune defects associated with malignancy and autoimmune disorders, to susceptibility to opportunistic infection, and to the fibrotic complications associated with chronic inflammatory conditions. In addition to these roles in disease pathogenesis, TGF-β is now established as a principal mediator of oral tolerance and can be recognized as the sine qua non of a unique subset of effector cells that are induced in this process. The accumulated knowledge gained through extensive in vitro functional analyses and from in vivo animal models, including newly established TGF-β gene knockout and transgenic mice, supports the concept that clinical therapies based on modulation of this cytokine represent an important new approach to the treatment of disorders of immune function.

Information is increasingly available concerning the molecular events that occur during primary and antigen-dependent stages of B cell development. In this review the roles of transcription factors and coactivators are discussed with respect to changes in expression patterns of various genes during B cell development. Transcriptional regulation is also discussed in the context of developmentally regulated immunoglobulin gene V(D)J recombination, somatic hypermutation, and isotype switch recombination.

Immunological memory can be defined as the faster and stronger response of an animal that follows reexposure to the same antigen. By this definition, it is an operational property of the whole animal or the immune system. Memory cells express a different pattern of cell surface markers, and they respond in several ways that are functionally different from those of naive cells. Murine memory cells are CD44 high and low in the expression of activation markers such as CD25 (IL-2R), whereas human memory cells are CD45RA⁻, CD45RO⁺. In contrast to naive cells, memory cells secrete a full range of T cell cytokines and can be polarized to secrete particular restricted patterns of secretion for both CD4 and CD8 T cells. The requirements for the activation of memory cells for proliferation and cytokine production are not quite as strict as those of naive cells, but costimulation in the broad sense is required for optimum responses and for responses to suboptimum antigen concentrations. It would appear that memory cells can persist in the absence of antigenic stimulation and persist as nondividing cells. Reencounter with the same antigen can expand the population to a new, stable, higher level and generate a separate population of CD44 high effectors that may be required for protection, while competition from other antigens can drive it down to a lower stable level. It is unclear how or where memory cells arise, but once generated they have different pathways of recirculation and homing.

The transcription factor NF-κB, more than a decade after its discovery, remains an exciting and active area of study. The involvement of NF-κB in the expression of numerous cytokines and adhesion molecules has supported its role as an evolutionarily conserved coordinating element in the organism's response to situations of infection, stress, and injury. Recently, significant advances have been made in elucidating the details of the pathways through which signals are transmitted to the NF-κB:IκB complex in the cytosol. The field now awaits the discovery and characterization of the kinase responsible for the inducible phosphorylation of IκB proteins. Another exciting development has been the demonstration that in certain situations NF-κB acts as an anti-apoptotic protein; therefore, elucidation of the mechanism by which NF-κB protects against cell death is an important goal. Finally, the generation of knockouts of members of the NF-κB/IκB family has allowed the study of the roles of these proteins in normal development and physiology. In this review, we discuss some of these recent findings and their implications for the study of NF-κB.

Considerable evidence suggests that the development of systemic lupus erythematosus (SLE) has a strong genetic basis. Recent studies have emphasized that this disease, like other autoimmune diseases, is a complex genetic trait with contributions from major histocompatibility complex (MHC) genes and multiple non-MHC genes. Etiologic genes in these disorders determine susceptibility, and no particular gene is necessary or sufficient for disease expression. Studies of murine models of lupus have provided important insight into the immunopathogenesis of IgG autoantibody production and lupus nephritis, and genetic analyses of these mice overcome certain obstacles encountered when studying patients. Genome-wide linkage studies of different crosses have mapped the position of at least 12 non-MHC disease-susceptibility loci in the New Zealand hybrid model of lupus. Although the identity of the actual genes is currently unknown, recent studies have begun to characterize how these genetic contributions may function in the autoimmune process, especially in terms of their role in autoantibody production. Studies of MHC gene contributions in New Zealand mice have shown that heterozygosity for particular haplotypes greatly increases pathogenic autoantibody production and the incidence of severe nephritis. The mechanism for this effect appears to be genetically complex. Studies in human SLE have mostly focused on the association of disease with alleles of immunologically relevant genes, especially in the MHC. Associations with various complement component deficiencies and an allele of a particular Fcγ receptor gene (FCGR2A) also have been described. In a diversion from previous association studies, a recent directed linkage analysis of sibpairs with SLE was based on mapping studies in murine lupus and may be an important step toward identifying a new disease-susceptibility gene in patients. Since the genes that predispose to autoimmunity are probably related to key events in pathogenesis, their identification in patients and murine models will almost certainly provide important insight into the breakdown of immunological self-tolerance and the cause of autoimmune disease.

Cytokines and interferons are molecules that play central roles in the regulation of a wide array of cellular functions in the lympho-hematopoietic system. These factors stimulate proliferation, differentiation, and survival signals, as well as specialized functions in host resistance to pathogens. Although cytokines are known to activate multiple signaling pathways that together mediate these important functions, one of these pathways, the Jak-STAT pathway, is the focus of this chapter. This pathway is triggered by both cytokines and interferons, and it very rapidly allows the transduction of an extracellular signal into the nucleus. The pathway uses a novel mechanism in which cytosolic latent transcription factors, known as signal transducers and activators of transcription (STATs), are tyrosine phosphorylated by Janus family tyrosine kinases (Jaks), allowing STAT protein dimerization and nuclear translocation. STATs then can modulate the expression of target genes. The basic biology of this system, including the range of known Jaks and STATs, is discussed, as are the defects in animals and humans lacking some of these signaling molecules.

Classical class I molecules assemble in the endoplasmic reticulum (ER) with peptides mostly generated from cytosolic proteins by the proteasome. The activity of the proteasome can be modulated by a variety of accessory protein complexes. A subset of the proteasome β-subunits (LMP2, LMP7, and MECL-1) and one of the accessory complexes, PA28, are upregulated by γ-interferon and affect the generation of peptides to promote more efficient antigen recognition. The peptides are translocated into the ER by the transporter associated with antigen processing (TAP). A transient complex containing a class I heavy chain–β2 microglobulin (β2m) dimer is assembled onto the TAP molecule by successive interactions with the ER chaperones calnexin and calreticulin and a specialized molecule, tapasin. Peptide binding releases the class I–β2m dimer for transport to the cell surface, while lack of binding results in proteasome-mediated degradation. The products of certain nonclassical MHC-linked class I genes bind peptides in a similar way. A homologous set of β2m-associated membrane glycoproteins, the CD1 molecules, appears to bind lipid-based ligands within the endocytic pathway.

NK cells are regulated by opposing signals from receptors that activate and inhibit effector function. While positive stimulation may be initiated by an array of co-stimulatory receptors, specificity is provided by inhibitory signals transduced by receptors for MHC class I. Three distinct receptor families, Ly49, CD94/NKG2, and KIR, are involved in NK cell recognition of polymorphic MHC class I molecules. A common pathway of inhibitory signaling is provided by ITIM sequences in the cytoplasmic domains of these otherwise structurally diverse receptors. Upon ligand binding and activation, the inhibitory NK cell receptors become tyrosine phosphorylated and recruit tyrosine phosphatases, SHP-1 and possibly SHP-2, resulting in inhibition of NK cell–mediated cytotoxicity and cytokine expression. Recent studies suggest these inhibitory NK cell receptors are members of a larger superfamily containing ITIM sequences, the inhibitory receptor superfamily (IRS).

An expanding family of BCL-2 related proteins share homology, clustered within four conserved regions, namely BCL-2 homology (BH1-4) domains, which control the ability of these proteins to dimerize and function as regulators of apoptosis. Moreover, BCL-XL, BCL-2, and BAX can form ion-conductive pores in artificial membranes. The BCL-2 family, comprised of both pro-apoptotic and anti-apoptotic members, acts as a checkpoint upstream of CASPASES and mitochondrial dysfunction. BID and BAD possess the minimal death domain BH3, and the phosphorylation of BAD connects proximal survival signals to the BCL-2 family. BCL-2 and BCL-XL display a reciprocal pattern of expression during lymphocyte development. Gain- and loss-of-function models revealed stage-specific roles for BCL-2 and BCL-XL. BCL-2 can rescue maturation at several points of lymphocyte development. The BCL-2 family also reveals evidence for a cell-autonomous coordination between the opposing pathways of proliferation and cell death.

Recent results obtained in mice deficient in either FcRs or complement have revealed distinct functions for these two classes of molecules. While each is capable of interacting with antibodies or immune complexes, the two systems mediate distinct biological effector responses. Complement-deficient mice are unable to mediate innate immune responses to several bacterial pathogens and bacterial toxins, yet respond normally to the presence of cytotoxic antibodies and pathogenic immune complexes. In contrast, FcR-deficient mice display no defects in innate immunity or susceptibility to a variety of pathogens, yet they are unable to mediate inflammatory responses to cytotoxic IgG antibodies or IgG immune complexes, despite the presence of a normal complement system. These results lead to the surprising conclusion that these two systems have evolved distinct functions in host immunity, with complement and its receptors mediating the interaction of natural antibodies (IgM) with pathogens to effect protection, while FcRs couple the interaction of IgG antibodies to effector cells to trigger inflammatory sequelae. These results necessitate a fundamental revision of the role of these antibody-binding systems in the immune response.

This review summarizes the clinical history and rationale for xenotransplantation; recent progress in understanding the physiologic, immunologic, and infectious obstacles to the procedure's success; and some of the strategies being pursued to overcome these obstacles. The problems of xenotransplantation are complex, and a combination of approaches is required. The earliest and most striking immunologic obstacle, that of hyperacute rejection, appears to be the closest to being solved. This phenomenon depends on the binding of natural antibody to the vascular endothelium, fixation of complement by that antibody, and finally, activation of the endothelium and initiation of coagulation. Therefore, these three pathways have been targeted as sites for intervention in the process. The mechanisms responsible for the next immunologic barrier, that of delayed xenograft/acute vascular rejection, remain to be fully elucidated. They probably also involve multiple pathways, including antibody and/or immune cell binding and endothelial cell activation. The final immunologic barrier, that of the cellular immune response, involves mechanisms that are similar to those involved in allograft rejection. However, the strength of the cellular immune response to xenografts is so great that it is unlikely to be controlled by the types of nonspecific immunosuppression used routinely to prevent allograft rejection. For this reason, it may be essential to induce specific immunologic unresponsiveness to at least some of the most antigenic xenogeneic molecules.

One of the characteristic features of Hodgkin's disease (HD) is the presence of a small population of often bizarre-looking large mono- or multinucleated Hodgkin and Reed-Sternberg (HRS) cells within the affected tissue. Recent cytogenetic investigations, studies of Epstein-Barr virus (EBV) genomes present in HRS cells, and analyses of Ig gene rearrangements amplified from single, micromanipulated HRS cells show that these cells largely represent clonal populations. The finding of Ig gene rearrangements in HRS cells in most cases of HD identifies B cells as the precursors of HRS cells in most if not all cases. Furthermore, the presence and pattern of somatic mutations within the rearranged Ig genes show that HRS cells in classical (i.e. nodular sclerosis, mixed cellularity, and lymphocyte depletion HD) as well as lymphocyte predominant (LP) HD originate from germinal center (GC) B cells. Ongoing somatic mutation and evidence for selection link HRS cells from LP HD to a mutating, antigen-selected GC B cell. In classical HD, the finding of “crippling” mutations and lack of stringent selection for antigen receptor expression suggests that in this case HRS cells are derived from a compartment of GC B cells that were destined to die but escaped apoptosis by some transforming event. One candidate for the latter is EBV infection.

Interleukin-12 (IL-12) is a heterodimeric cytokine that plays a central role in promoting type 1 T helper cell (Th1) responses and, hence, cell-mediated immunity. Its activities are mediated through a high-affinity receptor composed of two subunits, designated β1 and β2. Of these two subunits, β2 is more restricted in its distribution, and regulation of its expression is likely a central mechanism by which IL-12 responsiveness is controlled. Studies with neutralizing anti-IL-12 antibodies and IL-12-deficient mice have suggested that endogenous IL-12 plays an important role in the normal host defense against infection by a variety of intracellular pathogens. However, IL-12 appears also to play a central role in the genesis of some forms of immunopathology. Inhibition of IL-12 synthesis or activity may be beneficial in diseases associated with pathologic Th1 responses, such as multiple sclerosis or Crohn's disease. On the other hand, administration of recombinant IL-12 may have utility in the treatment of diseases associated with pathologic Th2 responses such as allergic disorders and asthma.

While still incomplete, the first data concerning the biochemistry of T cell receptor–ligand interactions in cell-free systems seem to have considerable predictive value regarding whether a T cell response is strong or weak or suppressive. This data will help considerably in elucidating the mechanisms behind T cell responsiveness. Also of great interest are the first structures of T cell receptor molecules and, particularly, TCR-ligand complexes. These appear to confirm earlier suggestions of a fixed orientation for TCR engagement with peptide/MHC and should form the basis for understanding higher oligomers, evidence for which has also just emerged. We conclude with an analysis of the highly diverse CDR3 loops found in all antigen receptor molecules and suggest that such regions form the core of both TCR and antibody specificity.

Covalent attachment of activated complement C3 (C3d) to antigen links innate and adaptive immunity by targeting antigen to follicular dendritic cells (FDC) and B cells via specific receptors CD21 and CD35. Recent characterization of knockout mice deficient in complement components C3, C4, or the receptors CD21 and CD35 as well as biochemical studies of the CD21/CD19/Tapa-1 coreceptor on B cells have helped to elucidate the mechanism of complement regulation of both B-1 and B-2 lymphocytes. Interestingly, natural antibody of the adaptive immune system provides a major recognition role in activation of the complement system, which in turn enhances activation of antigen-specific B cells. Enhancement of the primary and secondary immune response to T-dependent antigens is mediated by coligation of the coreceptor and the B cell antigen receptor, which dramatically increases follicular retention and B cell survival within the germinal center. Most recent evidence suggests that complement also regulates elimination of self-reactive B cells, as breeding of mice that are deficient in C4 or CD21/CD35 with the lupus-prone strain of lpr mice demonstrates an exacerbation of disease due to an increase in autoantibodies.