Showing papers in "Annual Review of Immunology in 1995"

Interleukin-12: A Proinflammatory Cytokine with Immunoregulatory Functions that Bridge Innate Resistance and Antigen-Specific Adaptive Immunity

Abstract: Interleukin-12 (IL-12) is a heterodimeric cytokine produced mostly by phagocytic cells in response to bacteria, bacterial products, and intracellular parasites, and to some degree by B lymphocytes. IL-12 induces cytokine production, primarily of IFN-gamma, from NK and T cells, acts as a growth factor for activated NK and T cells, enhances the cytotoxic activity of NK cells, and favors cytotoxic T lymphocyte generation. In vivo IL-12 acts primarily at three stages during the innate resistance/adaptive immune response to infection: 1. Early in the infection, IL-12 is produced and induces production from NK and T cells of IFN-gamma, which contributes to phagocytic cell activation and inflammation; 2. IL-12 and IL-12-induced IFN-gamma favor Th1 cell differentiation by priming CD4+ T cells for high IFN-gamma production; and 3. IL-12 contributes to optimal IFN-gamma production and to proliferation of differentiated Th1 cells in response to antigen. The early preference expressed in the immune response depends on the balance between IL-12, which favors Th1 responses, and IL-4, which favors Th2 responses. Thus, IL-12 represents a functional bridge between the early nonspecific innate resistance and the subsequent antigen-specific adaptive immunity.

Peptide antibiotics and their role in innate immunity.

Abstract: CONTENTS INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 FIVE CHEMICALLY DIFFERENT GROUPS OF PEPTIDE ANTIBIOTICS . . . . . . . . . . .. 63 Linear, Mostly Helical, Peptides Without Cys, With or Without a Hinge . . . . . . . . . . . . . . . 63 Linear Pep tides Without Cys and with a High Proportion of Certain Residues . . . . . . . . . 67 Antibacterial Peptides with One Disulfide Bond . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 Peptides with Two or More S-S Bonds Giving Mainly or Only fJ-Sheet Structures. . . . . . . 69 Antibacterial Peptides Derivedfrom Larger Polypeptides with Other Known Functions . . 72 ANTIBACTERIAL PROTEINS AND ACTIVE FRAGMENTS OF SUCH PROTEINS . . . . 73

Hepatitis B virus immunopathogenesis

Abstract: Approximately 5% of the world population is infected by the hepatitis B virus (HBV) that causes a necroinflammatory liver disease of variable duration and severity. Chronically infected patients with active liver disease carry a high risk of developing cirrhosis and hepatocellular carcinoma. The immune response to HBV-encoded antigens is responsible both for viral clearance and for disease pathogenesis during this infection. While the humoral antibody response to viral envelope antigens contributes to the clearance of circulating virus particles, the cellular immune response to the envelope, nucleocapsid, and polymerase antigens eliminates infected cells. The class I- and class II-restricted T cell responses to the virus are vigorous, polyclonal, and multispecific in acutely infected patients who successfully clear the virus, and the responses are relatively weak and more narrowly focused in chronically infected patients who do not. The pathogenetic and antiviral potential of the cytotoxic T lymphocyte (CTL) response to HBV has been demonstrated by the induction of a severe necroinflammatory liver disease following the adoptive transfer of HBsAg-specific CTL into HBV transgenic mice, and by the noncytolytic suppression of viral gene expression and replication in the same animals by a posttranscriptional mechanism mediated by interferon gamma, tumor necrosis factor alpha, and interleukin 2. The dominant cause of viral persistence during HBV infection is the development of a weak antiviral immune response to the viral antigens. While neonatal tolerance probably plays an important role in viral persistence in patients infected at birth, the basis for poor responsiveness in adult-onset infection is not well understood and requires further analysis. Viral evasion by epitope inactivation and T cell receptor antagonism may contribute to the worsening of viral persistence in the setting of an ineffective immune response, as can the incomplete downregulation of viral gene expression and the infection of immunologically privileged tissues. Chronic liver cell injury and the attendant inflammatory and regenerative responses create the mutagenic and mitogenic stimuli for the development of DNA damage that can cause hepatocellular carcinoma. Elucidation of the immunological and virological basis for HBV persistence may yield immunotherapeutic and antiviral strategies to terminate chronic HBV infection and reduce the risk of its life-threatening sequellae.

Receptor-Dependent Mechanisms of Cell Stimulation by Bacterial Endotoxin

Abstract: In humans and experimental animals the presence of bacterial lipopolysaccharide (endotoxin, LPS) signals the presence of gram-negative bacteria. Recognition of LPS triggers gene induction by myeloid and nonmyeloid lineage cells. These inducible genes encode proteins that include cytokines, adhesive proteins, and enzymes that produce low molecular weight proinflammatory mediators. Together the products of these inducible genes upregulate host defense systems that participate in eliminating the bacterial infection. Unfortunately, these same mediators contribute to a serious human disease known as septic shock. Considerable progress has been made during the past decade in determining the sources, identities, and sequence of release of these mediators. In contrast, until recently, marked gaps in our knowledge existed regarding the identity of the LPS receptor and intracellular signaling pathways responsible for LPS-induced cell activation. The discovery in 1986 of a plasma protein termed LPS binding protein (LBP) led to the discovery of unanticipated mechanisms of LPS-induced cell activation. CD14 was found as a soluble serum protein or as a glycosylphosphatidylinositol (GPI)-anchored protein of myeloid lineage cells; it now occupies a key role in LPS-induced cell activation as we understand it today. Here we discuss how LBP enables LPS binding to CD14 and how complexes of LPS and soluble or GPI-anchored CD14 participate in cell activation. We also review the evidence supporting a model for a functional LPS receptor of myeloid cells, which is multimeric, comprised of GPI-anchored CD14 and a presently unidentified transmembrane protein that together bind LPS and initiate cell activation via kinase cascades.

The regulation of immunity to Leishmania major.

Abstract: Experimental infection with the intracellular protozoan Leishmania major con­ stitutes a particularly versatile model for assessing the role of CD4+ subset de­ velopment in the host response to infectious disease. The association of Thl development with control of infection, and of Th2 cell development with pro­ gressive disease, has been well established. The capacity to manipulate the out­ come, using distinct immunologic interventions, in both genetically resistant and susceptible mice has identified key effector cytokines that must be present during the time of initial priming of T cells in order to affect the CD4 switch phenotype. Roles for interferon-y (IFN-y), interleukin 12 (IL-12), and IL-4 in Thl and Th2 maturation have been demonstrated, although additional undefined signals are required. Study of the genetically susceptible BALB/c mouse has shown fail­ ure to downmodulate IL-4 production in response to infection, a response that is critically associated with the failure to develop appropriate Thl responses. Use of the murine L. major model continues to elucidate new methods for vaccine development and suggests a promising system for identification of genes that determine susceptibil ity to i nfectio n.

The Three-Dimensional Structure of Peptide-MHC Complexes

Abstract: The ability of MHC molecules to present a broad spectrum of peptide antigens for T cell recognition requires a compromise between high affinity and broad specificity. Three-dimensional atomic structures of several class I and class II MHC molecules reveal a unique structural solution to this problem: Tight binding to the peptide main chain is supplemented by more or less restrictive interactions with peptide side chains. In spite of these contacts, peptide side-chain and conformational variability ensures that the resulting peptide-MHC complex presents an antigenically unique surface to T cell receptors. Extension of this understanding to other peptide-MHC complexes, including agonist/antagonist peptides and the identification of antigenic peptides within protein sequences, however, requires a detailed analysis of the interactions that determine both peptide-MHC binding affinity and the conformations of bound peptides. While many of these interactions can be modeled by homology with known structures, their specificity can depend sensitively on subtle and long-range structural effects. Structurally and immunologically important distinctions are also found between the class I and class II peptide-binding strategies. Taken together, these interactions ultimately determine the ability of an individual to respond successfully to immune challenges.

T Cell-Independent Antigens Type 2

Abstract: In this review we have attempted to define the characteristics of TI-2 antigens that enable them to stimulate antibody production in the absence of T cell help. One of the most critical properties of this group of antigens is their ability to deliver prolonged and persistent signaling to the B cell. This by itself is not however sufficient to stimulate Ig synthesis, and they must therefore stimulate non-T cells to interact with the B cells either directly or indirectly via cytokine production. There is evidence implicating the NK cell and T cell as playing this important role in response to TI antigens. Furthermore, we discuss the importance of cytokines such as IL-3, GMCSF, and IFN-gamma, which significantly enhance antibody production by these antigens. Finally, we present evidence demonstrating that B cell activation via TI stimuli does not play merely a permissive role in allowing for cell cycle entry and enhanced responsiveness to other stimuli. Rather, the nature of the B cell activating signal is critical in determining the quantitative and qualitative profile of Ig isotype production.

Genetic Control of Autoimmune Diabetes in the Nod Mouse

Abstract: The nonobese diabetic (NOD) mouse is a model of human autoimmune insulin-dependent diabetes mellitus. The NOD mouse also serves as a model for studying complex polygenic diseases because at least fourteen different loci are linked to disease development. The first Idd locus recognized, Idd1, is linked to the major histocompatibility complex (MHC), and its inheritance and expression are a paradigm for the other non-MHC Idd genes. The NOD allele at Idd1 does not behave as a recessive diabetes susceptibility gene, as it was originally thought to be, but instead it acts as a dominant gene with varying degrees of penetrance for the phenotypes of insulitis, a prediabetic inflammatory lesion, and spontaneous diabetes. MHC congenic strains of mice have shown that the NOD MHC is essential but, by itself, not sufficient for developing diabetes. The contributions of non-MHC Idd loci have also been assessed with NOD congenic strains derived by replacing NOD-specific chromosomal segments with those from diabetes-resistant strains of mice. While only partial protection from disease is provided by resistance alleles at single non-MHC Idd loci, epistatic interaction between two of the loci, Idd3 and Idd10, produced nearly complete protection from diabetes. Identifying Idd genes and defining their biologic functions should further our understanding of autoimmune disease pathogenesis and facilitate development of new treatments for diabetes.

Signaling through the hematopoietic cytokine receptors

Abstract: Hematopoiesis is regulated through the interaction of a variety of growth factors with specific receptors of the cytokine receptor superfamily. Although lacking catalytic domains, all the receptors couple ligand binding to the rapid induction of protein tyrosine phosphorylation. This is mediated through a novel family of protein tyrosine kinases termed the Janus kinases (Jaks) which associate with the receptors and are activated following ligand binding. Depending upon the cytokine/receptor system, one or more of the four known Jaks (Jak1, Jak2, Jak3, Tyk2) is/are involved. The activated Jaks phosphorylate both themselves and the receptor subunits, creating docking sites for SH2-containing proteins including SHC, which couples receptor engagement to activation of the ras pathway, and HCP, a protein tyrosine phosphatase which negatively affects the response. In addition, the Jaks phosphorylate one or more of a family of signal transducers and activators of transcription (Stats). Phosphorylation of Stats induces their nuclear translocation and DNA-binding activity. Activation of Stats is independent of activation of the ras pathway and represents a novel signaling pathway correlated with mitogenesis.

Positive selection of thymocytes.

Abstract: Differentiation of alpha beta T cell receptor (TCR)-expressing T cells involves an obligatory interaction with self-major histocompatibility complex (MHC) molecules in the thymus This process, called positive selection, both rescues thymocytes from programmed cell death and induces their differentiation into mature T cells Another critical event in thymic development is to prevent maturation of hazardous autoreactive T cells; thus, mechanisms exist to eliminate T cells with self-reactive receptors (negative selection) How can these two pathways be distinguished? This question, which has long taxed immunologists, is more opposite because many features of the interactions in positive and negative selection are shared: Both processes are exquisitely MHC-allele specific, they involve MHC-bound peptide recognition, and employ at least some overlapping signal transduction pathways However, resolution of this paradox has become much more feasible with the advent of powerful systems for withdrawing and reconstituting individual components involved in positive selection This review describes recent advances in our understanding of the cells, receptors, ligands, and signaling pathways involved in this process A pivotal part of this puzzle is the basis for discrimination between TCR ligands that induce positive vs negative selection Recent work suggests that the peptide/MHC ligand for positive selection may bind with low avidity to the TCR The implications of these data for the nature of T cell recognition during positive selection are discussed below

Potassium and calcium channels in lymphocytes.

Abstract: Over the past decade, a variety of ion channels have been identified and characterized in lymphocytes by use of the patch-clamp technique. This review discusses biophysical and regulatory aspects of lymphocyte potassium and calcium channels with the aim of understanding the role of these channels in lymphocyte functions. Lymphocytes express both voltage-dependent potassium [K(V)] channels and calcium-activated potassium [K(Ca)] channels, and each is upregulated as cells progress toward division following mitogenic stimulation. The genes encoding two K(V) channels, Kv1.3 (type n) and Kv3.1 (type l), have been cloned. Mutational analysis is revealing functionally important regions of these channel proteins. Exogenous expression studies and the use of highly specific channel blockers have helped to establish the roles of type n K(V) channels in sustaining the resting membrane potential, in regulating cell volume, and in enabling lymphocyte activation. Blockade of K(V) and K(Ca) channels effectively inhibits the antigen-driven activation of lymphocytes, probably by inducing membrane depolarization and thereby diminishing calcium influx. A prolonged rise in intracellular calcium ([Ca2+]i) is a required signal for lymphocyte activation by antigen or mitogens. Single-cell fluorescence measurements have revealed underlying [Ca2+]i oscillations that are linked closely to the opening and closing of Ca2+ and K+ channels. Sustained Ca2+ signaling and oscillations depend absolutely on plasma-membrane Ca2+ channels that are activated by the depletion of intracellular calcium stores. Under physiological conditions these channels open as a consequence of store depletion induced by inositol 1,4,5-trisphosphate (IP3), but they can also be activated experimentally by several agents that empty the stores without generating IP3, such as the microsomal Ca(2+)-ATPase inhibitor thapsigargin. The intricate causal relationships among ion channels, membrane potential, [Ca2+]i, and lymphokine gene expression can now be pursued at the single-cell level with patch-clamp recording, calcium-dependent dyes, reporter genes, and fluorescence video techniques. These approaches will help to clarify the essential roles of ion channels in the molecular pathways subserving activation and other lymphocyte behaviors.

Neuroendocrine-immune system interactions and autoimmunity.

Abstract: The concept of an integrated bidirectionally regulated neuroendocrine-immune adaptive response to stress has strong experimental support. The quality and intensity of this coordinated response to stress varies depending upon age, gender, reproductive status, and other genetically determined factors as well as the types and magnitudes of environmental challenges. These factors and dysfunctional communication between the nervous, endocrine, and immune systems appear to contribute to the development of autoimmune diseases in the Lewis and BB rats, the OS chicken, and the NOD, MRL, NZB, NZW, and NZB/NZW F1 mice. Neuroendocrine-immune dysfunction also contributes to the pathogenesis of human autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, thyroid diseases, and others. This review highlights these concepts. It includes discussions on various aspects of the stress response, the hypothalamic-pituitary-adrenal and -gonadal axes, corticotropin releasing hormone, luteinizing hormone releasing hormone, interleukin-1 and -6, corticosteroids, estrogens, testosterone, dehydroepiandrosterone, growth hormone, prolactin, and thyroid hormone. The role of the nervous and endocrine systems in regulating thymopoiesis and T cell development is also emphasized.

The CD19/CR2/TAPA-1 Complex of B Lymphocytes: Linking Natural to Acquired Immunity

Abstract: B lymphocytes must respond to low concentrations of antigen despite having low affinity antigen receptors during the primary immune response. CD19, a B cell-restricted membrane protein of the immunoglobulin superfamily that associates with the antigen receptor complex, may help the B cell meet this requirement. Cross-linking CD19 to membrane immunoglobulin (mIg) lowers, by two orders of magnitude, the number of mIg that must be ligated to activate phospholipase C (PLC) or to induce DNA synthesis. CD19 is coupled, via protein tyrosine kinases (PTKs), to PLC and phosphatidylinositol 3' kinase (PI3' kinase), and it interacts with the Src-type nonreceptor PTK lyn. It also associates with two other membrane proteins, CR2 (complement receptor type 2, CD21), which permits nonimmunologic ligation of CD19, and TAPA-1, a member of the tetraspan family of membrane proteins. CR2 binds fragments of C3 that are covalently attached to glycoconjugates. This indirectly enables CD19 to be cross-linked to mIg after preimmune recognition of an immunogen by the complement system. CR2 also can be ligated by CD23, a lectin-like membrane protein that resides on cells that may present antigen to B cells. TAPA-1 associates with several other membrane proteins on B and T cells, including MHC class II, CD4, and CD8, and it promotes Ca2(+)- and LFA-1-independent homotypic aggregation when ligated directly or indirectly through CD19 or CR2. This may facilitate interaction of the B cell with other cells essential for cellular activation. The formation of this membrane protein complex by representatives of three different protein families helps the B cell resolve its dilemma of combining broad specificity with high sensitivity.

Paracrine Cytokine Adjuvants in Cancer Immunotherapy

Abstract: Advances in our understanding of the molecular events of antigen recogni­ tion by T cells and T cell activation are opening up new approaches to cancer immunotherapy. The identification and cloning of cytokines provide one impor­ tant set of tools for manipulating immunologic responses. For cancer therapy, cytokines such as interleukin-2 have been administered systemically. However, systemic administration of cytokines ignores the paracrine nature of their ac­ tion. Recently, an alternative approach has been explored that produces high concentrations of cytokines local to the tumor cells. This is achieved either by transduction of the tumor cells the cytokine gene or by mixture of the tumor cells with cytokine containing biodegradable polymer microspheres. Under these circ umstances, the locally released cytokine produces a strong local inflammatory response specific to the particular cytokine. In some cases, a potent tumor-specific T cell response results, capable of mediating regression of systemi c tumor de­ posits. This paracrine delivery of cytokines can therefore be considered as a new type of adjuvant in the design of vaccines for cancer as well as microbial infections.

Regulation of Lymphocyte Survival by the BCL-2 Gene Family

Abstract: The control of cell survival is of central importance in tissues with high cell turnover such as the lymphoid system, and its disruption may be a critical step in tumorigenesis. Genes homologous to bcl-2, the oncogene implicated in human follicular lymphoma, play a key role in regulating physiologic cell death (apoptosis). Bcl-2 and its relatives bcl-x and bax encode intracellular membrane-bound proteins that share homology in three domains with a wider family of viral and cellular proteins. The Bcl-2 and Bcl-x proteins enhance the survival of lymphocytes and other cell types but do not promote their proliferation. High levels of Bax or of a smaller Bcl-x variant antagonize the survival function of Bcl-2. The mechanism by which Bcl-2 promotes cell survival remains unknown, but it appears to require association with Bax. Bcl-2 may combat the action of cysteine proteases thought to trigger apoptosis. Bcl-2 is not essential for embryogenesis or lymphoid development. However, upregulation of Bcl-2 appears to be the normal mechanism for positive selection of developing lymphocytes, and its continued expression is critical for survival of mature peripheral B and T cells. Constitutive expression of Bcl-2 does not abrogate deletion of self-reactive lymphocytes, nor disturb T lymphoid homeostasis; however, it substantially increases the pool of mature noncycling B cells. The risk of B lymphoid tumors is also enhanced, probably because Bcl-2 can countermand the apoptotic action of other oncoproteins such as Myc. Expression in tumors of bcl-2 and other cell survival genes may constitute a major barrier to the success of genotoxic cancer therapy.

New Concepts in the Immunopathogenesis of HIV Infection

Abstract: The typical course of HIV infection is characterized by multiple phases that occur over a period of eight to ten years. A critical event in the initial establishment of HIV infection is the localization of HIV in lymphoid organs that serve as major reservoirs for HIV and as primary sites for virus replication. Despite the fact that the majority of HIV-infected individuals do not show any clinical signs of disease activity for extended periods of time, HIV disease is active and progressive in lymphoid organs during this clinically latent period. Persistence of virus in lymphoid organs causes a chronic stimulation of the immune system that ultimately leads to destruction of the lymphoid tissue and loss of the ability to respond to HIV and/or other pathogens. Major expansions of restricted subsets of CD8+ T cells determined by the usage of certain variable domains (V) of the beta (beta) chain of the T cell receptor (TCR) occur in certain patients during primary HIV infection. These restricted expansions of CD8+ V beta subsets are oligoclonal and represent HIV-specific immune responses with cytolytic T cell activity. Although only limited numbers of patients were studied thus far, certain patterns have emerged that appear to correlate with the subsequent clinical outcome. It is conceivable that immunologic and virologic events associated with primary infection have a major impact on the ultimate course of HIV disease. Histopathologic, virologic, and immunologic studies of long-term nonprogressors (LTNP) indicate that a small proportion of patients who have been HIV-infected for approximately 10 years have normal lymph node architecture, brisk HIV-specific humoral and cellular immune responses, and high and stable CD4+ T cell counts serially determined over years. Viral burden and expression are low in these patients; however, low levels of viremia are present, and virus derived from mononuclear cells is replication competent and infectious in most patients. Studies of events associated with primary HIV infection, examination of lymphoid tissue at various stages of disease, and dissection of the immunologic and virologic components of LTNP should contribute substantially to our understanding of the pathogenesis of HIV disease.

Principles for Adoptive T Cell Therapy of Human Viral Diseases

Abstract: The development of successful adoptive immunotherapy for human virus infections is predicated on an understanding of the effector cells and mechanisms essential for providing the host with a protective response to acute infection and the requirements for long-term in vivo survival of transferred cells that will be necessary to provide memory responses to persistent and latent viral infections. In this review, we discuss the results of recent studies examining the effector mechanisms mediated by virus-specific αβ+ T cells and the strategies viruses have evolved to evade recognition by such T cells and/or to interfere with the expression of T cell effector functions. The evasion strategies employed by individual viruses can render T cell subsets or T cells of particular specificities less effective in eliminating virally infected cells, and consequently they are less desirable choices for use in adoptive therapy. Insights derived from described studies of the pathogenesis and immunobiology of virus infectio...

Superantigens of mouse mammary tumor virus.

Abstract: Superantigens (SAgs) are proteins of microbial origin that bind to major histocompatibility complex (MHC) class II molecules and stimulate T cells via interaction with the V beta domain of the T cell receptor (TCR). Mouse mammary tumor virus (MMTV) is a milk-transmitted type B retrovirus that encodes a SAg in its 3' long terminal repeat. Upon MMTV infection, B cells present SAg to the appropriate T cell subset, which leads to a strong "cognate" T-B interaction. This immune reaction results in preferential clonal expansion of infected B cells and differentiation of some of these cells into long-lived memory cells. In this way a stable MMTV infection is achieved that ultimately results in infection of the mammary gland and virus transmission via milk. Thus, in contrast to many microorganisms that attempt to evade the host immune system (reviewed in 1), MMTV depends upon a strong SAg-induced immune response for its survival. Because of their ability to stimulate very strong T cell responses in MHC-identical mice, minor lymphocyte stimulatory (Mls) antigens, discovered more than 20 years ago, are now known to be SAgs encoded by endogenous MMTV proviruses that have randomly integrated into germ cells. The aim of this review is to combine the extensive biology of Mls SAgs with our current understanding of the life cycle of MMTV.

Transcriptional regulation of complement genes.

Abstract: Complement is a major effector system of host defense against invading pathogens. The recently completed cloning and structural characterization of almost all complement genes has allowed investigation of their regulation at the molecular level. Transcription of most complement genes is accelerated during the acute-phase response that follows tissue injury. Mechanisms regulating transcription of other acute-phase proteins have been elucidated during recent years. The main mediators of acute phase proteins are IL-1- and IL-6-type cytokines. These cytokines and IFN gamma induce transcription of complement genes in the liver and in several extrahepatic sites. Consensus elements binding transcription factors activated by these cytokines have been identified in the promoters of several complement genes. However, only a few complement promoters have been characterized functionally. Structural analysis has indicated that TATA-less promoters are common among complement genes. However, no shared initiator elements (Inr) have been identified so far.

Immunology of reactive arthritides

Abstract: Reactive arthritis (ReA) and Lyme arthritis together comprise a pair of chronic inflammatory diseases of the joints. Although differing in detail, these relatively rare diseases are related in their immunopathology to the much commoner rheumatoid arthritis (RA), for which they serve as both model and control. The trigger for rheumatoid arthritis is unknown, but for these rarer diseases triggering occurs by certain well-defined bacterial infections. Arthritis is an uncommon outcome of these infections, for reasons unknown, and the development of chronic, as distinct from brief, arthritis is even rarer; again, the reasons are unknown. Not only does knowing the trigger greatly assist us in understanding these diseases, so also does knowing the contrasting pattern of Th1 versus Th2 cytokines observed in RA and ReA. ReA and Lyme arthritis are here considered in the wider setting of infections where chronic morbidity arises first from hypersensitivity, and perhaps finally from autoimmunity, such as occurs in some of the major tropical diseases. The immunology of ReA and Lyme disease is surveyed in detail, concentrating on T cells and including an update on the Lyme vaccine(s). Additional sections deal with the enigma of HLA B27, with epidemiological findings relevant to the chronicity of ReA and to the need for enlarged prospective studies of ReA in the setting of a developing country.

Immune Responses in MHC Class II-Deficient MICE

Abstract: Major histocompatibility complex (MHC) class II molecules are heterodimeric cell surface proteins that are critically important for the development and function of cells in the immune system. In particular, the maturation of CD4+ T cells is dependent on the expression of MHC class II molecules on thymic epithelium, while the activation of these cells requires the expression of class II molecules on specialized antigen-presenting cells in the periphery. The importance of class II molecules is especially evident in humans who are afflicted with MHC class II-deficient combined immunodeficiency, as these individuals die at an early age unless provided with a bone marrow transplant. Here we discuss the functional consequences of MHC class II deficiency in a mouse model generated by gene targeting in embryonic stem (ES) cells. These mice have proved to be valuable reagents for dissecting the mechanisms by which MHC class II molecules control the maturation and activation of lymphocytes as well as for elucidating the role of these cells in various immune responses.

Choices Following Antigen Entry: Antibody Formation or Immunologic Tolerance?

Abstract: The research briefly summarized here covers 38 years of work in cellular immunology, briefly devoted to understanding how antigen subserves the antithetical functions of stimulating antibody formation and inducing tolerance. The three interlocking themes running through the work are the development of methods to beat the problem of heterogeneity among lymphocytes by studying single cells and single clones; critical pursuit of antigen-trapping patterns within lymphoid tissues and analysis of consequent cellular events; and construction of models of tolerance that permit the detection of events subtler than direct purging of the B cell repertoire. One of the best features of this adventure has been its international character, the interaction with colleagues in many countries, and the influence that this work, despite its entirely fundamental character, has exerted in the practical world of preventive and clinical medicine.

Prevention of aids transmission through screening of the blood supply

Abstract: Shortly after the first cases of AIDS were reported in 1981, it became apparent that this disease was caused by a blood-borne infectious agent that could be transmitted by blood transfusion. Early reports documented a reduced ratio of CD4+ to CD8+ T cells not only in AIDS patients but also in likely carriers of the AIDS pathogen. On this basis, from July 1983 to June 1985, our blood center utilized flow cytometry to test each donated unit for the ratio of CD4 to CD8 T cells; we did not transfuse blood from donors with CD4/CD8 < 0.85. Despite available data supporting the utility of this or other surrogate blood tests to screen blood donors, the vast majority of blood banks did not initiate blood donor testing for AIDS until 1985, following the discovery of HIV and development of commercial HIV antibody tests. Retrospective analysis indicates that donor screening with surrogate markers would have removed the majority of AIDS-contaminated units from the blood supply and prevented a substantial fraction of the estimated 10,000 cases of transfusion-transmitted AIDS in the United States. In this report, we review the events that led to our decision to initiate blood donor testing prior to the identification of HIV, the results of such testing, the consequences of the decision by most blood banks not to initiate such testing, the current status of the blood supply with respect to HIV, and steps that can be taken in the future to protect the blood supply from new pathogens.