Current Pharmaceutical Design - Volume 9, Issue 23, 2003

The immune system protects organisms from pathogens. The immune cells, in particular T- and B-lymphocytes, develop and acquire effector functions in specialized tissues called the lymphoid organs. The lymphoid organs exhibit lower oxygen tensions than the blood or the atmosphere. Furthermore, inflammatory and tumor environments where lymphocytes execute effector functions also have very low oxygen tensions. These findings led to the hypothesis that lymphocytes may have evolved adaptive mechanisms to function under hypoxic conditions. Cellular responses to hypoxia are triggered by the hypoxia inducible factor-1α (HIF-1α). In this paper we review the development and function of T- and B-lymphocytes in the absence HIF-1a. Our studies suggest that HIF-1α deficiency depresses the function of cytotoxic T-lymphocytes and blocks B-cell development in the bone marrow. B1 lymphocytes of fetal origin, on the other hand, accumulate and may produce auto-antibodies and autoimmunity.

The mechanisms that maintain a steady state pool of B cells that is adequately diverse yet devoid of autoreactivity remain poorly understood. B cells are generated throughout life from pluripotent stem cells and transit a series of phenotypically and functionally defined subsets prior to final maturation in the periphery. Kinetic analyses of these subsets have revealed that considerable cell losses occur during late stages of B cell differentiation, such that only a fraction of newly formed B cells survive to join the mature peripheral pool. These losses reflect the aggregate of negative selection against autoreactive clonotypes and the positive selection of specificities. Because B cell genesis in the marrow is not coupled to peripheral numbers and most mature B ells are quiescent, homeostatic control of the peripheral pool relies largely upon the proportion of B cells that complete maturation and the lifespan of mature B cells. The newly discovered TNF family member, BLySä2, plays a critical role in the maturation, selection and survival of B cells. In these capacities, BLyS acts primarily through the Bcmd / BR3 receptor, affording B cell survival at least in part through the regulation of Bcl-2 family members via NFk-B mediated mechanisms. Recent evidence suggests that Bcmd / BR3 receptor expression is controlled by B cell antigen receptor signaling, forging a mechanistic link between specificity based selection and BLyS mediated survival. Our rapidly expanding understanding of BLyS and its receptors may eventually afford novel pharmacologic strategies aimed at the direct manipulation of peripheral B cell selection and homeostasis.

The role of complement in the development and regulation of antibody responses under both healthy and pathological conditions is known for long. Unraveling the elements involved and the molecular mechanisms underlying the events however is still in progress. This review focuses on the role of complement receptors CR1 (CD35) and CR2 (CD21) expressed on B lymphocytes, which interact with ligands generated upon activation of component C3, the major protein of the complement cascade. The binding and possible effects of immune complexes comprising antigen, antibody and complement on B-cell activation are discussed. Results of clinical studies of autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis and conclusions drawn from animal models used to investigate various aspects of human diseases are also debated. We discuss similarities regarding the overall structure and certain functions of complement and complement receptors in mice and men however, call the attention to major differences regarding tissue distribution and their role in B-cell functions.

Immune complexes are major pathogenic factors contributing to tissue injury in a number of autoimmune diseases. Immune complexes consist of autoantibodies to self-antigens, which initiate an inflammatory response through binding to immunoglobulin Fc receptors (FcRs) or via complement components. The significance of FcRs as regulators of inflammatory reactions was defined when mice with genetically engineered deficiencies of FcRs became available, giving new insight into the mechanisms involved in the pathogenesis of immune complex-mediated inflammation and autoimmunity. In this review, some of the most prominent work on inflammation and autoimmunity in animal models, will be presented. This body of knowledge has not only contributed to our understanding of the importance of FcRs in inflammatory autoimmune responses, but more specifically, has paved a new way for designing novel therapeutic compounds in treating autoimmune diseases.

Natural autoantibodies are immunoglobulins of isotypes IgM, IgG and IgA that are present under physiological conditions and that are directed toward self-antigens. Repertoires of self-reactive antibodies have been analysed intensively during the last decade and have been shown to be altered in a variety of autoimmune disorders, immunodeficiency syndromes and lymphoproliferative diseases. Immunoglobulin interactions via variable regions of antibody molecules account significantly for the functional integrity of natural self-reactive antibody repertoires. Recent data indicate that natural immunoglobulins of the isotype IgM might prove particularly useful for the control of antibodymediated autoimmune diseases under certain conditions. Warm autoimmune hemolytic anemia (WAIHA), an IgGmediated autoimmune disorder, turns out to be a clinically relevant in vivo model to analyse the impact of autologous IgM on the development of IgG-mediated autoimmunity in humans. We here summarize current knowledge on the role of autologous IgM for regulating self-reactivity. Since natural self-reactive antibodies are critical for the regulation not only of auto- but also of alloimmune responses, as they occur for example in the setting of organ transplantation, regulation of immune homeostasis by pools of human normal IgM might be an interesting therapeutic target of broad interest for clinical medicine.

The dogmatic and at one time prevalent concept that intact antibody molecules were not able to enter into viable cells has now been modified due to the availability of a large amount of experimental findings and clinical observations that indicate otherwise. Penetration of mature autoantibodies into living cells might participate in the pathogenesis of diverse autoimmune diseases, through inducing apoptosis of healthy tissues and cells, but also by contributing to the breakdown of self-tolerance through presentation of self-antigens to the immune system. Conversely, the penetration of naturally occurring autoantibodies into immature lymphoid cells might have a physiological role in the edition of the immune repertoire in healthy individuals. Increasing interest is being paid to the potential immunotherapeutic role of penetrating antibodies as tools to deliver drugs, isotopes or genes into cells.

There is compelling evidence in murine model systems and from human clinical trials that immunotherapy approaches can induce immune responses against tumors. The idiotypic determinants (Id) of the rearranged immunoglobulin proteins of malignant B cells were the first tumor-specific antigens to be recognized and provide a target of an immune mediated response against malignant B cells. Id was thought of as not only tumor-specific but also patient-specific since every patient's malignant B cell clone expresses a unique sequence that is determined by the third complementary determinant regions (CDRIII) of the Id. Although CD4+ T cell responses against Id have been demonstrated, the role of CD8+ T lymphocytes in induction of responses against Id has remained elusive. The requirements for peptides to bind to HLA molecules and elicit T cell responses have been studied extensively and are best characterized for HLA class I molecules that elicit CD8+ cytotoxic T lymphocyte (CTL) responses. We applied a bioinformatics approach to the immunoglobulin sequences of malignant and normal B cells. We identified and characterized epitopes recognized by CTLs within these sequences and could generate CTL responses against Id determinants of both normal B cells and malignant B cell. Class I binding immunoglobulin derived sequences had weak binding affinity but were capable in some cases of inducing CTL mediated immune response. More surprisingly, these sequences were not derived from unique sequences within the CDRIII region but were more often from framework region sequences that were often shared among patients and were also found in the immunoglobulin sequences of normal B cells. It was possible to increase binding affinity by single amino acid substitutions at the residues responsible for binding to HLA class I molecules. These “heteroclitic” peptides resulted in generation of T cells with increased ability to kill targets expressing not only the altered peptides, but also the native sequences from which these peptides had been derived. These findings have implications not only for tumor immunity, but also for regulation of B cell dependent autoimmune responses.

To acquire a functional view of human autoimmunity, we compared differences in gene expression (≥4000 genes) in the peripheral blood mononuclear cells of normal individuals following immunization to those in individuals with four different autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, insulin dependent diabetes mellitus, and multiple sclerosis). Each individual from all disease groups displayed a similar pattern of gene expression that was highly distinct from the gene expression pattern of the immunized group. These findings indicate that the expression pattern accompanying autoimmunity is not simply a recapitulation of the immune response to non-self. Of note, expression levels of genes that encode key proteins in several distinct apoptosis pathways were markedly reduced in all autoimmune disease groups. Taken together, these data indicate that the pattern of gene expression describes a molecular portrait of autoimmunity that is constant among individuals with autoimmune disease but is independent of the specific autoimmune disease and the clinical parameters associated with any individual autoimmune disease.