Springer seminars in immunopathology最新文献

The need for an effective HIV/AIDS vaccine is imperative to halt a pandemic that involves more than 40 million individuals worldwide as of 2005 and is causing enormous socio-economic losses, especially in developing countries (DC). The overall failure of more than two decades of HIV vaccine research justifies the demands for a concerted effort for the rapid development of new and efficacious vaccines against HIV/AIDS. In this context, building international collaborative networks is a must for speeding up scientific research and optimizing the use of funding in a synergistic fashion, as resources for HIV/AIDS are limited and do not involve most of the biggest Pharmas that are more interested in drug discovery. The AIDS Vaccine Integrated Project (AVIP) consortium is an example of synergistic partnership of international European Union and DC experts with a common research goal. AVIP is a European Commission-funded (FP-6), consortium-based, 5-year program directed to the fast development of new HIV/AIDS vaccine candidates to be tested in phase I clinical trials in Europe for future advancement to phase II/III testing in DC. To ensure their rapid development, AVIP novel combined vaccines include both regulatory and structural HIV antigens, which have already been tested, as single components, in phase I clinical trials. In particular, such combination vaccines may be superior to earlier vaccine candidates, the vast majority of which are based only on either structural or regulatory HIV products. In fact, the generation of immune responses to both types of viral antigens expressed either early (regulatory products) or late (structural products) during the viral life cycle can maximize immune targeting of both primary or chronic viral infection. Further, the rational design of combined vaccines allows exploitation of immunomodulatory functions of HIV regulatory proteins, which can improve immunity against structural vaccine components. The building of the AVIP consortium and its scientific strategy will be reviewed in this paper as an example of the establishment of a consortium regulated by a specific intellectual property agreement.

Systemic lupus erythematosus is an autoimmune disease characterized by the production of autoantibodies against a relatively limited range of nuclear antigens. These autoantibodies result in the formation of immune complexes that deposit in tissues and induce inflammation, thereby contributing to disease pathology. Growing evidence suggests that recognition of nucleic acid motifs by Toll-like receptors may play a role in both the activation of antinuclear B cells and in the subsequent disease progression after immune complex formation. The endosomal localization of the nucleic acid-sensing Toll-like receptors (TLRs), TLR3, 7, and 9, is believed to contribute to the distinction between endogenous nucleic acids and those of foreign origin. In this article we review recent work that suggests a role for the B-cell receptor and Fcgamma receptors in delivering nuclear antigens to intracellular compartments allowing TLR activation by endogenous nucleic acids. A number of in vitro studies have presented evidence supporting a role for TLRs in SLE pathology. However, recent studies that have examined the contributions of individual TLRs to SLE by using TLR-deficient mice suggest that the situation is far more complicated in vivo. These studies show that under different circumstances TLR signaling may either exacerbate or protect against SLE-associated pathology. Further understanding of the role of TLRs in pathological autoreactivity of the adaptive immune system will likely lead to important insights into the etiopathogenesis of SLE and potential targets for novel therapies.

T cells undergo full and productive activation when they traffic to lymph nodes where they encounter dendritic cells displaying foreign antigen in the context of MHC molecules on their surface. Recognition of these antigen-MHC complexes by the T cell's receptor for antigen, or T cell receptor, provides the first of two obligate signals needed to drive cell proliferation. The second antigen-independent signal is provided by the costimulatory receptor, CD28, as it engages its ligand on the antigen-presenting cells. Failure of the T cell to receive this second signal after antigen recognition leaves the T cell in a state of anergy. Understanding the role of T cell costimulatory receptors in T cell activation has led to the development of novel approaches for regulating immune responses in subjects with cancer or autoimmune disease by experimentally triggering or blocking costimulatory receptor signaling. In this review, we will discuss, first, several costimulatory pathways known to participate or regulate the progression of autoimmune disease, and, second, how manipulation of T cell costimulation and/or costimulation blockade has been used to treat systemic lupus erythematosus.

Programmed cell death and the disposal of cell corpses by phagocytic cells are highly regulated ongoing processes essential for the survival and well-being of higher organisms. Abnormalities in the susceptibility of certain cells to receptor-induced death are known to lead to certain human diseases (e.g., autoimmune lymphoproliferative syndrome) and may contribute to the pathogenesis of systemic lupus erythematosus. Impaired clearance of apoptotic cells is also likely to be an important factor in lupus pathogenesis, though the biological basis of such a defect remains elusive. Finally, the process of apoptosis has been shown to contribute to lupus disease effector mechanisms. A better understanding of the role of apoptosis in lupus very likely will lead to improved diagnosis and therapy.

Systemic lupus erythematosus (SLE) is a systemic antibody-mediated autoimmune disease that develops under the control of multiple susceptibility genes. Genetic studies in murine and human SLE have identified several chromosomal intervals that contain candidate susceptibility genes. However, the ultimate identification of the genes and their roles in disease process need much further investigation. Spontaneous murine SLE models provide useful tools in this respect. In this chapter, we show this line of investigation, particularly focusing on the roles of major histocompatibility complex (MHC) class II and immunoglobulin G Fc receptors (FcgammaRs). The existence of high-affinity autoantibodies is evidence that autoimmunity in SLE is antigen-driven. Thereby, MHC class II haplotypes have been implicated in SLE susceptibility; however, because of the linkage disequilibrium that exists among the class I, II and III genes within the MHC complex, it has been difficult to discriminate the relative contributions of individual loci. On the other hand, the extent of antibody synthesis upon antigen stimulation and associated inflammatory cascades are controlled in several ways by the balance of stimulatory and inhibitory signaling molecules on immune cells. Stimulatory/inhibitory FcgammaRs mediate one such mechanism, and there are reports indicating the association between polymorphic FcgammaRs and SLE. However, as stimulatory and inhibitory FcgammaRs cluster on the telomeric chromosome 1, the absolute contribution of individual genes has been difficult to dissect. In studies of genetic dissection using interval-congenic and intragenic recombinant mouse strains of SLE models, we show evidence and discuss how and to what extent MHC class II molecules and stimulatory/inhibitory FcgammaRs are involved in SLE susceptibility.

The pathogenesis of autoantibody-mediated cellular and tissue lesions in autoimmune diseases is most straightforwardly attributable to the combined action of self-antigen binding properties and effector functions associated with the Fc regions of the different immunoglobulin (Ig) isotypes. The analysis of two different sets of monoclonal autoantibodies derived from lupus-prone mice revealed remarkable differences in the pathogenic potentials of different IgG subclasses: (1) the IgG2a and IgG2b subclasses of anti-red blood cell (RBC) autoantibodies are the most pathogenic and efficiently activate two classes of activating IgG Fc receptors (FcgammaRIII and FcgammaRIV) and complement; (2) the IgG3 subclass is less pathogenic and activate only complement; and (3) the IgG1 subclass is the least pathogenic and interact only with FcgammaRIII. In addition, because of the unique property of IgG3 to form self-associating complexes and generate cryoglobulins, this subclass of rheumatoid factor and anti-DNA autoantibodies became highly pathogenic and induced lupus-like nephritis and/or vasculitis. Since the switch to IgG2a and IgG3 is promoted by Th1 cytokine interferon gamma, these results strongly suggest that Th1 autoimmune responses could be critically involved in the generation of more pathogenic autoantibodies in systemic lupus erythematosus. This finding is consistent with the observation that the progression of murine lupus nephritis is correlated with the relative dominance of Th1 autoimmune responses. Finally, the analysis of IgG glycosylation pattern revealed that more sialylated IgG autoantibodies remained poorly pathogenic because of limited Fc-associated effector functions and loss of cryoglobulin activity. This suggests that the terminal sialylation of the oligosaccharide side chains of IgG could be a significant factor determining the pathogenic potential of autoantibodies. Our results thus underline the importance of subpopulations of autoantibodies, induced by the help of Th1 cells, in the pathogenesis of autoantibody-mediated cellular and tissue injuries.

The capacity to locate polymorphisms on a virtually complete map of the human genome coupled with the ability to accurately evaluate large numbers (by historical standards) of genetic markers has led to gene identification in complex diseases, such as systemic lupus erythematosus (SLE or lupus). While this is a phenotype with enormous clinical variation, the twin studies and the observed familial aggregation, along with the genetic effects now known, suggest a strong genetic component. Unlike type 1 diabetes, lupus genetics is not dominated by the powerful effect of a single locus. Instead, there are at least six known genetic association effects in lupus of smaller magnitude (odds ratio <2), and at least 17 robust linkages (established and arguably confirmed independently) defining potentially responsible genes that largely remain to be discovered. The more convincing genetic associations include the human leukocyte antigen region (with multiple genes), C1q, PTPN22, PDCD1, Fc receptor-like 3, FcgammaRIIA, FcgammaRIIIA, interferon regulatory factor 5, and others. How they contribute to disease risk remains yet to be clarified, beyond the obvious speculation derived from what has previously been learned about these genes. Certainly, they are expected to contribute to lupus risk independently and in combination with each other, with genes not yet identified, and with the environment. A substantial number of genes (>10) are expected to be identified to contribute to lupus or in its many subsets defined by clinical and laboratory features.

The identification of genes for autoimmune diseases is just the first step towards our understanding of disease pathogenesis. In investigating how mutations, deletions or other types of polymorphic defects occur, it is important to determine the pathways and the mechanisms through which susceptibility leads to disease. In this review I touch on three examples of studies that have attempted to understand the mechanisms of genetic susceptibility in three genes identified recently for systemic lupus erythematosus: PDCD1, PTPN22 and IRF5. We are just beginning to comprehend and much needs to be done.

Genetic studies in spontaneous, induced, and gene-manipulated mouse models of SLE have provided significant insights into the potential number and diversity of genes that can promote, resist, and modify lupus susceptibility. Novel genes and mechanisms of disease pathogenesis have also been identified. Importantly, mouse models have provided an initial view of the genomic landscape of lupus-affecting genes, and have documented the complexities of verifying and determining the role of specific candidate loci and genes. Mouse models of lupus should continue to serve as a vital approach to defining the genetics of SLE.