Current directions in autoimmunity最新文献

{"title":"Human B lymphocyte malignancies: exploitation of BLyS and APRIL and their receptors.","authors":"Diane F Jelinek,&nbsp;Jaime R Darce","doi":"10.1159/000082107","DOIUrl":"https://doi.org/10.1159/000082107","url":null,"abstract":"<p><p>B lymphocyte stimulator (BLyS), also referred to as B cell activating factor of the TNF family, is a recently identified tumor necrosis factor (TNF) family member shown to be critical for maintenance of normal B cell development and homeostasis and it shares significant homology with another TNF superfamily member, a proliferation inducing ligand (APRIL). Currently, three receptors have been identified that transmit signals upon BLyS and APRIL binding and these include B cell maturation antigen, B cell activating factor receptor, and transmembrane activator and CAML interactor. The striking effects of BLyS on normal B cell maintenance and survival and the largely B lineage-restricted pattern of receptor expression, raises the possibility that these TNF family ligands and receptors may be involved not only in B cell autoimmunity, but also in the pathogenesis and maintenance of mature B lineage hematological malignancies. In this article, we will review the spectrum of human B lineage malignancies and discuss current evidence supporting a role for BLyS and APRIL in fueling the growth and survival of specific B cell malignancies.</p>","PeriodicalId":81058,"journal":{"name":"Current directions in autoimmunity","volume":"8 ","pages":"266-88"},"PeriodicalIF":0.0,"publicationDate":"2005-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000082107","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24830866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Determinations of B cell fate in immunity and autoimmunity.","authors":"Randolph J Noelle,&nbsp;Loren D Erickson","doi":"10.1159/000082084","DOIUrl":"https://doi.org/10.1159/000082084","url":null,"abstract":"<p><p>A hallmark of thymus-dependent immunity is the generation of long-lived humoral immune responses. The production of long-lived memory B cells (B(mem)) and plasma cells (PCs) form the cellular basis for sustaining antibody-mediated immunity. During an immune response, the differentiation of B cells to become a B(mem) or PC occurs largely at the level of single cell fate decisions. Both of these cell populations acquire longevity as a result of antigen-specific, CD40-dependent, cognate interactions with helper T cells within germinal centers (GCs). In addition to these cellular elements that sustain humoral immunity, a novel GC-derived B cell that is a precursor to PCs has also been described. This cell is long-lived, highly proliferative, and terminally differentiates to end-stage cells within the bone marrow, and represents yet another cellular element that contributes to the long-lived nature of humoral immunity. Recent studies have shown that abnormalities in the B cell compartment of patients and mice with antibody-mediated autoimmune disease results from spontaneous GC responses, leading to the dysregulation in the development of PCs that produce pathogenic autoantibodies with altered homeostasis. The underlying cellular and molecular events that drive the loss of self-tolerance remain poorly understood. However, newer studies demonstrate that the strength of signaling via the B cell receptor, CD40 and BAFF receptors controls B cell fate decisions. Alterations in the magnitude of signaling through these molecules likely contribute to immune dysregulation that leads to the loss of self-tolerance. Understanding the processes of normal PC differentiation will provide strategic insights into identifying therapeutic targets for the treatment of antibody-mediated autoimmunity.</p>","PeriodicalId":81058,"journal":{"name":"Current directions in autoimmunity","volume":"8 ","pages":"1-24"},"PeriodicalIF":0.0,"publicationDate":"2005-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000082084","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24829769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dendritic cells control B cell growth and differentiation.","authors":"Gaetan Jego,&nbsp;Virginia Pascual,&nbsp;A Karolina Palucka,&nbsp;Jacques Banchereau","doi":"10.1159/000082101","DOIUrl":"https://doi.org/10.1159/000082101","url":null,"abstract":"<p><p>We propose a model where human dendritic cell (DC) subsets control, in a coordinated fashion, B cell growth and differentiation. Plasmacytoid DCs drive memory B cell differentiation into effector plasma cell via type I interferon and IL-6. Type I interferon activates myeloid DCs that regulate B cell priming and acquisition of memory phenotype via IL-12, IL-6 and Blys/Baff. This model also integrates the role of antigen-specific T cells activated by myeloid DCs. Thus, protective humoral immunity results from a highly coordinated interplay of human DC subsets. This interplay may explain the spreading of immune response to deal with antigenic drift and to maintain an active immunity against mutating microbe. It may also provide an explanation for spreading of the autoimmune repertoire as autoimmunity develops.</p>","PeriodicalId":81058,"journal":{"name":"Current directions in autoimmunity","volume":"8 ","pages":"124-39"},"PeriodicalIF":0.0,"publicationDate":"2005-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000082101","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24830861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Complement and autoimmune glomerular diseases.","authors":"Richard J Quigg","doi":"10.1159/000075692","DOIUrl":"https://doi.org/10.1159/000075692","url":null,"abstract":"<p><p>The renal glomerulus is the specialized structure in the kidney responsible for generating over 150 liters of plasma ultrafiltrate per day in humans. Certain characteristics of this structure favor involvement in autoimmune diseases. Formation of immune complexes in the glomerulus, either deposited from the circulation or generated in situ, can activate the complement system. Active products of this system include the anaphylatoxins C3a and C5a, C3b, which covalently associates with immune complexes, and the C5b-9 membrane attack complex. If complement is activated in a site accessible to blood constituents, such as in the subendothelial and mesangial regions, generated C3a, C5a and C3b can interact with their respective receptors on inflammatory cells to lead to an exudative lesion. In addition, intrinsic glomerular cells bearing relevant receptors may also be activated and can proliferate to contribute to the inflammation. In a privileged site such as the subepithelial region, complement activation products are not accessible to blood cells, and as such, the resultant pathology is noninflammatory. In this setting, effects of C5b-9 predominate, which include activation and injury of cells through still incompletely characterized pathways. Various means to alter the complement pathway are now available, including antibody inhibitors and recombinant proteins based upon naturally occurring complement regulators. The use of these agents, as well as mice in which individual components of the complement system have been deleted, has given a great deal of insight into how the complement system is involved in glomerular disease. The ability to manipulate the complement pathway is now a reality in a clinical setting, yet conclusive human studies are difficult to achieve.</p>","PeriodicalId":81058,"journal":{"name":"Current directions in autoimmunity","volume":"7 ","pages":"165-80"},"PeriodicalIF":0.0,"publicationDate":"2004-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000075692","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24160841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Complement receptor 2 and autoimmunity.","authors":"V Michael Holers,&nbsp;Susan A Boackle","doi":"10.1159/000075686","DOIUrl":"https://doi.org/10.1159/000075686","url":null,"abstract":"<p><p>Complement receptor 2 (CR2/CD21) plays a major role in the immune response by linking innate and adaptive immunity to foreign pathogens and proteins. In addition, several lines of evidence strongly support a role for CR2 in the maintenance of tolerance to self-antigens. Both the absence of CR2 expression (along with the alternatively spliced gene product CR1) and the presence of a dysfunctional CR2 protein are tightly associated with the development of autoreactivity to nuclear antigens. Altered levels of expression of CR2 in patients with systemic lupus erythematosus support a clinically relevant role for this phenotype. Several possible mechanisms could underlie the loss of self-tolerance related to CR2, but the effect is most likely related to the failure of one or more specific checkpoints that limit autoreactivity during B cell development and immune reactions.</p>","PeriodicalId":81058,"journal":{"name":"Current directions in autoimmunity","volume":"7 ","pages":"33-48"},"PeriodicalIF":0.0,"publicationDate":"2004-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000075686","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24162145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apoptosis, complement and systemic lupus erythematosus: a mechanistic view.","authors":"Chau-Ching Liu,&nbsp;Jeannine S Navratil,&nbsp;Janice M Sabatine,&nbsp;Joseph M Ahearn","doi":"10.1159/000075687","DOIUrl":"https://doi.org/10.1159/000075687","url":null,"abstract":"<p><p>Deficiencies in the classical pathway of the complement system have been implicated in the etiology and pathogenesis of systemic lupus erythematosus (SLE) for several decades. Recent advances have suggested that this link is due to a critical role of complement in the recognition and clearance of the cellular remnants of apoptosis. In this review, we summarize the role of apoptosis in generation of an autoimmune response, and we integrate recent advances that link apoptosis, complement activation and the etiopathogenesis of SLE.</p>","PeriodicalId":81058,"journal":{"name":"Current directions in autoimmunity","volume":"7 ","pages":"49-86"},"PeriodicalIF":0.0,"publicationDate":"2004-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000075687","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24162146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The intricate role of complement component C4 in human systemic lupus erythematosus.","authors":"Yan Yang,&nbsp;Erwin K Chung,&nbsp;Bi Zhou,&nbsp;Karl Lhotta,&nbsp;Lee A Hebert,&nbsp;Daniel J Birmingham,&nbsp;Brad H Rovin,&nbsp;C Yung Yu","doi":"10.1159/000075689","DOIUrl":"https://doi.org/10.1159/000075689","url":null,"abstract":"<p><p>It was observed about 50 years ago that low serum complement activity or low protein concentrations of complement C4 concurred with disease activities of systemic lupus erythematosus (SLE). Complete deficiencies of complement components C4A and C4B, albeit rare in human populations, are among the strongest genetic risk factors for SLE or lupus-like disease, across HLA haplotypes and racial backgrounds. However, whether heterozygous or partial deficiency of C4A (C4AQ0) or C4B (C4BQ0) is a predisposing factor for SLE has been a highly controversial topic. In this review we critically analyzed past epidemiologic studies on deficiency of C4A or C4B in human SLE. Cumulative results from more than 35 different studies revealed that heterozygous and homozygous deficiencies of C4A were present in 40-60% of SLE patients from almost all ethnic groups or races investigated, which included northern and central Europeans, Anglo-Saxons, Caucasians in the US, African Americans, Asian Chinese, Koreans and Japanese. In addition, French SLE and control populations had relatively low frequencies of C4AQ0, but the difference between the patient and control groups was statistically significant. The relative risk of C4AQ0 in SLE varied between 2.3 and 5.3 among different ethnic groups. In Caucasian and African SLE patients, the two major causes for C4AQ0 are (1) the presence of a mono-S RCCX (RP-C4-CYP21-TNX) module with a single, short C4B gene in the major histocompatibility complex; and (2) a 2-bp insertion into the sequence for codon 1213 at exon 29 of the mutant C4A gene. Both mono-S structures and 2-bp insertion in exon 29 are absent or extremely rare in the C4AQ0 of Oriental SLE patients. The highly significant association of C4AQ0 with SLE across multiple HLA haplotypes and ethnic groups, and the presence of different mechanisms leading to a C4A protein deficiency among SLE patients suggested that deficiency or low expression level of C4A protein is a primary risk factor for SLE disease susceptibility per se. On the other hand, Spanish, Mexican, Australian Aborigine SLE patients had increased frequencies of C4B deficiency instead of C4A deficiency. Such observations underscore the importance of both C4A and C4B proteins in the fine control of autoimmunity. Different racial and genetic backgrounds could change the thresholds for the requirement of C4A or C4B protein levels in immune tolerance and immune regulation. Most past epidemiological studies of C4 in human SLE did not consider the polygenic and gene size variations of C4A and C4B. In addition, many studies were overly dependent on phenotypic observations or methods that did not distinguish differential C4A and C4B protein expression caused by unequal gene number or different gene size from the absence of a functional C4A or C4B gene. For further longitudinal studies on clinical manifestations of SLE, it would be informative to stratify the patients with accurately defined C4A and C4B genotypes. Lik","PeriodicalId":81058,"journal":{"name":"Current directions in autoimmunity","volume":"7 ","pages":"98-132"},"PeriodicalIF":0.0,"publicationDate":"2004-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000075689","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24162149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autoimmunity, complement activation, tissue injury and reciprocal effects.","authors":"George C Tsokos,&nbsp;Sherry D Fleming","doi":"10.1159/000075691","DOIUrl":"https://doi.org/10.1159/000075691","url":null,"abstract":"<p><p>Proteins of the complement system limit the expression of systemic autoimmunity by raising the threshold for negative selection and, in their absence, autoreactive lymphocytes seem to enter the periphery. On the other hand, complement activation in the course of systemic autoimmunity leads to tissue injury in a number of ways including direct lysis of cells, modification of cell function and by contributing to the formation of immune complexes. Excessive complement activation as a result of a regulator component deficiency leads to tissue injury that mimics that seen in autoimmune disease. Complement activation occurs during tissue injury and contributes in a major way to the expression of pathology. It appears that natural antibodies represent an early culprit in tissue injury following ischemia/reperfusion injury. Natural antibodies and probably autoantibodies present in sera of patients with systemic autoimmune disease bind to tissues already exposed to a damaging insult, activate complement and produce pathology.</p>","PeriodicalId":81058,"journal":{"name":"Current directions in autoimmunity","volume":"7 ","pages":"149-64"},"PeriodicalIF":0.0,"publicationDate":"2004-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000075691","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24162151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of complement in the antiphospholipid syndrome.","authors":"Jane E Salmon,&nbsp;Guillermina Girardi","doi":"10.1159/000075690","DOIUrl":"https://doi.org/10.1159/000075690","url":null,"abstract":"<p><p>The anti-phospholipid syndrome (APS) is characterized by recurrent fetal loss, vascular thrombosis and thrombocytopenia occurring in the presence of antiphospholipid (aPL) antibodies. We hypothesized that aPL antibodies activate complement in the placenta, generating split products that mediate placental injury and lead to fetal loss and growth restriction, and that complement activation by aPL antibodies in other vascular areas causes inflammation and thrombophilia. Here we review studies in a murine model of APS in which human aPL antibodies are passively transferred into pregnant mice. Blockade of complement activation using a C3 convertase inhibitor or genetic deletion of C3 protected mice from pregnancy complications induced by aPL antibodies. These findings demonstrate that complement activation is a central mechanism in aPL antibody-induced pregnancy loss and fetal growth restriction. Although the cause of tissue injury in APS is likely to prove multifactorial, we have shown that complement activation is an absolute requirement for the most serious phenotypic outcomes, pregnancy complications and thrombosis, and, therefore, that this pathway acts upstream of other important effector mechanisms.</p>","PeriodicalId":81058,"journal":{"name":"Current directions in autoimmunity","volume":"7 ","pages":"133-48"},"PeriodicalIF":0.0,"publicationDate":"2004-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000075690","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24162150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Signaling by the CD19/CD21 complex on B cells.","authors":"Robert H Carter,&nbsp;Robert A Barrington","doi":"10.1159/000075685","DOIUrl":"https://doi.org/10.1159/000075685","url":null,"abstract":"<p><p>Early studies, largely based on in vitro models, revealed potential functional roles for the components of the CD19/21/81 complex in B cell proliferation and antibody production. These studies also identified signal transduction pathways linked to these receptors. Over the last decade, studies on knockout mice defined the biologic functions of CD19, CD21 and CD81. This review focuses on current attempts to use these receptors as tools to understand how the immune system regulates responsiveness and tolerance, while correlating specific biochemical pathways with biologic function.</p>","PeriodicalId":81058,"journal":{"name":"Current directions in autoimmunity","volume":"7 ","pages":"4-32"},"PeriodicalIF":0.0,"publicationDate":"2004-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000075685","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24162144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}