Crystalline silica is among the environmental exposures associated with increased risk of autoimmune diseases, including rheumatoid arthritis, systemic sclerosis and systemic lupus erythematosus. Silica exposure has also been related to the development of ANCA-associated vasculitides (AAV), but past studies appear to conflict as to the presence and magnitude of the associated risks of disease. We aimed to conduct a systematic review of the existing studies and meta-analysis of their results.
We searched EMBASE, MEDLINE and international scientific conference abstract databases for studies examining the association of silica exposure with AAV. Studies in English, French, or Spanish were included and those examining the association of silica with ANCA-positivity alone were excluded. We assessed study quality using the Newcastle-Ottawa scale. We meta-analyzed the results using random effects models and tested for heterogeneity. We performed sensitivity and subgroup analyses, examining studies that adjusted for smoking and occupational risk factors as well as studies that analyzed by subtypes of AAV.
We identified 158 potential manuscripts and 3 abstracts related to silica exposure and risk of AAV. 147 were excluded after abstract review and 14 underwent detailed evaluation of full manuscript/abstract. After further application of exclusion criteria, 6 studies (all case-controls) remained. The studies had moderate heterogeneity in selection of cases and controls, exposure assessment, disease definition and controlling for potential confounders. We found an overall significant summary effect estimate of silica “ever exposure” with development of AAV (summary OR 2.56, 95% CI 1.51- 4.36), with moderate heterogeneity (I2=48.40%). ORs were similar for studies examining only MPA (OR 3.95, CI 95% 1.89-8.24), compared to those only studying GPA (OR 3.56, CI 95% 1.85-6.82).
Despite moderate heterogeneity among studies, the totality of the evidence after meta-analysis points to an association between silica exposure and risk for developing AAV.
Antineutrophil cytoplasmic antibodies; ANCA-associated vasculitides; Silica; Meta-analysis
Since intracellular proteins involved in carcinogenesis have been shown to provoke autoantibody responses, autoantibodies can be used as probes in immunoproteomics to isolate, identify, and characterize potential tumor-associated antigens (TAAs). Once a TAA is identified, several approaches will be used to comprehensively characterize and validate the identified TAA/anti-TAA systems that are potential biomarkers in certain types of cancer. Our ultimate goal is to establish rigorous criteria for designation of an autoantibody to a TAA as a cancer biomarker, examine candidate TAAs for sensitivity and specificity of anti-TAA antibody response, and further develop customized TAA arrays that can be used to enhance anti-TAA antibody detection in cancer. This review will mainly focus on the recent advances in our studies using immunoproteomic approach to identify and characterize TAAs as biomarkers in cancer.
autoantibody; tumor-associated antigen; immunoproteomics; immunodiagnosis; cancer
The etiology and pathogenesis of human autoimmune diseases remain unknown despite intensive investigations. Although remarkable progress has been accomplished through genome wide association studies in the identification of genetic factors that may predispose to their occurrence or modify their clinical presentation to date no specific gene abnormalities have been conclusively demonstrated to be responsible for these diseases. The completion of the human and chimpanzee genome sequencing has opened up novel opportunities to examine the possible contribution of human specific genes and other regulatory elements unique to the human genome, such as microRNAs and non-coding RNAs, towards the pathogenesis of a variety of human disorders. Thus, it is likely that these human specific genes and non-coding regulatory elements may be involved in the development or the pathogenesis of various disorders that do not occur in non-human primates including certain autoimmune diseases such as Systemic Sclerosis and Primary Sjögren's Syndrome. Here, we discuss recent evidence supporting the notion that human specific genes or human specific microRNA and other non-coding RNA regulatory elements unique to the human genome may participate in the development or in the pathogenesis of Systemic Sclerosis and Primary Sjögren's Syndrome.
Human specific genes; microRNAs; Non-coding RNA; Autoimmune diseases; Systemic Sclerosis; Sjögren's Syndrome
Autoimmune uveitis is an organ-specific disorder characterized by irreversible lesions to the eye that predominantly affect people in their most productive years and is among the leading causes of visual deficit and blindness. Currently available therapies are effective in the treatment of a wide spectrum of uveitis, but are often associated with severe side effects. Here, we review ongoing research with promising immunomodulatory therapeutic strategies, describing their specific features, interactions and the responses triggered by the targeted immune molecules that aim to minimize clinical complications and the likelihood of disease relapse. We first review the main features of the disease, diagnostic tools, and traditional forms of therapy, as well as the animal models predominantly used to understand the pathogenesis and test the novel intervention approaches aiming to control the acute immune and inflammatory responses and to dampen chronic responses. Both exploratory research and clinical trials have targeted either the blockade of effector pathways or of their companion co-stimulatory molecules. Examples of targets are T cell receptors (CD3), their co-stimulatory receptors (CD28, CTLA-4) and corresponding ligands (B7-1 and B7-2, also known as CD80 and CD86), and cytokines like IL-2 and their receptors. Here, we summarize the available evidence on effectiveness of these treatments in human and experimental uveitis and highlight a novel CD28 antagonist monovalent Fab′ antibody, FR104, which has shown preclinical efficacy suppressing effector T cells while enhancing regulatory T cell function and immune tolerance in a humanized graft-versus-host disease (GVHD) mice model and is currently being tested in a mouse autoimmune uveitis model with encouraging results.
Autoimmune uveitis; Experimental autoimmune uveitis; Costimulation blockade; Immune modulation; CD28 antagonists
Systemic lupus erythematosus (SLE) is characterized by imbalance redox state and increased apoptosis. The activation, proliferation and cell death of lymphocytes are dependent on intracellular levels of glutathione and controlled production of reactive oxygen species (ROS). Changes in the intracellular redox environment of cells, through oxygen-derived free radical production known as oxidative stress, have been reported to be critical for cellular immune dysfunction, activation of apoptotic enzymes and apoptosis. The shift in the cellular GSH-to-GSSG redox balance in favor of the oxidized species, GSSG, constitutes an important signal that can decide the fate of the abnormal apoptosis in the disease. The current review will focus on four main areas: (1) general description of oxidative stress markers in SLE, (2) alteration of redox state and complication of disease (3) role of redox mechanisms in the initiation and execution phases of apoptosis, and (4) intracellular glutathione and its checkpoints with lymphocyte apoptosis represent novel targets for pharmacological intervention in SLE.
Reactive oxygen species; redox state; apoptosis; glutathione; systemic lupus erythematosus (SLE)
Systemic sclerosis (SSc) is a complex and incompletely understood disease
associated with fibrosis in multiple organs. Recent findings identify
transforming growth factor-ß (TGF-ß), Wnt ligands, toll-like
receptor-mediated signaling, hypoxia, type I interferon, type 2 immune responses
and mechanical stress as extracellular cues that modulate fibroblast function
and differentiation, and as potential targets for therapy. Moreover, fibrillin-1
has a major role in storing and regulating the bioavailability of TGF-ß
and other cytokines, and fibrillin-1 mutations are implicated in a congenital
form of scleroderma called stiff skin syndrome. Fibrosis is due not only to the
activation of tissue-resident fibroblasts and their transdifferentiation into
myofibroblasts, but also the differentiation of bone marrow-derived fibrocytes,
and transition of endothelial and epithelial cells, pericytes and adipocytes
into activated mesenchymal cells. These responses are modulated by signaling
mediators and microRNAs that amplify or inhibit TGF-ß and Wnt signaling.
Gain-of-function and loss-of-function abnormalities of these mediators may
account for the characteristic activated phenotype of SSc fibroblasts. The
nuclear orphan receptor PPAR-γ plays a particularly important role in
limiting the duration and intensity of fibroblast activation and
differentiation, and impaired PPAR-γ expression or function in SSc may
underlie the uncontrolled progression of fibrosis.
Identifying the perturbations in signaling pathways, mediators and
differentiation programs that are responsible for SSc tissue damage allows their
selective targeting. This in turn opens the door for therapies utilizing novel
compounds, or drug repurposing by innovative uses of already-approved drugs. In
view of the heterogeneous clinical presentation and unpredictable course of SSc,
as well as its complex pathogenesis, only robust clinical trials incorporating
the judicious application of biomarkers will be able to clarify the clinical
utility of these innovative approaches.
Fibrosis; Systemic sclerosis; Fibroblast; TGF-ß; Wnt; Collagen
Common variable immunodeficiency (CVID) represents one of the most frequently diagnosed disorders of the immune system. Though several causative and associated genes have been identified, the origins of most cases remain unknown. Diagnostic delay is common due to the gradual evolution and wide spectrum of phenotypes, which can include autoimmune disease, enteropathy, and lung disease. A recent genome wide array identified novel gene associations with CVID, and also showed that identification of a genetic signature via a Support Vector Machine algorithm may be a powerful diagnostic tool. Studies utilizing whole genome or exome sequencing have also met with success in identifying new causes of CVID in subgroups of patients.
Immunodeficiency; immunoglobulin; genome
Numerous genes/SNPs in autoimmune diseases (ADs) are identified through genome-wide association studies (GWAS) and likely to contribute in developing autoimmune phenotypes. Constructions of biologically meaningful pathways are necessary to determine how these genes interact each other and with other small molecules to develop various complex ADs phenotypes prior to beginning time-consuming rigorous experimentation. We have constructed biological pathways with genetically identified genes leading to shared ADs phenotypes. Various environmental and endogenous factors interact with these ADs associated genes suggesting their critical role in developing diseases and further association studies could be designed for assessing the role of these factors with risk allele in a specific gene. Additionally, existing drugs that have been used long before the identification of these genetically associated genes also interact with these newly associated genes. Thus advanced therapeutic strategies could be designed by grouping patients with risk allele(s) in particular genes that directly or closely interact with the specified drugs. This drug-susceptible gene network will not only increase our understanding about the additional molecular basis for effectiveness against these diseases but also which drug could be more effective for those patients carrying risk allele(s) in that gene. Additionally, we have also identified several interlinking genes in the pathways that could be used for designing future association studies.
The purpose of this review is to underline important advancements in the understanding of cancer risks in systemic lupus erythematosus (SLE). In SLE, there is an increased risk of specific kinds of malignancy. For example, the risk of non-Hodgkin’s lymphoma is increased several-fold in SLE versus the general population. In addition, heightened risks for lung cancer, thyroid cancer and cervical dysplasia in SLE have been found. Some have postulated that immunosuppressive drugs play a role, as well as other important mediators, such as lupus disease activity itself. One new frontier being explored is the significant finding of a decreased risk of certain nonhematologic cancers (e.g., breast, ovarian, endometrial and prostate) in SLE. The reasons for this are currently under study.
cancer; immunosuppressive drug; malignancy; risk; systemic lupus erythematosus
Experimental models of autoimmune diseases have led to the conclusion that an immune response to nuclear antigens is a sentinel marker for loss of tolerance and potential tissue damage. Various proteins are targets of antinuclear antibodies in a variety of autoimmune diseases, ranging from systemic rheumatologic disorders to diseases affecting specific organs such as the liver. Autoantibodies against specific nuclear constituents have also been used as probes to understand the structure and the function of the targeted components and their relevance to disease pathogenesis. Approximately a quarter of patients with primary biliary cirrhosis (PBC) have antibodies targeting proteins of the nuclear pore complex (NPC), a multi-protein structure that mediates molecular transport across the nuclear envelope. Autoantibodies against the integral membrane glycoprotein gp210 and nucleoporin p62 appear to be highly specific for PBC, an autoimmune disease characterized by progressive destruction of intrahepatic biliary epithelial cells. This review discusses the diagnostic and clinical relevance of anti-NPC antibodies in PBC and the possibility that this autoimmune response may arise as a result of molecular mimicry.
autoantibody; autoantigen; autoimmunity; nuclear envelope; nuclear pore complex; nucleoporin; primary biliary cirrhosis
We have previously reported an increase in interleukin (IL)-1β and IL-17 levels, and a continuous activation of caspase-1 in early rheumatoid arthritis (RA) patients. These results suggest that drugs targeting IL-1β regulatory pathways, in addition to tumor necrosis factor (TNF), may constitute promising therapeutic agents in early RA. We have recently used a THP-1 macrophage-like cell line to screen 2320 compounds for those that down-regulate both IL-1β and TNF secretion. Celastrol was one of the most promising therapeutic candidates identified in that study. Our main goal in the present work was to investigate whether administration of celastrol is able to attenuate inflammation in a rat model of adjuvant-induced arthritis (AIA). Moreover, since IL-1β is known to play a role in the polarization of Th17 cells, we also investigate whether administration of digoxin, a specific inhibitor of Th17 cells polarization, is able to attenuate inflammation in the same rat model. We found that celastrol administration significantly suppressed joint inflammation. The histological and immunohistochemical evaluation revealed that celastrol-treated rats had a normal joint structure with complete abrogation of the inflammatory infiltrate and cellular proliferation. In contrast, we observed that digoxin administration significantly ameliorated inflammation but only if administrated in the early phase of disease course (after 4 days of disease induction), and it was not efficient at inhibiting the infiltration of immune cells within the joint and in preventing damage. Thus, our results suggest that celastrol has significant anti-inflammatory and anti-proliferative properties and can constitute a potential anti-inflammatory drug with therapeutic efficacy in the treatment of immune-mediated inflammatory diseases such as RA. Furthermore, we find that early inhibition of Th17 cells polarization ameliorates arthritis but it is not as effective as celastrol.
Celastrol; Digoxin; Wistar AIA rat model; IL-1β; Caspase-1; Th17 cells
Receptor editing is the process that replaces the heavy chain or light chain variable region genes in a B-cell immunoglobulin receptor that is already productively rearranged. It is a major mechanism in the bone marrow for maintaining B-cell tolerance to autoantigens. We propose that a pathological autoimmune process can use receptor editing to induce the de novo creation and activation of B cells with autoreactive receptors in the peripheral immune system.
receptor editing; autoimmunity; B cell; autoreactivity
Thyrotropin receptor autoantibodies (TSHR-Abs) of the stimulating variety are the hallmark of Graves’ disease. The presence of immune defects leading to synthesis of TSHR-Abs causes hyperthyroidism and is associated with other extrathyroidal manifestations. Further characterization of these antibodies has now been made possible by the generation of monoclonal antibodies with this unique stimulating capacity as well as similar TSHR-Abs not associated with hyperthyroidism. Their present classification divides TSHR-Abs into stimulating, blocking (competing with TSH binding) and neutral (no signaling). Recent studies using monoclonal TSHR-Abs has revealed that stimulating and blocking antibodies bind to the receptor using mostly conformational epitopes, whilst neutral antibodies utilize exclusively linear peptides. Subtle differences in epitopes for stimulating and blocking antibodies account for the diversity of their biological actions. Recently non-classical signaling elicited by neutral antibodies has also been described, raising the need for a new classification of TSHR-Abs.
thyroid autoimmunity; TSH receptor; Graves’ disease; TSHR antibodies; antibody epitopes; signal transduction
The characterization of functional CD8+ inhibitory or regulatory T cells and their gene regulation remains a critical challenge in the field of tolerance and autoimmunity. Investigating the genes induced in regulatory cells and the regulatory networks and pathways that underlie mechanisms of immune resistance and prevent apoptosis in the CD8+ T cell compartment are crucial to understanding tolerance mechanisms in systemic autoimmunity. Little is currently known about the genetic control that governs the ability of CD8+ Ti or regulatory cells to suppress anti-DNA Ab production in B cells. Silencing genes with siRNA or shRNA and overexpression of genes with lentiviral cDNA transduction are established approaches to identifying and understanding the function of candidate genes in tolerance and immunity. Elucidation of interactions between genes and proteins, and their synergistic effects in establishing cell-cell cross talk, including receptor modulation/antagonism, are essential for delineating the roles of these cells. In this review, we will examine recent reports which describe the modulation of cells from lupus prone mice or lupus patients to confer anti-inflammatory and protective gene expression and novel associated phenotypes. We will highlight recent findings on the role of selected genes induced by peptide tolerance in CD8+ Ti.
Autoimmunity; Systemic Lupus Erythematosus; CD8+ Treg; Genes and Tolerance
Sexual dimorphism in human immune systems is most apparent in the female predominance of certain autoimmune diseases (ADs) like systemic lupus erythematosus (SLE). Epidemiologic, observational and experimental evidence strongly suggest sex steroids are important modulators of genetic risk in human AD. In this regard, the roles of progesterone (Pg), an immunomodulatory female sex steroid, are poorly understood. Several lines of investigation indicate Pg and synthetic progestins impact risk of AD and immune-mediated injury in different ways depending on their concentrations and their engagement of various Pg receptors expressed in immune organs, immune cells or tissues targeted by immune attack. At low physiologic levels, Pg may enhance interferon-alpha (IFN-α) pathways important in SLE pathogenesis. Commonly used synthetic progestins may have the opposite effect. At pregnancy levels, Pg may suppress disease activity in rheumatoid arthritis (RA) and multiple sclerosis (MS) via inhibition of T helper type 1 (Th1) and Th17 pathways and induction of anti-inflammatory molecules. Importantly, Pg’s immunomodulatory effects differ from those of estrogens and androgens. An additional layer of complexity arises from apparent interdependence of sex hormone signaling pathways. Identifying mechanisms by which Pg and other sex steroids modulate risk of AD and immune-mediated injury will require clarification of their cellular and molecular targets in vivo. These future studies should be informed by recent genetic discoveries in human AD, particularly those revealing their sex-specific genetic associations.
progesterone; autoimmunity; sex hormones; sex steroids; systemic lupus erythematosus; SLE
Many autoimmune diseases (ADs) share similar underlying pathology and have a tendency to cluster within families, supporting the involvement of shared susceptibility genes. To date, most of the genetic variants associated with systemic lupus erythematosus (SLE) susceptibility also show association with others ADs. ITGAM and its associated ‘predisposing’ variant (rs1143679, Arg77His), predicted to alter the tertiary structures of the ligand-binding domain of ITGAM, may play a key role for SLE pathogenesis. The aim of this study is to examine whether the ITGAM variant is also associated with other ADs. We evaluated case-control association between rs1143679 and ADs (N=18,457) including primary Sjögren’s syndrome, systemic sclerosis, multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis, celiac disease, and type-1 diabetes. We also performed meta-analyses using our data in addition to available published data. Although the risk allele ‘A’ is relatively more frequent among cases for each disease, it was not significantly associated with any other ADs tested in this study. However, the meta-analysis for systemic sclerosis was associated with rs1143679 (pmeta=0.008). In summary, this study explored the role of ITGAM in general autoimmunity in seven non-lupus ADs, and only found association for systemic sclerosis when our results were combined with published results. Thus ITGAM may not be a general autoimmunity gene but this variant may be specifically associated with SLE and systemic sclerosis.
ITGAM; autoimmune diseases; genetic susceptibility
Recent advances in the field of genetics have dramatically changed our understanding of autoimmune disease. Candidate gene and, more recently, genome-wide association (GWA) studies have led to an explosion in the number of loci and pathways known to contribute to autoimmune phenotypes. Since the 1970s, researchers have known that several alleles in the MHC region play a role in the pathogenesis of many autoimmune diseases. More recent work has identified numerous risk loci involving both the innate and adaptive immune responses. However, much remains to be learned about the heritability of autoimmune conditions. Most regions found through GWA scans have yet to isolate the association to the causal allele(s) responsible for conferring disease risk. A role for rare variants (allele frequencies of <1%) has begun to emerge. Future research will use next generation sequencing (NGS) technology to comprehensively evaluate the human genome for risk variants. Whole transcriptome sequencing is now possible, which will provide much more detailed gene expression data. The dramatic drop in the cost and time required to sequence the entire human genome will ultimately make it possible for this technology to be used as a clinical diagnostic tool.
Genetics; Genomics; Genome-wide association study; Autoimmune disease
Vitiligo is an autoimmune disease presenting with progressive loss of skin pigmentation. The disease strikes 1% of the world population, generally during teenage years. The progressive loss of melanocytes from depigmenting vitiligo skin is accompanied by cellular infiltrates containing both CD4+ and CD8+ T lymphocytes. Infiltrating cytotoxic T cells with high affinity T cell receptors have likely escaped clonal deletion in the thymus, allowing such T cells to enter the circulation. Through the expression of CLA, these T cells home to the skin where they express type 1-cytokine profiles and mediate melanocyte apoptosis via the granzyme/perforin pathway. T cells found juxtapositionally apposed to remaining melanocytes can be isolated from the skin. Vitiligo T cells have demonstrated reactivity to antigens previously recognized as target antigens for T cells infiltrating melanoma tumors. In a comparison to existing melanoma-derived T cells, vitiligo T cells displayed superior reactivity towards melanoma cells. It is thought that genes encoding the TCRs expressed by vitiligo skin infiltrating T cells can be cloned and expressed in melanoma T cells, thereby generating a pool of circulating T cells with high affinity for their targets that can re-direct the immune response towards the tumor.
Melanocytes; T cells; T cell avidity; T cell receptors; Melanosomes; Antigen presentation
Consistent with the common embryonic origin of liver and pancreas as well the similar glucose-sensing systems in hepatocytes and pancreatic β-cells, it should not be surprising that liver stem cells/hepatocytes can transdifferentiate into insulin-producing cells under high-glucose culture conditions or by genetic reprogramming. Persistent expression of the pancreatic duodenal homeobox-1 (Pdx1) transcription factor or its super-active form Pdx1-VP16 fusion protein in hepatic cells reprograms these cells into pancreatic β-cell precursors. In vitro culture at elevated glucose concentrations or in vivo exposure to a hyperglycemia are required for further differentiation and maturation of liver-derived pancreatic β-cell precursor into functional insulin-producing pancreatic β-like cells. Under appropriate conditions, multiple pancreatic transcription factors can work in concert to reprogram liver stem/adult liver cells into functional insulin-producing cells. If such autologous liver-derived insulin-producing cells can be made to escape the type 1 diabetes-associated autoimmunity, they may serve as a valuable cell source for future cell replacement therapy without the need for life-long immunosuppression.
MicroRNAs are endogenous non-coding RNAs, approximately 22 nucleotides in length. They regulate gene expression and are important in a wide range of physiological and pathological processes. MicroRNA expression is tightly regulated during hematopoiesis and lymphoid cell differentiation and disruption of the entire microRNA network or selected microRNAs may lead to dysregulated immune responses. Abnormalities in microRNA expression related to inflammatory cytokines, Th-17 and regulatory T cells as well as B cells have been described in several autoimmune diseases. Sjögren’s syndrome is characterized by features of systemic autoimmunity and chronic inflammation and dysfunction in exocrine organs. Its clinical characteristics along with the relatively easy access to the target tissue and its product makes Sjögren’s syndrome appealing to study many aspects of microRNAs in a systemic autoimmune disease, such as their potential as diagnostic or prognostic biomarkers and their role in pathogenesis of autoimmunity, inflammation or organ dysfunction. Encouraging preliminary data from pilot studies in Sjögren’s syndrome demonstrate the potential of microRNAs as putative diagnostic and prognostic biomarker candidates which should be tested in larger more definite studies. Combining the comparison of microRNA expression profiles between various clinical subsets of Sjögren’s syndrome with bioinformatic modeling tools may predict formerly unsuspected pathways which may contribute to the disease process and lead to the generation of testable novel hypothesis of pathogenesis.
biomarker; autoimmunity; epigenetics; exocrine dysfunction; pathogenesis
The pathogenesis of RA, a disabling autoimmune disease, is incompletely understood. Early in the development of RA there appears to be loss of immune homeostasis and regulation, and premature immunosenescence. While identification of risk factors and understanding of the phases of RA pathogenesis are advancing, means of accurately predicting an individual’s risk of developing RA are currently lacking. Telomere length has been proposed as a potential new biomarker for the development of RA that could enhance prediction of this serious disease. Studies examining telomere length in relation to RA have found that telomere erosion appears to proceed more rapidly in subjects with RA than in healthy controls, and that telomere lengths are shorter in those with the RA-risk HLA-shared epitope genes. These studies have been small, however, with retrospective or cross-sectional designs. The potential role of telomere shortening as an independent biomarker for future RA risk, perhaps strongly genetically determined by HLA-SE genes, after controlling for known risk factors such as smoking, body mass index and immunosuppressant medication use, as well as systemic inflammation, is an unanswered question.
immunosenescence; rheumatoid arthritis; telomere; biomarker; risk factor; aging; autoimmune
Pituitary autoimmunity encompasses a spectrum of conditions ranging from histologically proven forms of lymphocytic hypophysitis to the presence of pituitary antibodies in apparently healthy subjects. Hypophysitis is a rare but increasingly recognized disorder that typically presents as a mass in the sella turcica. It mimics clinically and radiologically other non-secreting sellar masses, such as the more common pituitary adenoma. Hypophysitis shows a striking temporal association with pregnancy, and it has been recently described during immunotherapies that block CTLA-4. Several candidate pituitary autoantigens have been described in the last decade, although none has proven useful as a diagnostic tool. This review summarizes the advances made in the field since the publication of the first review on pituitary autoimmunity, and the challenges that await clarification.
Hypophysitis; Pituitary antigens; Pituitary antibodies
Recent evidence supports the idea that following a break in tolerance, CD8 cytotoxic T lymphocytes (CTL) may be an important but unrecognized mechanism for limiting expansion of autoreactive B cells. Failure of this mechanism could allow persistence of CD4 T cell driven polyclonal B cell activation resulting in clinical lupus. Although CD8 CTL failure may occur early in disease, work in mice supports the concept that therapeutic CTL enhancement may be both practical and beneficial in lupus. Devising such therapy for humans will first require an understanding of the in vivo mechanisms critical in CTL expansion and down regulation, particularly in the lupus setting which may differ from CTL generation in other clinical settings (e.g. tumors, infections).
Lupus; Cytotoxic T cells; Graft-vs-host disease
The loss of immune tolerance to self antigens leads to the development of autoimmune responses. Since self antigens are often multiple and/or their sequences may not be known, one approach to restore immune tolerance uses synthetic artificial peptides that interfere or compete with self peptides in the networks of cellular interactions that drive the autoimmune process. This review describes the rationale behind the use of artificial peptides in autoimmunity and their mechanisms of action. Examples of use of artificial peptides in preclinical studies and in the management of human autoimmune diseases are provided.
Artificial peptides; Immune tolerance; Multiple Sclerosis; Systemic Lupus Erythematosus; Glatiramer Acetate
Systemic lupus erythematosus (SLE) is prototypic autoimmune disease characterized by the production of autoantibodies to DNA among other nuclear molecules. These antibodies can form immune complexes that promote pathogenesis by stimulating cytokine production and depositing in the kidney to instigate nephritis. The antigens that form these complexes arise from the blood nucleome, a pool of circulating macromolecules comprised of DNA, RNA and nuclear proteins released from cells. Cell death is a major source of these molecules, releasing DNA in a process that can be modeled in mice by the administration of cells killed ex vivo. In the mouse model, the appearance of blood DNA requires macrophages and differs between males and females. This finding raises the possibility that augmented levels of extracellular DNA and other nuclear antigens can contribute to the increased frequency of SLE in females. Extracellular DNA can occur in both a soluble and particulate form, with microparticles generated in vitro displaying antigenically active DNA. Together, these findings suggest that cell death is an important event in lupus pathogenesis and can provide a supply of blood DNA essential for immune complex formation.
systemic lupus erythematosus; immune complexes; DNA; nucleome; apoptosis; macrophages