The Experts below are selected from a list of 39789 Experts worldwide ranked by ideXlab platform
Athanasios G Tzioufas - One of the best experts on this subject based on the ideXlab platform.
-
toll like receptor 3 stimulation promotes ro52 trim21 synthesis and nuclear redistribution in salivary gland epithelial cells partially via type i interferon pathway
Clinical and Experimental Immunology, 2014Co-Authors: Nikolaos C Kyriakidis, Efstathia K Kapsogeorgou, Vasiliki C Gourzi, O D Konsta, G E Baltatzis, Athanasios G TzioufasAbstract:Up-regulated expression of Ro52/tripartite motif-containing protein 21 (TRIM21), Ro60/TROVE domain family, member 2 (TROVE2) and lupus LA protein/Sjogren's syndrome antigen B (La/SSB) Autoantigens has been described in the salivary gland epithelial cells (SGEC) of patients with Sjogren's syndrome (SS). SGECs, the key regulators of autoimmune SS responses, express high levels of surface functional Toll-like receptor (TLR)-3, whereas Ro52/TRIM21 negatively regulates TLR-3-mediated inflammation. Herein, we investigated the effect of TLR-3-signalling on the expression of Ro52/TRIM21, as well as Ro60/TROVE2 and La/SSB Autoantigens, by SGECs. The effect of TLR-3 or TLR-4 stimulation on Autoantigen expression was evaluated by polyI:C or lipopolysaccharide (LPS) treatment, respectively, of SGEC lines (10 from SS patients, 12 from non-SS controls) or HeLa cells, followed by analysis of mRNA and protein expression. PolyI:C, but not LPS, resulted in a two-step induction of Ro52/TRIM21 mRNA expression by SGECs, a 12-fold increment at 6 h followed by a 2·5-fold increment at 24–48 h, whereas it induced a late two-fold up-regulation of Ro60/TROVE2 and La/SSB mRNAs at 48 h. Although protein expression levels were not affected significantly, the late up-regulation of Ro52/TRIM21 mRNA was accompanied by protein redistribution, from nucleolar-like pattern to multiple coarse dots spanning throughout the nucleus. These late phenomena were mediated significantly by interferon (IFN)-β production, as attested by cognate secretion and specific inhibition experiments and associated with IFN regulatory factor (IRF)3 degradation. TLR-3-signalling had similar effects on SGECs obtained from SS patients and controls, whereas it did not affect the expression of these Autoantigens in HeLa cells. TLR-3 signalling regulates the expression of Autoantigens by SGECs, implicating innate immunity pathways in their over-expression in inflamed tissues and possibly in their exposure to the immune system.
-
Toll‐like receptor 3 stimulation promotes Ro52/TRIM21 synthesis and nuclear redistribution in salivary gland epithelial cells, partially via type I interferon pathway
Clinical and Experimental Immunology, 2014Co-Authors: Nikolaos C Kyriakidis, Efstathia K Kapsogeorgou, Vasiliki C Gourzi, O D Konsta, G E Baltatzis, Athanasios G TzioufasAbstract:Up-regulated expression of Ro52/tripartite motif-containing protein 21 (TRIM21), Ro60/TROVE domain family, member 2 (TROVE2) and lupus LA protein/Sjogren's syndrome antigen B (La/SSB) Autoantigens has been described in the salivary gland epithelial cells (SGEC) of patients with Sjogren's syndrome (SS). SGECs, the key regulators of autoimmune SS responses, express high levels of surface functional Toll-like receptor (TLR)-3, whereas Ro52/TRIM21 negatively regulates TLR-3-mediated inflammation. Herein, we investigated the effect of TLR-3-signalling on the expression of Ro52/TRIM21, as well as Ro60/TROVE2 and La/SSB Autoantigens, by SGECs. The effect of TLR-3 or TLR-4 stimulation on Autoantigen expression was evaluated by polyI:C or lipopolysaccharide (LPS) treatment, respectively, of SGEC lines (10 from SS patients, 12 from non-SS controls) or HeLa cells, followed by analysis of mRNA and protein expression. PolyI:C, but not LPS, resulted in a two-step induction of Ro52/TRIM21 mRNA expression by SGECs, a 12-fold increment at 6 h followed by a 2·5-fold increment at 24–48 h, whereas it induced a late two-fold up-regulation of Ro60/TROVE2 and La/SSB mRNAs at 48 h. Although protein expression levels were not affected significantly, the late up-regulation of Ro52/TRIM21 mRNA was accompanied by protein redistribution, from nucleolar-like pattern to multiple coarse dots spanning throughout the nucleus. These late phenomena were mediated significantly by interferon (IFN)-β production, as attested by cognate secretion and specific inhibition experiments and associated with IFN regulatory factor (IRF)3 degradation. TLR-3-signalling had similar effects on SGECs obtained from SS patients and controls, whereas it did not affect the expression of these Autoantigens in HeLa cells. TLR-3 signalling regulates the expression of Autoantigens by SGECs, implicating innate immunity pathways in their over-expression in inflamed tissues and possibly in their exposure to the immune system.
-
Autoimmune response and target Autoantigens in Sjogren’s syndrome
European Journal of Clinical Investigation, 2010Co-Authors: John G. Routsias, Athanasios G TzioufasAbstract:Eur J Clin Invest 2010; 40 (11): 1026–1036 Abstract Background Primary Sjogren’s syndrome (pSS) is characterized by the presence of autoantibodies targeting mainly the Ro/La ribonucleoprotein complex. It is now appreciated that the production of autoantibodies is an antigen-driven immune response. Design In this review, candidate mechanisms for Autoantigen presentation and perpetuation of the autoimmune response within the autoimmune tissue lesion of pSS are discussed. Results Several studies have shown that the epithelial cell in labial salivary glands of patients with Sjogren’s syndrome is activated, bearing characteristics of an antigen-presenting cell, as suggested by inappropriate expression of class II HLA and co-stimulatory molecules. Other studies have confirmed that in salivary glands, there is an increased Autoantigen presentation via apoptotic blebs and bodies, exosomes and heat shock protein-mediated cross-priming. There is also an increased expression of interferon (IFN)-induced genes, such as the Autoantigen Ro52, which provide negative feedback regulation in inflammation. Ro60 and La Autoantigens also appear to play a major role in the local autoimmune response in Sjogren’s syndrome. In this regard, La and Ro60 the messenger RNA (mRNA) expression is upregulated in the affected salivary glands with different isoforms of La Autoantigen mRNA to be expressed in patients with pSS. At the protein level, La/SSB in pSS salivary glands is found to be post-translationally modified. Conclusions Autoantigen alterations in a microenvironment of local inflammation with increased in situ apoptosis, Toll-like receptor (TLR) signalling and antigen presentation may drive the autoimmune response and local autoantibody production in pSS.
-
Autoimmune response and target Autoantigens in Sjogren's syndrome
European Journal of Clinical Investigation, 2010Co-Authors: John G. Routsias, Athanasios G TzioufasAbstract:BACKGROUND: Primary Sjogren's syndrome (pSS) is characterized by the presence of autoantibodies targeting mainly the Ro/La ribonucleoprotein complex. It is now appreciated that the production of autoantibodies is an antigen-driven immune response.\n\nDESIGN: In this review, candidate mechanisms for Autoantigen presentation and perpetuation of the autoimmune response within the autoimmune tissue lesion of pSS are discussed.\n\nRESULTS: Several studies have shown that the epithelial cell in labial salivary glands of patients with Sjogren's syndrome is activated, bearing characteristics of an antigen-presenting cell, as suggested by inappropriate expression of class II HLA and co-stimulatory molecules. Other studies have confirmed that in salivary glands, there is an increased Autoantigen presentation via apoptotic blebs and bodies, exosomes and heat shock protein-mediated cross-priming. There is also an increased expression of interferon (IFN)-induced genes, such as the Autoantigen Ro52, which provide negative feedback regulation in inflammation. Ro60 and La Autoantigens also appear to play a major role in the local autoimmune response in Sjogren's syndrome. In this regard, La and Ro60 the messenger RNA (mRNA) expression is upregulated in the affected salivary glands with different isoforms of La Autoantigen mRNA to be expressed in patients with pSS. At the protein level, La/SSB in pSS salivary glands is found to be post-translationally modified.\n\nCONCLUSIONS: Autoantigen alterations in a microenvironment of local inflammation with increased in situ apoptosis, Toll-like receptor (TLR) signalling and antigen presentation may drive the autoimmune response and local autoantibody production in pSS.
-
sjogren s syndrome study of Autoantigens and autoantibodies
Clinical Reviews in Allergy & Immunology, 2007Co-Authors: John G. Routsias, Athanasios G TzioufasAbstract:The presence of autoantibodies is the hallmark of systemic autoimmune diseases. During the past 30 years, intense clinical and basic research have dissected the clinical value of autoantibodies in many autoimmune diseases and offered new insights into a better understanding of the molecular and functional properties of the targeted Autoantigens. Unraveling the immunologic mechanisms underlying the autoimmune tissue injury, provided useful conclusions on the generation of autoantibodies and the perpetuation of the autoimmune response. Primary Sjogren’s syndrome (pSS) is characterized by the presence of autoantibodies binding on a vast array of organ and non-organ specific Autoantigens. The most common autoantibodies are those targeting the Ro/La RNP complex, and they serve as disease markers, as they are included in the European–American Diagnostic Criteria for pSS. Other autoantibodies are associated with particular disease manifestations, such as anti-centromere antibodies with Raynaud’s phenomenon, anti-carbonic anhydrase II with distal renal tubular acidosis, anti-mitochondrial antibodies with liver pathology, and cryoglobulins with the evolution to non-Hodgkin’s lymphoma. Finally, autoantibodies against Autoantigens such as alpha- and beta-fodrin, islet cell Autoantigen, poly(ADP)ribose polymerase (PARP), NuMA, Golgins, and NOR-90 are found in a subpopulation of SS patients without disease specificity, and their utility remains to be elucidated. In this review, the molecular and clinical characteristics (divided according to their clinical utility) of the Autoantigens and autoantibodies associated with pSS are discussed.
Antony Rosen - One of the best experts on this subject based on the ideXlab platform.
-
Autoantigens as partners in initiation and propagation of autoimmune rheumatic diseases
Annual Review of Immunology, 2016Co-Authors: Antony Rosen, Livia CasciolarosenAbstract:Systemic autoimmune diseases are characterized by specific targeting of a limited group of ubiquitously expressed Autoantigens by the immune system. This review examines the mechanisms underlying their selection as immune targets. Initiation of autoimmune responses likely reflects the presentation of antigens with a distinct structure not previously encountered by the immune system, in a proimmune context (injury, malignancy, or infection). Causes of modified structure include somatic mutation and posttranslational modifications (including citrullination and proteolysis). Many Autoantigens are components of multimolecular complexes, and some of the other components may provide adjuvant activity. Propagation of autoimmune responses appears to reflect a bidirectional interaction between the immune response and the target tissues in a mutually reinforcing cycle: Immune effector pathways generate additional Autoantigen, which feeds further immune response. We propose that this resonance may be a critical prin...
-
immune mediated pore forming pathways induce cellular hypercitrullination and generate citrullinated Autoantigens in rheumatoid arthritis
Science Translational Medicine, 2013Co-Authors: Violeta Romero, Antony Rosen, Justyna Fertbober, Peter A Nigrovic, Uzma Haque, Erika Darrah, Felipe AndradeAbstract:Autoantibodies to citrullinated protein antigens are specific markers of rheumatoid arthritis (RA). Although protein citrullination can be activated by numerous stimuli in cells, it remains unclear which of these produce the prominent citrullinated Autoantigens targeted in RA. In these studies, we show that RA synovial fluid cells have an unusual pattern of citrullination with marked citrullination of proteins across the broad range of molecular weights, which we term cellular hypercitrullination. Although histone citrullination is a common event during neutrophil activation and death induced by different pathways including apoptosis, NETosis, and necroptosis/autophagy, hypercitrullination is not induced by these stimuli. However, marked hypercitrullination is induced by two immune-mediated membranolytic pathways, mediated by perforin and the membrane attack complex (MAC), which are active in the RA joint and of importance in RA pathogenesis. We further demonstrate that perforin and MAC activity on neutrophils generate the profile of citrullinated Autoantigens characteristic of RA. These data suggest that activation of peptidylarginine deiminases during complement and perforin activity may be at the core of citrullinated Autoantigen production in RA. These pathways may be amenable to monitoring and therapeutic modulation.
-
peptidylarginine deiminase 2 3 and 4 have distinct specificities against cellular substrates novel insights into Autoantigen selection in rheumatoid arthritis
Annals of the Rheumatic Diseases, 2012Co-Authors: Erika Darrah, Antony Rosen, Jon T Giles, Felipe AndradeAbstract:Objective To define the relationship between Autoantigen citrullination and different peptidylarginine deiminase (PAD) enzymes in rheumatoid arthritis (RA). Methods Citrullinated Autoantigens were identified by immunoblotting control and ionomycin-activated human primary neutrophil lysate with RA sera. Autoantigen identity and citrullination sites were defined by mass spectrometry. PAD isoenzyme expression in human neutrophils was determined by immunoblotting. PAD substrate specificity was addressed in HL-60 cell lysates co-incubated with human recombinant PAD2, PAD3 and PAD4. Results Although prominent protein citrullination is observed in ionomycin-activated neutrophils, RA sera only recognised a limited number of these citrullinated molecules. Among these, the authors identified that β and γ-actins are citrullinated on at least 10 arginine residues, generating a novel 47 kDa species that is frequently recognised by RA autoantibodies. Interestingly, the authors showed that the PAD enzymes expressed in human neutrophils (ie, PAD2, PAD3 and PAD4) have unique substrate specificities, independent of their subcellular distribution. Thus, only PAD2 was able to citrullinate native β/γ-actin, while histone H3 was only citrullinated by PAD4. Conclusion These studies identified β and γ-actins as novel citrullinated Autoantigens in RA, allowing enzyme specificity against intracellular substrates to be addressed. The studies provide evidence that PAD enzymes have the intrinsic capacity to select unique protein targets. The authors propose that unique PAD specificity may play a role in Autoantigen selection in RA.
-
Granzyme B cleavage of Autoantigens in autoimmunity
Cell Death & Differentiation, 2010Co-Authors: Erika Darrah, Antony RosenAbstract:The systemic autoimmune diseases are a complex group of disorders characterized by elaboration of high titer autoantibodies and immune-mediated damage of tissues. Two striking features of autoimmune rheumatic diseases are their self-sustaining nature and capacity for autoamplification, exemplified by disease flares. These features suggest the presence of a feed-forward cycle in disease propagation, in which immune effector pathways drive the generation/release of Autoantigens, which in turn fuel the immune response. There is a growing awareness that structural modification during cytotoxic granule-induced cell death is a frequent and striking feature of Autoantigens, and may be an important principle driving disease. This review focuses on granzyme B (GrB)-mediated cleavage of Autoantigens including (i) features of GrB cleavage sites within Autoantigens, (ii) co-location of cleavage sites with autoimmune epitopes, and (iii) GrB sensitivity of Autoantigens in disease-relevant target tissue. The mechanisms whereby GrB-induced changes in Autoantigen structure may contribute to the initiation and propagation of autoimmunity are reviewed and reveal that GrB has the potential to create or destroy autoimmune epitopes. As there remains no direct evidence showing a causal function for GrB cleavage of antigens in the generation of autoimmunity, this review highlights important outstanding questions about the function of GrB in Autoantigen selection.
-
enhanced Autoantigen expression in regenerating muscle cells in idiopathic inflammatory myopathy
Journal of Experimental Medicine, 2005Co-Authors: Livia Casciolarosen, Paul H. Plotz, Kanneboyina Nagaraju, Kondi Wang, Stuart M Levine, Edward Gabrielson, Andrea M Corse, Antony RosenAbstract:Unique autoantibody specificities are strongly associated with distinct clinical phenotypes, making autoantibodies useful for diagnosis and prognosis. To investigate the mechanisms underlying this striking association, we examined Autoantigen expression in normal muscle and in muscle from patients with autoimmune myositis. Although myositis Autoantigens are expressed at very low levels in control muscle, they are found at high levels in myositis muscle. Furthermore, increased Autoantigen expression correlates with differentiation state, such that myositis Autoantigen expression is increased in cells that have features of regenerating muscle cells. Consistent with this, we found that cultured myoblasts express high levels of Autoantigens, which are strikingly down-regulated as cells differentiate into myotubes in vitro. These data strongly implicate regenerating muscle cells rather than mature myotubes as the source of ongoing antigen supply in autoimmune myositis. Myositis Autoantigen expression is also markedly increased in several cancers known to be associated with autoimmune myositis, but not in their related normal tissues, demonstrating that tumor cells and undifferentiated myoblasts are antigenically similar. We propose that in cancer-associated myositis, an autoimmune response directed against cancer cross-reacts with regenerating muscle cells, enabling a feed-forward loop of tissue damage and antigen selection. Regulating pathways of antigen expression may provide unrecognized therapeutic opportunities in autoimmune diseases.
Lucienne Chatenoud - One of the best experts on this subject based on the ideXlab platform.
-
Immune therapy for type 1 diabetes mellitus—what is unique about anti-CD3 antibodies?
Nature Reviews Endocrinology, 2010Co-Authors: Lucienne ChatenoudAbstract:Immune therapies that induce or, in the case of established type 1 diabetes mellitus (T1DM), restore immune tolerance to target Autoantigens hold potential to cure T1DM whilst avoiding the need for chronic immunosuppression. This Review discusses different immune therapies for T1DM and, in particular, focuses on two promising strategies in clinical development—the use of candidate Autoantigens and anti-CD3 monoclonal antibodies—that aim to restore immune tolerance. Type 1 diabetes mellitus (T1DM) is a prototypic organ-specific autoimmune disease that results from selective destruction of insulin-secreting β-cells by immune-mediated inflammation (insulitis), that is, the infiltration of pancreatic islets by autoreactive CD4^+ and CD8^+ T lymphocytes. Current treatment is substitutive—chronic use of exogenous insulin—which, in spite of considerable advances, is still associated with constraints and lack of effectiveness over the long-term in relation to the prevention of vascular and neurological complications. Finding a cure for T1DM is an important medical health challenge, as the disease's incidence is steadily increasing in industrialized countries and projections of future prevalence are alarming. Crucially, as T1DM mainly affects children and young adults, any candidate immune therapy must be safe and avoid chronic use of immunosuppressants that promote sustained depression of immune responses. The ideal approach would, therefore, involve induction or, in the case of established T1DM, restoration of immune tolerance to target Autoantigens. This Review presents, in particular, two strategies that are still in clinical development but hold great promise. These strategies are focused on the use of candidate Autoantigens and anti-CD3 monoclonal antibodies. Type 1 diabetes mellitus (T1DM) is a prototypic autoimmune disease whose pathophysiology involves Autoantigen-presenting cells (dendritic cells, macrophages and B lymphocytes), T lymphocytes and target insulin-secreting β cells Immune destruction of β cells in humans starts months to years before the advent of overt hyperglycemia The incidence of T1DM has steadily increased in developed countries over the past few decades; prevalence in children
-
Proinsulin: a unique Autoantigen triggering autoimmune diabetes
Journal of Clinical Investigation, 2006Co-Authors: Lucienne ChatenoudAbstract:In healthy individuals the immune system does not react aggressively toward host cells, a phenomenon defined as self tolerance. If self tolerance is broken autoimmune disease can develop, during which autoreactive lymphocytes are directed to a variety of Autoantigenic epitopes. However, researchers have yet to determine whether immune responses to multiple Autoantigens develop independently of each other or are the result of the response “spreading” from one Autoantigen to another. In a study of NOD mice in this issue of the JCI, Krishnamurthy et al. show that the autoreactive T cell response to the Autoantigen proinsulin lies upstream of that to islet-specific glucose-6-phosphatase catalytic subunit–related protein, suggesting that the pathogenic autoimmune response to proinsulin subsequently spreads to other antigens (see the related article beginning on page 3258). These data support the current view that this pancreatic β cell hormone is the first Autoantigen targeted by the immune response in autoimmune diabetes.
-
tolerance to islet Autoantigens in type 1 diabetes
Annual Review of Immunology, 2001Co-Authors: Jeanfrancois Bach, Lucienne ChatenoudAbstract:Tolerance to β cell Autoantigens represents a fragile equilibrium. Autoreactive T cells specific to these Autoantigens are present in most normal individuals but are kept under control by a number of peripheral tolerance mechanisms, among which CD4+ CD25+ CD62L+ T cell–mediated regulation probably plays a central role. The equilibrium may be disrupted by inappropriate activation of Autoantigen-specific T cells, notably following to local inflammation that enhances the expression of the various molecules contributing to antigen recognition by T cells. Even when T cell activation finally overrides regulation, stimulation of regulatory cells by CD3 antibodies may reset the control of autoimmunity. Other procedures may also lead to disease prevention. These procedures are essentially focused on Th2 cytokines, whether used systemically or produced by Th2 cells after specific stimulation by Autoantigens. Protection can also be obtained by NK T cell stimulation. Administration of β cell antigens or CD3 antibodie...
Hans Lehrach - One of the best experts on this subject based on the ideXlab platform.
-
profiling of alopecia areata Autoantigens based on protein microarray technology
Molecular & Cellular Proteomics, 2005Co-Authors: Angelika Lueking, Christopher Wirths, Kirsten Schulte, Karola Stieler, Ulrike Blumepeytavi, Axel Kowald, Karin Henselwiegel, Rudolf Tauber, Otmar Huber, Hans LehrachAbstract:: Protein biochips have a great potential in future parallel processing of complex samples as a research tool and in diagnostics. For the generation of protein biochips, highly automated technologies have been developed for cDNA expression library production, high throughput protein expression, large scale analysis of proteins, and protein microarray generation. Using this technology, we present here a strategy to identify potential Autoantigens involved in the pathogenesis of alopecia areata, an often chronic disease leading to the rapid loss of scalp hair. Only little is known about the putative Autoantigen(s) involved in this process. By combining protein microarray technology with the use of large cDNA expression libraries, we profiled the autoantibody repertoire of sera from alopecia areata patients against a human protein array consisting of 37,200 redundant, recombinant human proteins. The data sets obtained from incubations with patient sera were compared with control sera from clinically healthy persons and to background incubations with anti-human IgG antibodies. From these results, a smaller protein subset was generated and subjected to qualitative and quantitative validation on highly sensitive protein microarrays to identify novel alopecia areata-associated Autoantigens. Eight Autoantigens were identified by protein chip technology and were successfully confirmed by Western blot analysis. These Autoantigens were arrayed on protein microarrays to generate a disease-associated protein chip. To confirm the specificity of the results obtained, sera from patients with psoriasis or hand and foot eczema as well as skin allergy were additionally examined on the disease-associated protein chip. By using alopecia areata as a model for an autoimmune disease, our investigations show that the protein microarray technology has potential for the identification and evaluation of Autoantigens as well as in diagnosis such as to differentiate alopecia areata from other skin diseases.
David A. Hafler - One of the best experts on this subject based on the ideXlab platform.
-
oral tolerance immunologic mechanisms and treatment of animal and human organ specific autoimmune diseases by oral administration of Autoantigens
Annual Review of Immunology, 1994Co-Authors: Howard L Weiner, Aharon Friedman, Ariel Miller, Samia J Khoury, Ahmad Alsabbagh, David E Trentham, Leonilda M. B. Santos, Mohamed H Sayegh, Robert B. Nussenblatt, David A. HaflerAbstract:: Oral tolerance is a long recognized method to induce peripheral immune tolerance. The primary mechanisms by which orally administered antigen induces tolerance are via the generation of active suppression or clonal anergy. Low doses of orally administered antigen favor active suppression whereas higher doses favor clonal anergy. The regulatory cells that mediate active suppression act via the secretion of suppressive cytokines such as TGF beta and IL-4 after being triggered by the oral tolerogen. Furthermore, antigen that stimulates the gut-associated lymphoid tissue preferentially generates a Th2 type response. Because the regulatory cells generated following oral tolerization are triggered in an antigen-specific fashion but suppress in an antigen nonspecific fashion, they mediate "bystander suppression" when they encounter the fed Autoantigen at the target organ. Thus it may not be necessary to identify the target Autoantigen to suppress an organ-specific autoimmune disease via oral tolerance; it is necessary only to administer orally a protein capable of inducing regulatory cells that secrete suppressive cytokines. Orally administered Autoantigens suppress several experimental autoimmune models in a disease- and antigen-specific fashion; the diseases include experimental autoimmune encephalomyelitis (EAE), uveitis, and myasthenia, collagen- and adjuvant-induced arthritis, and diabetes in the NOD mouse. In addition, orally administered alloantigen suppresses alloreactivity and prolongs graft survival. Initial clinical trials of oral tolerance in multiple sclerosis, rheumatoid arthritis, and uveitis have demonstrated positive clinical effects with no apparent toxicity and decreases in T cell autoreactivity.
-
Presentation of Autoantigen by human T cells.
Journal of Immunology, 1991Co-Authors: Janine M. Lasalle, David A. HaflerAbstract:Activated human T cells express MHC class II and have been shown to present foreign Ag to autologous T cells. We now demonstrate that MHC class II+ T cell clones can present myelin basic protein (MBP) peptide Autoantigen in the absence of traditional APC to autologous MBP reactive T cell clones. MBP peptide-pulsed T cell clones specifically stimulated autologous MBP-reactive T cell clones to flux calcium and proliferate. Activation responses were peptide epitope specific and blocked by mAb to MHC class II, indicating a TCR-mediated response. In addition, mAb to the adhesion molecules LFA-3, CD2, LFA-1, CD29, and to the tyrosine phosphatase CD45 also inhibited proliferation, indicating the involvement of T to T cell interactions. In contrast to peptide Ag, T cell clones did not respond to autologous T cells pulsed with HPLC-purified MBP, suggesting that T cells are unable to process whole MBP. However, batch-purified MBP Ag preparations containing lower m.w. breakdown products were presented by T cells, indicating that naturally occurring breakdown products of Autoantigens could be presented by activated T cells in vivo. These results raise the possibility that T cell presentation of Autoantigen at inflammatory sites may be important in regulation of immune responses to self Ag.