mechanisms of lymphocyte activation and immune regulation viii autoimmunity and beyond advances in experimental medicine and biology v 8 sudhir.
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- Frederick W. Alt's Advances in Immunology: 117 PDF
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Until recently, the leukocyte infiltrates in the adventitia during atherogenesis have not been characterized in detail and adventitial inflammation has largely been regarded as an epiphenomenon with little relevance to disease progression although the role of adventitial vasa vasora has received some attention Virmani et al. Importantly, the accumulation of leukocytes in the adventitia during atherogenesis has been noted decades ago.
Small round cell infiltrates were reported in the adventitia of patients afflicted with coronary artery disease. The adventitia has been the subject of original reports and its potential role in atherogenesis has been reviewed Gerlis, ; Schwartz and Mitchell, ; Stefanadis et al. Local humoral immune responses have been suggested to be organized by atherosclerosis-associated adventitial lymphoid aggregates containing B cells and FDCs Houtkamp et al.
ATLOs show striking similarities to TLOs in prototypic organ-specific autoimmune disorders including immune cell subtypes, distinct structures such as HEVs, and a high degree of territoriality adjacent to the target organ for atherosclerosis adjacent to atherosclerotic plaques; Moos et al. Thus, while early atherosclerosis is associated with significant T cell infiltrates in the intima, T cell density in plaques decreases over time whereas it dramatically increases in the adventitia during aging.
Furthermore, B cells, which are absent in the normal aorta and in atherosclerotic plaques, form aggregates during intermediate stages of ATLO neogenesis, whereas advanced stages of ATLOs are characterized by large B cell follicles and ectopic GCs containing FDC networks with proliferating B cells Figure 1. Importantly, FDCs indicate adaptive B cell responses, antigen-specific B memory cell formation, and affinity maturation of B cells.
Delineation of ATLO cellularity suggests that the diseased artery is capable of organizing both T cell and B cell autoimmune responses and that these responses are not observed in young animals. Apparently, the connective tissue of the adventitia of the abdominal aorta provides particularly permissive conditions for ATLO formation but the molecular basis for this preferred location is not known. We never observed ATLO neogenesis in artery segments that are not burdened by advanced atherosclerotic plaques in the intima nor did we observe ATLOs in the intima.
TLO formation requires long-lasting interactions between immune cells and lymphoid tissue organizer cells in multiple feedback loops involving a series of hematopoietic and connective-tissue-derived cytokines Zinkernagel et al. In atherosclerosis, lymphoid tissue organizer cells may arise from media smooth muscle cells as indicated by in vitro studies. Alternatively, myofibroblasts in the adventitia of large arteries during atherogenesis may act as lymphoid tissue organizer cells to support ATLO formation.
A more detailed knowledge about development and function of ATLOs will likely help to better understand both innate and adaptive atherosclerosis immunity. Immune response-regulating cells in atherosclerosis in plaques have also been termed vascular-associated lymphoid tissue Wick et al. Several immune cells are systemically altered by hyperlipidemia in mouse models Swirski et al.
Under conditions of acute myocardial infarction, spleen monocytes are rapidly mobilized into the heart Leuschner et al. However, it is much less clear whether there are systemic alterations in the number, activation, or lymphocyte subset composition during atherogenesis in hyperlipidemic mice maintained under normal mouse chow. Systemic vaccination approaches using various presumptive autoantigens including LDL, oxLDL, and heat shock protein in hyperlipidemic mice resulted in attenuation or acceleration of disease severity providing circumstantial evidence for systemic immune activity.
Moreover, T cell-oriented intervention in mice vaccinated with oxLDL also led to a decrease in atherosclerosis severity but the mice generated a marked T cell response against LDL rather than oxLDL epitopes Hermansson et al. Depletion of T regulatory cells using anti-CD25 antibodies in hyperlipidemic mice increased atherosclerosis pathology and anti-CD20 antibody-induced B cell depletion also resulted in a decrease in disease severity implicating anti-atherogenic actions of natural T regulatory nTregs and pro-atherogenic actions of B cell subsets Ait-Oufella et al.
All these observations provide circumstantial evidence that T and B cell responses affect atherosclerosis systemically and dichotomically. A number of recent studies including our own are more consistent with the view, however, that atherosclerosis is an organ-specific disease. In addition, age has been associated with some autoimmune diseases Weyand et al.
The first initial stages of ATLOs were noted at around 52 weeks of age with preferential formation in the upper abdominal aorta where aortic aneurysms are formed Zhao et al. Atherosclerosis becomes clinically significant only when the late stages are reached, often after short periods of violent progression of plaque growth, leading eventually to plaque instability and rupture see above.
Unfortunately, such stages are difficult to study in mouse models as hyperlipidemic mice have a normal lifespan and never develop myocardial infarction under steady state conditions and normal mouse chow, indicating that poorly understood secondary events are required to initiate clinically severe disease Figure 2. Several caveats merit consideration regarding a pathogenic role of ATLOs in atherosclerosis. First, TLOs as organizers of adaptive immune responses generate both effector lymphocytes and concomitantly their immunosuppressive counterparts in an apparent equilibrium Figure 2.
It is therefore not clear whether, when, and how the balance between effector and tolerogenic lymphocytes is disturbed to cause autoimmune tissue injury. Second, the relative contribution of inflammation and specific lymphocyte responses to tissue injury have not yet been defined. The important question what triggers this lymphocyte activation still has to be answered but molecular mimicry, i.
A large body of evidence supports the assumption that atherosclerosis involves T and B cell immune responses that promote or inhibit plaque growth Ramshaw and Parums, ; Wick et al. The dichotomic nature of organ-specific autoimmune diseases is well established for EAE as shown by the various immune cell subsets in meningeal TLOs Aloisi and Pujol-Borrell, The presence of discrete T cell areas and FDC networks within activated GCs of ATLOs provides the first indirect evidence that the transmural inflammation of the arterial wall generates atherosclerosis-specific antigen s that may trigger specific T cell and B cell immune responses.
We speculate that ATLOs contain pro-atherogenic and anti-atherogenic T cells as well as B cells in apparent equilibria, raising the important question how this balance might be disturbed during disease progression Figures 1 and 2. The complexity of the immune response in atherosclerosis precludes for now to predict what these mechanisms may be.
For instance, the tolerogenic arms of the atherosclerosis adaptive immune response might be compromised. Marked increase of local lymphocyte recirculation, recruitment, functional conduit formation, blood vessel, and HEV neogenesis as well as pathological lymphangiogenesis are all indicative for autoimmune reactivity but not consequentially of autoimmune disease or arterial wall injury. It is recognized that autoimmune diseases in humans develop in separable steps and that only in the late stages, when tolerance against autoantigen s is breaking down, conversion to explicit self-reactivity associated with debilitating tissue destruction can be observed Lang et al.
In the respective EAE and CIA mouse models for human multiple sclerosis TLOs form in the meninges and rheumatoid arthritis TLOs form in the synovial membrane and bone adjacent to the joint cartilage , the disease appears to go through phases of relapses and attenuation and relapses are often triggered by infections and it has been suggested that toll-like receptor signaling may be involved in disease progression Leadbetter et al.
The autoimmune hypothesis of atherosclerosis is based on indirect and circumstantial evidence. Much work is needed to obtain more direct evidence for participation of autoreactive lymphocytes in the clinically important stages of the disease when stable clinically silent atherosclerosis proceeds to vulnerable plaques. ATLO immune cell phenotypes, formation of conduits, HEVs, and aberrant lymph vessels indicate that hyperlipidemia-driven atherosclerosis involves significant innate and adaptive autoimmune responses.
Mouse and human ATLOs may provide new experimental systems to isolate atherogenic autoantibodies and atherogenic T and B cell effectors and their antigen-specific counterparts carrying T and B cell receptors with specificity for epitopes of arterial wall-derived autoantigen s. Studies of adventitial tissues could also facilitate identification of atherosclerosis-related autoantigens.
Moreover, ATLOs may provide a new experimental model to identify the mechanisms how overt autoimmune atherosclerosis disease emerges from clinically silent autoimmune reactivity. This will require a considerably improved understanding of the functional impacts of adaptive immune cell subsets that act on the arterial wall.
Delineation of the mechanisms underlying the disturbance of the equilibrium between these subsets may provide clues for translational research into human atherosclerosis and open avenues for immune-based therapeutics. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Frederick W. Alt's Advances in Immunology: 117 PDF
This work was supported by the German Research Council: We thank Andrea Kirsch for art work. B cell depletion reduces the development of atherosclerosis in mice. Natural regulatory T cells control the development of atherosclerosis in mice. Abnormal development of secondary lymphoid tissues in lymphotoxin beta-deficient mice. Imaging of germinal center selection events during affinity maturation. Lymphoid neogenesis in chronic inflammatory diseases. B1b lymphocytes confer T cell-independent long-lasting immunity.
Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes. Pneumococcal vaccination decreases atherosclerotic lesion formation: The role of natural antibodies in atherogenesis. Unraveling the autoimmune translational research process layer by layer. B cells move to centre stage: Lymphotoxin-beta receptor signaling is required for the homeostatic control of HEV differentiation and function. Myocardial infarction mediated by endothelin receptor signaling in hypercholesterolemic mice.
Protective immunity against atherosclerosis carried by B cells of hypercholesterolemic mice.
Ectopic lymphoid tissues and local immunity. Adventitial microvessel formation after coronary stenting and the effects of SU, a tyrosine kinase inhibitor. Flt3 signaling-dependent dendritic cells protect against atherosclerosis. Unexpected protective role for Toll-like receptor 3 in the arterial wall. Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients.
Induction of secondary and tertiary lymphoid structures in the skin. Cellular interactions in lymph node development. Pubmed Abstract Pubmed Full Text. Lymphoid organ development and cell migration.
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Ectopic LT alpha beta directs lymphoid organ neogenesis with concomitant expression of peripheral node addressin and a HEV-restricted sulfotransferase. Mature follicular dendritic cell networks depend on expression of lymphotoxin beta receptor by radioresistant stromal cells and of lymphotoxin beta and tumor necrosis factor by B cells. A critical role for lymphotoxin-beta receptor in the development of diabetes in nonobese diabetic mice. Toll-like receptor 2 and poly ADP-ribose polymerase 1 promote central nervous system neuroinflammation in progressive EAE.
A well adapted regulatory contrivance: Lymphotoxin beta receptor signaling is required for inflammatory lymphangiogenesis in the thyroid. The lymphotoxin beta receptor controls organogenesis and affinity maturation in peripheral lymphoid tissues. Lymphocyte recruitment into the aortic wall before and during development of atherosclerosis is partially L-selectin dependent.
Immune and inflammatory mechanisms of atherosclerosis. Toll-like receptor 4 signaling by follicular dendritic cells is pivotal for germinal center onset and affinity maturation. Unravelling mononuclear phagocyte heterogeneity. Development of monocytes, macrophages, and dendritic cells. The significance of adventitial infiltrations in coronary atherosclerosis. Plasticity and heterogeneity in the generation of memory B cells and long-lived plasma cells: Multistep pathogenesis of autoimmune disease. Aging, autoimmunity and arthritis: T-cell senescence and contraction of T-cell repertoire diversity — catalysts of autoimmunity and chronic inflammation.
Heat shock protein 60 and immune inflammatory responses in atherosclerosis. Inflammation, atherosclerosis, and coronary artery disease. The immune system in atherosclerosis. Detection of activated T lymphocytes in the human atherosclerotic plaque. Toll in the vessel wall — for better or worse? T cell-independent and toll-like receptor-dependent antigen-driven activation of autoreactive B cells.
Inhibition of T cell response to native low-density lipoprotein reduces atherosclerosis. Coronary vasa vasorum neovascularization precedes epicardial endothelial dysfunction in experimental hypercholesterolemia. Adventitial infiltrates associated with advanced atherosclerotic plaques: Antigen presentation to naive CD4 T cells in the lymph node.
Plasma cell development in synovial germinal centers in patients with rheumatoid and reactive arthritis. Intranasal immunization with an apolipoprotein B fusion protein induces antigen-specific regulatory T cells and reduces atherosclerosis. How dendritic cells shape atherosclerosis. Are follicular dendritic cells really good for nothing? Chronic inflammation caused by lymphotoxin is lymphoid neogenesis. Dysregulation of immune homeostasis in autoimmune diseases. Adventitial vasa vasorum in balloon-injured coronary arteries: Conventional B2 B cell depletion ameliorates whereas its adoptive transfer aggravates atherosclerosis.
Time course and importance of neoadventitial formation in arterial remodeling following balloon angioplasty of porcine coronary arteries.
Frederick W. Alt's Advances in Immunology: PDF - Arienda kvartir Book Archive
Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease. Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self. Recruitment and activation of naive T cells in the islets by lymphotoxin beta receptor-dependent tertiary lymphoid structure. Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis. Progress and challenges in translating the biology of atherosclerosis. J Am Geriatr Soc 58, — Age-related changes in lymphocyte development and function.
Novel therapeutic strategies for multiple sclerosis — a multifaceted adversary. Linking immune-mediated arterial inflammation and cholesterol-induced atherosclerosis in a transgenic mouse model. Effector and regulatory B cells: Chemokines — chemotactic cytokines that mediate inflammation. BLC expression in pancreatic islets causes B cell recruitment and lymphotoxin-dependent lymphoid neogenesis. Reduction of atherosclerosis in mice by inhibition of CD40 signalling. Turning off follicular dendritic cells. B-lymphocyte deficiency increases atherosclerosis in LDL receptor-null mice.
Dendritic cells in atherosclerosis: The pathogenesis of rheumatoid arthritis. T cells caught in the act. Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis.
Organogenesis of lymphoid tissues. T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Topological determinants and consequences of adventitial responses to arterial wall injury. The lamina adventitia is the major site of immune cell accumulation in standard chow-fed apolipoprotein E-deficient mice.
Role of inducible bronchus associated lymphoid tissue iBALT in respiratory immunity. Pathogen-sensing plasmacytoid dendritic cells stimulate cytotoxic T-cell function in the atherosclerotic plaque through interferon-alpha. A conduit system distributes chemokines and small blood-borne molecules through the splenic white pulp.
Perivascular inflammation after balloon angioplasty of porcine coronary arteries. A virus-induced molecular mimicry model of multiple sclerosis. Autoreactive T lymphocytes in multiple sclerosis determined by antigen-induced secretion of interferon-gamma. Innate and adaptive immunity in atherosclerosis. Oligoclonal T cell expansions in atherosclerotic lesions of apolipoprotein E-deficient mice.
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Adventitial angiogenesis early after coronary angioplasty correlation with arterial remodeling. Antigen microarrays identify unique serum autoantibody signatures in clinical and pathologic subtypes of multiple sclerosis. Immunohistochemical characterization of inflammatory cells associated with advanced atherosclerosis.
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