To promote their pathology, CD4 T-cells from patients with rheumatoid arthritis (RA) have to clonally expand and differentiate into cytokine-producing effector cells. In contrast to healthy T-cells, naïve RA T-cells have a defect in glycolytic flux due to upregulation of glucose-6-phosphate dehydrogenase (G6PD). Excess G6PD shunts glucose into the pentose phosphate pathway (PPP), resulting in NADPH accumulation and ROS consumption. With surplus reductive equivalents, RA T-cells insufficiently activate the redox-sensitive kinase ATM; bypass the G2/M cell cycle checkpoint and hyperproliferate. Insufficient ATM activation biases T-cell differentiation towards the Th1 and Th17 lineages, imposing a hyper-inflammatory phenotype. We have identified several interventions that replenishing intracellular ROS, correct the abnormal proliferative behavior of RA T-cells and successfully suppress synovial inflammation. Rebalancing glucose utilization and restoring oxidant signaling may provide a novel therapeutic strategy to prevent autoimmunity in RA.
Vaccination with attenuated live varicella zoster virus (VZV) can prevent zoster reactivation, but protection is incomplete especially in an older population. To decipher the molecular mechanisms underlying variable vaccine responses, T- and B-cell responses to VZV vaccination were examined in individuals of different ages including identical twin pairs. Contrary to the induction of VZV-specific antibodies, antigen-specific T cell responses were significantly influenced by inherited factors. Diminished generation of long-lived memory T cells in older individuals was mainly caused by increased T cell loss after the peak response while the expansion of antigen-specific T cells was not affected by age. Gene expression in activated CD4 T cells at the time of the peak response identified gene modules related to cell cycle regulation and DNA repair that correlated with the contraction phase of the T cell response and consequently the generation of long-lived memory cells. These data identify cell cycle regulatory mechanisms as targets to reduce T cell attrition in a vaccine response and to improve the generation of antigen-specific T cell memory, in particular in an older population.
Vaccination is one of the most successful medical interventions, but it loses its effectiveness in an older population that is of particular risk for infectious diseases. Shingles, caused by the reactivation of the chickenpox virus, is a prime example. Nearly every second individual has experienced shingles by the age of 80 years, and the shingles vaccine is only partially protective. Attempts to improve the vaccine response are mostly empiric. Vaccinations induce a rapid expansion of antigen-specific T cells with frequencies peaking after one to two weeks. Most expanded T cells die after the peak response, and only few T cells survive to provide protection from infection or, as in case of shingles, from reactivation of latent viruses. Most vaccine studies have focused on the early stages of the response; how T cells are activated and expand. Surprisingly, in our study with the shingle vaccine, T cell survival after the peak response was the major factor determining memory T cell frequencies. T cell attrition was increased with age, independent of genetic predisposition. Using systems biology tools we found several pathways involved in T cell division and DNA repair that could be targeted to improve T cell survival and thereby increase the effectiveness of vaccination.
Shirai et al. show that the glycolytic enzyme PKM2 serves as a molecular integrator of metabolic dysfunction, oxidative stress and tissue inflammation in macrophages from patients with atherosclerotic coronary artery disease.
Abnormal glucose metabolism and enhanced oxidative stress accelerate cardiovascular disease, a chronic inflammatory condition causing high morbidity and mortality. Here, we report that in monocytes and macrophages of patients with atherosclerotic coronary artery disease (CAD), overutilization of glucose promotes excessive and prolonged production of the cytokines IL-6 and IL-1β, driving systemic and tissue inflammation. In patient-derived monocytes and macrophages, increased glucose uptake and glycolytic flux fuel the generation of mitochondrial reactive oxygen species, which in turn promote dimerization of the glycolytic enzyme pyruvate kinase M2 (PKM2) and enable its nuclear translocation. Nuclear PKM2 functions as a protein kinase that phosphorylates the transcription factor STAT3, thus boosting IL-6 and IL-1β production. Reducing glycolysis, scavenging superoxide and enforcing PKM2 tetramerization correct the proinflammatory phenotype of CAD macrophages. In essence, PKM2 serves a previously unidentified role as a molecular integrator of metabolic dysfunction, oxidative stress and tissue inflammation and represents a novel therapeutic target in cardiovascular disease.
Immune aging results in progressive loss of both protective immunity and T cell–mediated suppression, thereby conferring susceptibility to a combination of immunodeficiency and chronic inflammatory disease. Here, we determined that older individuals fail to generate immunosuppressive CD8+CCR7+ Tregs, a defect that is even more pronounced in the age-related vasculitic syndrome giant cell arteritis. In young, healthy individuals, CD8+CCR7+ Tregs are localized in T cell zones of secondary lymphoid organs, suppress activation and expansion of CD4 T cells by inhibiting the phosphorylation of membrane-proximal signaling molecules, and effectively inhibit proliferative expansion of CD4 T cells in vitro and in vivo. We identified deficiency of NADPH oxidase 2 (NOX2) as the molecular underpinning of CD8 Treg failure in the older individuals and in patients with giant cell arteritis. CD8 Tregs suppress by releasing exosomes that carry preassembled NOX2 membrane clusters and are taken up by CD4 T cells. Overexpression of NOX2 in aged CD8 Tregs promptly restored suppressive function. Together, our data support NOX2 as a critical component of the suppressive machinery of CD8 Tregs and suggest that repairing NOX2 deficiency in these cells may protect older individuals from tissue-destructive inflammatory disease, such as large-vessel vasculitis.
Autophagy is a protective and life-sustaining process in which cytoplasmic components are packaged into double-membrane vesicles and targeted to lysosomes for degradation. This process of cellular self-digestion is an essential stress response and is cytoprotective by removing damaged organelles and proteins that threaten the cell’s survival. Key outcomes include energy generation and recycling of metabolic precursors. In the immune system, autophagy regulates processes such as antigen uptake and presentation, removal of pathogens, survival of short- and long-lived immune cells and cytokine-dependent inflammation. In all cases, a window of optimal autophagic activity appears critical to balance catabolic, reparative and inflammation-inducing processes. Dysregulation of autophagosome formation and autophagic flux can have deleterious consequences, ranging from a failure to “clean house” to the induction of autophagy-induced cell death. Abnormalities in the autophagic pathway have been implicated in numerous autoimmune diseases. Genome-wide association studies have linked polymorphisms in autophagy-related genes with predisposition for tissue-destructive inflammatory disease, specifically in inflammatory bowel disease and systemic lupus erythematosus. Although the precise mechanisms by which dysfunctional autophagy renders the host susceptible to continuous inflammation remain unclear, autophagy’s role in regulating the long-term survival of adaptive immune cells has recently surfaced as a defect in multiple sclerosis and rheumatoid arthritis. Efforts are underway to identify autophagy-inducing and autophagy-suppressing pharmacologic interventions that can be added to immunosuppressive therapy to improve outcomes of patients with autoimmune disease.
Constant exposure to new and persisting antigens and the need to replace cellular attrition with newly build cells lead to profound remodeling of the immune system during the second half of life. The impact of the immunosenescence process varies amongst the different functional subsets represented within the immune system, and emerging data suggest that progressive aging significantly affects frequencies, subset distribution and functional competence of regulatory T cells (Treg). Given the central role of Treg cells in immune homeostasis, age-related loss of Treg function would be predicted to render the host susceptible to excessive immunity, encountered in elderly humans as a syndrome of chronic-smoldering inflammation. Conversely, age-dependent gain of Treg activity would expose the host to greater risk of immune failure, such as the rising risk of malignancies and infections in the aging population. Emerging data suggest that some Treg populations, specifically naturally occurring Tregs (nTreg), seem to accumulate with advancing age, whereas inducible Tregs (iTreg) appear to be less available in the older host. More studies are necessary to elucidate functional competence of old Tregs, with emphasis on comparing efficacy of young on old Tregs for defined functional domains. Mechanisms of declining Treg inducibility are not understood, but may provide an opportunity for targeted immunomodulation in the elderly. On the horizon is the potential to develop novel therapeutic interventions that target Tregs to make the elderly more efficient in fighting cancers and infections and dampen the risk for senescence-associated inflammation.
naturally occurring regulatory T cells; inducible regulatory T cells; immune aging
Many of the aging-related morbidities, including cancer, cardiovascular disease, neurodegenerative disease and infectious susceptibility are linked to a decline in immune competence with a concomitant rise in proinflammatory immunity, placing the process of immune aging at the center of aging biology. Immune aging affects individuals over the age of 50 years and is accelerated in patients with the autoimmune disease rheumatoid arthritis. Curiously, immune aging results in a marked decline of protective immune responses and in a parallel increase in tissue inflammatory responses. By studying immune cells in patients with rheumatoid arthritis several of the molecular underpinnings of the immune aging process have been delineated, such as the loss of telomeres, and inefficiencies in the repair of damaged DNA. Aging T cells display a series of abnormalities, including the unopposed upregualtion of cytoplasmic phosphatases and the loss of glycolytic competence which alter their response to stimulating signals and undermine their longevity. Understanding the connection between accelerated immune aging and autoimmunity remains an area of active research. With increasing knowledge of the molecular pathways causing immunosenescence therapeutic interventions can be designed to slow or halt the seemingly inevitable deterioration of protective immunity with aging.
Autophagy; PFKFB3; Glycolysis; ROS; NADPH
Diversity and size of the antigen-specific T cell receptor (TCR) repertoire are two critical determinants for successful control of chronic infection. Varicella zoster virus (VZV) that establishes latency during childhood is able to escape control mechanisms, in particular with increasing age. We examined the TCR diversity of VZV-reactive CD4 T cells in individuals older than 50 years by studying three identical twin pairs and three unrelated individuals before and after vaccination with live attenuated VZV. While all individuals had a small number of dominant T cell clones, the breadth of the VZV-specific repertoire differed markedly. A genetic influence was seen for the sharing of individual TCR sequences from antigen-reactive cells, but not for repertoire richness or the selection of dominant clones. VZV vaccination favored the expansion of infrequent VZV antigen-reactive TCRs including those from naïve T cells with lesser boosting of dominant T cell clones. Thus, vaccination does not reinforce the in vivo selection occurred during chronic infection but leads to a diversification of the VZV-reactive T cell repertoire. However, a single booster immunization seems insufficient to establish new clonal dominance. Our results suggest that repertoire analysis of antigen-specific TCRs can be an important read-out to assess whether a vaccination was able to generate memory cells in clonal sizes that are necessary for immune protection.
In studies of immune aging, naïve T cells frequently take center stage. Describing the complexity of the human naïve T cell repertoire remains a daunting task; however, emerging data suggest that homeostatic mechanisms are robust enough to maintain a large and diverse CD4 T cell repertoire with age. Compartment shrinkage and clonal expansions are challenges for naïve CD8 T cells. In addition to population aspects, identification of potentially targetable cellular defects is receiving renewed interest. The last decade has seen remarkable progress in identifying genetic and biochemical pathways that are pertinent for aging in general and that are instructive to understand naïve T cell dysfunction. One hallmark sets naïve T cell aging apart from most other tissues except stem cells: they initiate but do not complete differentiation programs towards memory cells. Maintaining quiescence and avoiding differentiation may be the ultimate challenge to maintain the functions unique for naïve T cells.
With increasing age, naïve CD4 T cells acquire intrinsic defects that compromise their ability to respond and differentiate. Type I IFNs, pervasive constituents of the environment in which adaptive immune responses occur, are known to regulate T cell differentiation and survival. Activated naïve CD4 T cells from older individuals have reduced responses to type I IFN, a defect that develops during activation and is not observed in quiescent naïve CD4 T cells. Naïve CD4 T cells from young adults upregulate the expression of STAT1 and STAT5 after activation, lowering their threshold to respond to type I IFN stimulation. The heightened STAT signaling is critical to maintain the expression of CD69 that regulates lymphocyte egress and the ability to produce IL-2 and to survive. Although activation of T cells from older adults also induces transcription of STAT1 and STAT5, failure to exclude SHP1 to the signaling complex blunts their type I IFN response. In summary, our data show that type I IFN signaling thresholds in naïve CD4 T cells after activation are dynamically regulated to respond environmental cues for clonal expansion and memory cell differentiation. Naïve CD4 T cells from older adults have a defect in this threshold calibration. Restoring their ability to respond to type I IFN emerges as a promising target to restore T cell responses and improve the induction of T cell memory.
Atherosclerosis is a complex inflammatory disease involving aberrant immune and tissue healing responses, which begins with endothelial dysfunction and ends with plaque development, instability and rupture. The increased risk for coronary artery disease in patients with rheumatologic diseases highlights how aberrancy in the innate and adaptive immune system may be central to development of both disease states and that atherosclerosis may be on a spectrum of immune-mediated conditions. Recognition of the tight association between chronic inflammatory disease and complications of atherosclerosis will impact the understanding of underlying pathogenic mechanisms and change diagnostic and therapeutic approaches in patients with rheumatologic syndromes as well as patients with coronary artery disease. In this review, we provide a summary of the role of the immune system in atherosclerosis, discuss the proposed mechanisms of accelerated atherosclerosis seen in association with rheumatologic diseases, evaluate the effect of immunosuppression on atherosclerosis and provide updates on available risk assessment tools, biomarkers and imaging modalities.
atherosclerosis; arthritis; cardiac; cardiovascular disease; coronary artery disease; immune system; inflammation; rheumatologic
Purpose of review
With progressive age, the immune system and the propensity for abnormal immunity change fundamentally. Individuals >50 years of age are more susceptible to infection and cancer, but also at higher risk for chronic inflammation and immune-mediated tissue damage. The process of immunosenescence is accelerated in rheumatoid arthritis.
Premature T cell senescence occurs not only in RA, it has also been involved in morbidity and mortality of chronic HIV infection. Senescent cells acquire the “senescence associated secretory phenotype (SASP)”, which promotes and sustains tissue inflammation. Molecular mechanisms underlying T cell aging are beginning to be understood. Besides the contraction of T cell diversity due to uneven clonal expansion, senescent T cells have defects in balancing cytoplasmic kinase and phosphatase activities, changing their activation thresholds. Also, leakiness in repairing DNA lesions and uncapped telomeres imposes genomic stress. Age-induced changes in the tissue microenvironment may alter T cell responses.
Gain- and loss-of-function in senescent T cells undermine protective immunity and create the conditions for chronic tissue inflammation, a combination typically encountered in RA. Genetic programs involved in T cell signaling and DNA repair are of high interest in the search for underlying molecular defects.
immune aging; DNA damage; telomere; T cell signaling; SASP
Giant cell arteritis (GCA) is an important cause of preventable blindness, most
commonly due to anterior ischemic optic neuropathy. Ischemic tissue injury is the end
result of a process that begins within the walls of susceptible arteries in which local
dendritic cells (DCs) recruit and activate CD4 T cells that, in turn, direct the activity
of effector macrophages. In response to the granulomatous inflammation, the blood vessel
forms lumen- stenosing intima. Multiple cascades of excessive T-cell reactivity contribute
to the autoimmune features of giant cell arteritis with TH1 and TH17 immunity responsible
for the early phase and TH1 immunity promoting chronic-smoldering inflammation. These
cascades are only partially overlapping, supporting the concept that a multitude of
instigators jeopardize the immune privilege of the vessel wall. The artery actively
participates in the abnormal immune response through endogenous immune sentinels,
so-called vascular DCs embedded in the adventitia. Advancing age, the strongest of all
risk factors for GCA, likely contributes to the dysfunction of the immune system and the
vascular system. Expansion of the therapeutic armamentarium for GCA needs to focus on
approaches that mitigate the impact of the aging artery and adapt to the needs of the
Vasculitis of the medium and large arteries, most often presenting as giant cell arteritis (GCA), is an infrequent, but potentially fatal type of immune-mediated vascular disease. The site of the aberrant immune reaction, the mural layers of the artery, is strictly defined by vascular dendritic cells, endothelial cells, vascular smooth muscle cells and fibroblasts which engage in an interaction with T cells and macrophages to ultimately cause luminal stenosis or aneurysmal wall damage of the vessel. A multitude of effector cytokines, all known as critical mediators in host-protective immunity, has been identified in the vasculitic lesions. Two dominant cytokine clusters, one centering on the IL-6/IL-17 axis, the other on the IL-12/IFN-γ axis, have been connected with disease activity. These two clusters appear to serve different roles in the vasculitic process. The IL-6/IL-17 cluster is highly responsive to standard corticosteroid therapy, whereas the IL-12/IFN-γ cluster is resistant to steroid-mediated immunosuppression. The information exchange between vascular and immune cells and stabilization of the vasculitic process involves members of the NOTCH receptor and ligand family. Focusing on elements in the tissue context of GCA, instead of broadly suppressing host immunity, may allow for a more tailored therapeutic approach and spare patients the unwanted side-effects of aggressive immunosuppression.
Giant cell arteritis (GCA) is a granulomatous vasculitis of the aorta and its branches that causes blindness, stroke and aortic aneurysm. CD4 T-cells are key pathogenic regulators, instructed by vessel wall dendritic cells (DC) to differentiate into vasculitic T cells. The unique pathways driving this DC-T-cell interaction are incompletely understood but may provide novel therapeutic targets for a disease in which the only established therapy is chronic treatment with high doses of corticosteroids.
Methods and Results
Immunohistochemical and gene expression analysis of GCA-affected temporal arteries revealed abundant expression of the NOTCH receptor and its ligands Jagged1 and Delta1. Cleavage of the NOTCH intracellular domain (NICD) in wall-infiltrating T cells indicated ongoing NOTCH pathway activation in large vessel vasculitis. NOTCH activation did not occur in small vessel vasculitis affecting branches of the vasa vasorum tree. We devised two strategies to block NOTCH pathway activation; γ-secretase inhibitor treatment, preventing nuclear translocation of the NICD, and competing for receptor-ligand interactions through excess soluble ligand, Jagged1-Fc. In humanized mice carrying human arteries NOTCH pathway disruption had strong immunosuppressive effects, inhibiting T-cell activation in the early and established phase of vascular inflammation. NOTCH inhibition was particularly effective in downregulating Th17 responses, but also markedly suppressed Th1 responses.
Blocking NOTCH signaling depleted T cells from the vascular infiltrates, implicating NOTCH-NOTCH ligand interactions in regulating T-cell retention and survival in vessel wall inflammation. Modulating the NOTCH signaling cascade emerges as a promising new strategy for immunosuppressive therapy of large vessel vasculitis.
Arteries; Inflammation; T-cell; NOTCH; Costimulation; IFN-γ; IL-17
T cells from RA patients are hypoglycolytic due to insufficient induction of the glycolytic activator PFKFB3, resulting in impaired autophagy and reduced ROS production.
In the HLA class II–associated autoimmune syndrome rheumatoid arthritis (RA), CD4 T cells are critical drivers of pathogenic immunity. We have explored the metabolic activity of RA T cells and its impact on cellular function and fate. Naive CD4 T cells from RA patients failed to metabolize equal amounts of glucose as age-matched control cells, generated less intracellular ATP, and were apoptosis-susceptible. The defect was attributed to insufficient induction of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a regulatory and rate-limiting glycolytic enzyme known to cause the Warburg effect. Forced overexpression of PFKFB3 in RA T cells restored glycolytic flux and protected cells from excessive apoptosis. Hypoglycolytic RA T cells diverted glucose toward the pentose phosphate pathway, generated more NADPH, and consumed intracellular reactive oxygen species (ROS). PFKFB3 deficiency also constrained the ability of RA T cells to resort to autophagy as an alternative means to provide energy and biosynthetic precursor molecules. PFKFB3 silencing and overexpression identified a novel extraglycolytic role of the enzyme in autophagy regulation. In essence, T cells in RA patients, even those in a naive state, are metabolically reprogrammed with insufficient up-regulation of the glycolytic activator PFKFB3, rendering them energy-deprived, ROS- and autophagy-deficient, apoptosis-sensitive, and prone to undergo senescence.
Granuloma formation, bringing into close proximity highly activated macrophages and T cells, is a typical event in inflammatory blood vessel diseases, and is noted in the name of several of the vasculitides. It is not known whether specific properties of the microenvironment in the blood vessel wall or the immediate surroundings of blood vessels contribute to granuloma formation and, in some cases, generation of multinucleated giant cells. Granulomas provide a specialized niche to optimize macrophage–T cell interactions, strongly activating both cell types. This is mirrored by the intensity of the systemic inflammation encountered in patients with vasculitis, often presenting with malaise, weight loss, fever, and strongly upregulated acute phase responses. As a sophisticated and highly organized structure, granulomas can serve as an ideal site to induce differentiation and maturation of T cells. The granulomas possibly seed aberrant Th1 and Th17 cells into the circulation, which are known to be the main pathogenic cells in vasculitis. Through the induction of memory T cells, aberrant innate immune responses can imprint the host immune system for decades to come and promote chronicity of the disease process. Improved understanding of T cell–macrophage interactions will redefine pathogenic models in the vasculitides and provide new avenues for immunomodulatory therapy.
macrophage; dendritic cell; T cell; granuloma; vasculitis
In an immune response, CD4+ T cells expand into effector T cells and then contract to survive as long-lived memory cells. To identify age-associated defects in memory cell formation, we profiled activated CD4+ T cells and found an increased induction of the ATPase CD39 with age. CD39+ CD4+ T cells resembled effector T cells with signs of metabolic stress and high susceptibility to undergo apoptosis. Pharmacological inhibition of ATPase activity dampened effector cell differentiation and improved survival, suggesting that CD39 activity influences T cell fate. Individuals carrying a low-expressing CD39 variant responded better to vaccination with an increase in vaccine-specific memory T cells. Increased inducibility of CD39 after activation may contribute to the impaired vaccine response with age.
CD8 T cells stimulated with a suboptimal dose of anti-CD3 antibodies (100 pg/ml) in the presence of IL-15 retain a naïve phenotype with expression of CD45RA, CD28, CD27 and CCR7 but acquire new functions and differentiate into immunosuppressive T cells. CD8+CCR7+ Tregs express FOXP3 and prevent CD4 T cells from responding to T-cell receptor stimulation and entering the cell cycle. Naïve CD4 T cells are more susceptible to inhibition than memory cells. The suppressive activity of CD8+CCR7+ Tregs is not mediated by IL-10, TGF-β, CTLA-4, CCL4 or adenosine and relies on interference with very early steps of the TCR signaling cascade. Specifically, CD8+CCR7+ Tregs prevent TCR-induced phosphorylation of ZAP70 and dampen the rise of intracellular calcium in CD4 T cells. The inducibility of CD8+CCR7+ Tregs is correlated to the age of the individual with peripheral blood lymphocytes of donors older than 60 years yielding low numbers of FOXP3low CD8 Treg cells. Loss of CD8+CCR7+ Tregs in the elderly host may be of relevance in the aging immune system as immunosenescence is associated with a state of chronic smoldering inflammation.
Vascular oxidative injury accompanies many common conditions associated with hypertension. In the present study, we employed mouse models with excessive vascular production of ROS (tgsm/p22phox mice, which overexpress the NADPH oxidase subunit p22phox in smooth muscle, and mice with vascular-specific deletion of extracellular SOD) and have shown that these animals develop vascular collagen deposition, aortic stiffening, renal dysfunction, and hypertension with age. T cells from tgsm/p22phox mice produced high levels of IL-17A and IFN-γ. Crossing tgsm/p22phox mice with lymphocyte-deficient Rag1–/– mice eliminated vascular inflammation, aortic stiffening, renal dysfunction, and hypertension; however, adoptive transfer of T cells restored these processes. Isoketal-protein adducts, which are immunogenic, were increased in aortas, DCs, and macrophages of tgsm/p22phox mice. Autologous pulsing with tgsm/p22phox aortic homogenates promoted DCs of tgsm/p22phox mice to stimulate T cell proliferation and production of IFN-γ, IL-17A, and TNF-α. Treatment with the superoxide scavenger tempol or the isoketal scavenger 2-hydroxybenzylamine (2-HOBA) normalized blood pressure; prevented vascular inflammation, aortic stiffening, and hypertension; and prevented DC and T cell activation. Moreover, in human aortas, the aortic content of isoketal adducts correlated with fibrosis and inflammation severity. Together, these results define a pathway linking vascular oxidant stress to immune activation and aortic stiffening and provide insight into the systemic inflammation encountered in common vascular diseases.
In rheumatoid arthritis (RA), hematopoietic progenitor cells (HPC) have age-inappropriate telomeric shortening suggesting premature senescence and possible restriction of proliferative capacity. In response to hematopoietic growth factors RA-derived CD34+ HPC expanded significantly less than age-matched controls. Cell surface receptors for stem cell factor (SCF), Flt 3-Ligand, IL-3 and IL-6 were intact in RA HPC but the cells had lower transcript levels of cell cycle genes, compatible with insufficient signal strength in the ERK pathway. Cytokine-induced phosphorylation of ERK1/2 was diminished in RA HPC whereas phosphorylated STAT3 and STAT5 molecules accumulated to a similar extent as in controls. Confocal microscopy demonstrated that the membrane-proximal colocalization of K-Ras and B-Raf were less efficient in RA-derived CD34+ cells. Thus, hyporesponsiveness of RA HPC to growth factors results from dampening of the ERK signaling pathways; with a defect localized in the very early steps of the ERK signaling cascade.
rheumatoid arthritis; hematopoietic progenitor cells; CD34; ERK signaling; STAT signaling
Autoimmune rheumatic diseases can affect the cardiac vasculature, valves, myocardium, pericardium, and conduction system, leading to a plethora of cardiovascular manifestations that can remain clinically silent or lead to substantial cardiovascular morbidity and mortality. Although the high risk of cardiovascular pathology in patients with autoimmune inflammatory rheumatological diseases is not owing to atherosclerosis alone, this particular condition contributes substantially to cardiovascular morbidity and mortality—the degree of coronary atherosclerosis observed in patients with rheumatic diseases can be as accelerated, diffuse, and extensive as in patients with diabetes mellitus. The high risk of atherosclerosis is not solely attributable to traditional cardiovascular risk factors: dysfunctional immune responses, a hallmark of patients with rheumatic disorders, are thought to cause chronic tissue-destructive inflammation. Prompt recognition of cardiovascular abnormalities is needed for timely and appropriate management, and aggressive control of traditional risk factors remains imperative in patients with rheumatic diseases. Moreover, therapies directed towards inflammatory process are crucial to reduce cardiovascular disease morbidity and mortality. In this Review, we examine the multiple cardiovascular manifestations in patients with rheumatological disorders, their underlying pathophysiology, and available management strategies, with particular emphasis on the vascular aspects of the emerging field of ‘cardiorheumatology’.