Cornelia Weyand - Academia.edu (original) (raw)

Papers by Cornelia Weyand

Circulation, 2011

Background-Giant cell arteritis is a granulomatous vasculitis of the aorta and its branches that ... more Background-Giant cell arteritis 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 to differentiate into vasculitic T cells. The unique pathways driving this dendritic cell-T-cell interaction are incompletely understood, but may provide novel therapeutic targets for a disease in which the only established therapy is long-term treatment with high doses of corticosteroids. Methods and Results-Immunohistochemical and gene expression analyses of giant cell arteritis-affected temporal arteries revealed abundant expression of the NOTCH receptor and its ligands, Jagged1 and Delta1. Cleavage of the NOTCH intracellular domain 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 2 strategies to block NOTCH pathway activation: ␥-secretase inhibitor treatment, preventing nuclear translocation of the NOTCH intracellular domain, and competing for receptor-ligand interactions through excess soluble ligand, Jagged1-Fc. In a humanized mouse model, NOTCH pathway disruption had strong immunosuppressive effects, inhibiting T-cell activation in the early and established phases of vascular inflammation. NOTCH inhibition was particularly effective in downregulating Th17 responses, but also markedly suppressed Th1 responses. Conclusions-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. (Circulation. 2011;123:309-318.) Key Words: arteries Ⅲ costimulation Ⅲ inflammation Ⅲ interferon-␥ Ⅲ interleukin-17 Ⅲ NOTCH Ⅲ T cell G iant cell arteritis (GCA) is characterized by intramural and perivascular granulomatous lesions that destroy the vascular wall structure and induce luminal occlusion through fast and concentric neointimal outgrowth. 1 Clinical manifestations include blindness, stroke, and aortic aneurysm, and arterial inflammation is almost always combined with a syndrome of severe systemic inflammation. 2

Circulation, 2010

Background-In giant cell arteritis (GCA), vasculitic damage of the aorta and its branches is comb... more Background-In giant cell arteritis (GCA), vasculitic damage of the aorta and its branches is combined with a syndrome of intense systemic inflammation. Therapeutically, glucocorticoids remain the gold standard because they promptly and effectively suppress acute manifestations; however, they fail to eradicate vessel wall infiltrates. The effects of glucocorticoids on the systemic and vascular components of GCA are not understood. Methods and Results-The immunoprofile of untreated and glucocorticoid-treated GCA was examined in peripheral blood and temporal artery biopsies with protein quantification assays, flow cytometry, quantitative real-time polymerase chain reaction, and immunohistochemistry. Plasma interferon-␥ and interleukin (IL)-17 and frequencies of interferon-␥producing and IL-17-producing T cells were markedly elevated before therapy. Glucocorticoid treatment suppressed the Th17 but not the Th1 arm in the blood and the vascular lesions. Analysis of monocytes/macrophages in the circulation and in temporal arteries revealed glucocorticoid-mediated suppression of Th17-promoting cytokines (IL-1␤, IL-6, and IL-23) but sparing of Th1-promoting cytokines (IL-12). In human artery-severe combined immunodeficiency mouse chimeras, in which patient-derived T cells cause inflammation of engrafted human temporal arteries, glucocorticoids were similarly selective in inhibiting Th17 cells and leaving Th1 cells unaffected. Conclusions-Two pathogenic pathways mediated by Th17 and Th1 cells contribute to the systemic and vascular manifestations of GCA. IL-17-producing Th17 cells are sensitive to glucocorticoid-mediated suppression, but interferon-␥-producing Th1 responses persist in treated patients. Targeting steroid-resistant Th1 responses will be necessary to resolve chronic smoldering vasculitis. Monitoring Th17 and Th1 frequencies can aid in assessing disease activity in GCA. (Circulation. 2010;121:906-915.) Key Words: glucocorticoids Ⅲ inflammation Ⅲ interferons Ⅲ interleukin-17 Ⅲ Th1 cells Ⅲ vasculitis G iant cell arteritis (GCA) is a systemic vasculitis with 2 disease components: vessel wall inflammation inducing arterial stenosis/occlusion and a systemic inflammation leading to polymyalgias, anemia, failure to thrive, and malaise. 1 Prototypical vessel wall inflammation preferentially affects the upper extremity and extracranial branches of the aorta, causing blindness, stroke, aortic arch syndrome, aortic aneurysm, or dissection. 1,2 Clinical Perspective on p 915 Glucocorticoids remain the gold standard of therapy; attempts to introduce steroid-sparing agents, including antitumor necrosis factor blockers, have not been successful. 3,4 Methotrexate may have minor benefits when given over prolonged periods. 5 In a double-blind, placebo-controlled study employing glucocorticoid pulse therapy, patients pulsed at diagnosis had fewer disease flares and discontinued therapy earlier than patients without initial pulse therapy. How

Arthritis & Rheumatism, 2002

Objective. In giant cell arteritis (GCA), inflammatory lesions typically produce interferon-␥ (IF... more Objective. In giant cell arteritis (GCA), inflammatory lesions typically produce interferon-␥ (IFN␥)-and nuclear factor B (NF-B)-dependent monokines. Corticosteroids influence disease activity by repressing NF-B-dependent genes but have only marginal effects on IFN␥. The current study explored whether acetylsalicylic acid (ASA) had cytokine-repressing activity in GCA and could function as a steroid-sparing agent.

Journal of immunology (Baltimore, Md. : 1950), Jan 19, 2015

With increasing age, naive CD4 T cells acquire intrinsic defects that compromise their ability to... more With increasing age, naive 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 naive CD4 T cells from older individuals have reduced responses to type I IFN, a defect that develops during activation and that is not observed in quiescent naive CD4 T cells. Naive 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 SHP-1 from the signaling complex blunts their type I IFN response. In summary, our data show t...

Journal of immunology (Baltimore, Md. : 1950), 2015

In studies of immune aging, naive T cells frequently take center stage. Describing the complexity... more In studies of immune aging, naive T cells frequently take center stage. Describing the complexity of the human naive 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 naive 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 naive T cell dysfunction. One hallmark sets naive T cell aging apart from most other tissues except stem cells: they initiate but do not complete differentiation programs toward memory cells. Maintaining quiescence and avoiding differentiation may be the ultimate challenge to maintain the functions unique for naive T...

Frontiers in immunology, 2014

Granuloma formation, bringing into close proximity highly activated macrophages and T cells, is a... more 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...

Nature reviews. Rheumatology, 2013

Vasculitis of the medium and large arteries, most often presenting as giant cell arteritis (GCA),... more 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, have been identified in vasculitic lesions. Two dominant cytokine clusters--the IL-6-IL-17 axis and the IL-12-IFN-γ axis--have been linked to disease activity. These two clusters seem 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 immunosuppr...

Current cardiology reports, 2008

Several studies published in the past three decades have suggested that the adaptive immune syste... more Several studies published in the past three decades have suggested that the adaptive immune system contributes to hypertension. Recent studies have shown that T cells play a crucial role in the blood pressure elevation caused by angiotensin II and in response to sodium and volume challenge. Hypertensive stimuli cause effector T cells to enter visceral fat, in particular perivascular fat, where they release cytokines that promote vasoconstriction. Similarly, effector T cells accumulate in the kidney in hypertension and contribute to renal dysfunction, promoting sodium and volume retention. These findings provide some insight into the relationship between inflammation and hypertension and suggest that efforts to reduce T-cell activation may be useful in preventing or treating this disease.

The Journal of rheumatology, 2015

To evaluate clinical characteristics, treatment, and outcomes of patients with visual changes fro... more To evaluate clinical characteristics, treatment, and outcomes of patients with visual changes from giant cell arteritis (GCA) and to examine trends over the last 5 decades. We reviewed the medical records of a population-based cohort of patients with GCA diagnosed between 1950 and 2004. The clinical, ophthalmological, and laboratory features of patients with visual manifestations attributable to GCA were compared to patients without visual complications. Trends over time were examined using logistic regression modeling adjusted for age and sex. In a cohort of 204 cases of GCA (mean age 76.0 ± 8.2 yrs, 80% female), visual changes from GCA were observed in 47 patients (23%), and 4.4% suffered complete vision loss. A higher proportion of patients with visual manifestations reported jaw claudication than did patients without visual changes (55% vs 38%, p = 0.04). Over a period of 55 years, we observed a significant decline in the incidence of visual symptoms due to GCA. There was a lowe...

Proceedings of the National Academy of Sciences of the United States of America, Jan 9, 2014

T-cell receptor (TCR) diversity, a prerequisite for immune system recognition of the universe of ... more T-cell receptor (TCR) diversity, a prerequisite for immune system recognition of the universe of foreign antigens, is generated in the first two decades of life in the thymus and then persists to an unknown extent through life via homeostatic proliferation of naïve T cells. We have used next-generation sequencing and nonparametric statistical analysis to estimate a lower bound for the total number of different TCR beta (TCRB) sequences in human repertoires. We arrived at surprisingly high minimal estimates of 100 million unique TCRB sequences in naïve CD4 and CD8 T-cell repertoires of young adults. Naïve repertoire richness modestly declined two- to fivefold in healthy elderly. Repertoire richness contraction with age was even less pronounced for memory CD4 and CD8 T cells. In contrast, age had a major impact on the inequality of clonal sizes, as estimated by a modified Gini-Simpson index clonality score. In particular, large naïve T-cell clones that were distinct from memory clones...

Autophagy, 2014

T lymphocytes, the master regulators of immunity, have an unusual lifestyle. Equipped with a clon... more T lymphocytes, the master regulators of immunity, have an unusual lifestyle. Equipped with a clonally distributed receptor they remain resting for long periods of time but go into overdrive when encountering antigen. Antigen recognition triggers an activation program that results in massive proliferation, differentiation into effector/memory cells, egress from lymphoid storage sites, and production of an array of cytokines. To adapt to the sudden demand for energy and biosynthetic macromolecules, T cells resort to aerobic glycolysis, relying on the Warburg effect to provide sufficient ATP and precursor molecules. Metabolic adaptation to the biosynthetic needs includes upregulation of autophagy, a catabolic process resulting in the degradation of cytoplasmic contents. The close connection between a metabolic switch, proliferative expansion, and functional differentiation connects the metabolic conditions in the cell to normal and pathogenic immunity.

New England Journal of Medicine, 2003

Review Article from The New England Journal of Medicine — Medium-and Large-Vessel Vasculitis.

Journal of Molecular Medicine, 2008

Dendritic cells (DCs) shape T-cell response patterns and determine early, intermediate, and late ... more Dendritic cells (DCs) shape T-cell response patterns and determine early, intermediate, and late outcomes of immune recognition events. They either facilitate immunostimulation or induce tolerance, possibly determined by initial DC activation signals, such as binding Toll-like receptor (TLR) ligands. Here we report that DC stimulation through the TLR3 ligand dsRNA [poly(I:C)] limits CD4 T-cell proliferation, curtailing adaptive immune responses. CD4 + T cells instructed by either LPS or poly(I:C)-conditioned DCs promptly upregulated the activation marker CD69. Whereas LPS-pretreated DCs subsequently sustained T-cell clonal expansion, proliferation of CD4 + T cells exposed to poly(I:C)-pretreated DCs was markedly suppressed. This proliferative defect required DC-T cell contact, was independent of IFN-α, and was overcome by exogenous IL-2, indicating T-cell anergy. Coinciding with the downregulation, CD4 + T cells expressed the inhibitory receptor PD-1. Antibodies blocking the PD-1 ligand PD-L1 restored proliferation. dsRNA-stimulated DCs preferentially induced PD-L1, whereas poly(I:C) and LPS both upregulated the costimulatory molecule CD86 to a comparable extent. Poly(dA-dT), a ligand targeting the cytoplasmic RNA helicase pattern-recognition pathway, failed to selectively induce PD-L1 upregulation, assigning this effect to the TLR3 pathway. Poly(I:C)-conditioned DCs promoted accumulation of phosphorylated SHP-2, the intracellular phosphatase mediating PD-1 inhibitory effects. The ability of dsRNA to bias DC differentiation toward providing inhibitory signals to interacting CD4 + T cells may be instrumental in viral immune evasion. Conversely, TLR3 ligands may have therapeutic value in silencing pathogenic immune responses.

The Journal of Immunology, 2012

CD8 T cells stimulated with a suboptimal dose of anti-CD3 Abs (100 pg/ml) in the presence of IL-1... more CD8 T cells stimulated with a suboptimal dose of anti-CD3 Abs (100 pg/ml) in the presence of IL-15 retain a naive phenotype with expression of CD45RA, CD28, CD27, and CCR7 but acquire new functions and differentiate into immunosuppressive T cells. CD8+CCR7+ regulatory T cells (Tregs) express FOXP3 and prevent CD4 T cells from responding to TCR stimulation and entering the cell cycle. Naive 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 with the age of the individual with PBLs of donors older than 60 y yielding low numbers of FOXP3(low) CD8 Tregs. 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.

Gerontology, 2014

Constant exposure to new and persisting antigens and the need to replace cellular attrition with ... more Constant exposure to new and persisting antigens and the need to replace cellular attrition with newly built cells lead to profound remodeling of the immune system after the age of 50 years. The impact of the immunosenescence process varies amongst the different cellular subsets represented within the immune system. Emerging data suggest that progressive aging significantly affects frequencies, subset distribution and functional competence of regulatory T cells (Tregs). Given the central role of Tregs in immune homeostasis, age-related loss of Treg function would be predicted to cause excessive immunity, encountered in elderly humans as a syndrome of chronic, smoldering inflammation as well as the age-related increase in the risk for autoimmunity. Conversely, age-dependent gain of Treg activity would result in failing immunity, such as the rising risk of malignancies and infections amongst the elderly. Emerging data suggest that some Treg populations, specifically naturally occurring Tregs, seem to accumulate with advancing age, whereas inducible Tregs appear to be less available in the older host. More studies are necessary to elucidate functional competence of old Tregs, with an emphasis on comparing the efficacy of young and 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.

Experimental Gerontology, 2014

The ability of the human immune system to repel infections is drastically diminished with age. El... more The ability of the human immune system to repel infections is drastically diminished with age. Elderly individuals are more susceptible to new threats and are less able to control endogenous infections. The thymus, which is the sole source of new T cells, has been proposed as a target for regenerative efforts to improve immune competence, as thymic activity is dramatically reduced after puberty. In this review, we review the role of the thymus in the maintenance of T cell homeostasis throughout life and contrast the differences in mice and humans. We propose that in humans, lack of thymic T cell generation does not explain a decline in T cell receptor diversity nor would thymic rejuvenation restore diversity. Initial studies using next generation sequencing are beginning to establish lower boundaries of T cell receptor diversity. With increasing sequencing depth and the development of new statistical models, we are now in the position to test this model and to assess the impact of age on T cell diversity and clonality.

EMBO Molecular Medicine, 2010

Clinical Immunology, 2009

were devoid of CD21 expression. Western blot analysis revealed complete absence of CD21 protein e... more were devoid of CD21 expression. Western blot analysis revealed complete absence of CD21 protein expression in the patient. A compound heterozygous mutation in the CD21 gene was identified as the underlying molecular defect, leading to premature mRNA decay, respectively to a rapidly degraded CD21 protein. Despite reduced class-switched memory B cell numbers the patient mounts protective and long-lived specific antibody responses. This is in contrast to the severely impaired capacity of patient's B cells to bind C3d-containing immune complexes. Further experiments detecting alterations in CD21 dependent calcium flux in the patient are in progress. Our findings also impact the biology of EBV infection and associated human disorder. We provide evidence for EBV infection of human B cells in vitro and in vivo in the absence of CD21 expression, and we could demonstrate almost absent binding of EBV gp350 to the patient's B cells.

Clinical Immunology, 2009

Circulation, 2011

Background-Giant cell arteritis is a granulomatous vasculitis of the aorta and its branches that ... more Background-Giant cell arteritis 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 to differentiate into vasculitic T cells. The unique pathways driving this dendritic cell-T-cell interaction are incompletely understood, but may provide novel therapeutic targets for a disease in which the only established therapy is long-term treatment with high doses of corticosteroids. Methods and Results-Immunohistochemical and gene expression analyses of giant cell arteritis-affected temporal arteries revealed abundant expression of the NOTCH receptor and its ligands, Jagged1 and Delta1. Cleavage of the NOTCH intracellular domain 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 2 strategies to block NOTCH pathway activation: ␥-secretase inhibitor treatment, preventing nuclear translocation of the NOTCH intracellular domain, and competing for receptor-ligand interactions through excess soluble ligand, Jagged1-Fc. In a humanized mouse model, NOTCH pathway disruption had strong immunosuppressive effects, inhibiting T-cell activation in the early and established phases of vascular inflammation. NOTCH inhibition was particularly effective in downregulating Th17 responses, but also markedly suppressed Th1 responses. Conclusions-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. (Circulation. 2011;123:309-318.) Key Words: arteries Ⅲ costimulation Ⅲ inflammation Ⅲ interferon-␥ Ⅲ interleukin-17 Ⅲ NOTCH Ⅲ T cell G iant cell arteritis (GCA) is characterized by intramural and perivascular granulomatous lesions that destroy the vascular wall structure and induce luminal occlusion through fast and concentric neointimal outgrowth. 1 Clinical manifestations include blindness, stroke, and aortic aneurysm, and arterial inflammation is almost always combined with a syndrome of severe systemic inflammation. 2

Circulation, 2010

Background-In giant cell arteritis (GCA), vasculitic damage of the aorta and its branches is comb... more Background-In giant cell arteritis (GCA), vasculitic damage of the aorta and its branches is combined with a syndrome of intense systemic inflammation. Therapeutically, glucocorticoids remain the gold standard because they promptly and effectively suppress acute manifestations; however, they fail to eradicate vessel wall infiltrates. The effects of glucocorticoids on the systemic and vascular components of GCA are not understood. Methods and Results-The immunoprofile of untreated and glucocorticoid-treated GCA was examined in peripheral blood and temporal artery biopsies with protein quantification assays, flow cytometry, quantitative real-time polymerase chain reaction, and immunohistochemistry. Plasma interferon-␥ and interleukin (IL)-17 and frequencies of interferon-␥producing and IL-17-producing T cells were markedly elevated before therapy. Glucocorticoid treatment suppressed the Th17 but not the Th1 arm in the blood and the vascular lesions. Analysis of monocytes/macrophages in the circulation and in temporal arteries revealed glucocorticoid-mediated suppression of Th17-promoting cytokines (IL-1␤, IL-6, and IL-23) but sparing of Th1-promoting cytokines (IL-12). In human artery-severe combined immunodeficiency mouse chimeras, in which patient-derived T cells cause inflammation of engrafted human temporal arteries, glucocorticoids were similarly selective in inhibiting Th17 cells and leaving Th1 cells unaffected. Conclusions-Two pathogenic pathways mediated by Th17 and Th1 cells contribute to the systemic and vascular manifestations of GCA. IL-17-producing Th17 cells are sensitive to glucocorticoid-mediated suppression, but interferon-␥-producing Th1 responses persist in treated patients. Targeting steroid-resistant Th1 responses will be necessary to resolve chronic smoldering vasculitis. Monitoring Th17 and Th1 frequencies can aid in assessing disease activity in GCA. (Circulation. 2010;121:906-915.) Key Words: glucocorticoids Ⅲ inflammation Ⅲ interferons Ⅲ interleukin-17 Ⅲ Th1 cells Ⅲ vasculitis G iant cell arteritis (GCA) is a systemic vasculitis with 2 disease components: vessel wall inflammation inducing arterial stenosis/occlusion and a systemic inflammation leading to polymyalgias, anemia, failure to thrive, and malaise. 1 Prototypical vessel wall inflammation preferentially affects the upper extremity and extracranial branches of the aorta, causing blindness, stroke, aortic arch syndrome, aortic aneurysm, or dissection. 1,2 Clinical Perspective on p 915 Glucocorticoids remain the gold standard of therapy; attempts to introduce steroid-sparing agents, including antitumor necrosis factor blockers, have not been successful. 3,4 Methotrexate may have minor benefits when given over prolonged periods. 5 In a double-blind, placebo-controlled study employing glucocorticoid pulse therapy, patients pulsed at diagnosis had fewer disease flares and discontinued therapy earlier than patients without initial pulse therapy. How

Arthritis & Rheumatism, 2002

Objective. In giant cell arteritis (GCA), inflammatory lesions typically produce interferon-␥ (IF... more Objective. In giant cell arteritis (GCA), inflammatory lesions typically produce interferon-␥ (IFN␥)-and nuclear factor B (NF-B)-dependent monokines. Corticosteroids influence disease activity by repressing NF-B-dependent genes but have only marginal effects on IFN␥. The current study explored whether acetylsalicylic acid (ASA) had cytokine-repressing activity in GCA and could function as a steroid-sparing agent.

Journal of immunology (Baltimore, Md. : 1950), Jan 19, 2015

With increasing age, naive CD4 T cells acquire intrinsic defects that compromise their ability to... more With increasing age, naive 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 naive CD4 T cells from older individuals have reduced responses to type I IFN, a defect that develops during activation and that is not observed in quiescent naive CD4 T cells. Naive 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 SHP-1 from the signaling complex blunts their type I IFN response. In summary, our data show t...

Journal of immunology (Baltimore, Md. : 1950), 2015

In studies of immune aging, naive T cells frequently take center stage. Describing the complexity... more In studies of immune aging, naive T cells frequently take center stage. Describing the complexity of the human naive 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 naive 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 naive T cell dysfunction. One hallmark sets naive T cell aging apart from most other tissues except stem cells: they initiate but do not complete differentiation programs toward memory cells. Maintaining quiescence and avoiding differentiation may be the ultimate challenge to maintain the functions unique for naive T...

Frontiers in immunology, 2014

Granuloma formation, bringing into close proximity highly activated macrophages and T cells, is a... more 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...

Nature reviews. Rheumatology, 2013

Vasculitis of the medium and large arteries, most often presenting as giant cell arteritis (GCA),... more 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, have been identified in vasculitic lesions. Two dominant cytokine clusters--the IL-6-IL-17 axis and the IL-12-IFN-γ axis--have been linked to disease activity. These two clusters seem 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 immunosuppr...

Current cardiology reports, 2008

Several studies published in the past three decades have suggested that the adaptive immune syste... more Several studies published in the past three decades have suggested that the adaptive immune system contributes to hypertension. Recent studies have shown that T cells play a crucial role in the blood pressure elevation caused by angiotensin II and in response to sodium and volume challenge. Hypertensive stimuli cause effector T cells to enter visceral fat, in particular perivascular fat, where they release cytokines that promote vasoconstriction. Similarly, effector T cells accumulate in the kidney in hypertension and contribute to renal dysfunction, promoting sodium and volume retention. These findings provide some insight into the relationship between inflammation and hypertension and suggest that efforts to reduce T-cell activation may be useful in preventing or treating this disease.

The Journal of rheumatology, 2015

To evaluate clinical characteristics, treatment, and outcomes of patients with visual changes fro... more To evaluate clinical characteristics, treatment, and outcomes of patients with visual changes from giant cell arteritis (GCA) and to examine trends over the last 5 decades. We reviewed the medical records of a population-based cohort of patients with GCA diagnosed between 1950 and 2004. The clinical, ophthalmological, and laboratory features of patients with visual manifestations attributable to GCA were compared to patients without visual complications. Trends over time were examined using logistic regression modeling adjusted for age and sex. In a cohort of 204 cases of GCA (mean age 76.0 ± 8.2 yrs, 80% female), visual changes from GCA were observed in 47 patients (23%), and 4.4% suffered complete vision loss. A higher proportion of patients with visual manifestations reported jaw claudication than did patients without visual changes (55% vs 38%, p = 0.04). Over a period of 55 years, we observed a significant decline in the incidence of visual symptoms due to GCA. There was a lowe...

Proceedings of the National Academy of Sciences of the United States of America, Jan 9, 2014

T-cell receptor (TCR) diversity, a prerequisite for immune system recognition of the universe of ... more T-cell receptor (TCR) diversity, a prerequisite for immune system recognition of the universe of foreign antigens, is generated in the first two decades of life in the thymus and then persists to an unknown extent through life via homeostatic proliferation of naïve T cells. We have used next-generation sequencing and nonparametric statistical analysis to estimate a lower bound for the total number of different TCR beta (TCRB) sequences in human repertoires. We arrived at surprisingly high minimal estimates of 100 million unique TCRB sequences in naïve CD4 and CD8 T-cell repertoires of young adults. Naïve repertoire richness modestly declined two- to fivefold in healthy elderly. Repertoire richness contraction with age was even less pronounced for memory CD4 and CD8 T cells. In contrast, age had a major impact on the inequality of clonal sizes, as estimated by a modified Gini-Simpson index clonality score. In particular, large naïve T-cell clones that were distinct from memory clones...

Autophagy, 2014

T lymphocytes, the master regulators of immunity, have an unusual lifestyle. Equipped with a clon... more T lymphocytes, the master regulators of immunity, have an unusual lifestyle. Equipped with a clonally distributed receptor they remain resting for long periods of time but go into overdrive when encountering antigen. Antigen recognition triggers an activation program that results in massive proliferation, differentiation into effector/memory cells, egress from lymphoid storage sites, and production of an array of cytokines. To adapt to the sudden demand for energy and biosynthetic macromolecules, T cells resort to aerobic glycolysis, relying on the Warburg effect to provide sufficient ATP and precursor molecules. Metabolic adaptation to the biosynthetic needs includes upregulation of autophagy, a catabolic process resulting in the degradation of cytoplasmic contents. The close connection between a metabolic switch, proliferative expansion, and functional differentiation connects the metabolic conditions in the cell to normal and pathogenic immunity.

New England Journal of Medicine, 2003

Review Article from The New England Journal of Medicine — Medium-and Large-Vessel Vasculitis.

Journal of Molecular Medicine, 2008

Dendritic cells (DCs) shape T-cell response patterns and determine early, intermediate, and late ... more Dendritic cells (DCs) shape T-cell response patterns and determine early, intermediate, and late outcomes of immune recognition events. They either facilitate immunostimulation or induce tolerance, possibly determined by initial DC activation signals, such as binding Toll-like receptor (TLR) ligands. Here we report that DC stimulation through the TLR3 ligand dsRNA [poly(I:C)] limits CD4 T-cell proliferation, curtailing adaptive immune responses. CD4 + T cells instructed by either LPS or poly(I:C)-conditioned DCs promptly upregulated the activation marker CD69. Whereas LPS-pretreated DCs subsequently sustained T-cell clonal expansion, proliferation of CD4 + T cells exposed to poly(I:C)-pretreated DCs was markedly suppressed. This proliferative defect required DC-T cell contact, was independent of IFN-α, and was overcome by exogenous IL-2, indicating T-cell anergy. Coinciding with the downregulation, CD4 + T cells expressed the inhibitory receptor PD-1. Antibodies blocking the PD-1 ligand PD-L1 restored proliferation. dsRNA-stimulated DCs preferentially induced PD-L1, whereas poly(I:C) and LPS both upregulated the costimulatory molecule CD86 to a comparable extent. Poly(dA-dT), a ligand targeting the cytoplasmic RNA helicase pattern-recognition pathway, failed to selectively induce PD-L1 upregulation, assigning this effect to the TLR3 pathway. Poly(I:C)-conditioned DCs promoted accumulation of phosphorylated SHP-2, the intracellular phosphatase mediating PD-1 inhibitory effects. The ability of dsRNA to bias DC differentiation toward providing inhibitory signals to interacting CD4 + T cells may be instrumental in viral immune evasion. Conversely, TLR3 ligands may have therapeutic value in silencing pathogenic immune responses.

The Journal of Immunology, 2012

CD8 T cells stimulated with a suboptimal dose of anti-CD3 Abs (100 pg/ml) in the presence of IL-1... more CD8 T cells stimulated with a suboptimal dose of anti-CD3 Abs (100 pg/ml) in the presence of IL-15 retain a naive phenotype with expression of CD45RA, CD28, CD27, and CCR7 but acquire new functions and differentiate into immunosuppressive T cells. CD8+CCR7+ regulatory T cells (Tregs) express FOXP3 and prevent CD4 T cells from responding to TCR stimulation and entering the cell cycle. Naive 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 with the age of the individual with PBLs of donors older than 60 y yielding low numbers of FOXP3(low) CD8 Tregs. 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.

Gerontology, 2014

Constant exposure to new and persisting antigens and the need to replace cellular attrition with ... more Constant exposure to new and persisting antigens and the need to replace cellular attrition with newly built cells lead to profound remodeling of the immune system after the age of 50 years. The impact of the immunosenescence process varies amongst the different cellular subsets represented within the immune system. Emerging data suggest that progressive aging significantly affects frequencies, subset distribution and functional competence of regulatory T cells (Tregs). Given the central role of Tregs in immune homeostasis, age-related loss of Treg function would be predicted to cause excessive immunity, encountered in elderly humans as a syndrome of chronic, smoldering inflammation as well as the age-related increase in the risk for autoimmunity. Conversely, age-dependent gain of Treg activity would result in failing immunity, such as the rising risk of malignancies and infections amongst the elderly. Emerging data suggest that some Treg populations, specifically naturally occurring Tregs, seem to accumulate with advancing age, whereas inducible Tregs appear to be less available in the older host. More studies are necessary to elucidate functional competence of old Tregs, with an emphasis on comparing the efficacy of young and 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.

Experimental Gerontology, 2014

The ability of the human immune system to repel infections is drastically diminished with age. El... more The ability of the human immune system to repel infections is drastically diminished with age. Elderly individuals are more susceptible to new threats and are less able to control endogenous infections. The thymus, which is the sole source of new T cells, has been proposed as a target for regenerative efforts to improve immune competence, as thymic activity is dramatically reduced after puberty. In this review, we review the role of the thymus in the maintenance of T cell homeostasis throughout life and contrast the differences in mice and humans. We propose that in humans, lack of thymic T cell generation does not explain a decline in T cell receptor diversity nor would thymic rejuvenation restore diversity. Initial studies using next generation sequencing are beginning to establish lower boundaries of T cell receptor diversity. With increasing sequencing depth and the development of new statistical models, we are now in the position to test this model and to assess the impact of age on T cell diversity and clonality.

EMBO Molecular Medicine, 2010

Clinical Immunology, 2009

were devoid of CD21 expression. Western blot analysis revealed complete absence of CD21 protein e... more were devoid of CD21 expression. Western blot analysis revealed complete absence of CD21 protein expression in the patient. A compound heterozygous mutation in the CD21 gene was identified as the underlying molecular defect, leading to premature mRNA decay, respectively to a rapidly degraded CD21 protein. Despite reduced class-switched memory B cell numbers the patient mounts protective and long-lived specific antibody responses. This is in contrast to the severely impaired capacity of patient's B cells to bind C3d-containing immune complexes. Further experiments detecting alterations in CD21 dependent calcium flux in the patient are in progress. Our findings also impact the biology of EBV infection and associated human disorder. We provide evidence for EBV infection of human B cells in vitro and in vivo in the absence of CD21 expression, and we could demonstrate almost absent binding of EBV gp350 to the patient's B cells.

Clinical Immunology, 2009