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1.  Canadian Society of Allergy and Clinical Immunology annual scientific meeting 2016 
Alsayegh, Mohammad A. | Alshamali, Hanan | Khadada, Mousa | Ciccolini, Amanda | Ellis, Anne K. | Quint, Diana | Powley, William | Lee, Laurie | Fiteih, Yahya | Baksh, Shairaz | Vliagoftis, Harissios | Gerega, Sebastien K. | Millson, Brad | Charland, Katia | Barakat, Stephane | Sun, Xichun | Jimenez, Ricardo | Waserman, Susan | FitzGerald, Mark J. | Hébert, Jacques | Cognet-Sicé, Josiane | Renahan, Kevin E. | Huq, Saiful | Chooniedass, Rishma | Sawyer, Scott | Pasterkamp, Hans | Becker, Allan | Smith, Steven G. | Zhang, Shiyuan | Jayasundara, Kavisha | Tacon, Claire | Simidchiev, Alex | Nadeau, Gilbert | Gunsoy, Necdet | Mullerova, Hana | Albers, Frank | Kim, Young Woong | Shannon, Casey P. | Singh, Amrit | Neighbour, Helen | Larché, Mark | Tebbutt, Scott J. | Klopp, Annika | Vehling, Lorena | Becker, Allan B. | Subbarao, Padmaja | Mandhane, Piushkumar J. | Turvey, Stuart E. | Sears, Malcolm R. | Azad, Meghan B. | Loewen, Keely | Monchka, Barret | Mahmud, Salaheddin M. | Jong, Geert ‘t | Longo, Cristina | Bartlett, Gillian | Ducharme, Francine M. | Schuster, Tibor | MacGibbon, Brenda | Barnett, Tracie | North, Michelle L. | Brook, Jeff | Lee, Elizabeth | Omana, Vanessa | Thiele, Jenny | Steacy, Lisa M. | Evans, Greg | Diamond, Miriam | Sussman, Gordon L. | Amistani, Yann | Abiteboul, Kathy | Tenn, Mark W. | Yang, ChenXi | Carlsten, Christopher | Conway, Edward M. | Mack, Douglas | Othman, Yasmin | Barber, Colin M. | Kalicinsky, Chrystyna | Burke, Andrea E. | Messieh, Mary | Nair, Parameswaran | Che, Chun T. | Douglas, Lindsay | Liem, Joel | Duan, Lucy | Miller, Charlotte | Dupuis, Pascale | Connors, Lori A. | Fein, Michael N. | Shuster, Joseph | Hadi, Hani | Polk, Brooke | Raje, Nikita | Labrosse, Roxane | Bégin, Philippe | Paradis, Louis | Roches, Anne Des | Lacombe-Barrios, Jonathan | Mishra, Sanju | Lacuesta, Gina | Chiasson, Meredith | Haroon, Babar | Robertson, Kara | Issekutz, Thomas | Leddin, Desmond | Couban, Stephen | Connors, Lori | Roos, Adrienne | Kanani, Amin | Chan, Edmond S. | Schellenberg, Robert | Rosenfield, Lana | Cvetkovic, Anna | Woodward, Kevin | Quirt, Jaclyn | Watson, Wade T. A. | Castilho, Edson | Sullivan, Jennifer A. | Temple, Beverley | Martin, Donna | Cook, Victoria E. | Mills, Christopher | Portales-Casamar, Elodie | Fu, Lisa W. | Ho, Alexander | Zaltzman, Jeffrey | Chen, Lucy | Vadas, Peter | Gabrielli, Sofianne | Clarke, Ann | Eisman, Harley | Morris, Judy | Joseph, Lawrence | LaVieille, Sebastien | Ben-Shoshan, Moshe | Graham, François | Barnes, Charles | Portnoy, Jay | Stagg, Vincent | Simons, Elinor | Lefebvre, Diana | Dai, David | Mandhane, Piushkumar | Sears, Malcolm | Tam, Herman | Simons, F. Estelle R. | Alotaibi, Dhaifallah | Dawod, Bassel | Tunis, Matthew C. | Marshall, Jean | Desjardins, Marylin | Béland, Marianne | Lejtenyi, Duncan | Drolet, Jean-Phillipe | Lemire, Martine | Tsoukas, Christos | Noya, Francisco J.D. | Alizadehfar, Reza | McCusker, Christine T. | Mazer, Bruce D. | Maestre-Batlle, Danay | Gunawan, Evelyn | Rider, Christopher F. | Bølling, Anette K. | Pena, Olga M. | Suez, Daniel | Melamed, Isaac | Hussain, Iftikhar | Stein, Mark | Gupta, Sudhir | Paris, Kenneth | Fritsch, Sandor | Bourgeois, Christelle | Leibl, Heinz | McCoy, Barbara | Noel, Martin | Yel, Leman | Scott, Ori | Reid, Brenda | Atkinson, Adelle | Kim, Vy Hong-Diep | Roifman, Chaim M. | Grunebaum, Eyal | AlSelahi, Eiman | Aleman, Fernando | Oberle, Amber | Trus, Mike | Sussman, Gordon | Kanani, Amin S. | Chambenoi, Olivier | Chiva-Razavi, Sima | Grodecki, Savannah | Joshi, Nikhil | Menikefs, Peter | Holt, David | Pun, Teresa | Tworek, Damian | Hanna, Raphael | Heroux, Delia | Rosenberg, Elli | Stiemsma, Leah | Turvey, Stuart | Denburg, Judah | Mill, Christopher | Teoh, Timothy | Zimmer, Preeti | Avinashi, Vishal | Paina, Mihaela | Darwish Hassan, Ahmed A. | Oliveria, John Paul | Olesovsky, Chris | Gauvreau, Gail | Pedder, Linda | Keith, Paul K. | Plunkett, Greg | Bolner, Michelle | Pourshahnazari, Persia | Stark, Donald | Vostretsova, Kateryna | Moses, Andrew | Wakeman, Andrew | Singer, Alexander | Gerstner, Thomas | Abrams, Elissa | Johnson, Sara F. | Woodgate, Roberta L.
doi:10.1186/s13223-017-0192-y
PMCID: PMC5390240
2.  Primum non nocere—first do no harm. And then feed peanut 
The Addendum Guidelines for the Prevention of Peanut Allergy in the United States—Report of the NIAID-Sponsored Expert Panel were developed to build on previous food allergy guidelines after several key studies demonstrated the benefit of early introduction of allergenic foods. These landmark studies including the Learning Early about Peanut (LEAP), LEAP-On and Enquiring about Tolerance trials created a paradigm shift in food allergy prevention. The “take home” messages of this guideline include that peanut should be introduced early in the first year of life, and for the majority of infants, peanut can be introduced at home. The only group of infants for which medical assessment is recommended is those with severe eczema, egg allergy or both. Here we summarize the Guideline recommendations, endorsed by the Canadian Society of Allergy and Clinical Immunology, and highlight important aspects relevant to Canadian practitioners.
doi:10.1186/s13223-017-0180-2
PMCID: PMC5299733
Peanut allergy; Prevention; High-risk; Infant
3.  Metal-specific CD4+ T cell responses induced by beryllium exposure in HLA-DP2 transgenic mice 
Mucosal immunology  2015;9(1):218-228.
Chronic beryllium disease (CBD) is a granulomatous lung disorder that is associated with the accumulation of beryllium (Be)-specific CD4+ T cells into the lung. Genetic susceptibility is linked to HLA-DPB1 alleles that possess a glutamic acid at position 69 (βGlu69), and HLA-DPB1*02:01 is the most prevalent βGlu69-containing allele. Using HLA-DP2 transgenic (Tg) mice, we developed a model of CBD that replicates the major features of the human disease. Here, we characterized the T cell receptor repertoire of Be-responsive CD4+ T cells derived from the lungs of Be oxide-exposed HLA-DP2 Tg mice. The majority of Be-specific T cell hybridomas expressed TCR Vβ6, and a subset of these hybridomas expressed identical or nearly identical β-chains that were paired with different α-chains. We delineated mimotopes that bind to HLA-DP2 and form a complex recognized by Be-specific CD4+ T cells in the absence of Be. These Be-independent peptides possess an arginine at p5 and a tryptophan at p7 that surround the Be-binding site within the HLA-DP2 acidic pocket and likely induce charge and conformational changes that mimic those induced by the Be2+ cation. Collectively, these data highlight the interplay between peptides and Be in the generation of an adaptive immune response in metal-induced hypersensitivity.
doi:10.1038/mi.2015.54
PMCID: PMC4698108  PMID: 26129650
beryllium; granulomatous lung disease; T cell receptor; lung; metals; hypersensitivity
4.  MyD88 Dependence of Beryllium-Induced Dendritic Cell Trafficking and CD4+ T Cell Priming 
Mucosal immunology  2015;8(6):1237-1247.
Beryllium exposure results in beryllium hypersensitivity in a subset of exposed individuals, leading to granulomatous inflammation and fibrosis in the lung. In addition to its antigenic properties, beryllium has potent adjuvant activity that contributes to sensitization via unknown pathways. Here, we show that beryllium induces cellular death and release of IL-1α and DNA into the lung. Release of IL-1α was inflammasome-independent and required for beryllium-induced neutrophil recruitment into the lung. Beryllium enhanced classical dendritic cell (cDC) migration from the lung to draining LNs in an IL-1R-independent manner, and the accumulation of activated cDCs in the LN was associated with increased priming of CD4+ T cells. DC migration was reduced in TLR9KO mice; however, cDCs in the LNs of TLR9-deficient mice were highly activated, suggesting a role for more than one innate receptor in the effects on DCs. The adjuvant effects of beryllium on CD4+ T cell priming were similar in WT, IL-1R, caspase-1, TLR2, TLR4, TLR7, and TLR9 deficient mice. In contrast, DC migration, activation and the adjuvant effects of beryllium were significantly reduced in MyD88KO mice. Collectively, these data suggest that beryllium exposure results in the release of DAMPs that engage MyD88-dependent receptors to enhance pulmonary DC function.
doi:10.1038/mi.2015.14
PMCID: PMC4567547  PMID: 25760420
danger-associated molecular pattern (DAMP); dendritic cells; environmental exposure; beryllium; granulomatous lung disease
5.  CSACI position statement: epinephrine auto-injectors and children < 15 kg 
Epinephrine (adrenaline) is the treatment of choice for anaphylaxis. While other medications, including H1-antihistamines, H2-antihistamines, corticosteroids, and inhaled beta-2 agonists are often used to treat anaphylaxis in the emergency setting, none of these medications has been shown to reverse anaphylaxis. Fatal anaphylaxis is related to the delayed use of epinephrine. In community settings, epinephrine is available as an auto-injector in two doses, 0.15 mg and 0.3 mg. The recommended dose for children is 0.01 mg per kilogram. For infants at risk of anaphylaxis in the community, there are few options with regard to providing an optimal epinephrine dose for first-aid treatment. The Canadian Society of Allergy and Immunology (CSACI) therefore recommends, for the child weighing less than 15 kg, given the lack of a suitable alternative, prescribing the 0.15 mg epinephrine autoinjector. Adverse effects of an epinephrine dose of 0.15 mg given intramuscularly in infants or children weighing less than 15 kg are expected to be mild and transient at the plasma epinephrine concentrations achieved; therefore, these effects need to be measured against the consequences of not receiving epinephrine at all, which can include fatality.
doi:10.1186/s13223-015-0086-9
PMCID: PMC4485331  PMID: 26131015
Epinephrine; Anaphylaxis; Infant; CSACI position statement; Allergy
6.  Identification of Multiple Public T Cell Receptor Repertoires in Chronic Beryllium Disease1 
Chronic beryllium disease (CBD) is a granulomatous lung disease characterized by the accumulation of beryllium (Be)-specific CD4+ T cells in bronchoalveolar lavage (BAL). These expanded CD4+ T cells are composed of oligoclonal T cell subsets, suggesting their recruitment to the lung in response to conventional antigen. In the present study, we noted that all BAL-derived T cell lines from HLA-DP2-expressing CBD patients contained an expansion of Be-responsive Vβ5.1+ CD4+ T cells. Using Be-loaded HLA-DP2-peptide tetramers, the majority of tetramer-binding T cells also expressed Vβ5.1with a highly conserved CDR3β motif. Interestingly, Be-specific, Vβ5.1-expressing CD4+ T cells displayed differential HLA-DP2-peptide tetramer staining intensity, and sequence analysis of the distinct tetramer-binding subsets showed that the two populations differed by a single, conserved amino acid in the CDR3β motif. TCR Vα chain analysis of purified Vβ5.1+ CD4+ T cells based on differential tetramer-binding intensity showed differing TCR Vα chain pairing requirements, with the high affinity population having promiscuous Vα chain pairing and the low affinity subset requiring restricted Vα chain usage. Importantly, disease severity, as measured by loss of lung function, was inversely correlated with the frequency of tetramer-binding CD4+ T cells in the lung. Our findings suggest the presence of a dominant Be-specific, Vβ5.1-expressing public T cell repertoire in the lungs of HLA-DP2-expressing CBD patients using promiscuous Vα chain pairing to recognize an identical HLA-DP2-peptide/Be complex. Importantly, the inverse relationship between expansion of CD4+ T cells expressing these public TCRs and disease severity suggests a pathogenic role for these T cells in CBD.
doi:10.4049/jimmunol.1400007
PMCID: PMC4011988  PMID: 24719461
Human; T cells; MHC; Lung; T cell receptors
7.  Up-Regulation of Programmed Death-1 Expression on Beryllium-Specific CD4+ T Cells in Chronic Beryllium Disease1 
Chronic beryllium disease (CBD) is caused by workplace exposure to beryllium and is characterized by the accumulation of memory CD4+ T cells in the lung. These cells respond vigorously to beryllium salts in culture by producing proinflammatory Th1-type cytokines. The presence of these inflammatory cytokines leads to the recruitment of alveolar macrophages, alveolitis, and subsequent granuloma development. It has been shown that chronic exposure to conventional Ags leads to up-regulation in the expression of negative regulators of T cells such as programmed death-1 (PD-1). Due to the persistence of beryllium in the lung after the cessation of exposure, aberrant regulation of the PD-1 pathway may play an important role in CBD development. In the present study, PD-1 expression was measured on blood and bronchoalveolar lavage (BAL) CD4+ T cells from beryllium-sensitized and CBD subjects. PD-1 expression was significantly higher on BAL CD4+ T cells compared with those cells in blood, with the highest expression on the beryllium-specific T cell subset. In addition, the expression of PD-1 on BAL CD4+ T cells directly correlated with the severity of the T cell alveolitis. Increased expression of the PD-1 ligands, PD-L1 and PD-L2, on BAL CD14+ cells compared with blood was also seen. The addition of anti-PD-1 ligand mAbs augmented beryllium-induced CD4+ T cell proliferation, and an inverse correlation was seen between PD-1 expression on beryllium-specific CD4+ T cells and beryllium-induced proliferation. Thus, the PD-1 pathway is active in beryllium-induced disease and plays a key role in controlling beryllium-induced T cell proliferation.
PMCID: PMC4347847  PMID: 18250483
10.  Dietary exposures and allergy prevention in high-risk infants: a joint position statement of the Canadian Society of Allergy and Clinical Immunology and the Canadian Paediatric Society 
Allergic conditions in children are a prevalent health concern in Canada. The burden of disease and the societal costs of proper diagnosis and management are considerable, making the primary prevention of allergic conditions a desirable health care objective. This position statement reviews current evidence on dietary exposures and allergy prevention in infants at high risk of developing allergic conditions. It revisits previous dietary recommendations for pregnancy, breastfeeding and formula-feeding, and provides an approach for introducing solid foods to high-risk infants. While there is no evidence that delaying the introduction of any specific food beyond six months of age helps to prevent allergy, the protective effect of early introduction of potentially allergenic foods (at four to six months) remains under investigation. Recent research appears to suggest that regularly ingesting a new, potentially allergenic food may be as important as when that food is first introduced. This article has already been published (Paediatr Child Health. 2013 Dec;18(10):545–54), and is being re-published with permission from the original publisher, the Canadian Paediatric Society.
doi:10.1186/1710-1492-10-45
PMCID: PMC4407306  PMID: 25908933
Allergy prevention; Atopic dermatitis; Breastfeeding; Food allergy; Formula feeding; Solid food introduction
11.  Impaired Function of CTLA-4 in the Lungs of Patients with Chronic Beryllium Disease Contributes to Persistent Inflammation1 
Chronic beryllium disease (CBD) is an occupational lung disorder characterized by granulomatous inflammation and the accumulation of beryllium-responsive CD4+ T cells in the lung. These differentiated effector memory T cells secrete IL-2, IFN-γ, and TNF-α upon in vitro activation. Beryllium-responsive CD4+ T cells in the lung are CD28 independent and have increased expression of the coinhibitory receptor, programmed death 1, resulting in antigen-specific T cells that proliferate poorly yet retain the ability to express Th1-type cytokines. To further investigate the role of coinhibitory receptors in the beryllium-induced immune response, we examined the expression of CTLA-4 in blood and bronchoalveolar lavage cells from subjects with CBD. CTLA-4 expression was elevated on CD4+ T cells from the lungs of study subjects compared to blood. Furthermore, CTLA-4 expression was greatest in the beryllium-responsive subset of CD4+ T cells that retained the ability to proliferate and express IL-2. Functional assays show that the induction of CTLA-4 signaling in blood cells inhibited beryllium-induced T cell proliferation while having no effect on the proliferative capacity of beryllium-responsive CD4+ T cells in lung. Collectively, our findings suggest a dysfunctional CTLA-4 pathway in the lung and its potential contribution to the persistent inflammatory response that characterizes CBD.
doi:10.4049/jimmunol.1300282
PMCID: PMC3750981  PMID: 23851684
Human; T Cells; Cell Surface Molecules; Cytokines; Lung
13.  Identification of beryllium-dependent peptides recognized by CD4+ T cells in chronic beryllium disease 
The Journal of Experimental Medicine  2013;210(7):1403-1418.
Identification of peptides that form complexes with beryllium and class II HLA molecules and are recognized by CD4+ T cells from patients with chronic beryllium disease.
Chronic beryllium disease (CBD) is a granulomatous disorder characterized by an influx of beryllium (Be)-specific CD4+ T cells into the lung. The vast majority of these T cells recognize Be in an HLA-DP–restricted manner, and peptide is required for T cell recognition. However, the peptides that stimulate Be-specific T cells are unknown. Using positional scanning libraries and fibroblasts expressing HLA-DP2, the most prevalent HLA-DP molecule linked to disease, we identified mimotopes and endogenous self-peptides that bind to MHCII and Be, forming a complex recognized by pathogenic CD4+ T cells in CBD. These peptides possess aspartic and glutamic acid residues at p4 and p7, respectively, that surround the putative Be-binding site and cooperate with HLA-DP2 in Be coordination. Endogenous plexin A peptides and proteins, which share the core motif and are expressed in lung, also stimulate these TCRs. Be-loaded HLA-DP2–mimotope and HLA-DP2–plexin A4 tetramers detected high frequencies of CD4+ T cells specific for these ligands in all HLA-DP2+ CBD patients tested. Thus, our findings identify the first ligand for a CD4+ T cell involved in metal-induced hypersensitivity and suggest a unique role of these peptides in metal ion coordination and the generation of a common antigen specificity in CBD.
doi:10.1084/jem.20122426
PMCID: PMC3698527  PMID: 23797096
15.  Beryllium-Specific CD4+ T Cells in Blood as a Biomarker of Disease Progression 
Background
CD4+ T cells are responsible for the progressive lung damage seen in patients with chronic beryllium disease (CBD), a granulomatous lung disorder in which antigen-specific, Th1-type cytokine-secreting T cells have been characterized. Compared to beryllium (Be)-sensitized subjects, an increased number of Be-responsive T cells are present in the blood of CBD patients.
Objective
The aim of this study was to determine whether the number of Be-specific T cells in blood predicted the development of CBD in a cohort of Be-exposed subjects.
Methods
Using IFN-γ ELISPOT and proliferation-based assays, we determined the frequency and proliferative capacity of Be-responsive T cells in blood.
Results
Compared with the Be lymphocyte proliferation test which detected an abnormal Be-induced proliferative response in 11 of 260 (4.2%) workers from a Be-machining facility, IFN-γ ELISPOT detected a sensitization rate of 10% (χ2 = 55.7; P < 0.0001). A significant positive correlation was also noted between the number of Be-responsive CD4+ T cells in blood and lung of CBD patients. Importantly, the transition from Be sensitization to CBD was associated with an increased number of antigen-specific T cells in blood.
Conclusion
These findings have important implications for Be-induced disease and potentially other immune-mediated disorders, suggesting that the frequency of antigen-specific T cells in blood can serve as a noninvasive biomarker to predict disease development and severity of the Be-specific CD4+ T cell alveolitis.
Clinical implications
These findings suggest that the number of Be-responsive T cells in the circulation can serve as a biomarker of disease progression and as an estimate of the severity of Be-induced lung inflammation.
doi:10.1016/j.jaci.2011.08.022
PMCID: PMC3205205  PMID: 21943943
Human; Lung; CD4-Positive T-Lymphocytes; Beryllium; Cytokines; Granuloma; ELISPOT
16.  Mutagenesis of beryllium-specific T cell receptors suggests an unusual binding topology for antigen recognition1 
Unconventional antigens, such as metals, stimulate T cells in a very specific manner. To delineate the binding landscape for metal-specific T cell recognition, alanine screens were performed on a set of beryllium (Be)-specific T cell receptors (TCR) derived from the lung of a chronic beryllium disease patient. These TCRs are HLA-DP2-restricted and express nearly identical TCR Vβ5.1 chains coupled with different TCR α-chains. Site-specific mutagenesis of all amino acids comprising the complementarity determining regions of the TCRA and TCRB genes showed a dominant role for Vβ5.1 residues in Be recognition, with little contribution from the TCR α-chain. Solvent-exposed residues along the α-helices of the HLA-DP2 α- and β-chains were also mutated to alanine. Two β-chain residues, located near the proposed Be binding site of HLA-DP2, played a dominant role in T cell recognition with no contribution from the HLA-DP2 α-chain. These findings suggest that Be-specific T cells recognize antigen using an unconventional binding topology, with the majority of interactions contributed by TCR Vβ5.1 residues and the HLA-DP2 β1-chain. Thus, unusual docking topologies are not exclusively used by autoreactive T cells, but also for the recognition of unconventional metal antigens, such as Be.
doi:10.4049/jimmunol.1101872
PMCID: PMC3178675  PMID: 21873524
Human; T cells; MHC; Lung; T cell receptors
17.  Altered Immune Phenotype in Peripheral Blood Cells of Patients with Scleroderma-Associated Pulmonary Hypertension 
Pulmonary arterial hypertension is a common and fatal complication of scleroderma that may involve inflammatory and autoimmune mechanisms. Alterations in the gene expression of peripheral blood mononuclear cells have been previously described in patients with pulmonary arterial hypertension. Our goal is to identify differentially expressed genes in peripheral blood mononuclear cells in scleroderma patients with and without pulmonary hypertension as biomarkers of disease.
Gene expression analysis was performed on a Microarray Cohort of scleroderma patients with (n=10) and without (n=10) pulmonary hypertension. Differentially expressed genes were confirmed in the Microarray Cohort and validated in a Validation Cohort of scleroderma patients with (n=15) and without (n=19) pulmonary hypertension by RT-qPCR. We identified inflammatory and immune-related genes including interleukin-7 receptor (IL-7R) and chemokine receptor 7 as differentially expressed in patients with scleroderma-associated pulmonary hypertension. Flow cytometry confirmed decreased expression of IL-7R on circulating CD4+ T-cells from scleroderma patients with pulmonary hypertension.
Differences exist in the expression of inflammatory and immune-related genes in peripheral blood cells from patients with scleroderma-related pulmonary hypertension compared to those with normal pulmonary artery pressures. These findings may have implications as biomarkers to screen at-risk populations for early diagnosis and provide insight into mechanisms of scleroderma-related pulmonary hypertension.
doi:10.1111/j.1752-8062.2010.00218.x
PMCID: PMC2966033  PMID: 20973920
Pulmonary Hypertension; Gene Array; Gene Expression; Interleukins; Inflammation
18.  Deficient and Dysfunctional Regulatory T Cells in the Lungs of Chronic Beryllium Disease Subjects 
Rationale: Chronic beryllium disease (CBD) is a CD4+ T cell–mediated disorder characterized by persistent lung inflammation. Naturally occurring regulatory T (Treg) cells modulate adaptive immune responses. The role of this T-cell subset in beryllium-induced lung disease is unknown.
Objectives: The aim of this study was to determine whether dysfunctional Treg cells in the lung contribute to the “unchecked” inflammatory response that characterizes CBD.
Methods: Using blood and bronchoalveolar lavage (BAL) cells from normal control subjects and individuals with beryllium-induced disease, we determined the frequency and function of naturally occurring Treg cells.
Measurements and Main Results: A significantly decreased percentage and expression of FoxP3 in BAL CD4+ T cells from CBD patients compared with beryllium-sensitized subjects was seen, and the percentage of FoxP3-expressing CD4+ Treg cells in BAL inversely correlated with disease severity. In contrast to blood Treg cells derived from beryllium-sensitized subjects and patients with CBD that completely suppressed blood responder T-cell proliferation, BAL FoxP3-expressing Treg cells from patients with CBD are unable to suppress anti–CD3-mediated BAL T-cell proliferation. Mixing studies showed that blood Treg cells are capable of suppressing autologous BAL responder T cells. Conversely, BAL CD4+ Treg cells are incapable of suppressing blood T cells, confirming that the failure of BAL Treg cells to suppress T-cell proliferation is caused by a dysfunctional Treg cell subset and not by resistance of BAL effector T cells to suppression.
Conclusions: These findings suggest that the deficient and dysfunctional Treg cells in the lung of patients with CBD contribute to the persistent inflammatory response in this disease.
doi:10.1164/rccm.201001-0025OC
PMCID: PMC2891494  PMID: 20299529
fibrosis; human; granuloma; inflammation
19.  CD27 Expression on CD4+ T Cells Differentiates Effector from Regulatory T Cell Subsets in the Lung1 
Beryllium exposure in the workplace can result in chronic beryllium disease, a granulomatous lung disorder characterized by CD4+ T cell alveolitis and progressive lung fibrosis. A large number of the CD4+ T cells recruited to the lung in chronic beryllium disease recognize beryllium in an Ag-specific manner and express Th1-type cytokines following T cell activation. Beryllium-responsive CD4+ T cells in the bronchoalveolar lavage (BAL) express an effector memory T cell phenotype and recognize beryllium in a CD28-independent manner. In this study, we show that the majority of beryllium-responsive CD4+ T cells in BAL have lost CD27 expression, whereas a subset of beryllium-responsive cells in blood retains expression of this costimulatory molecule. In addition, loss of CD27 on BAL CD4+ T cells inversely correlates with markers of lung inflammation. A small population of BAL CD4+ T cells retains CD27 expression, and these CD4+CD27+ T cells contain the FoxP3-expressing, naturally occurring regulatory T (Treg) cell subset. Coexpression of CD27 and CD25 identifies the majority of FoxP3-expressing Treg cells in blood and BAL, and these cells express potent suppressor function. Taken together, these findings suggest that CD27 is differentially expressed between effector T cells from the inflamed lung and can be used in conjunction with CD25 to isolate Treg cells and assess their functional capacity in an ongoing adaptive immune response in a target organ.
doi:10.4049/jimmunol.0804305
PMCID: PMC3061566  PMID: 19454729
20.  4-1BB Enhances Proliferation of Beryllium-Specific T Cells in the Lung of Subjects with Chronic Beryllium Disease1 
In contrast to naive T cells, reactivation of memory cells is less dependent on CD28-mediated costimulation. We have shown that circulating beryllium-specific CD4+ T cells from chronic beryllium disease patients remain CD28-dependent, while those present in the lung no longer require CD28 for T cell activation. In the present study, we analyzed whether other costimulatory molecules are essential for beryllium-induced T cell function in the lung. Enhanced proliferation of a beryllium-responsive, HLA-DP2-restricted T cell line was seen after the induction of 4-1BB ligand expression on the surface of HLA-DP2-expressing fibroblasts. Following beryllium exposure, CD4+ T cells from blood and bronchoalveolar lavage of chronic beryllium disease patients up-regulate 4-1BB expression, and the majority of beryllium-responsive, IFN-γ-producing CD4+ T cells in blood coexpress CD28 and 4-1BB. Conversely, a significant fraction of IFN-γ-producing bronchoalveolar lavage (BAL) T cells express 4-1BB in the absence of CD28. In contrast to blood, inhibition of the 4-1BB ligand-4-1BB interaction partially blocked beryllium-induced proliferation of BAL CD4+ T cells, and a lack of 4-1BB expression on BAL T cells was associated with increased beryllium-induced cell death. Taken together, these findings suggest an important role of 4-1BB in the costimulation of beryllium-responsive CD4+ T cells in the target organ.
PMCID: PMC3057106  PMID: 18768897
21.  Immunomodulatory strategies prevent the development of autoimmune emphysema 
Respiratory Research  2010;11(1):179.
Background
The presence of anti-endothelial cell antibodies and pathogenic T cells may reflect an autoimmune component in the pathogenesis of emphysema. Whether immune modulatory strategies can protect against the development of emphysema is not known.
Methods
Sprague Dawley rats were immunized with human umbilical vein endothelial cells (HUVEC) to induce autoimmune emphysema and treated with intrathymic HUVEC-injection and pristane. Measurements of alveolar airspace enlargement, cytokine levels, immuno histochemical, western blot analysis, and T cell repertoire of the lung tissue were performed.
Results
The immunomodulatory strategies protected lungs against cell death as demonstrated by reduced numbers of TUNEL and active caspase-3 positive cells and reduced levels of active caspase-3, when compared with lungs from HUVEC-immunized rats. Immunomodulatory strategies also suppressed anti-endothelial antibody production and preserved CNTF, IL-1alpha and VEGF levels. The immune deviation effects of the intrathymic HUVEC-injection were associated with an expansion of CD4+CD25+Foxp3+ regulatory T cells. Pristane treatment decreased the proportion of T cells expressing receptor beta-chain, Vβ16.1 in the lung tissue.
Conclusions
Our data demonstrate that interventions classically employed to induce central T cell tolerance (thymic inoculation of antigen) or to activate innate immune responses (pristane treatment) can prevent the development of autoimmune emphysema.
doi:10.1186/1465-9921-11-179
PMCID: PMC3009635  PMID: 21162738
23.  Altered Immune Phenotype in Peripheral Blood Cells of Patients with Scleroderma‐Associated Pulmonary Hypertension 
Abstract
Pulmonary arterial hypertension is a common and fatal complication of scleroderma that may involve inflammatory and autoimmune mechanisms. Alterations in the gene expression of peripheral blood mononuclear cells have been previously described in patients with pulmonary arterial hypertension. Our goal is to identify differentially expressed genes in peripheral blood mononuclear cells in scleroderma patients with and without pulmonary hypertension as biomarkers of disease.
Gene expression analysis was performed on a Microarray Cohort of scleroderma patients with (n= 10) and without (n= 10) pulmonary hypertension. Differentially expressed genes were confirmed in the Microarray Cohort and validated in a Validation Cohort of scleroderma patients with (n= 15) and without (n= 19) pulmonary hypertension by RT‐qPCR. We identified inflammatory and immune‐related genes including interleukin‐7 receptor (IL‐7R) and chemokine receptor 7 as differentially expressed in patients with scleroderma‐associated pulmonary hypertension. Flow cytometry confirmed decreased expression of IL‐7R on circulating CD4+ T‐cells from scleroderma patients with pulmonary hypertension.
Differences exist in the expression of inflammatory and immune‐related genes in peripheral blood cells from patients with scleroderma‐related pulmonary hypertension compared to those with normal pulmonary artery pressures. These findings may have implications as biomarkers to screen at‐risk populations for early diagnosis and provide insight into mechanisms of scleroderma‐related pulmonary hypertension. Clin Trans Sci 2010; Volume 3: 210–218
doi:10.1111/j.1752-8062.2010.00218.x
PMCID: PMC2966033  PMID: 20973920
pulmonary hypertension; gene array; gene expression; interleukins; inflammation
24.  Paclitaxel Arrests Growth of Intracellular Toxoplasma gondii 
Addition of paclitaxel (Taxol) at a concentration of 1 μM to Toxoplasma gondii-infected human foreskin fibroblasts arrested parasite multiplication. Division of the T. gondii tachyzoite nucleus was inhibited, leading to syncytium-like parasite structures within the fibroblasts by 24 h after infection and treatment of the cultures. By 4 days after infection and treatment of the cultures with paclitaxel, this inhibition was irreversible, since the arrested intracellular form was incapable of leaving the host cell, infecting new cells, and initiating the growth of tachyzoites with normal morphology. Specifically, when paclitaxel was added to infected cells for 4 days and then removed by washing and the infected, paclitaxel-treated cells were cultured for 4 more days, there were no remaining T. gondii organisms with normal morphology. Syncytium-like structures in the cultures that were infected and treated with paclitaxel for 8 days were similar in appearance to those in preparations of infected paclitaxel-treated fibroblasts that had been cultured for 24 to 48 h. Pretreatment of the tachyzoites for 1 h with paclitaxel followed by the removal of the paclitaxel by repeatedly centrifuging and resuspending the parasites in fresh medium without paclitaxel and then adding fresh medium prior to culture of the parasites with fibroblasts did not prevent their invasion of fibroblasts but did affect their subsequent ability to replicate within fibroblasts. Pretreatment of the fibroblasts with paclitaxel also diminished subsequent replication of T. gondii in such host cells after 8 days. Thus, paclitaxel alters the ability of T. gondii to replicate in host cells. Inhibition of parasite microtubules by such compounds at concentrations which do not interfere with the function of host cell microtubules may be useful for development of novel medicines to treat T. gondii infections in the future.
PMCID: PMC105729  PMID: 9687403

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