Deficiency of plasminogen activator inhibitor 2 in plasma of patients with hereditary angioedema with normal C1 inhibitor levels Kusumam Joseph, PhD,

Slides:

Advertisements

Similar presentations

Control of immunopathology during chikungunya virus infection Caroline Petitdemange, PhD, Nadia Wauquier, PhD, Vincent Vieillard, PhD Journal of Allergy.

Advertisements

D-dimer: A biomarker for antihistamine-resistant chronic urticaria

Peter Vadas, MD, PhD, Boris Perelman, PhD, Gary Liss, MD, MS

Treatment of attacks with plasma-derived C1-inhibitor concentrate in pediatric hereditary angioedema patients Henriette Farkas, MD, PhD, DSc, Dorottya.

Erika Kajdácsi, MSc, Péter K

Novel pathogenic mechanism and therapeutic approaches to angioedema associated with C1 inhibitor deficiency Fleur Bossi, PhD, Fabio Fischetti, MD, Domenico.

Activation of the tissue factor pathway of blood coagulation in patients with chronic urticaria Riccardo Asero, MD, Alberto Tedeschi, MD, Raffaella Coppola,

Margaretha A. Faber, MD, Vito Sabato, MD, Chris H

IL-13 and TH2 cytokine exposure triggers matrix metalloproteinase 7–mediated Fas ligand cleavage from bronchial epithelial cells Samuel J. Wadsworth,

Homozygous C1 inhibitor deficiency: The conclusion of a long search

Plasmin is a natural trigger for bradykinin production in patients with hereditary angioedema with factor XII mutations Steven de Maat, MSc, Jenny Björkqvist,

Santa Jeremy Ono, BA, PhD, Mark B. Abelson, MD

Ann-Marie M. Schoos, MD, PhD, Jacob D

Factor XII–independent cleavage of high-molecular-weight kininogen by prekallikrein and inhibition by C1 inhibitor Kusumam Joseph, PhD, Baby G. Tholanikunnel,

Correction The Journal of Allergy and Clinical Immunology: In Practice

Is 9 more than 2 also in allergic airway inflammation?

Activation of the ficolin-lectin pathway during attacks of hereditary angioedema Dorottya Csuka, PhD, Lea Munthe-Fog, PhD, Estrid Hein, MSc, Zsuzsanna.

Treatment of attacks with plasma-derived C1-inhibitor concentrate in pediatric hereditary angioedema patients Henriette Farkas, MD, PhD, DSc, Dorottya.

Erika Kajdácsi, MSc, Péter K

Hereditary angioedema: Molecular and clinical differences among European populations Matthaios Speletas, MD, PhD, Agnes Szilagyi, PhD, Fotis Psarros,

Lieuwe D. Bos, MSc, PhD, Peter J. Sterk, MD, PhD, Stephen J

Toll-like receptor 3 enhances late-phase reaction of experimental allergic conjunctivitis Mayumi Ueta, MD, PhD, Satoshi Uematsu, MD, PhD, Shizuo Akira,

Cleaved kininogen as a biomarker for bradykinin release in hereditary angioedema Zonne L.M. Hofman, MSc, Steven de Maat, PhD, Chiara Suffritti, PhD, Andrea.

Corticosteroid insensitivity of chemokine expression in airway smooth muscle of patients with severe asthma Po-Jui Chang, MD, Pankaj K. Bhavsar, PhD,

The National Biome Initiative: An allergy perspective

Physician needs in health informatics: Just ask the docs

Gut microbiome variations during hematopoietic stem cell transplant in severe combined immunodeficiency Jonathan P. Lane, MBBS, Christopher J. Stewart,

A focused parameter update: Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor–associated angioedema

Treatment of chronic autoimmune urticaria with omalizumab

First case of homozygous C1 inhibitor deficiency

Hereditary angioedema: Key role for kallikrein and bradykinin in vascular endothelial- cadherin cleavage and edema formation Laurence Bouillet, MD, PhD,

Corticosteroid-resistant asthma is associated with classical antimicrobial activation of airway macrophages Elena Goleva, PhD, Pia J. Hauk, MD, Clifton.

Peter M. Wolfgram, MD, David B. Allen, MD

Successful treatment of idiopathic angioedema with ecallantide

William J. Calhoun, MD, Tmirah Haselkorn, PhD, Dave P

Angioedema and estrogen-dependent angioedema with activation of the contact system François Hentges, MD, Christiane Hilger, PhD, Marianne Kohnen, BSc,

Airway smooth muscle remodeling is a dynamic process in severe long-standing asthma Muhannad Hassan, MD, Taisuke Jo, MD, PhD, Paul-André Risse, PhD,

Time for a paradigm shift in asthma treatment: From relieving bronchospasm to controlling systemic inflammation Leif Bjermer, MD Journal of Allergy.

Serum free light chains in the differential diagnosis and prognosis of primary and secondary hypogammaglobulinemia Nicolò Compagno, MD, Francesco Cinetto,

Food allergy: A review and update on epidemiology, pathogenesis, diagnosis, prevention, and management Scott H. Sicherer, MD, Hugh A. Sampson, MD Journal.

Karen C. Dannemiller, PhD, Janneane F. Gent, PhD, Brian P

Reply Journal of Allergy and Clinical Immunology

Peter Vadas, MD, PhD, Boris Perelman, PhD, Gary Liss, MD, MS

A new case of homozygous C1-inhibitor deficiency suggests a role for Arg378 in the control of kinin pathway activation Alberto López-Lera, MS, Bertrand.

What is an “eosinophilic phenotype” of asthma?

Inflammatory responses of human eosinophils to cockroach are mediated through protease-dependent pathways Kota Wada, MD, Yoshinori Matsuwaki, MD, PhD,

Pathways for bradykinin formation and inflammatory disease

Autophagy: Nobel Prize 2016 and allergy and asthma research

Food allergy: Epidemiology, pathogenesis, diagnosis, and treatment

Advances in the approach to the patient with food allergy

MicroRNA-4443 regulates mast cell activation by T cell–derived microvesicles Irit Shefler, PhD, Pazit Salamon, PhD, Francesca Levi-Schaffer, PharmD, Adam.

Sara Paveglio, PhD, MS, Erin Bennett, MS, Kelly L. Hawley, PhD, Adam P

Benjamin Chaigne, MD, Hervé Watier, MD, PhD

Biology of nasal polyposis

Self-administration of C1-inhibitor concentrate in patients with hereditary or acquired angioedema caused by C1-inhibitor deficiency Marcel Levi, MD,

TH9 immunodeficiency in patients with hyper-IgE syndrome

Pedro Gamboa, MD, PhD, Rosa Sanchez-Monge, PhD, M

Usa Tantibhaedhyangkul, MD, Carla M. Davis, MD, Lenora M

Systemic and localized seminal plasma hypersensitivity patients exhibit divergent immunologic characteristics Debajyoti Ghosh, PhD, Jonathan A. Bernstein,

Cytokine and estrogen stimulation of endothelial cells augments activation of the prekallikrein-high molecular weight kininogen complex: Implications.

Päivi M. Salo, PhD, Samuel J. Arbes, DDS, MPH, PhD, Patrick W

Macrolide antibiotics and asthma treatment

Statistical issues in clinical trials that involve the double-blind, placebo-controlled food challenge Vernon M. Chinchilli, PhD, Laura Fisher, MD, Timothy.

Asthma: The past, future, environment, and costs

Functional assessment of pathogenic IgG subclasses in chronic autoimmune urticaria Sridharan Soundararajan, PhD, Yoko Kikuchi, DVM, Kusumam Joseph, PhD,

Combination treatment with omalizumab and rush immunotherapy for ragweed-induced allergic rhinitis: Inhibition of IgE-facilitated allergen binding Sven.

Endogenous bradykinin and B1-B5 during angiotensin-converting enzyme inhibitor– associated angioedema Scott A. Hubers, MD, Kevin Kohm, MS, Shouzuo Wei,

Natural history of cow’s milk allergy

Primary prevention of asthma and allergy

De novo homozygous mutation of the C1 inhibitor gene in a patient with hereditary angioedema Valeria Bafunno, PhD, Chiara Divella, PhD, Francesco Sessa,

Presentation transcript:

Deficiency of plasminogen activator inhibitor 2 in plasma of patients with hereditary angioedema with normal C1 inhibitor levels Kusumam Joseph, PhD, Baby G. Tholanikunnel, PhD, Bethany Wolf, PhD, Konrad Bork, MD, Allen P. Kaplan, MD Journal of Allergy and Clinical Immunology Volume 137, Issue 6, Pages 1822-1829.e1 (June 2016) DOI: 10.1016/j.jaci.2015.07.041 Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Assays to determine functional C1-INH levels, functional α2-macroglobulin levels, and degradation of bradykinin in plasma of patients with HAE-N and control subjects. A, C1-INH functional assay based on inhibition of kallikrein. B, C1-INH functional assay based on inhibition of Factor XIIa. C, α2-Macroglobulin functional assay based on inhibition of kallikrein. D, Degradation of bradykinin by plasma kininases. Assays were performed as described in the Methods section. HAE-N (+) indicates a Factor XII mutation is present, and HAE-N (−) indicates there is no Factor XII mutation. FXIIa, Factor XIIa. Journal of Allergy and Clinical Immunology 2016 137, 1822-1829.e1DOI: (10.1016/j.jaci.2015.07.041) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Spontaneous activation of the bradykinin-forming pathway in patients with HAE-N compared with patients with HAE type I and control subjects (A) and inhibition of activation by using C1-INH (B). Plasma was diluted 1:2 with HEPES-buffered saline and incubated at room temperature, and kallikrein activity was measured by using a chromogenic substrate (S2302; diaPharma, West Chester Township, Ohio). About half of the samples from patients with HAE-N were activated at 1:2 dilution, and the curves looked similar. Thus a representative profile is shown. For inhibition studies (Fig 2, B), selected plasma samples with spontaneous activation (8 samples, 4 from each group) were incubated in the presence of 100 μg/mL purified C1-INH, and kallikrein activity was measured after 1 hour. FXII, Factor II. Journal of Allergy and Clinical Immunology 2016 137, 1822-1829.e1DOI: (10.1016/j.jaci.2015.07.041) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 PAI-2 levels in plasma of patients with HAE-N and control subjects. PAI-2 levels in plasma of patients and control subjects were measured by means of ELISA. A, Each bar represents individual subjects (HAE-N) expressed as nanograms per milliliter. B, Means ± SEs of 23 control samples, 11 samples from patients with HAE-N without the Factor XII mutation and 12 samples from patients with HAE-N with the Factor XII mutation, and 23 samples from patients with HAE type I. C, Individual values for patients with HAE type I. Values that exceeded the detection limit of 100 are shown as 100. ∗Significant difference at P < .01 and ∗∗significant difference at P < .001. FXII, Factor II. Journal of Allergy and Clinical Immunology 2016 137, 1822-1829.e1DOI: (10.1016/j.jaci.2015.07.041) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 PAI-1 levels in plasma of patients with HAE-N and control subjects. PAI-1 levels in plasma of patients and control subjects were measured by means of ELISA. A, Each bar represents individual subjects (HAE-N) expressed as nanograms per milliliter. B, Means ± SEs of 19 control samples, 11 samples from patients with HAE-N without the Factor XII mutation and 12 samples from patients with HAE-N with the Factor XII mutation, and 20 samples from patients with HAE type I. C, Individual values for patients with HAE type I. ∗∗Significant difference at P < .001. FXII, Factor II. Journal of Allergy and Clinical Immunology 2016 137, 1822-1829.e1DOI: (10.1016/j.jaci.2015.07.041) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Proposed mechanism of angioedema formation in patients with HAE-N. Assuming a source of urokinase and/or tissue plasminogen activator (eg, endothelial cell activation), deficiency of PAI-2 and diminished levels of PAI-1 (in some cases, such as Fig 4, A) can lead to excessive plasmin formation. The connection to the bradykinin-forming cascade is through plasmin activation of Factor XII.37 In those with the Factor XII mutation, susceptibility to plasmin activation can be enhanced. Later steps include conversion of prekallikrein to kallikrein by Factor XIIa or Factor XIIf,37 the kallikrein feedback activation of Factor XII,21,31 and kallikrein cleavage of HK to release bradykinin. Journal of Allergy and Clinical Immunology 2016 137, 1822-1829.e1DOI: (10.1016/j.jaci.2015.07.041) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions