Mast Cells and Basophil Biology and Disorders. Sarbjit S. Saini, M.D. Associate Professor of Medicine Johns Hopkins University
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1 Mast Cells and Basophil Biology and Disorders Sarbjit S. Saini, M.D. Associate Professor of Medicine Johns Hopkins University
2 Disclosure Research Interests-NIH, AstraZeneca, Genentech, Novartis Consultant: Genentech, MedImmune Organizational Interests: AAAAI, Journal of Investigative Dermatology, UptoDate
3 Learning Objectives Upon completion of this session, participants should be able to : Describe the development, subtypes, activation stimuli, and mediator release patterns of mast cell and basophils Describe select diseases associated with mast cells and basophils
4 Role of Mast Cells (MC) Acquired Immunity Immediate Hypersensitivity (H, M) Intestinal Parasites (M) IgG and cell-mediated hypersensitivity ( M) Innate Immunity (M) Bacterial, viral infections, venoms Tissue homeostasis fibrosis, angiogenesis M=mouse, H=human Mononuclear, Microplicae
5 Role of human blood basophils discovered by Ehrlich <1% of WBC, rarest granulocyte 1970 s - cellular source of histamine and leukotrienes in blood -surrogate for tissue mast cell 1980 s - express IgE receptor (Fc RI) Wright s Stain (original magnification 1000x) 1990 s - a source of IL-4 and IL-13 -Mediators support a role in allergic disease - Basophils accumulate in allergic tissues (lung, skin, nose) - Activation in vitro leads to mediator release or increased surface marker (CD203c, CD63)- Basophil Activation Test (BAT) -Mouse basophils-role in Th2 development and EoE Schroeder,Adv. Immunol. 109:123; 2009; Siracusa JACI 2013
6 Overview of Mast Cell Development Figure 14-1 Middleton, 8 th Edition
7 Development of MCs and basophils MC progenitors in bone marrow Stem cell factor (SCF) critical, binds c-kit (CD117) Circulating precursor moves to tissues Mature in tissues into 2 subtypes; long lifespan MC T =tryptase MC TC =tryptase/chymase Basophils mature in bone marrow Share progenitor with MC & Eosinophils IL-3 required for maturation, binds CD123 (IL-3R) Short life span in blood (1-2 days)
8 Development of Tissue Mast Cells, Basophils Tissue MC T Tryptase? SCF+? Mast Cell (committed) progenitor Circulation MC TC Tryptase Chymase Carboxypeptidase A Cathepsin G CD88 (C5aR) Progenitor Bone Marrow LB Schwartz SCF MC IL-5 IL-3 Eosinophil Basophil TSLP?? Elicited basophil in mouse
9 Question 1 Which of the following growth factors are critical for hematopoietic progenitors to differentiate into mast cells? A. Interleukin-3 B. Interleukin-5 C. Transforming Growth Factor-β D. Stem cell factor
10 Human Mast Cells Subtypes Skin, Intestinal submucosa, Perivascular, Conjunctiva Heart, ASM LB Schwartz Alveolar wall Respiratory epithelium Small intestinal mucosa
11 Anti-Tryptase Immunocytochemistry & Immunogold Electron Microscopy Tryptase+/Chymase- MC T MC T Tryptase+/Chymase+ Scrolls Lattice Courtesy LB Schwartz, M.D., Ph.D. MC TC anti-tryptase ~ 5 nm gold anti-chymase ~ 15 nm gold MC TC
12 MC T and MC TC Mast Cells in the Lung Alveolar wall Bronchus Subepithelium MC TC MC T Epithelium Courtesy LB Schwartz, M.D., Ph.D.
13 Sorting Lung MC T and MC TC cells based on CD88 ( C5aR) 88% 11% Kit + /CD88-98% 0.2% Kit 0.5% 99.5% Kit + /CD88 + Kit 1% 0% CD88 Kit 2% 0% CD88 0% 0% CD88 MC T Oskeritzian JACI , anti-chymase MC TC
14 MC T and MC TC Mast Cells in Nasal Mucosal Normal subepithelium Seasonal allergic subepithelium epithelium lumen Courtesy LB Schwartz, M.D., Ph.D.
15 Question 2 Which of the following characteristics best distinguishes the MC TC from the MC T type of mature mast cell? A. C5a receptor B. Tryptase C. ckit expression D.Dependence on SCF for development
16 Activation Pathways of Mast Cells FcεRI-dependent and independent Multivalent Antigen C T/TC MC TC ** C3a?C3aR Y Y Anti-IgE blocking Ab C5a CD88 Morphine/Codeine Vancomycin MBP CD32a ±CD64 IgG ICs Neuropeptides Substance P Neurokinin A CGRP
17 IgE-dependent and Independent activation of MCs Figure *HLMC-Human lung MC. HSMC-Human skin. HCBMC- Human cord blood derived. MCTC subset of HLMC. ǁHPBMC-Human peripheral blood derived.
18 Stimulus response differences in Human MC subtypes & B Degranulation Skin MC Lung MC Basophil Fc RI cross-linking Morphine Substance P C5a F-met-leu-phe
19 Human basophil responses (in vitro) to adaptive and innate immune stimuli stimulates augments Adv. Immunol. 109:123; 2009 inhibitory
20 Mast cell vs. Basophil Mediator Profiles: Preformed, Lipid, Cytokines (Human) Mediator MC Baso Histamine Tryptase +++ +/- LTs PG s Dvorak AM, J. Histochem Cytochem 53:1043, 2005 IL-4 +/- +++ IL Other cytokines Courtesy J Schroeder., Ph.D.
21 Question 3 Which of the following stimuli/pathways do not activate basophils? A. Allergen B. F-met-leu-phe C. C5a D. Morphine
22 FcεRI Coupled Activation-Mediator Release α IgE α β γ 2 β ITAM Lyn/Fyn Syk Lipids PLAse A2 Degranulation (LT, PG) Nucleus Cytokines/Chemokines ITAM-Immunoreceptor tyrosine activation motifs
23 Mediators Released from Activated Mast Cells &/or Basophils 5-15 minutes Granule Lipid minutes minutes hours days Cytokine Chemokine Histamine LTC 4 IL-4 (B) chondroitin SO 4 PGD 2 (M) IL-13 (M,B) heparin, tryptase (M>B) PAF (B) TNF-, GM-CSF chymase, carboxypeptidase A3, IL-5, 6, 8, 16 cathepsin G (TC) MCP-1, MIP-1 (M)
24 IgE effects on Mast Cells & Basophils IgE binding stabilizes & increases Fc RI levels on both cells 1 Capture of free IgE by IgG anti-ige reduces Fc RI levels, activation and mediators 1 Basophils: Fc RI levels are correlated to serum IgE levels across diseases 1 Mast cells: IgE binding can increase survival, activation, proliferation in mice 2 1 Saini and MacGlashan, 2002; 2 Kawakami and Galli, 2002
25 Cellular Effects of Omalizumab Stephen T. Holgate & Riccardo Polosa Nature Reviews Immunology 8, (March 2008)
26 Omalizumab reduces IgE receptors faster on basophils then skin mast cells FceRI expression reduced % Reduction Basophils 7 days (1 week) 80% Mast Cells 70 days (10 weeks) 90% MacGlashan DW Jr, et al. J Immunol 1997;158: Saini SS, et al. J Immunol 1999;162: Beck LA. et al. J Allergy Clin Immunol 2004;114: Ong, YE, et al. J Allergy Clin Immunol 2004; 113: S84
27 Question 4 Monoclonal IgG anti-ige mab (omalizumab) therapy of asthma is most likely to diminish which of the following: A. Skin test wheal size to allergen B. FcεRI levels on blood basophils C. FcεRI levels on tissue mast cells D. IgE receptor activation of basophils E. All the above
28 Release of Tryptase by Constitutive and Regulated Pathways MARKER OF MAST CELL NUMBER Constitutive Secretion ~ / -pro/pro tryptase (vesicular) tryptase gene / 1 / 2 / 1 spontaneous precursors mature (secretory granules) Fc RI cross-linking (regulated) ACTIVATION MARKER Regulated Secretion ~ mature -tryptase (degranulation)
29 Release of Tryptase by Constitutive and Regulated Pathways Mature assay IgE receptor acti Caughey GH.2006;JACI 117: Commercial total tryptase
30 Characteristics of the Total Tryptase & Mature Tryptase Immunoassays (ng/ml) Tryptase Type Recognized Mature Tryptase Total Tryptase B12/G5 B12/G4 mature ( ) pro+pro +mature + Normal Serum (ng/ml) Systemic Anaphylaxis (acute) < >1 RATIO: Total/Mature < 10 Systemic Mastocytosis (nonacute) Schwartz,LB, Immunol Allergy Clin N Am;26 (2006) 20 RATIO: Total/Mature > 20
31 Total Tryptase & Histamine levels Insect Sting-Induced Systemic Anaphylaxis Histamine pre and 15 min * Onset of symptoms after 15 min SGA Brown 2004
32 Anaphylaxis & Mast Cells/Basophils 1. Venoms/Drugs: Peak tryptase ~ clinical severity 2. Mature tyrptase more specific than total tryptase, but acute vs baseline total tryptase levels work well 3. Foods: tryptase often not elevated 4. Food-dependent exercise-induced: tryptase often elevated 5. Baseline total tryptase ~ risk for severe venom reactions 6. Mast cell releasability (D816V Kit) 7. Low PAF acetyl hydrolase levels (~ PAF) may increase severity in food-induced cases 8. Idiopathic anaphylaxis may have evidence for mast cell clonality
33 Anaphylaxis without Elevated Tryptase? 1. Local mast cell-mediated angioedema (laryngeal). 2. Mast cells with less tryptase (MC T < MC TC ). 3. Mast cells further from circulation (mucosal v perivascular). 4. Non-mast cell-mediated (basophils). 5. Early (mast cell) v late (basophil/eosinophil) phase.
34 Question 5 24 y/o male stung by bee while hiking; dyspnea, dizzy, hypotension/tachycardia; ER: epi 0.5 mg SQ; BP normalized Mature tryptase : 25 ng/ml in ER Repeat total tryptase 2 months later: 5 ng/ml Your best diagnosis is: A. Systemic mastocytosis and systemic anaphylaxis B. Systemic anaphylaxis only C. Exercise related asthma due to hiking D. Vasovagal reaction
35 Classification of Mast cell activation diseases (MCAD) Akin, Valent and Metcalfe JACI 2010
36 SYSTEMIC MASTOCYTOSIS ~ somatic activating c-kit mutations (e.g., D816V) I Cutaneous (UP, DCM, MP, mastocytoma) II Indolent (+ isolated BM, smoldering) (40%) III Systemic with an associated clonal hematologic (40%) disorder (AML, MDS, MPD, CMML, NHL, CEL) IV Systemic Aggressive (+lymphadenopathic w eos) (12%) IV Mast cell leukemia(1%) V Mast cell sarcoma VI Extracutaneous mastocytoma Valent Leuk Res 2001, Pardanani Curr Opin Hematol 2010
37 Pardanani Curr Opin Hematol 2010
38 Systemic Mastocytosis. Ozdemir, Didem; Dagdelen, Selcuk; Erbas, Tomris American Journal of the Medical Sciences. 342(5): , November DOI: /MAJ.0b013e
39 Criteria for Diagnosis Systemic Mastocytosis Major: Multifocal dense infiltrates of MC in the bone marrow or other extracutaneous organ(s) (>15 MC per aggregate) Minor: abnormal MC morphology (e.g., >25% spindle-shaped) KIT mutation at codon 816 ( extracutaneous) CD2 and/or CD25+ MC Serum total tryptase >20 ng/ml MC, mast cells 1 major and 1 minor or 3 minor criteria systemic mastocytosis ** activating mutations at codon 816 of KIT, ~90% D816V
40 Mastocytoma Urticaria Pigmentosa Diffuse Cutaneous Mastocytosis
41 Urticaria Pigmentosa/Darier Sign Ispas et al. AAAI 87:6-15, 2001
42 Mast cell activation syndrome (MCAS) disorders Sx s of MC mediator release (pruritis, flushing, tachycardia, abdominal pain, diarrhea, syncope), without criteria SM. Monoclonal MCAS CD25 and/or D816V in BM without other abnormal features (1 or 2 minor criteria) Idiopathic MCAS- no abnormal BM features Akin Blood 2007, Bonnadonna JACI 2007
43 Comparison of features of MC disorders Akin, JACI, 2010
44 Diagnostic criteria for Mast Cell Activation Syndrome Akin, Valent, Metcalfe JACI 2010: Valent, Int Arch Allergy Immunol 2012
45 Question 6 Which of the following is not a criteria for the diagnosis of systemic mastocytosis? A. Ckit mutation at codon 816 B. CD2 or CD25 + MC C. Urticaria pigmentosa D. Serum tryptase greater than 20 ng/ml
46 Differential Diagnosis of Elevated Total Tryptase Level in Serum 1. Systemic mastocytosis 2. Hypereosinophilic syndrome: FIP1L1-PDGFRA 3. Acute Myelocytic Leukemia (~30%) 4. Refractory anemias 5. Myelodysplastic syndromes 6. SCF administration 7. End-stage kidney disease with elevated SCF 8.?Normal variant 9.?Transient mastocytosis
47 Mast Cells Are Constitutively Activated in Human Asthma 1. Elevated levels of histamine and tryptase in baseline BALF. 2. Elevated levels of PGD 2 in baseline BALF. 3. Histamine-dependent bronchospasm and elevated BALF tryptase to inhaled adenosine. 4. Increased MC numbers occur in the airway smooth muscle of asthmatics. 5. Increased MCtc numbers present the airways of severe asthmatics.
48 Mast Cells/mm 2 of smooth muscle MC TC Cells in Airway Smooth Muscle of Subjects with Asthma smooth muscle MC ~ PC 20 MC n=4, 83% MC TC cells (chymase + ) Atopic Nonatopic Brightling et al. NEJM 346: , 2002
49 Roles for basophils in allergic diseases Source of IL-4/ IL-13 modulate TH2 responses IgE dependent release of histamine, LTC4, cytokines Infiltrate allergic tissues in skin, nose, lung; and airways of fatal asthma Primed phenotype in allergic subjectsincreased mediator release (IL-13)
50 Basophils and allergic inflammation, JACI;132:
51 Advances in Mouse Basophils Heterogeneity of basophil subtypes-can develop under IL-3 or TSLP Role of TSLP derived basophils in EoE ( mouse) Shown to participate in TH2 development amplify Th2 development Mouse models show migration of basophils to lymph nodes Siracusa et al Basophils in Allergic Inflammation JACI 2013
52 Answers 1. D. IL-3 is critical for basophils. IL-5 is needed for eosinophil development while SCF is required for mast cells. TGF-b may inhibit MC growth. 2. A. C5aR presence is a major difference between MC tc and MC t cells besides the presence of chymase. All other noted features are common to both. 3. D.Blood basophils can respond to all but morphine. Morphine selectively activates MCtc mast cells. 4. E. Omalizumab lowers free IgE levels which reduces IgE receptor levels on both mast cells and basophils. As a result of lowered receptor levels, allergen mediated activation responses such as histamine release and wheal and flare reactions are also reduced. 5. B. Systemic anaphylaxis only. Mastocytosis is unlikely with a normal total tryptase on a second measure. Asthma and vasovagal reactions do not fit the clinical picture. 6. C. Urticaria pigmetosa is may be seen in skin limited of mast cells disease as well as SM. Therefore it is not among the WHO major and minor criteria for systemic mastocytosis.
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