The Beloved Neutrophil: Its Function in Health and Disease
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1 The Beloved Neutrophil: Its Function in Health and Disease
2 Stem Cell Multipotent Progenitor Committed Progenitor Myeloid MEP CMP IL-3, SCF, GM-CSF GMP Lymphoid CLP EPO TPO GM-CSF, IL-3, SCF Mature Cell RBC Platelet G-CSF Neutrophil M-CSF Monocyte/ IL-5 IL-3 Basophil SCF B-cells Macrophage Eosinophil T-Cells Mast cell NK cells Dendritic cells
3 PRODUCTION AND KINETICS OF NEUTROPHILS CELLS % CELLS TIME Bone Marrow: Mitotic Myeloblast Promyelocyte Myelocyte Days Maturation/ Storage Metamyelocyte Band Seg Days Vascular: Peripheral Blood Marginating Pool Seg hours Tissue Apoptosis and clearance by macrophages? 0 3 days
4 PHAGOCYTOSIS 1. Mobilization 2. Chemotaxis 3. Recognition (Opsonization) 4. Ingestion 5. Degranulation 6. Peroxidation 7. Killing and Digestion 8. Net formation
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6 Adhesion: β 2 Integrins Heterodimer of and chain Tight adhesion, migration, ingestion, costimulation of other PMN responses LFA-1 Mac-1 (CR3) p150, CD11a CD11b CD11c CD11d CD18 CD18 CD18 CD18 Cells All leukocytes PMN, mono/mac, LGL Dendritic Mac, mono, PMN, T cell Ligands ICAMs ICAM-1 C3bi Fibrinogen other C3bi, other ICAM-3, other
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8 GRANULOCYTE CHEMOATTRACTANTS Chemoattractants Source Activators Lipids PAF Neutrophils C5a, LPS, FMLP Endothelium LTB 4 Neutrophils FMLP, C5a, LPS Chemokines ( ) IL-8 Monocytes, endothelium LPS, IL-1, TNF, IL-3 other cells Gro,, Monocytes, endothelium IL-1, TNF other cells NAP-2 Activated platelets Platelet activation Others FMLP Bacteria C5a Activation of complement
9 Other Important Receptors on PMNs Pattern recognition receptors Detect microbes Toll receptor family Mannose receptor Glucan receptor fungal cell walls Cytokine receptors enhance PMN function G-CSF, GM-CSF TNF Receptor Opsonin receptors trigger phagocytosis Fc RI, II, III Complement receptors Mac1/CR3 (CD11b/CD18) C3bi CR-1 C3b, C4b, C3bi, C1q, Mannose binding protein
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12 From JG Hirsch, J Exp Med 116:827, 1962, with permission.
13 CONTENTS OF NEUTROPHIL GRANULES I. Azurophil granules Functions Acid Hydrolases (glycosidases) Degradation of ingested material Neutral proteases (cathespin G, elastase) Lysozyme Defensins and bactericidal/proteins Myeloperoxidase Destruction of inflamed tissue Digestion of bacterial cell wall Oxygen-independent bacterial killing Oxygen-dependent bacterial killing
14 CONTENTS OF NEUTROPHIL GRANULES II. Specific granules Functions Lysozyme Digestion of bacterial cell wall Cobalamin-binding proteins Binding of cobalamin analogues Apolactoferrin Binding of free iron Collagenase Digestion of connective tissue C5a-splitting enzyme Release of C5a Heparinase Digestion of connective tissue Laminin and thrombospondin Adhesion to basement receptors membrane CD11/18 (C3bi) receptor Adhesion to ICAM-1, 2, 3 on endothelium and phagocytosis of C3bi coated particles Cytochrome B 558 Component of NADPH
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16 Infectious complications of phagocyte disorders (either quantitative or functional) Frequent and/or unusually severe bacterial, fungal infections - Skin, lymph nodes, lungs (portals of entry); other sites via bloodstream or tissue extension Unusual site - e.g. liver or brain abscess Recurrent/chronic gingivitis, aphthous ulcers Staphylococcal common. Also Strep; Gramnegatives, unusual or opportunistic pathogens e.g. Aspergillus, Serratia, B. cepacia, Klebsiella, atypical Mtb
17 Inherited Defects in Neutrophil Functions Adhesion: Chemotaxis: Leukocyte Adhesion Deficiencies (LAD) I, II, III Phagocytosis: LADI Chediak-Higashi LADI HyperIgE Syndrome Chediak-Higashi Actin defects Killing: Chronic granulomatous disease Specific granule deficiency Chediak-Higashi MPO deficiency (with DM)
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19 LEUKOCYTE ADHESION DEFICIENCY In Vitro Leukocyte Functional Abnormalities Clinical Features Pediatric age group Delayed umbilical cord separation Persistent leukocytosis Defective neutrophil mobilization (reduced pus formation) Impaired wound healing Recurrent (life-threatening) bacterial and sometimes viral infections PMN/Mo adherence and spreading PMN aggregation
20 Lekstrom-Himes JA, Gallin JI. Immunodeficiency diseases caused by defects in phagocytes. N Eng J Med 343:1703,2000.
21 Leukocyte Adhesion Deficiency I (LAD I) Prevalence Age Genetics Pathogenesis Clinical Labs Management Rare Usually presents in infancy AR mutation in CD18 subunit of 2 integrin, leading to complete or partial loss of 2 integrin expression Defects in adhesion, migration, phagocytosis Omphalitis, periodontitis, skin/soft tissue infections, pneumonia, sepsis, poor wound healing, delayed cord separation. Staph, gram negatives Neutrophilia, absent CD11/CD18 (including Mac-1) HSCT, otherwise supportive care
22 SUMMARY OF CGD Incidence: 4 per million births Infections: Pneumonia (70%) Aspergillus Supportive Adenitis (53%) Staphylococcus Subcutaneous Abscess (42%) Staphylococcus Liver Abscesses (27%) Staphylococcus Osteomyelitis (25%) Serratia Sepsis (18%) Salmonella
23 INFECTIONS IN CGD Pathogen Bacterial Staphylococcus aureus Burkholderia Serratia marcescans Nocardia species Fungal Aspergillus species Candida species Presentations Soft tissue infection, Lymphadenitis, Liver Abscess, Osteomyelitis, Pneumonia, Sepsis Pneumonia, Sepsis Pneumonia, Osteomyelitis, Sepsis, Soft tissue infection Pneumonia, Osteomyelitis, Brain abscess Pneumonia, Osteomyelitis, Brain abscess Sepsis, Soft tissue infection, Liver abscess
24 Examples of Infectious Complications of CGD Impetigo Lymphadenitis Aspergillus pneumonia Lekstrom-Himes and Gallin, NEJM 343, 1703, Massachusetts Medical Society. All rights reserved. Lung resection for persistent Aspergillus Pathology: Chronic inflammatory infiltrate, foci of neutrophils Silver stain: Aspergillus hyphae
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26 SUMMARY OF CGD Other complications: Gastric Outlet Obstruction (15%) Urinary Tract Obstruction (10%) Colitis (17%) Cause of Death: Pneumonia/Sepsis, Aspergillus B cepacia
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28 NET C Yost, C., Cody, M., Harris, E., Thornton, N., McInturff, A., Martinez, M., Chandler, N., Rodesch, C., Albertine, K., Petti, C., Weyrich, A., & Zimmerman, G. (2009). Impaired neutrophil extracellular trap (NET) formation: a novel innate immune deficiency of human neonates. Blood. 113 (25),
29 Chronic Granulomatous Disease (CGD) Pathogenesis Impaired microbial killing due to deficient production of oxidants Clinical Labs Management a) Lymphadenitis, skin infections, pneumonia, hepatic abscess, pneumonia b) Aspergillus, B. cepacia most problematic; Staph most common. Gram-negative (eg. Serratia). Pathogens often opportunistic or unusual. However, can kill catalase-negative organisms (eg. Strep) using microbial H2O2. c) Granulomatous inflammation, including GI tract Absent or markedly reduced NADPH oxidase activity Prophylactic trimethoprim/sulfa, itraconazole, IFN ; Aggressive/prolonged treatment of infections; Prednisone/ immunisuppr for inflammation
30 Neutropenia Definition: Reduction in the absolute neutrophil count (includes bands and segmented PMNs) below norms for age and ethnic groups in the blood circulation. Age-related ANC: Term newborn (1 week): < 1500 Infant (1 month 4 years): < 1000 Child, adolescent, adult: < 1500 Ethnicity: < 800
31 Clinical Risk Assessment None: ANC of 1,000 to 1,500/µL Moderate: ANC of 500 to 999/µL Severe: ANC of 300 to 499/µL Very severe: ANC of < 300/µL
32 Clinical Risk Assessment Acute vs. chronic lasting more than three months (ANC < 500/µL). Can neutrophils be mobilized from bone marrow? Production vs. destruction.
33 Epidemiology Acute neutropenia occurs frequently. Congenital neutropenia: ~ 2 per million. Cyclic neutropenia: ~ 0.6 per million.
34 Suspicion of Neutropenia Acute severe bacterial infections. History of recurrent infections. Prolonged or elevated temperature (> 101 F). Pneumonia, peritonitis, GU tract infection, buccal and tongue ulcers, chronic gingivitis, cellulitis, perirectal infections. Findings associated with a malignancy, immunodeficiency syndrome, viral infection or drug exposure.
35 Laboratory Evaluation of Neutropenia CBCPD and blood smear. If neutropenia is recurrent, repeat CBCPD 3x/week for 6 weeks. Coombs test. Immunoglobulin levels and lymphocyte subsets. Antineutrophil antibodies. Serology for viral infections if acute process. ANA, LDH, uric acid. Bone marrow exam and cytogenetics.
36 Human Neutrophil Alloantigens Clinical Significance Allele Frequency (%) Africans+ Allele Frequency (%) Whites Antigens Previous Names Carrier Glycoproteins Allele Frequency (%) Asians* HNA-1a NA1 FcȣR IIIb (CD16) AIN, ANN, TRALI HNA-1b NA2 FcȣR IIIb (CD16) AIN, ANN, TRALI HNA-1c SH FcȣR IIIb (CD16) < AIN, ANN, TRALI HNA-2 NB kda (CD177) AIN, ANN, TRALI, febrile transfusion reaction, drug-induced neutropenia HNA-3 5b CTL2 (Unknown) nt nt ANN, TRALI, febrile transfusion reaction HNA-4 HART CR3 (CD11b) nt nt 99 AIN, ANN HNA-5 OND LFA-1 (CD11a) unknown
37 Severe Chronic Neutropenia Heterogeneous group of disorders of myelopoiesis Associated with - decreased production of neutrophils - recurrent bacterial infections Severity of disease related to degree of neutropenia
38 Severe Congenital Neutropenia (SCN) Early childhood onset with ANC < 200 Bone marrow shows maturation arrest at promyelocyte-myelocyte stage Recurrent life-threatening bacterial infections Associated with ELANE (ELA2) mutations
39 Clinical Issues in SCN 10% 30% risk of evolving into MDS/AML HCT should be considered in G-CSF non responders to > 20µg/kg/day or converting to MDS/AML Need for annual bone marrow to survey for cytogenetic changes Patients remain at risk for infection because of impaired neutrophil function
40 Cyclic Neutropenia Dominantly inherited Cycle of neutropenia q 21 days Marrow during neutropenia: myelocyte arrest Stem cell regulatory defect
41 Cyclic Neutropenia Like autosomal dominant SCN, cyclic neutropenia has been linked to mutations in neutrophil elastase ELANE (ELA2) mutations found in essentially 90% of cyclic neutropenia NOT associated with an increased risk of AML
42 Dynamics of the Absolute Monocyte Count 6000 Congenital Neutropenia Cyclic Neutropenia Peripheral Leukocyte Count (counts/µl) Days ANC ANC AMC AMC
43 Table 3: Classification of Congenital Neutropenia Disorders Main hematologic Other clinical Gene Disease (inheritance) features features (chromosomal location) Disorders of Myelopoiesis -Cyclic neutropenia (AD) Periodic neutropenia None ELANE (19q13.3) -Severe congenital neutropenia (AD) Neutropenia, MDS/AML None ELANE (19q13.3) -Severe congenital neutropenia (AD) Neutropenia, MDS/AML None Gfi1 (1p22) -Severe congenital neutropenia (AD) Neutropenia None G-CSFR (1p ) -Severe congenital neutropenia (AR) Neutropenia, MDS/AML Neurologic HAX1 (1q21.3) or Kostmann disease impairment Disorders of ribosomal and telomere dysfunction -Shwachman-Diamond (AR) Neutropenia Exocrine SBDS (7q11.22) Aplastic anemia pancreas deficiency MDS/AML Metaphyseal dysostosis -Dyskeratosis congenita (XLR) Pancytopenia Abnormal skin pigmentation, DKC1(Xq28) -Dyskeratosis congenita (AD) MDS/AML nail dystrophy, TERC (3q26)* -Dyskeratosis congenital (AR) oral leukoplakia, TERT (5p33)* epiphora, pulmonary fibrosis, TINF2 (14q11.2) short stature, hair loss, NOP10 (15q14-q15) developmental delay, NHP2 (5q35.3) squamous cell carcinoma of TCAB1(17q13.1) head and neck Disorders of Metabolism -Reticular dysgenesis (AR) Neutropenia Sensorineural hearing loss AK2 (1p31-p34) Lymphopenia -Barth syndrome (XLR) Neutropenia Cardiomyopathy TAZ1 (Xq28) -Glycogen storage disease type 1b (AR) Neutropenia Hypoglycemia, G6PT1 (11q23) hyperlipidemia, hyperuricemia, growth retardation, osteopenia, renal hypertrophy -Glucose-6-phosphatase Neutropenia Cardiac abnormality, G6PC3 (17q21) catalytic subunit 3 (AR) Thrombocytopenia prominent superficial venous pattern, hepatosplenomegaly, cryptorchidism, microcephaly -Pearson syndrome (mitochondrial) Neutropenia Vacuolization of erythroid Mitochondrial DNA Pancytopenia and myeloid precursors deletion Ringed sideroblasts
44 Table 3: Classification of Congenital Neutropenia Disorders Cont. Main hematologic Other clinical Gene Disease (inheritance) features features (chromosomal location) Disorders of vesicular transport -Chediak-Higashi syndrome (AR) Neutropenia Pigmentary dilution affecting LYST/CHS (1q42.1- Platelet and NK cell hair, skin and ocular fundus, q42.2) dysfunction risk for hemophagocytic syndrome -Cohen syndrome (AR) Neutropenia Developmental delay, facial COH1 (8q22-q23) dysmorphism, retinitis pigmentosa -Griselli syndrome type II (AR) Pancytopenia Pigmentary dilution of the skin RAB 27A (15q14.1) and hair -Hermansky-Pudlak type II (AR) Neutropenia Oculocutaneous albinism AP3B1 (5q14.1) -p14 deficiency (AR) Neutropenia, Short stature, MAPBPIP (1q21) Decreased B&T hypopigmentation lymphocytes, hypogammaglobulinemia Disorders of Immune Function -Cartilage-hair hypoplasia (AR) Neutropenia Short-limbed dwarfism, RMRP (9p21-p12) Lymphopenia fine hair, immodeficiency, Macrocytic anemia increased risk of malignancy -Hyper-IgM syndrome (XLR) Neutropenia Defective humoral immunity CD4OLG (Xq26) -Schminke immuno-osseous dysplasia (AR) Neutropenia Spondyloeiphyseal dysplasia, SMARCAL1 (2q34-36) Pancytopenia nephrotic syndrome, Lymphopenia defective cellular immunity -WHIM syndrome (AD) Neutropenia Warts, hypogammaglobulinemia CXCR4 (2q21) Lymphopenia Infections, myelokathexis Neutrophil hyperplasia in the bone marrow, neutrophil nuclear hypersegmentation with thin filaments connecting pyknotic-appearing lobes -Wiskott-Aldrich syndrome (XLR) Neutropenia Increased risk for acute WAS (Xp11.22-Xp11.3) Lymphopenia myeloid leukemia, Monocytopenia diminished cellular immune function *AD= autosomal dominant, AD dyskeratosis dyskeratosis congenita disorders are identified in italics; AR= autosomal recessive
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