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My Beloved Neutrophil Dr Boxer 2014 Neutropenia Family Conference

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My Beloved Neutrophil Dr Boxer 2014 Neutropenia Family Conference The Beloved Neutrophil: Its Function in Health and Disease Stem Cell Multipotent Progenitor Myeloid Lymphoid CMP IL-3, SCF, GM-CSF CLP Committed Progenitor MEP GMP GM-CSF, IL-3, SCF EPO TPO G-CSF M-CSF IL-5 IL-3 SCF RBC Platelet Neutrophil Monocyte/ Basophil B-cells Macrophage Eosinophil T-Cells Mast cell NK cells Mature Cell Dendritic cells PRODUCTION AND KINETICS OF NEUTROPHILS CELLS % CELLS TIME Bone Marrow: Myeloblast 1 7 - 9 Mitotic Promyelocyte 4 Days Myelocyte 16 Maturation/ Metamyelocyte 22 3 – 7 Storage Band 30 Days Seg 21 Vascular: Peripheral Blood Seg 2 6 – 12 hours 3 Marginating Pool Apoptosis and ? Tissue clearance by 0 – 3 macrophages days PHAGOCYTOSIS 1. Mobilization 2. Chemotaxis 3. Recognition (Opsonization) 4. Ingestion 5. Degranulation 6. Peroxidation 7. Killing and Digestion 8. Net formation Adhesion: β 2 Integrins ▪ Heterodimer of a and b chain ▪ Tight adhesion, migration, ingestion, co- stimulation of other PMN responses LFA-1 Mac-1 (CR3) p150,95 a2b2 a CD11a CD11b CD11c CD11d b CD18 CD18 CD18 CD18 Cells All PMN, Dendritic Mac, mono, leukocytes mono/mac, PMN, T cell LGL Ligands ICAMs ICAM-1 C3bi, ICAM-3, C3bi other other Fibrinogen other GRANULOCYTE CHEMOATTRACTANTS Chemoattractants Source Activators Lipids PAF Neutrophils C5a, LPS, FMLP Endothelium LTB4 Neutrophils FMLP, C5a, LPS Chemokines (a) IL-8 Monocytes, endothelium LPS, IL-1, TNF, IL-3 other cells Gro a, b, g Monocytes, endothelium IL-1, TNF other cells NAP-2 Activated platelets Platelet activation Others FMLP Bacteria C5a Activation of complement Other Important Receptors on PMNs ñ Pattern recognition receptors – Detect microbes - Toll receptor family - Mannose receptor - bGlucan receptor – fungal cell walls ñ Cytokine receptors – enhance PMN function - G-CSF, GM-CSF - TNF Receptor ñ Opsonin receptors – trigger phagocytosis - FcgRI, II, III - Complement receptors – ñ Mac1/CR3 (CD11b/CD18) – C3bi ñ CR-1 – C3b, C4b, C3bi, C1q, Mannose binding protein From JG Hirsch, J Exp Med 116:827, 1962, with permission. CONTENTS OF NEUTROPHIL GRANULES I. Azurophil granules Functions Acid Hydrolases (glycosidases) Degradation of ingested material Neutral proteases (cathespin G, Destruction of inflamed tissue elastase) Lysozyme Digestion of bacterial cell wall Defensins and bactericidal/proteins Oxygen-independent bacterial killing Myeloperoxidase Oxygen-dependent bacterial killing 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 B558 Component of NADPH Infectious complications of phagocyte disorders (either quantitative or functional) ñ Frequent and/or unusually severe bacterial, fungal infections - Skin, lymph nodes, lungs (portals of entry); other sites via bloodstream or tissue extension ñ Unusual site - e.g. liver or brain abscess ñ Recurrent/chronic gingivitis, aphthous ulcers ñ Staphylococcal common. Also Strep; Gram- negatives, unusual or opportunistic pathogens e.g. Aspergillus, Serratia, B. cepacia, Klebsiella, atypical Mtb Inherited Defects in Neutrophil Functions Adhesion: Chemotaxis: Leukocyte Adhesion Deficiencies (LAD) I, II, III LADI HyperIgE Syndrome Chediak-Higashi Phagocytosis: Actin defects LADI Killing: Chediak-Higashi Chronic granulomatous disease Specific granule deficiency Chediak-Higashi MPO deficiency (with DM) LEUKOCYTE ADHESION DEFICIENCY In Vitro Leukocyte Functional Abnormalities Clinical Features ñ Pediatric age group ñ Delayed umbilical cord separation ñ Persistent leukocytosis ñ Defective neutrophil mobilization (reduced pus formation) ñ Impaired wound healing ñ Recurrent (life-threatening) bacterial and sometimes viral infections ñ PMN/Mo adherence and spreading ñ PMN aggregation Lekstrom-Himes JA, Gallin JI. Immunodeficiency diseases caused by defects in phagocytes. N Eng J Med 343:1703,2000. Leukocyte Adhesion Deficiency I (LAD I) Prevalence Rare Age Usually presents in infancy Genetics AR mutation in CD18 subunit of b2 integrin, leading to complete or partial loss of b2 integrin expression Pathogenesis Defects in adhesion, migration, phagocytosis Clinical Omphalitis, periodontitis, skin/soft tissue infections, pneumonia, sepsis, poor wound healing, delayed cord separation. Staph, gram negatives Labs Neutrophilia, absent CD11/CD18 (including Mac-1) Management HSCT, otherwise supportive care SUMMARY OF CGD Incidence: 4 per million births Infections: ñ Pneumonia (70%) Aspergillus ñ Supportive Adenitis (53%) Staphylococcus ñ Subcutaneous Abscess (42%) Staphylococcus ñ Liver Abscesses (27%) Staphylococcus ñ Osteomyelitis (25%) Serratia ñ Sepsis (18%) Salmonella INFECTIONS IN CGD Pathogen Presentations Bacterial ¢ Staphylococcus aureus Soft tissue infection, Lymphadenitis, Liver Abscess, Osteomyelitis, Pneumonia, Sepsis ¢ Burkholderia Pneumonia, Sepsis ¢ Serratia marcescans Pneumonia, Osteomyelitis, Sepsis, Soft tissue infection ¢ Nocardia species Pneumonia, Osteomyelitis, Brain abscess Fungal ¢ Aspergillus species Pneumonia, Osteomyelitis, Brain abscess ¢ Candida species Sepsis, Soft tissue infection, Liver abscess Examples of Infectious Complications of CGD Impetigo Lymphadenitis Aspergillus Lekstrom-Himes and Gallin, NEJM 343, 1703, 2000. ≤ 2000 pneumonia Massachusetts Medical Society. All rights reserved. Pathology: Lung resection for Silver stain: Chronic inflammatory persistent Aspergillus Aspergillus infiltrate, foci of hyphae neutrophils SUMMARY OF CGD ñ Other complications: Gastric Outlet Obstruction (15%) Urinary Tract Obstruction (10%) Colitis (17%) ñ Cause of Death: Pneumonia/Sepsis, Aspergillus B cepacia 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), 6419-6427. Chronic Granulomatous Disease (CGD) Pathogenesis Impaired microbial killing due to deficient production of oxidants Clinical 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 Labs Absent or markedly reduced NADPH oxidase activity Management Prophylactic trimethoprim/sulfa, itraconazole, IFNg; Aggressive/prolonged treatment of infections; Prednisone/ immunisuppr for inflammation 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 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 Clinical Risk Assessment • Acute vs. chronic lasting more than three months (ANC < 500/µL). • Can neutrophils be mobilized from bone marrow? • Production vs. destruction. Epidemiology • Acute neutropenia occurs frequently. • Congenital neutropenia: ~ 2 per million. • Cyclic neutropenia: ~ 0.6 per million. 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. 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. Human Neutrophil Alloantigens Clinical Significance Allele Frequency Allele Frequency (%) Africans+ (%) Whites Previous Allele Frequency Antigens Names Carrier Glycoproteins (%) Asians* HNA-1a NA1 FcȣR IIIb (CD16) 88-91 46-66 57-62 AIN, ANN, TRALI HNA-1b NA2 FcȣR IIIb (CD16) 51-54 78-84 88-89 AIN, ANN, TRALI HNA-1c SH FcȣR IIIb (CD16) < 1 23-31 5 AIN, ANN, TRALI HNA-2 NB1 58-64 kDa (CD177) 89-99 98 87-97 AIN, ANN, TRALI, febrile transfusion reaction, drug-induced neutropenia HNA-3 5b CTL2 (Unknown) nt nt 89-96 ANN, TRALI, febrile transfusion reaction HNA-4 HART CR3 (CD11b) nt nt 99 AIN, ANN HNA-5 OND LFA-1 (CD11a) 81 88 86-92 unknown 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 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 Clinical Issues in SCN • 10% – 30% risk of evolving into MDS/AML • HCT should be considered
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