Cells and Tissues of the Immune System
Jeffrey Sosnowski M.D., Ph.D.
Lecture Objectives
• Comprehension of blood cell development • Knowledge of the various types of white blood cells
– Cell morphology – Functions
• Discuss the types of lymphoid organs
– Tissue morphology – Functions
Origin of Blood Cell Progenitors
• Hematopoietic stem cells (HSCs) migrate to
– Yolk sac
• 3rd week of development
– Liver
• 3rd month of development to birth • Main site of blood cell development until birth
– Bone marrow
• 4th month of development to birth • HSCs are active throughout the skeleton until birth except for scattered foci • During puberty, HSCs become active again throughout the bone marrow • Adulthood, about half of the bone marrow remains active
Differentiation of Blood Cells
Lineage specific markers – cKIT + CD34+ Stem Cell
SCF, IL-6, FLT3-L Lymphopoiesis Myelopoiesis
Common Lymphoid Progenitor
Common myeloid progenitor
Myelopoiesis
Lineage specific markers – cKIT + CD34+
Common Myeloid Progenitor
IL-3, GM-CSF, IL-6
GM-CSF
IL-5 CFU-eo
Thrombopoietin, IL-11 CFU-b/Mg/E
CFU-GM
Neutrophil and Monocyte Maturation
CFU-GM
CFU-G
CFU-M
G-CSF
Blast
M-CSF
Neutrophil
Monocyte
Neutrophil
• Most common white blood cell and most common granulocyte (cells containing granules), 50-68% of white cells • 10-12 microns • Polymorphonuclear, up to four lobes attached by nuclear strands • Lifespan, 3-4 days, once activated and digested bacteria their lifespan is 12 hours • First to respond to an infection
Neutrophil Functions
• Phagocytic
– Granules contain; IV collagenase, phospholipase, complement activators – myeloperoxidase (MPO), Cl- and H202 to HOCL. hypochlorous radical – Defensins, peptides that create holes in microbes – Lysozyme, degradation of bacteria wall
• Motility
– Diapedesis, migrate through venules with recognition of endothelial receptors such as selectins and integrin receptors
Case 1
• 25-year-old homeless male presents to the ED with a chief complaint of “chills and coughing when he smokes”
• Vital signs: T 101.5F, HR 82, BP 135/85 RR 17 • Labs: Left shift with bandemia
Left shift with Bandemia
Chest X-Ray And Pathologic Specimen, Diagnosis?
Monocyte
• Largest white cell, 18 microns • Nucleus is indented or kidney bean shaped • Monocytes differentiate into macrophages once they leave blood vessels
– – – – – Histiocytes, in connective tissue Osteoclasts, in bone Alveolar cells, lung Kupffer cells, liver Macrophages, lymph nodes, spleen and bone marrow
• Lifespan, 3 days
Monocyte Functions
• Monocytes transform into macrophages and function as antigen-presenting cells in the immune system
– Degraded antigens are presented on MHC II molecules to CD4+ T lymphocytes
• Macrophages phagocytose bacteria, other cells and debris
– Reactive oxygen species generated from the oxidative burst – Reactive nitrogen species, NO
Case 2
• A 55-year-old nun presents to the ED with a chief complaint of “chest pain” • HPI: She is 5’0” tall and 85lbs. She was watching a boxing match when she felt a crushing pain in her chest. The pain lasted about 15 minutes and ended shortly after she finished her cigarette and beer
Lung Histology
Heart failure cells, siderophages
Antigen-Presenting cells
• Macrophages • Dendritic cells, initiation of T cell response • Follicular dendritic cells, display of antigen to B cells • Common portals of entry for microbes contain antigen presenting cells (APCs), dendritic cells
– Skin – Gastrointestinal tract – Respiratory tract
Eosinophil Maturation
CFU-eo
IL-5
Blast Eosinophil
Eosinophil
• 1-5% of white blood cells, increased in numbers in patients with allergies, parasitic infections and chronic inflammation • 10-12 microns • Bilobed nucleus • Eosinophilic granules • Lifespan, 3-4 weeks
Eosinophil Functions
• Destruction of protozoans and helminthic parasites
– Granules contain
• • • • Major basic protein (MPO), arginine rich Eosinophil cationic protein (ECP) eosinophil peroxidase (EPO) Eosinophil-derived neurotoxin (EDN)
Basophil, Erythrocyte and Platelet Maturation
CFU-b/Mg/E
CFU-b
BFU-E
CFU-Mg
Erythropoietin
Thrombopoietin
Basophil
Blast
Platelets
Erythrocyte
Basophil
• Least numerous white cell, <0.5% of total white cells • 10-12 microns • Lobulated nucleus • Basophilic granules • Fc cell membrane receptors for IgE • CD40L cell membrane receptors that bind to CD40 on B lymphocytes • Lifespans, days to weeks
Basophil Functions
• Basophilic granules contain
– Heparin an anticoagulant – Histamine and heparin sulfate are vasoactive agents that cause vasodilation of small vessels – Leukotrienes modified lipids that produce prolonged constriction of smooth muscle in the pulmonary airway
• Fc binding of IgE triggers
– Release of vasoactive agents
• Cause severe vascular reaction associated with hypersensitivity and anaphylaxis
– Functionally related to mast cells of the connective tissue
Differentiation of Blood Cells
Lineage specific markers – cKIT + CD34+ Stem Cell
SCF, IL-6, FLT3-L Lymphopoiesis Myelopoiesis
Common Lymphoid Progenitor
Common myeloid progenitor
Lymphopoiesis
Common Lymphoid Progenitor
Pro-B cell
Pro-T cell
Pre-B cell
Immature T cell
B Cell Maturation
Pre B cell
Immature B cell
Mature B cells
IgM
IgG
IgA
IgE
T Cell Maturation
Pro T cell
Immature T cell
CD8+
CD4+
Mature T cells
Case 3
• A 68-year-old male presents to your clinic with a chief complaint of “pain in my arm and backbone” • HPI: The back pain is constant x1 month and not relieved with OTC meds • Vital Signs: within normal limits • Labs? • Imaging?
?
Biopsy
lymphocyte
• The only cells that produce specific receptors for antigens • All lymphocytes arise from stem cells in bone marrow • 30% of all nucleated cells in the bone marrow • 10-30 microns • Mononucleated cells with scant cytoplasm and few organelles • Lifespan, days to months and longer?
Lymphocyte Functions
• Approximately 70% of lymphocytes in the blood and lymph represent a circulating pool of immunocompetent cells
– These cells enter lymphatic tissues and are responsible for immunologic surveillance – Long-lived mainly T cells.
• The remaining 30% of lymphocytes move from the blood directly to specific tissues
– Activated or immature cells – Short-lived
Three Types of Functioning Lymphocytes
• T lymphocytes leave the bone marrow, reside in the thymus, differentiate and become educated to self vs non-self • B lymphocytes arise in bone marrow, mucosa/gut associated lymphatic tissues and spleen • Natural killer (NK) cells arise from the same B and T cell precursor
– They target cells infected with microbes or tumor cells – They do not mature in the thymus
Cluster of Differentiation (CD) Molecules
• • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • Antibody (CD) Reactivity CD1a Thymocytes and immature T cells CD2 T cells, Large granular lymphocytes (LGL), NK cells, some APL, neoplastic mast cells CD3 T cells, primary effusion lymphoma CD4 T cells (helper/inducer), monocytes, myeloblasts, NK cell lymphoma CD5 T cells, B-CLL/SLL, MCL CD7 T cells, some myeloblasts CD8 T cells (suppressor/cytotoxic), large granular lymphocytes (LGL) CD10 Follicle center cells, FL, some DLBCL, pre-B-ALL, pre-T-ALL, thymocytes, BL CD11b Granulocytes, monocytes CD11c Monocytes, HCL, LGL, activated T cells, MZL CD13 Myeloid cells, rare pre-B-ALL CD14 Monocytes CD15 Granulocytes, Hodgkin's lymphoma CD16 Granulocytes, NK cells, LGL CD19 B cells, pre B-ALL, subset of AML (AML1/ETO with t(8;21)) CD20 B cells, rare plasma cell myelomas CD22 B cells CD23 B-CLL/SLL, plasma cells, follicular dendridic cells CD25 HCL, subset of B and T cell lymphomas CD30 Hodgkin's lymphoma, anaplastic large cell lymphoma, subset of DLBCL, subset of B cell lymphoma CD33 Myeloid cells, rare pre B-ALL, rare blastic NK lymphoma CD34 myeloblasts, lymphoblasts, endothelial cells CD38 Plasma cells, activated T and B cells, subset B-CLL/SLL, epithelial cells CD41 Megakaryocytes CD43 Myeloid cells, T-cell lymphoma, pre B ALL, pre T ALL, B cell lymphoma (subset), plasma cells CD56 NK cells, LGL CD57 NK cells, LGL CD61 Megakaryocytes CD79a B cells, plasma cells, megakaryocytes CD103 HCL, rare T cell lymphomas CD117 AML, mast cells, stromal tumors (GIST), plasma cells bcl-2 Mature B cells, (except benign GCC), T cells, and FL Heavy Chains (IgG, IgA, IgM, IgD) B cells, plasma cells, DLBCL with ALK expression HLA Dr AML (except APL), B cells monocytes Light chains (kappa or lambda) B cells (surface), plasma cells (cytoplasmic) TdT pre-B-ALL, pre-T-ALL, some AML and hematogones
Maturation/Education of Lymphocytes
Lymphatic System and Organs
• The lymphatic system originates as vessels more permeable than capillaries (without a basement membrane) • Most numerous beneath the skin and mucous membranes
Lymph Node
• Lymphocytes within lymphatic vessels enter lymph nodes through afferent lymphatic vessels • Lymphocytes within the blood vessels enter lymph nodes through postcapillary venules (high endothelial venules) • Lymphocytes and macrophages occupy different areas of the lymph node.
Lymph Node Architecture
• Cortex
– Lymphocytic follicles
• Primary nodules • Secondary nodules (with germinal centers)
– Lymphocytes that have recognized an antigen returns to the lymph node and proliferates – Follicular dendritic cells
• Medulla
– Medullary cords and sinuses
• B cells, plasma cells and macrophages
Lymph Nodes Anatomy
Mucosa-Associated Lymphoid Tissues
Case 4
• A 15-year-old female presents to your clinic with a chief complaint of “it hurts when I swallow food” • HPI?
Physical Exam
Granulomas
Thymus
• A lymphoepithelial organ located in the superior mediastinum • Develops from the 3rd and 4th branchial pouch • CFU-Ls migrate from the bone marrow to develop into immunocompetent T cells • Thymus is fully formed at birth and undergoes apoptosis at puberty
Thymus
Bone Marrow
• Bone marrow is found within medullary cavities of long bone and the spaces of spongy bone • Bone marrow not involved in blood cell formation consists of adipose tissue • Sinusoids are unique blood vessels found between arterioles and venules, replacing capillaries • Bone marrow sinusoids are a closed circulation that new blood cells must enter to leave the bone marrow
Bone Marrow cellularity changes with age Subtract the patients age from 100
100 – 30yr = 70% cellularity 100 – 70 yr = 30% cellularity
Spleen
• Largest lymphatic organ, about the size of ones fist • Most commonly traumatized solid organ in the abdomen • Consists of red and white pulp
– Red pulp removes old red blood cells – White pulp consists of lymphatic tissue, mainly lymphocytes arranged around a central artery, periarterial lymphatic sheath (PAL)