Hematology - 02 Hematopoiesis

HEMATOLOGY HEMATOPOIESIS OUTLINE • Hematopoiesis o Hematopoiesis o Theories in Hematopoiesis o Hematopoietic Stem Cell o 3 phases of Hematopoiesis o Types of Hematopoiesis o Hematopoietic Tissues o Bone Marrow o Cell Development • Erythropoiesis o Erythropoiesis o Three Erythroid Precursor Nomenclature • Leukopoiesis o Leukocytes o Leukopoiesis o Granulopoiesis o Monopoiesis o Lymphopoiesis HEMATOPOIESIS HEMATOPOIESIS • • • • • aka Hemopoiesis The process of blood cell production, differentiation, and development. Continuous and regulated process that results in the formation, development, and specialization of all functional blood cells Occurs in the reticuloendothelial system (RES) Lineage-Specific Hematopoiesis o production, differentiation, maturation, development of specific mature cell o Erythropoiesis - erythrocytes o Leukopoiesis - leukocytes ▪ Granulopoiesis - granulocytes (basophil, eosinophil, neutrophil) ▪ Monopoiesis - monocytes and macrophages ▪ Lymphopoiesis - lymphocytes o Megakaryopoiesis - megakaryocytes (fragments become platelets) • • Totipotential Stem Cells o The most versatile type of stem cells o Present few hours after ovum is fertilized o May develop into any human cell types (including development of embryo to fetus) Pluripotential Stem Cells o o Can develop into any cell type o Cannot develop into a fetus THEORIES IN HEMATOPOIESIS • • Polyphylectic Theory o Suggests that each of the blood cell lineages is derived from its own unique stem cell o E.g.: erythrocyte have a unique stem cell o An obsolete theory Monophylectic Theory o Suggests that all blood cells are derived from a single progenitor stem cell (pluripotential stem cell system) o Most widely accepted theory among experimental hematologist HEMATOPOIETIC STEM CELL • • • • • The foundation of adult hematopoietic system. Self-renewal Gives rise to different progeny o Hematopoietic stem cell may give rise to common myeloid progenitor and common lymphoid progenitor Reconstitute the hematopoietic system in a lethargy irradiated individual Types of Human Stem Cells: o Totipotential Stem Cells o Pluripotential Stem Cells o Multipotential Stem cells • Multipotential Stem Cell o Derived from pluripotential stem cell o Limited to specific types of cell to form tissues • • • 3 PHASES OF HEMATOPOIESIS • Mesoblastic Phase o aka Yolk-sac phase o Start: 19th day after fertilization o End: 2nd to 4th month after fertilization o Site: Yolk-sac, intravascularly (inside blood vessel) o Product: Primitive erythroblasts ▪ Erythroblast - immature erythrocyte • Embryonic Hemoglobin Globin Chains Gower I (EZ) 2 Epsilon; 2 Zeta Gower II (TAE) 2 Epsilon; 2 Alpha Portland (ZGA) 2 Zeta; 2 Gamma Hepatic Phase o Start: 4 to 5 weeks after fertilization o Peak: 3rd month o Remains active 1-2 weeks after birth o Primary Site: Liver o Secondary site: thymus, spleen, kidneys o Product: RBC, and some other blood cells o Majority of blood cell produced are RBCs Proportion among Hemoglobin Globin Chains Newborns Hemoglobin F 2 Alpha, 2 Gamma 80% Hemoglobin A1 2 alpha, 2 beta 20% Hemoglobin A2 2 alpha, 2 delta <0.5% o Hemoglobin F - fetal hemoglobin ▪ Not an effective hemoglobin ▪ Decreases during aging Medullary Phase o aka Myeloid phase o Start: 5th to 6th month of development o End: throughout lifetime o Primary Site: Bone marrow o Secondary Site: Liver and spleen ▪ Functions when primary site is distressed/dysfunctional o Product: Cells of various lineages are seen ▪ Granulocytes are more abundant o Myeloid to Erythroid ratio = 3:1 Hemoglobin Globin Chains Hemoglobin A1 2 alpha, 2 beta Hemoglobin A2 2 alpha, 2 delta o Hemoglobin A1 & A2 - adult hemoglobin • • • • BONE MARROW • • • • • TYPES OF HEMATOPOIESIS • • Medullary Hematopoiesis o Blood cell production within the bone marrow o Begins in the 5th month of gestation and continuous throughout life Extramedullary Hematopoiesis o Blood cell production mainly in the liver and spleen o Occurs when bone marrow cannot meet the body requirements • Bone marrow Liver – major site of hematopoiesis during hepatic stage Spleen – largest lymphoid organ of the body. Function as indiscriminate filter of circulating blood Thymus – maturation site of T-cell o T-cell - type of lymphocyte Major site of hematopoiesis Composed of: o Red Bone Marrow (hematopoietic tissue) ▪ The only capable of producing blood cells ▪ Located in sternum, skull, vertebrae, scapula, ribs, pelvic bones, and proximal ends of long bones o Yellow Bone Marrow – composed of adipose tissue Red-to-Yellow Bone Marrow Ratio: o Decreases during aging Before Birth 100% Red Bone Marrow At birth 90:10 19-20 years old 60:40 Adulthood 50:50 65 years old 40:60 o If the need arises, yellow bone marrow may revert to red bone marrow to help produce hematopoietic cells Cellularity o Ratio of marrow cells to fat o Normocellular : 30-70% hematopoietic cells o Hypercellular/Hyperplastic: >70% o Hypocellular/Hypoplastic: <30% o Aplastic: few to none Myeloid-Erythroid Ratio o The ratio of granulocytes to nucleated erythroid precursors o Lymphocytes and monocytes are excluded o Reason why granulocyte is abundant than RBC ▪ Production of granulocyte is rapid and abundant dure to their shorter survival rate than RBC Disease M:E Ratio Normal 2:1 - 4:1 (3:1) Infection 6:1 Leukemia 25:1 Myeloid hyperplasia 20:1 Myeloid hypoplasia 3:20 Erythroid hyperplasia 1:20 Erythroid Hypoplasia 5:1 CELL DEVELOPMENT HEMATOPOIETIC TISSUES • • • Lymph nodes – lymphocyte production, processing of immunoglobulins, filter debris. Kidneys – produces erythropoietin (hormone influencing production of erythrocyte) Stomach – produces intrinsic factor (protein facilitating absorption of Vit.B12 for morphology of RBCs) Yolk-sac – site of primitive erythropoiesis Mononuclear Phagocyte System Bursa equivalent organ • Normal cell development depends on the interaction of: o Pluripotent Stem Cell o Microenvironment o Hematopoietic Growth Factors CYTOKINES • • • • aka Growth Factors Soluble proteins that have direct or indirect effects on hematopoiesis Includes: o Interleukins (IL) o Lymphokines o Monokines o Interferons o Chemokines o Colony-Stimulating-Factors (CSF) General Cellular Characteristics 1. As the cells mature, they decrease in size. 2. As the cells mature, cytoplasmic staining becomes less basophilic. 3. As the cells mature, Nucleus-to-Cytoplasm (N:C) ratio decreases. 4. As the cells mature, nuclear chromatin becomes denser. 5. As the cells mature, nucleoli start to disappear. ERYTHROPOIESIS ERYTHROPOIESIS • • • • • • • Refers to the production and development of RBC Erythropoietin (EPO) – primary regulator of erythropoiesis o Produced by the parafollicular cells of kidneys Erythrokinetics – the term describing the dynamics of RBC production and destruction. Erythron – refers to all stages of erythrocytes development encompassing the earliest precursor cells in the bone marrow to the mature red blood cells in the circulation. BFU-E - earliest recognizable colony o BFU-E to CFU-E - takes one week Pronormoblast - earliest identifiable RBC precursor cell o CFU-E to pronormoblast - one week o Matures to RBC - 6 day o Maturation is influenced by EPO 18-21 days from BFU-E to erythrocyte STIMULUS FOR RED BLOOD CELL PRODUCTION • • • • • • Hypoxia - decreased oxygen in blood o RBC production to compensate for lost oxygen o Induces kidneys to produce erythropoietin Growth Hormone - direct stimulators of erythropoiesis o Erythropoietin-independent Testosterone - indirect stimulator (erythropoietindependent) o Acts first to kidney Prolactin - direct stimulator Estrogen - indirect inhibitor (acts on kidney to inhibit EPO production) o Reduced RBC of females compared to males Pituitary and thyroid hormones SUBSTANCES NEEDED FOR NORMAL MATURATION OF RBC • • • • • • RUBRIBLAST Iron Folic Acid and Vitamin B12 o B12 - absorbed with intrinsic factor Mn, Co, Cu, Zn, Vitamin C, Vitamin E, Vitamin B6, Thiamine, Riboflavin, Pantothenic Acid EPO, thyroxine, androgens Intrinsic Factor Healthy bone marrow • • • • • • CRITERIA USED IN IDENTIFICATION OF THE ERYTHROID PRECURSOR • • • • • • Nuclear chromatin pattern – becomes coarser, clumped, and condensed Nuclear diameter – decreases Nucleus:Cytoplasm Ratio (N:C) Ratio – decreases Cellular diameter - decreases Presence or Absence of nucleoli o Absent - mature Cytoplasmic Color – blue to gray to pink o Basophilic - basic stain attraction (Methylene blue) o Acidophilic - acquires acidic stain (Eosin Red) • • • • aka Pronormoblast, Proerythroblast Earliest recognizable erythroid precursor cell using the light microscope Size: 12-20 um Nucleoli: present (1-2) usually very faint Nucleus: round or slightly oval o Thin nuclear membrane o Central or slightly eccentric Cytoplasm: small in amount o Moderately basophilic (dark blue) o Affinity to basic stain due to high conc. of RNA (acid) o No granules N:C Ratio: 8:1 Division: 2 daughter prorubricyte Cell Activity: protoporphyrin synthesis begins. Globin production begins. The stage only last for 24 hours PRORUBRICYTE • • • • • • • • • • aka Basophilic normoblast, basophilic erythroblast Size: 10-15 um Nucleoli: 0-1 Nucleus: round, thin nuclear membrane, small, slightly eccentric o Coarser chromatin Cytoplasm: more abundant o Richer blue than pronormoblast N:C Ratio: 6:1 Division: 2 daughter rubricyte (through mitosis) Cellular activity: detectable hemoglobin synthesis occurs o RNA mask hemoglobin concentration producing blue Stage last slightly more than 24 hrs Last stage with nucleoli RUBRICYTE • • • • • THREE ERYTHROID PRECURSOR NOMENCLATURE • • • • • • Rubriblastic Nomenclature Rubiblast Prorubricyte Rubricyte Metarubricyte Polychromatophilic Erythrocyte Erythrocyte • • • • • • Normoblastic Nomenclature Pronormoblast Basophilic normoblast Polychromatophilic normoblast Orthochromic normoblast Polychromatophilic Erythrocyte* Erythrocyte • • • • • • Erythroblastic Nomenclature Proerythroblast Basophilic erythroblast Polychromatophilic erythroblast Orthochromic erythroblast Polychromatophilic erythrocyte* Erythrocyte • • • • aka Polychromatophilic normoblast, polychromatophilic erythroblast o polychromatophilic = polychromatic Size: 10-12 um Nucleoli: none Nucleus: round and smaller; thick nuclear membrane; eccentric nucleus o Condensed chromatin o Checkboard appearance from condensed chromatin Cytoplasm: more abundant than rubriblast and prorubricyte o Combination of pink and blue (Murky gray-blue) N:C Ratio: 4:1 Division: 2 daughter metarubricyte First stage capable of hemoglobin synthesis Last stage capable of cell division (mitosis) METARUBRICYTE • • • aka Orthochromic normoblast, orthochromic erythroblast, nucleated RBC, acidophilic normoblast, pyknotic erythroblast Size: 8-10 um Nucleus: Pyknotic (dense mass of degenerated chromatin) o Dense chromatic cannot undergo cell division • • • • • Cytoplasm: salmon-pink / pink-orange (high Hgb content) o Orthochromic - the same; cytoplasm is the same color with Eosin stain (red acid) N:C Ratio: 1:2 Nucleus is extruded at this stage o Nucleus will be phagocytized by circulating macrophage Stage last for 48 hours Howell-Jolly Bodies - small fragment of nucleus left behind during extrusion which is not normal o Will be removed through pitting process of spleen ERYTHROCYTES • • • • • • • • • RETICULOCYTE • • • • • • • aka Polychromatophilic erythrocyte, diffusely basophilic erythrocyte o reticulocyte - when used supravital stain o polychromatophilic erythrocyte - when used Wright/Giemsa stain Size: 7-10 um Anucleated Cytoplasm: Salmon-pink o Presence of small amount of RNA may cause polychromasia (reticulum) o Polychromasia - diffused color; mixture of blue & red Young RBC containing residual RNA (last immature erythrocyte stage) Last stage capable of Hgb synthesis due to residual RNA Location: o Bone Marrow: 2-3 days o Peripheral blood: 1 day STAINING DIFFERENCE BETWEEN RETICULOCYTES AND ERYTHROCYTES • • Reticulocytes o Supravital Stain ▪ New Methylene Blue ▪ Brilliant Cresyl Blye ▪ Allow visualization of residual RNA (dark blue spots) Polychromatophilic Erythrocyte o Romanowsky Stain (Wright/Giemsa Stain) o Use two stains (Wright) ▪ Eosin (Red) - acid; stains basic component ▪ Methylene Blue - basic; stains acid component Size: 6-8 um Thickness: 1.5-2.5 um Shape: biconcave disc o Due to two concavities Anucleated Cytoplasm: Salmon-pink with central pallor area o Central pallor area - 1/3 of diameter of the cell Primary function is to manufacture/utilize hemoglobin for gas transport Average life span: 120 days Mature stage/ last stage in erythropoietic cycle Erythrocyte Destruction o Most cell experience enzyme deterioration ▪ But some cell can replenish enzyme activity ▪ RBCs are anucleated which cannot produce new proteins and enzymes resulting to cell death o Senescence - process of cellular aging o 120 days lifespan ▪ RBCs only have sufficient enzyme activity for 120d o Unable to generate new proteins o Loss of sialic acid ▪ Occurs during aging of RBC ▪ Makes RBC permeable to water o Water cause swelling making RBC become sphere ▪ A sphere RBC cannot pass through splenic sieve ▪ Splenic sieve filter blood ▪ Sphere RBC are trapped and are phagocytized by splenic macrophage o Mechanical Hemolysis (Fragmentation or Intravascular hemolysis) ▪ Sensitization of RBC with complement in the classic pathway ▪ Membrane attack complex (MAC) - end-product of complement which result to cell lysis o Macrophage-mediated Hemolysis (Extravascular hemolysis) ▪ Phagocytosis of macrophage in liver and spleen LEUKOPOIESIS LEUKOCYTES • • aka White Blood Cells Nucleated cells that function in body defense (immunity) LEUKOPOIESIS • • • • Refers to production, development, and maturation of WBC Divided into three major categories: o Granulopoiesis – development of granulocytes o Monopoiesis – development of monocytes and macrophages o Lymphopoiesis – development and maturation of lymphocytes Common myeloid progenitor (CMP) - precursor granulopoiesis and monopoiesis Common lymphoid progenitor - precursor for lymphopoiesis • Criteria for Identification of Granulocyte precursors 1. Nuclear chromatin becomes more condensed 2. Nucleoli disappear 3. Abundant basophilic cytoplasm with nonspecific granulation progresses to more scant cytoplasm containing specific granules 4. The nucleus indents and becomes segmented 5. Overall cell size decreases MYELOBLAST • • • • • • • • • 1-2% of nucleated cells in the bone marrow Earliest recognizable granulocytic precursor using light microscope Size: 15-20 um Cytoplasm: Basophilic o Presence of Primary granules/non-specific granules Nucleus: Round to slightly oval; centrally located Nuclear Chromatin: Fine Nucleoli: 2-5 N:C Ratio: 4:1 Subtypes: o Type I Myeloblast – no visible granules o Type II and III Myeloblast - granular GRANULOPOIESIS • • • • Development of granulocytes Granulocytes o WBC with visible granules present in the cytoplasm o Includes neutrophils, eosinophils, and basophils Granulocytes have similar stages of development and are often discussed as a group. Growth factors: o Granulocyte-Macrophage Colony-Stimulating-Factor (GM-CSF) o Granulocyte Colony-Stimulating Factor (G-CSF) STAGES OF DEVELOPMENT OF GRANULOCYTES Type I Type II and III PROMYELOCYTE • • • • • • • • 1-6% of nucleated cells in the bone marrow The stage of synthesis of “hof” primary granules/non-specific granules/azurophilic granules Size: 15-21 um Cytoplasm: Basophilic Nucleus: Round to oval; eccentric o Presence of “hof” ▪ Clear zone next to nucleus ▪ Stage of primary granule synthesis Nuclear Chromatin: Slightly coarser Nucleoli: 2-3 N:C Ratio: 3:1 to 2:1 PRIMARY GRANULES: • • • CFU-GEMM - CMP Each cell line develop from their unique precursors o Neutrophil develop from neutrophilic myeloblast o Eosinophil develop from eosinophilic myeloblast o Basophil develop from basophilic myeloblast Stages of development have almost indistinguishable characteristics across the 3 cells • • aka Non-specific granules, azurophilic granules Contains: o Myeloperoxidase o Acid ß-glycerophosphatase o Cathepsins o Defensins o Elastase o Proteinase-3 o Charcot-Leyden Crystal Protein (only found in eosinophilic promyelocyte) MYELOCYTE NEUTROPHIL SECRETORY GRANULES • • • • • • • • • • • • • Last stage capable of mitosis & last stage with nucleoli Stage of secondary/ specific granules synthesis o Lineage specific Early myelocytes – “dawn of neutrophilia” Size: 12-18 um Cytoplasm: Blue-pink Nucleus: Round to oval with flattened side Nuclear Chromatin: Coarse N:C ratio: 1:1 Light areas indicate presence of secondary granules MATURE GRANULOCYTE • METAMYELOCYTE • • • • • • • • • • aka Juvenile cells Stage which is most abundant in normal bone marrow Stage of tertiary granules development o Neutrophilic metamyelocyte only have tertiary granules Size: 10-15 um Nucleus: Indented (<1/2 of nuclear width) Nuclear Chromatin: Coarse and clumped No nucleoli Cytoplasm: Pink Only located in bone marrow (in normal condition) Presence in peripheral blood indicate abnormality Formed during metamyelocyte to band stages Contains: o Gelatinase o Collagenase o Lysozyme o Acetyltransferase o ß2-microglobulin NEUTROPHIL BANDS/STAB/STAFF • • • • • • • • 9-32% of nucleated cells in the bone marrow 0-5% of nucleated cells in the circulation The youngest granulocytic precursor to normally appear in the peripheral blood Start of Secretory Granules/vesicle synthesis o Only in neutrophil o Eosinophil & basophil do not have band stage Size: 9-15 um Cytoplasm: Lilac-pink granules Nucleus: C, S, or Z shape o Indented (>1/2 of nuclear width) Nuclear Chromatin: Coarse and clumped Neutrophils (Segmented) o Unsegmented - immature o aka polymorphonuclear neutrophil (PMN) ▪ due to multilobulation o 7-30% of nucleated marrow cells o Size: 9-15 um o Cytoplasm: Lilac-pink to purple granules o Nucleus: multilobed (2-5) ▪ Connected by thin filaments o Nuclear Chromatin: Coarse and clumped o TERTIARY GRANULES • • aka Secretory vesicles Formed during band to segmented stages Contains: o CD11b/CD18 o Alkaline phosphatase o Vesicle-associated membrane-2 o CD10, CD13, CD14, CD16 o Cytochrome b558 o Complement 1q receptor o Complement receptor-1 • Neutrophil Secondary Granules ▪ Formed during myelocyte stage ▪ Contains: • ß2-macroglobulin • Collagenase • Gelatinase • Lactoferrin • Neutrophil gelatinase-associated lipocalin (NGAL) • Transcobalamin Eosinophils o 1-3% of nucleated marrow cells o Size: 9-15 um o Cytoplasm: Coarse reddish-orange granules ▪ Granules do not overlap with the nucleus o Nucleus: bilobed (2 lobes) o Nuclear Chromatin: Coarse and clumped o IL-5 – critical for eosinophil growth and survival o • Eosinophil Secondary Granules ▪ Formed during myelocyte stage ▪ Contains: • Major Basic Protein • Eosinophil cationic protein • Eosinophil-derived neurotoxin • Eosinophil peroxidase • Lysozyme • Catalase • β-glucoronidase • Cathepsin D • IL-2, IL-4, IL-6 • GM-CSF Basophils o 0-2% of circulating WBC o <1% of nucleated marrow cells o Size: 10-16 um o Cytoplasm: coarse bluish-black granules ▪ Granules often obscure/overlap nucleus o Nucleus: multilobed (3-4) ▪ Often not visible o Nuclear Chromatin: Coarse and clumped o Basophil Secondary Granules ▪ Formed during myelocyte stage ▪ Contains: • Histamine • Platelet-activating factor • Leukotriene C4 • IL-4 and IL-13 • Vascular endothelial growth factors A and B • Chondroitin sulfate (eg. Heparan sulfate) MONOCYTES • • • • • • • Size: 14-20um Cytoplasm: blue-gray with ground glass appearance (due to azure dust) o With or without vacuoles Nucleus: Kidney-bean shaped with brain-like convolutions o May be coffee bean or horseshoe shape The only stage found in the circulation The largest cell in the circulation Presence of vacuoles indicate active immune response A precursor for macrophage Vacuolated Non-vacuolated MACROPHAGE • • • • • • Tissue monocytes Found in peripheral tissues Most abundant cell in the body Size: 15-85 um Nucleus: oval with net-like (reticulated) chromatin pattern Cytoplasm: pale, frequently vacuolated, and often filled with debris of phagocytized cells or organisms MONOPOIESIS • • • • Development and maturation of monocytes. Monocytes – precursor of macrophages Macrophage Colony Stimulating Factor (M-CSF) – major cytokine responsible for growth and differentiation of monocytes Morphologic stages: 1. Monoblasts - morphologically similar with myeloblast ▪ Similar to similar precursor (CMP) 2. Promonocytes 3. Monocytes Active Macrophage MONOCYTE DESTINATION • LOCATION Liver Lungs Kidneys Brain Skin Spleen Bone Placenta PROMONOCYTES • • • • • • Specific name of a monocyte/macrophage depends on its location Size: 14-18 um Cytoplasm: blue-gray Nucleus: irregularly shaped with 0-1 nucleoli o Shape can be folded or indented N:C Ratio: 2:1 to 3:1 Last stage capable of mitosis in monopoiesis Confined to bone marrow SPECIFIC NAME Kupffer cells Alveolar macrophage/Dust cell Mesangial cells Microglial cells Langerhans cells Splenic macrophage/Littoral Cells Osteoclasts Hoffbauer cells LYMPHOPOIESIS • • Refers to production, development and maturation of lymphocytes Lymphocytes are divided into 3 major groups: o T-cells o B-cells o Natural Killer Cells (NK Cells) • Morphologic stages: 1. Lymphoblast 2. Prolymphocyte 3. Lymphocyte 4. Plasma cells VARIANT LYMPHOCYTES • LYMPHOBLAST • • • • • • First morphologically recognizable cell of the lymphopoiesis Size: 10-18 um Cytoplasm: Moderate to dark blue Nucleus: Round to oval; eccentric Nucleoli: 1-2 N:C Ratio: 4:1 • • aka Reactive lymphocytes, atypical lymphocytes, virocytes, stress lymphocytes, Downey cells, transformed lymphocytes, transitional lymphocytes, glandular fever cells. o Reactive lymphocytes - enlargement and indentation due to stimulation of antigens Denotes that lymphocyte is not normal but does not further classify a lymphocyte Evidence of normal immune mechanism TYPES OF LYMPHOCYTES • PROLYMPHOCYTE • • • • • • May be seen in the bone marrow, thymus and secondary lymphoid tissues Size: 10-18um Cytoplasm: Moderate to dark blue o With few azurophilic granules Nucleus: Round, oval, or slightly indented Nucleoli: 1-2 N:C Ratio: 4:1 LYMPHOCYTE • • • Sizes: o Small Lymphocytes: 7-10 um o Medium Lymphocytes: 10-12 um o Large Lymphocytes: 11-25 um Cytoplasm: Sky blue/Robin egg blue Nucleus: Round and compact o Crushed velvet appearance • • • B-cells o aka “short-live lymph”, B lymphocyte o Found in the bone marrow o Needs to mature to plasma cells in order to produce antibodies T-cells o aka “long-live lymph”, T lymphocyte o Found in the thymus ▪ Develop in bone marrow but mature in thymus o Direct killing from cell-to-cell NK cells o Aka Natural Killer cells, large granular lymphocytes o Part of innate immunity that are capable of killing certain tumor cells and virus-infected cells without prior sensitization ▪ Innate immunity - present at birth Plasma Cells o Final maturation stage of B-cells o Produces antibodies for immune response o Size: 10-28 um o Nucleus: small/oval shaped; eccentric o Cytoplasm: Dark blue; ovoid shaped; non-granular ▪ “Tortoise shell” or “Cartwheel” in appearance ▪ Contains Russel Bodies • Round, discreet globules • Immunoglobulin in plasma cell