Pharm immuno2 cells of the immune system


Published on

Published in: Education
  • Be the first to comment

No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide
  • Uncommitted cells have no specialized receptor Committed B cells possess a specific receptor that recognizes one and only one EPITOPE of an antigen
  • T-cell large granular lymphocyte (LGL) leukemia is a clonal proliferation of cytotoxic T cells, which causes neutropenia, anemia, and/or thrombocytopenia. This condition is often associated with autoimmune disorders, especially rheumatoid arthritis, and other lymphoproliferative disorders. The diagnosis is suggested by flow cytometry demonstrating an expansion of CD8 + CD57 + T cells and is confirmed by T-cell receptor gene rearrangement studies. Mounting evidence suggests that LGL leukemia is a disorder of dysregulation of apoptosis through abnormalities in the Fas/Fas ligand pathway. In most patients, this is an indolent disorder, and significant improvement of cytopenias can be achieved with immunosuppressive agents such as steroids, methotrexate, cyclophosphamide, and cyclosporin A. This review provides a concise, up-to-date summary of LGL leukemia and the related, more aggressive, malignancies of cytotoxic T cells and natural killer cells. Key Words. Chronic T-cell leukemia • Felty’s syndrome • Neutropenia • Natural killer cell T-cell large granular lymphocyte (LGL) leukemia is caused by a clonal proliferation of cytotoxic (CD8 + ) T cells and is characterized clinically by neutropenia, anemia and/or thrombocytopenia, and a modest lymphocytosis. It can occur in association with multiple autoimmune conditions. In most cases, it follows an indolent clinical course. Since the first description of this syndrome by McKenna et al . in 1977 [ 1 ], our understanding of the natural history, immunophenotype, pathophysiology, and treatment of this disorder has greatly expanded, and LGL leukemia is now recognized as a well-defined clinical entity. This disorder has been described by many terms over the years (Table 1 ), but in modern literature, including the most recent World Health Organization (WHO) classification of the hematologic malignancies [ 2 ], the term T-cell LGL leukemia has been used and is used in this review. The purposes of this review are to provide a concise, up-to-date summary of this uncommon, but probably underdiagnosed, malignancy and to describe the current approach to its diagnosis and management. Other suppressor T-cell and natural killer (NK) cell malignancies are reviewed briefly to·tip·o·ten·cy (t½-t¹p“…-t…n-s¶, t½”t¹-p½t“n-s¶) also to·tip·o·tence (t½-t¹p“…-t…ns, t½”t¹-p½t“ns) -- n. , pl. to·tip·o·ten·cies also to·tip·o·ten·ces . The ability of a cell, such as an egg, to give rise to unlike cells and thus to develop into or generate a new organism or part. [Latin t½tus , whole; see TOTAL + potency.] --to·tip“o·tent adj.
  • Fig 2-1 Cells involved in the immune response
  • Polymorphonuclear neutrophil. The blue arrow points to the primary granules. They take up the eosin of the H&E stain poorly which accounts for their designation as a neutrophil. The green arrow indicates the lightly staining secondary granules indicating they do take up small amounts of the dye. (from Microscopic Anatomy , copyright Gold Standard Multimedia) The blue arrow points to the primary granules . They take up the eosin of the hematoxylin and eosin (H&E) stain poorly which accounts for their designation as a neutrophil The green arrow indicates the lightly staining secondary granules indicating they do take up small amounts of the dye Azure: basic blue methylthionine or phenothiazine dye az·ure ( ² zh “… r) n. 1. Abbr. az. a. Color. A light purplish blue. b. Heraldry. The color blue. 2. The blue sky. [Middle English, from Old French azur , from Medieval Latin azura , from Arabic al-l ³ zaward , from Persian l ³ jvard , lapis lazuli.] Lysosomes in neutrophils contain granules of two types. Primary (azurophilic) granules contain acid hydrolases, myeloperoxidase and lysozyme. The secondary, or specific, granules contain lysozyme and lactoferrin
  • Neutrophils are characterized by their multilobed nuclei Their primary function is phagocytosis , which is enhanced by opsonization with complement and Abs An important secondary function is to promote inflammation Like the mononuclear cells, neutrophils produce reactive oxygen metabolites and hydrolytic enzymes. In addition, neutrophils produce nitric oxide and antibiotic proteins such as defensins, seprocidins, cathelicidins, and bacterial permeability inducing protein Lysosomes in neutrophils contain granules of two types. Primary (azurophilic) granules contain acid hydrolases, myeloperoxidase and lysozyme. The secondary, or specific, granules contain lysozyme and lactoferrin
  • RANTES A member of the interleukin-8 superfamily of cytokines. This cytokine is an 8-kD protein that is a selective chemoattractant for memory T lymphocytes and monocytes. Origin [ R egulated on a ctivation, n ormal T e xpressed and s ecreted]
  • Basophils and mast cells These two cells have similar functions, but must be considered distinct because of their different developmental histories . Basophils are found in circulation where they comprise about 0.2% of the leukocytes. They are rounded cells about 8-10 in diameter. They have a elongated nucleus usually with two constrictions which is sometimes folded into an S shape . Mast cells are associated with tissues; stationary
  • Eosinophils express low affinity Fc receptors specific for IgE and are important in reactions to antigens (e.g. parasites) that induce high levels of IgE. Eosinophils are particularly effective at destroying helminthic parasites, which are often resistant to the lysosomal enzymes of neutrophils and macrophages. The granules in eosinophils release major basic protein and eosinophil cationic protein , which are toxic to the worm, and substances like histaminase and arylsulfatase that reduce inflammation
  • Monocytes/Macrophages Monocytes enter circulation from bone marrow then migrate into various organs and tissues. There they mature into macrophages, Kupffer cells (liver), histiocytes, dendritic cells (lymph nodes and spleen), glial cells (brain), and Langerhans' cells (skin). Collectively, these cells form a network known as the reticuloendothelial system (RES) or the mononuclear phagocyte system.
  • Cmm = cubic millimeter
  • LGL =large granulocyte
  • N:C = nucleus : cytoplasm LGL = Large granular lymphocytes. Do not confuse LGL with Granulocytes
  • Final Diagnosis -- Rheumatoid Arthritis and Peripheral Leukocytosis FINAL DIAGNOSIS: Peripheral blood - Hypochromic microcytic anemia, Neutropenia, Large granular lymphocytosis, Monocytosis and Thrombocytopenia. Bone marrow biopsy and aspirate - Large granular lymphocyte leukemia. Hypercellular marrow with erythroid predominance. DISCUSSION: Large granular lymphocyte (LGL) comprises about 10-15% of normal peripheral blood mononuclear cells. Morphologically they are bigger than a normal lymphocyte and have azurophilic granules in their cytoplasm. LGL can be further divided into CD3- and CD3+ cells depending on their cell lineage. The LGL identified in the peripheral blood of normal individuals are usually CD3 -, lack CD3/TCR complex and mediate MHC-restricted killing. The CD3+ LGL express CD3/TCR complex and represent activated cytotoxic T cells (2). Therefore clonal proliferation of LGL can either arise from NK or T cell lineage (3). These lympho proliferative disorders range from reactive process to indolent and aggressive neoplasm. T-cell large granular lymphocyte leukemia (T-LGL) is a heterogeneous disorder that is characterized by lymphocytosis of large granular cells in the peripheral blood usually between 2 - 20x109/L, is persistent for more than 6 months and has no identifiable cause (1). The hallmark of T-LGL is the expansion of a discrete or clonal population of cytolytic lymphocytes in the peripheral blood. They represent 2 - 3% of all cases of small lymphocytic leukemia. They usually involve the peripheral blood, bone marrow, liver, and spleen. The problem of identifying T-LGL from a benign granular lymphocytic process is difficult based just on the morphology of the lymphocytes, since they do not have any distinguishing features. This is especially true with hematoxylin and eosin stained bone marrow biopsy specimens where the granular lymphocytes often do not have any distinctive cytologic features (4). Immunohistochemistry of bone marrow biopsy therefore helps in highlighting interstitial clusters of LGL cells. The important antibodies that help in identifying these cells include CD 57, CD 3, TIA-1 and granzyme B (7). However the presence of a population of T - large granular lymphocyte is not synonymous with T-cell malignancy, since minor T-cell clones can be found in oligoclonal immune reactions, especially in the elderly and immunosuppressed individuals Therefore other criteria such as an increase in blood LGL population, demonstration of T-cell clonality, and demonstration of a distinct peripheral blood T-cell population by flow cytometry are needed (5). The median age of onset of T-LGL is about 55 years. Clinically they can present with various hematologic abnormalities that include chronic neutropenia, anemia, cyclic neutropenia, pure red cell aplasia, autoimmune hemolytic anemia, ITP, aplastic anemia, and MDS (6). One of the prominent features of T-LGL is its association with autoimmune diseases especially rheumatoid arthritis and Felty's syndrome. Many of the cases have serologic abnormalities, which include positive rheumatoid factor, ANA, high levels of circulating immune complexes, polyclonal hypergammaglobulinemia, and high levels of b2-microglobulin (6). The above case highlights some of the distinctive characteristics and difficulties associated with T-LGL. Our patient had a history of rheumatoid arthritis, which has a strong association with T-LGL. Although morphologically it was difficult to make a diagnosis, immunohistochemistry on the bone marrow biopsy, flow cytometry, and molecular studies helped in identifying the clonal population present. In our case the cytogenetics results were also interesting because an unbalanced translocation was noted between chromosomes 14 and 15. This resulted in a trisomy 14q and a possible involvement of 14q11, which is the region where the Ta/Td are mapped. The rearrangement of these genes is frequently associated with T-cell leukemia/lymphoma (8). It also highlights the fact that it is important to examine the peripheral blood smear where it is frequently possible to pick up the large granular cells and a diagnosis of a large granular lymphocyte leukemia can be considered, which might otherwise be overlooked in a bone marrow biopsy specimen. REFERENCES T-cell large granular lymphocyte leukemia from the WHO Classification of tumors - Tumors of haematopoietic and lymphoid tissues, 197-198, 2001. Lanier LL, Phillips JH, Hackell J Jr, Tutt M, Kumar V. Natural killer cells: Definition of a cell type rather than a function. J. Immunol, 1986; 137; 2735 -2739. Loughran TP Jr. Clonal disease of large granular lymphocytes. Blood, 1993; 82: 1-4. Agnarsson BA, Loughran TP Jr, Starkebanum G. The pathology of large granular lymphocyte leukemia. Hum Pathol. 1989; 20: 643-651. Evans HL, Burks E, Viswanatha D, Larson RS. Utility of Immunohistochemistry in Bone Marrow Evaluation of T-lineage Large granular lymphocyte leukemia. Hum Pathol. 2000; 31: 1266. Greer JP, Kinney MC, Loughran TP. T cell and NK cell lymphoproliferative Disorders. Hematology 2001; 259 - 281 Morice WG, Kurtin PJ, Tefferi A, Hanson CA. Distinct bone marrow findings in T cell granular lymphocytic leukemia revealed by paraffin section immunoperoxidase stains for CD 8, TIA-1 and granzyme B. Blood. 2002, 99 (1): 268 - 274. Toyama T, Chaganti R.S.K, Yamada Y, Tsukasaki K, Atogami S, Nakamura H, Tomonaga M, Ohshima K, Kikuchi M, Sadamori N. Cytogenetic analysis and clinical significance in adult T - cell leukemia/lymphoma: a study of 50 cases from the human T-cell leukemia virus type-1 endemic area, Nagasaki. Blood 2001, 97 (11) : 3612 - 3620. Contributed by Leena Lourduraj, MD and Lydia C Contis, MD
  • B cells have MHC I (like all nucleated cells) and MHC II proteins on their surfaces. MHC proteins are members of the immunoglobulin superfamily that have antigen binding capabilities but are not nearly as specific as antigen binding by immunoglobulins or T cell antigen receptors. The latter allow B cells to function as antigen presenting cells for induction of immune responses. B cells have two different receptors for complement, CR1 (CD35) and CR2 (CD21) that probably have regulatory functions. CR2 is the target for Epstein-Barr virus binding.
  • How can you distinguish NK from T & B? No specific receptor NK can lyse certain tumor cell lines in vitro without prior sensitization
  • All are MHC II positive, so they communicate with CD4 T cells Only macrophages are capable of phagocytosis
  • mesentery mescen-ter-T 1. A double layer of peritoneum attached to the abdominal wall and enclosing in its fold a portion or all of one of the abdominal viscera, conveying to it its vessels and nerves. 2. The fan-shaped fold of peritoneum suspending the greater part of the small intestines (jejunum and ileum) and attaching it to the posterior abdominal wall at the root of the mesentery (radix mesenterii). Syn: mesenterium dorsale commune, mesostenium. Syn: mesenterium [TA]. Origin [Mod. L. mesenterium, fr. G. mesenterion, fr. G. mesos, middle, + enteron, intestine] mesentery of appendix mesentery of cecum mesentery of lung mesentery of sigmoid colon mesentery of transverse colon urogenital mesentery
  • There are two major primary lymphoid organs, one in which T cells develop (thymus), and the other in which B cells develop (bone marrow). The structure of the thymus is presented below. Progenitor cells from the bone marrow migrate to the thymus gland to develop into T lymphocytes. The thymus is a bilobed structure, whose size reaches its maximum at birth, then atrophies with age. The cortex contains mostly immature thymocytes, some of which mature and migrate to the medulla, where they learn to discriminate between self and nonself during fetal development and for a short time after birth. T cells leave the medulla to enter the peripheral blood circulation, through which they are transported to the secondary lymphoid organs. It is in these secondary lymphoid organs that the T cells encounter and respond to foreign antigens. Removal of the thymus from an adult generally has little immediate effect on the number and quality of the T lymphocytes, which have already matured and populated the secondary lymphoid organs. In contrast, congenital absence of a thymus results in an immediate and drastic reduction in T cells that produces a potentially lethal wasting disease (DiGeorge syndrome). Patients who survive the immediate neonatal period are prone to developing recurrent or chronic infections with viral, bacterial, fungal or protozoal agents
  • Schematic representation of the spleen and a cross-section of the periarteriolar lymphoid sheath (PALS). The spleen is the major organ in which antibodies are synthesized and released into circulation. The spleen is composed of two types of tissue-the red pulp and the white pulp. The red pulp contains plasma cells, resident macrophages, erythrocytes, platelets, granulocytes and lymphocytes. It is the site where aged platelets and erythrocytes are destroyed (hemocatheresis). The white pulp contains the lymphoid tissue clustered around a central arteriole in an arrangement known as a periarteriolar lymphoid sheath (PALS). T cells are found around the central arteriole, while B cells are organized into either primary follicles (unstimulated), or secondary follicles (stimulated by contact with antigen) that contain a germinal center complete with memory cells. About 50% of spleen cells are B lymphocytes and 30-40% are T cells. Arterial blood lymphocytes enter the spleen through the trabecular artery and return to venous circulation through the trabecular vein.
  • The lymph node consists of a B cell area (cortex), a T cell area (paracortex) and a central medulla, which contains a mix of B cells, T cells, plasma cells and macrophages. As in the spleen, B cells are arranged in unstimulated primary follicles, and in antigen-stimulated secondary follicles with germinal centers. Antigen and lymphocytes enter the lymph node through the afferent lymphatic vessels and high endothelial venules (HEVs). Lymph, antibodies and cells leave the node through the efferent lymphatic vessel. As the lymph passes across the nodes from afferent to efferent lymphatic vessels, particulate antigens are removed by phagocytic cells and are transported to the interior of the node where they stimulate responses by B and T lymphocytes. Lymphoid cells return to circulation via the thoracic duct, which empties into the left subclavian vein. mediastinum mecdT-as-tUcn\\m 1. A septum between two parts of an organ or a cavity. 2. [TA]; The median partition of the thoracic cavity, covered by the mediastinal part of the parietal pleura and containing all the thoracic viscera and structures except the lungs. It is divided arbitrarily into two major divisions: a superior mediastinum [TA] (mediastinum superus [TA]), which lies directly superior to a horizontal plane intersecting the sternal angle and approximately the T4–5 intervertebral disk, and an inferior mediastinum [TA] (mediastinum inferius [TA]) inferior to that plane; the latter is, in turn, subdivided in 3 parts: a middle mediastinum [TA] (mediastinum medium [TA]), which is coterminus with the pericardial sac containing the heart, a nearly potential anterior mediastinum [TA] (mediastinum anterius [TA]) lying in front, and a posterior mediastinum [TA] (mediastinum posterius [TA]) behind, containing the esophagus, descending aorta, and thoracic duct. Syn: interpulmonary septum, septum mediastinale, interpleural space, mediastinal space. Origin [Mod. L. a middle septum, fr. Mediev. L. mediastinus, medial, fr. L. mediastinus, a lower servant, fr. medius, middle] anterior mediastinum inferior mediastinum mediastinum anterius mediastinum inferius mediastinum medium mediastinum of testis mediastinum posterius mediastinum superius mediastinum testis middle mediastinum posterior mediastinum superior mediastinum
  • Diffuse accumulations of lymphoid tissue are seen in the lamina propria of the intestinal wall. The intestinal epithelium overlying the Peyer's patches is specialized to allow the transport of antigens into the lymphoid tissue. This particular function is carried out by epithelial cells termed "M" cells , so called because they have numerous microfolds on their luminal surface . M cells absorb, transport, process and present antigens to subepithelial lymphoid cells
  • Pharm immuno2 cells of the immune system

    1. 1. Clonal Selection Theory <ul><li>T and B cells exist with almost unlimited specificities before any contact with foreign Ags </li></ul><ul><li>Ag-specific receptors that recognize foreign Ags: </li></ul><ul><ul><li>Abs are the B cell receptors on the surface of B cell & </li></ul></ul><ul><ul><li>T-cell receptor ( TCR ) on T cell </li></ul></ul><ul><li>Each lymphocyte has a single specificity </li></ul><ul><li>The antigenic determinant ( epitope ) on the Ag binds with lymphocyte (B or T) and triggers their differentiation and proliferation </li></ul><ul><li>Negative selection by self Ags  shut off cells that recognize them during maturation </li></ul>
    2. 2. Clonal Selection Epitopes 2, 103, 821 No specialized receptor Epitopes 2, 103, 821
    3. 3. Harmful Effects of the Immune System <ul><li>Hypersensitivity or allergic reactions: </li></ul><ul><ul><li>Type I, immediate hypersensitivity </li></ul></ul><ul><ul><li>Type II, cytotoxic Ab-mediated reactions </li></ul></ul><ul><ul><li>Type III,immune complex Ab-mediated </li></ul></ul><ul><ul><li>Type IV, delayed-type cell-mediated </li></ul></ul><ul><li>Autoimmune diseases </li></ul><ul><ul><li>The immune system attacks body’s own Ags causing diseases like rheumatoid arthritis, diabetes mellitus and systemic lupus erythematosus </li></ul></ul><ul><li>Immunodeficiencies </li></ul><ul><ul><li>Occur when one or more components of the immune system fail to function properly </li></ul></ul><ul><ul><li>This can be result of genetic defect (SCID) or acquired (AIDS) </li></ul></ul><ul><li>Graft rejection </li></ul><ul><ul><li>Occurs because of immune response against transplant’s Ags </li></ul></ul>
    4. 4. Genetic Recombination & Immune Response Diversity <ul><li>10 6 -10 7 of antigenic specificities might exist </li></ul><ul><li>If 1 gene = 1 response, are 10 7 genes needed? </li></ul><ul><ul><li>No </li></ul></ul><ul><li>Genetic recombination “within “ a gene that encodes the Ig proteins is the answer </li></ul><ul><li>So, the basic Ab is composed of 2 types of polypeptides : H-chain , L-chain and each chain has a variable domain </li></ul><ul><li>This mechanism generates Ab & T cell receptor (TCR) specificity </li></ul>
    5. 5. Regulation of the immune system <ul><li>Why regulation? </li></ul><ul><li>Immune response  proliferation and increased synthesis of specific molecules that will not be useful after their job is finished (infection  response  cure) </li></ul><ul><li>Homeostasis or equilibrium must be established by shutting down the system </li></ul><ul><li>Deregulation of the immune system has severe consequences </li></ul><ul><li>Immune response to self Ags  Autoimmunity </li></ul>
    6. 6. LECOM-Pharmacy School Immunology 02 Cells, Tissues & Organs of the Immune System Dr. Saber Hussein
    7. 7. Objectives <ul><li>B and T lymphocytes and NK cells </li></ul><ul><li>T cells Subpopulations: Helper, cytotoxic and suppressor </li></ul><ul><li>Antigen presenting cells </li></ul><ul><li>Phagocytes: Monocytes (macrophages) & granulocytes (eosinophil, neutrophil, basophil & mast cells) </li></ul><ul><li>granulocyte and platelet role in inflammatory response </li></ul><ul><li>Primary tissues of the Immune System: </li></ul><ul><ul><li>Bone marrow & </li></ul></ul><ul><ul><li>Thymus </li></ul></ul><ul><li>Secondary tissues: </li></ul><ul><ul><li>Lymph nodes, </li></ul></ul><ul><ul><li>spleen, </li></ul></ul><ul><ul><li>Payer’s patches </li></ul></ul>
    8. 8. Cells of the Immune System <ul><li>Lymphoid Lineage </li></ul><ul><ul><li>T helper cells (T H ) </li></ul></ul><ul><ul><li>Cytotoxic T cells (Tc or CTL) </li></ul></ul><ul><ul><li>B cells </li></ul></ul><ul><ul><li>Natural Killer [ NK cells. A type of white blood cell that contains granules with enzymes that can kill tumor cells or microbial cells. Also called large granular lymphocytes ( LGL )] </li></ul></ul><ul><li>Myeloid Lineage </li></ul><ul><ul><li>Polymorphonuclear granulocytes </li></ul></ul><ul><ul><ul><li>Neutrophil </li></ul></ul></ul><ul><ul><ul><li>Basophil & Mast cells </li></ul></ul></ul><ul><ul><ul><li>Eosinophil </li></ul></ul></ul><ul><ul><li>Mononuclear phagocytes </li></ul></ul><ul><ul><ul><li>Dendritic cells & Macrophages </li></ul></ul></ul><ul><li>Megakaryocytic Lineage </li></ul><ul><ul><li>Platelets </li></ul></ul>
    9. 9. Hematopoiesis <ul><li>Hematopoiesis is the process of blood cell maturation from the stem cell to the active, functional blood cell (red or white) </li></ul><ul><li>Red blood cells and white blood cells are formed in the bone marrow </li></ul><ul><li>Stem cells are totipotent or pluripotent </li></ul><ul><ul><li>Totipotency  - The ability of a cell, such as an egg, to give rise to unlike cells [differentiate] and thus to develop into or generate a new organism or part . </li></ul></ul><ul><ul><li>Pluripotency  - The potential of a cell to develop into more than one type of mature cell, depending on environment </li></ul></ul><ul><li>Myeloid cells and lymphoid cells are pluripotent cells with a common ancestor, a totipotent cell </li></ul>
    10. 10. Hematopoiesis <ul><li>Myeloid cell Erythrocyte; </li></ul><ul><ul><ul><ul><ul><li>Neutrophil, </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Monocyte  Macrophage; Eosinophil; </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Basophil & Mast cell; Megakaryocyte  Platelet </li></ul></ul></ul></ul></ul><ul><li>Lymphoid cell Lymphocytes: </li></ul><ul><li>T cell </li></ul><ul><li>B cell  Plasma cell </li></ul><ul><li>NK cell </li></ul>
    11. 11. Cells involved in the immune response Cells involved in the immune response
    12. 12. Polymorphonuclear neutrophil <ul><li>Subject to chemotactic stimulation by : </li></ul><ul><ul><li>Complement fragments (C5a) </li></ul></ul><ul><ul><li>Products of platelets & leukocytes </li></ul></ul><ul><ul><li>Bacterial products </li></ul></ul><ul><ul><li>Other protein products of fibrinolysis </li></ul></ul><ul><li>Lysosomes contain </li></ul><ul><li>i. Primary granules (Azurophilic) contain </li></ul><ul><ul><ul><li>Hydrolases </li></ul></ul></ul><ul><ul><ul><li>Peroxidases </li></ul></ul></ul><ul><ul><ul><li>Lysozyme </li></ul></ul></ul><ul><li>ii. Secondary , specific, granules contain: </li></ul><ul><ul><ul><li>Lactoferrin </li></ul></ul></ul><ul><ul><ul><li>Lysozyme </li></ul></ul></ul>Primary granules Secondary granules
    13. 13. Neutrophils <ul><li>Have multilobed nuclei </li></ul><ul><li>Their primary function is </li></ul><ul><ul><li>Phagocytosis </li></ul></ul><ul><ul><ul><li>enhanced by opsonization with complement and Abs </li></ul></ul></ul><ul><li>Important secondary function </li></ul><ul><ul><li>promote inflammation </li></ul></ul><ul><li>Neutrophils produce </li></ul><ul><ul><li>reactive oxygen metabolites </li></ul></ul><ul><ul><li>hydrolytic enzymes </li></ul></ul><ul><ul><li>nitric oxide and </li></ul></ul><ul><ul><li>antibiotic proteins such as </li></ul></ul><ul><ul><ul><li>defensins </li></ul></ul></ul><ul><ul><ul><li>seprocidins </li></ul></ul></ul><ul><ul><ul><li>cathelicidins </li></ul></ul></ul><ul><ul><ul><li>bacterial permeability inducing protein </li></ul></ul></ul>
    14. 14. Polymorphonuclear Granulocytes <ul><li>PMNs include </li></ul><ul><ul><li>Mainly neutrophils </li></ul></ul><ul><ul><li>Eosinophils </li></ul></ul><ul><ul><li>Basophil & mast cells </li></ul></ul><ul><li>From bone marrow at 7 million/minute </li></ul><ul><li>Short lived (2-3 days) </li></ul><ul><li>About 60-70% of WBCs </li></ul><ul><li>Diapedesis : </li></ul><ul><ul><li>PMNs leave the circulation by adhering to the endothelium & squeezing out </li></ul></ul><ul><ul><li>It is promoted by chemokines </li></ul></ul><ul><ul><ul><li>IL-1 </li></ul></ul></ul><ul><ul><ul><li>IL-8 (RANTES [ R egulated on a ctivation, n ormal T e xpressed and s ecreted]) </li></ul></ul></ul>
    15. 15. Functions of PMNs <ul><li>Important part in acute inflammation </li></ul><ul><li>No specificity for Ags </li></ul><ul><li>Cooperate with Abs & complement </li></ul><ul><li>Phagocytosis </li></ul><ul><li>Polymorph extravasation deficient individuals and those with low numbers of PMNs  increased susiptibility to infections </li></ul>
    16. 16. Basophils & Mast cells <ul><li>Basophils are in circulation </li></ul><ul><ul><li>Have S-shaped nucleus </li></ul></ul><ul><ul><li>Are round </li></ul></ul><ul><li>Mast cells are stationary : </li></ul><ul><ul><li>Mucosal mast cells (MMC) </li></ul></ul><ul><ul><li>Connective tissue mast cells (CTMC) </li></ul></ul><ul><li>Granules ’ contents are called mediators such as: </li></ul><ul><ul><li>Heparin , </li></ul></ul><ul><ul><li>Histamine </li></ul></ul><ul><ul><li>SRS-A (slow-reacting substance of anaphylaxis) </li></ul></ul><ul><ul><li>ECF-A (eosinophil chemotactic factor A) </li></ul></ul>
    17. 17. Basophils and mast cells <ul><li>Basophils and mast cells are the least prevalent of the leukocytes </li></ul><ul><li>They possess high affinity Fc receptors for IgE </li></ul><ul><li>They release the chemical mediators of immediate hypersensitivity, including: </li></ul><ul><ul><li>Histamine </li></ul></ul><ul><ul><li>Prostaglandins </li></ul></ul><ul><ul><li>Thromboxanes </li></ul></ul><ul><ul><li>Leukotrienes </li></ul></ul><ul><ul><li>Heparin </li></ul></ul><ul><li>They also produce eosinophil chemotactic factor (ECF) </li></ul><ul><ul><li>which causes eosinophils to enter the area of worm infestation or allergen localization </li></ul></ul>MC
    18. 18. Eosinophils <ul><li>Bilobed nucleus </li></ul><ul><li>Granules stain with acid dyes - eosin </li></ul><ul><li>Capable of phagocytosing & killing microorganisms </li></ul><ul><li>Degranulation : release of contents in surrounding area </li></ul><ul><li>Can kill parasites with basic proteins and cationic proteins </li></ul><ul><ul><li>Schistosoma mansoni </li></ul></ul>
    19. 19. Monocytes/Macrophages <ul><li>Monocytes enter circulation from bone marrow then migrate into various organs and tissues </li></ul><ul><li>There they mature into: </li></ul><ul><ul><li>macrophages </li></ul></ul><ul><ul><li>Kupffer cells (liver) </li></ul></ul><ul><ul><li>histiocytes ( M  found in connective tissue) </li></ul></ul><ul><ul><li>dendritic cells (lymph nodes, spleen) </li></ul></ul><ul><ul><li>glial cells (brain) </li></ul></ul><ul><ul><li>Langerhans' cells (skin) </li></ul></ul><ul><li>Collectively, these cells form a network known as the reticuloendothelial system (RES) or the mononuclear phagocyte system </li></ul>M  in the process of surrounding tumor cell
    20. 20. Differential White Blood Cell Count *% of lymphocytes in peripheral blood 3000 - 7000 50 – 400 25 – 100 1000 – 4000 100 - 600 50 – 60 1 – 4 0.5 – 2 20 – 40 80 - 85* 5 - 15* 5 - 15* 2 - 9 Neutrophil Eosinophil Basophil Lymphocyte T cell B cell NK cell Monocyte CELLS/cmm % OF WBC'S CELL TYPE
    21. 21. Reticuloendothelial System (mononuclear phagocyte System)
    22. 22. Platelets <ul><li>Anucleate </li></ul><ul><li>Derived from megakaryocytes </li></ul><ul><li>Contain granules at the ultrastructural level </li></ul><ul><li>Their major functions are </li></ul><ul><ul><li>blood clotting </li></ul></ul><ul><ul><li>inflammation </li></ul></ul><ul><ul><ul><li>Following injury to endothelial cells, platelets adhere to the surface of the damaged tissue, where they release substances that </li></ul></ul></ul><ul><ul><ul><ul><li>increase vascular permeability , </li></ul></ul></ul></ul><ul><ul><ul><ul><li>activate complement and </li></ul></ul></ul></ul><ul><ul><ul><ul><li>attract leukocytes </li></ul></ul></ul></ul>Platelets aggregating at the site of a wound in a blood vessel
    23. 23. Functions of Lymphocytes NK
    24. 24. B and T lymphocytes <ul><li>T cells develop in the thymus </li></ul><ul><li>B cells differentiate </li></ul><ul><ul><li>in fetal liver & </li></ul></ul><ul><ul><li>in postnatal bone marrow </li></ul></ul><ul><li>Ag recognition via specific receptors </li></ul><ul><li>NK (natural killer) cells do not express Ag receptor </li></ul><ul><li>Lymphocytes have </li></ul><ul><ul><li>high N:C (nucleus : cytoplasm) ratio </li></ul></ul><ul><li>LGL (NK; Large granular lymphocytes) have </li></ul><ul><ul><li>lower N:C ratio </li></ul></ul>
    25. 25. T Cells <ul><li>Majority of T cells express  -TCR </li></ul><ul><ul><li>T-helper cells ( T H ) </li></ul></ul><ul><ul><li>T-cytotoxic cells ( T c ) </li></ul></ul><ul><li>TCR is an immunoglobulin </li></ul><ul><li>Carry Gall body (Gb) in the cytoplasm </li></ul><ul><ul><li>Gb: A cluster of lysosomes + Lipid droplet </li></ul></ul>MHC-I CD4 CD8 T H Cell T C Cell
    26. 26. Subpopulations of T cells  T T H CD4  T T H 2 Tc CD  T H 1 T 0
    27. 27. B cells have: <ul><ul><li>MHC I (like all nucleated cells) & </li></ul></ul><ul><ul><li>MHC II proteins on their surfaces </li></ul></ul><ul><li>MHC proteins are members of the Ig superfamily that have Ag binding capabilities but are not nearly as specific as Ag binding by Ig or T cell antigen receptors </li></ul><ul><li>B cells function as APCs for induction of immune response </li></ul><ul><li>B cells have two different receptors for complement: </li></ul><ul><ul><li>CR1 (CD35) and </li></ul></ul><ul><ul><li>CR2 (CD21) </li></ul></ul><ul><li>that probably have regulatory functions </li></ul><ul><li>CR2 is the target for Epstein-Barr virus (EBV) binding </li></ul>MHC-I <ul><li>Resting B cells have: </li></ul><ul><ul><li>No Gall bodies </li></ul></ul><ul><ul><li>No LGL morphology </li></ul></ul><ul><ul><li>Monoribosomes scattered in </li></ul></ul><ul><ul><li>the cytoplasm </li></ul></ul><ul><li>Activated B cells have rough ER </li></ul>MHC-II MHC-I EBV
    28. 28. NK Cell <ul><li>Have LGL morphology </li></ul><ul><li>Contain larger number of azurophilic granules than granular T cells </li></ul><ul><li>Have no specific receptor for Ag recognition </li></ul><ul><li>Derived from lymphoid cell progenitors in the bone marrow </li></ul><ul><li>How can you distinguish NK from T & B? </li></ul><ul><li>No specific receptor </li></ul><ul><li>NK can lyse certain tumor cell lines </li></ul><ul><li>in vitro without prior sensitization </li></ul>
    29. 29. <ul><li>APCs are heterogenous leucocytes </li></ul><ul><li>They present Ags to T H or Tc cells </li></ul><ul><li>Ability to digest protein Ags is important </li></ul><ul><li>Present primarily in: </li></ul><ul><li>Skin </li></ul><ul><li>Spleen </li></ul><ul><li>Lymph nodes </li></ul>Antigen presenting cells
    30. 30. What cells can serve as APC? <ul><li>Langerhans’ cells (LC) </li></ul><ul><li>Dendritic cells </li></ul><ul><ul><li>Interdigitating dendritic cells (IDC) </li></ul></ul><ul><ul><li>Follicular dendritic cells (FDC) </li></ul></ul><ul><ul><li>Germinal center dendritic cells (GCDC) </li></ul></ul><ul><li>B cells </li></ul><ul><li>Macrophages </li></ul>
    31. 31. Lymphoid organs <ul><li>The lymphoid organs are those organs in which maturation , differentiation and proliferation of lymphocytes take place </li></ul><ul><li>The primary , or central , lymphoid organs are those in which T and B lymphocytes begin expressing their antigen receptors </li></ul><ul><li>The secondary lymphoid organs are those in which lymphocytes are induced to proliferate and differentiate by contact with antigen </li></ul>
    32. 32. Primary lymphoid organs <ul><li>Bone marrow in which B cells develop </li></ul><ul><li>Thymus , where T cells develop. Progenitor cells from the bone marrow migrate to the thymus gland to develop into T cells </li></ul><ul><ul><li>The thymus is a bilobed structure, whose size reaches its maximum at birth , then atrophies with age . </li></ul></ul><ul><ul><li>The cortex contains mostly immature thymocytes , some of which </li></ul></ul><ul><ul><ul><li>mature & migrate to the medulla , where they learn to discriminate between self and nonself during fetal development and for a short time after birth . </li></ul></ul></ul><ul><ul><li>T cells leave the medulla to enter the peripheral blood circulation , through which they are transported </li></ul></ul><ul><ul><li>to the secondary </li></ul></ul><ul><ul><li>lymphoid organs </li></ul></ul><ul><li>DiGeorge syndrome: </li></ul><ul><li>congenital absence of thymus </li></ul><ul><li>results in an immediate and </li></ul><ul><li>drastic reduction in T cells </li></ul><ul><li>that produces a potentially </li></ul><ul><li>lethal wasting disease </li></ul>
    33. 33. Secondary lymphoid organs <ul><li>The secondary lymphoid organs have two major functions: </li></ul><ul><ul><li>they trap and concentrate foreign substances, and </li></ul></ul><ul><ul><li>they are the main sites of production of antibodies and antigen-specific T cells </li></ul></ul><ul><li>The major secondary lymphoid organs include the </li></ul><ul><ul><li>Spleen , which is responsive to blood-borne antigens </li></ul></ul><ul><ul><li>Lymph nodes , which protect the body from antigens that come from skin or internal surfaces via the lymphatic system </li></ul></ul><ul><ul><li>Mucosa-associated lymphoid tissue (MALT) scattered along mucosal linings, which protects the body from antigens entering the body directly through mucosal surfaces </li></ul></ul>
    34. 34. Spleen <ul><li>Schematic representation of the spleen and a cross-section of the periarteriolar lymphoid sheath (PALS) </li></ul>
    35. 35. Lymph nodes <ul><li>Clusters of lymph nodes (ovoid structures usually less than 1 cm in diameter) are strategically placed in the neck , axillae , groin , mediastinum and abdominal cavity , where they act to filter antigens from the interstitial tissue fluid and the lymph during its passage from the periphery to the thoracic duct </li></ul><ul><li>Somatic nodes : Lymph nodes that protect the skin </li></ul><ul><li>Visceral nodes: Deep lymph nodes protecting the respiratory, digestive and genitourinary tracts </li></ul>
    36. 36. Mucosa-associated lymphoid tissue (MALT) <ul><li>The bulk of the body's lymphoid tissue (>50%) is found associated with the mucosal system. </li></ul><ul><li>MALT is composed of </li></ul><ul><ul><li>gut -associated lymphoid tissues ( GALT ) lining the intestinal tract, </li></ul></ul><ul><ul><li>bronchus -associated lymphoid tissue ( BALT ) lining the respiratory tract, </li></ul></ul><ul><ul><li>lymphoid tissue lining the genitourinary tract. </li></ul></ul><ul><li>The major effector mechanism at these sites is secretory IgA ( sIgA ) secreted directly onto the mucosal epithelial surfaces. Examples of MALT include </li></ul><ul><ul><li>the Peyer's patches lining the small intestine, </li></ul></ul><ul><ul><li>the tonsils and </li></ul></ul><ul><ul><li>the appendix . </li></ul></ul><ul><li>&quot;M&quot; cells ( because they have numerous m icrofolds on their luminal surface) </li></ul><ul><ul><li>absorb, </li></ul></ul><ul><ul><li>transport, </li></ul></ul><ul><ul><li>process and </li></ul></ul><ul><ul><li>present antigens to subepithelial lymphoid cells </li></ul></ul>