Basic Course of Immunology PDF

Basic Course of Immunology AlNeelain University Faculty of Science and Technology 4th class (Biochemistry, Microbiology, Biology) Dr. Atif S. M. Idrees Assistant Professor of Immunology & Immunotherapy Department of Biology Cells and...

Basic Course of Immunology AlNeelain University Faculty of Science and Technology 4th class (Biochemistry, Microbiology, Biology) Dr. Atif S. M. Idrees Assistant Professor of Immunology & Immunotherapy Department of Biology Cells and Organs of the Immune System  Cells and Organs of the Immune System Primary or central lymphoid organs bone marrow and thymus —regulate the development of immune cells from immature precursors. Secondary or peripheral lymphoid organs - including the spleen, lymph nodes, and specialized sites in the gut and other mucosal tissues. - trap antigen from defined tissues or vascular spaces and are sites where mature lymphocytes can interact effectively with that antigen. - “where adaptive immune responses are initiated”. These organs are connected by blood vessels and lymphatic systems. Immune System cells are derived from pluripotent hematopoietic stem cells in the bone marrow.  Hematopoiesis All blood cells arise from a type of cell called the he m ato p o i e ti c ste m c e l l ( H S C). T he y c an differentiate into other cell types; they are self- renewing. I n h um a ns, h e m a to p o i e si s, b e g i ns i n t h e embryonic yolk sac during the f ir st weeks of development. In the third month of gestation, HSCs migrate from the yolk sac to the fetal liver and then to the spleen; these two organs have major roles in hematopoiesis from the third to the seventh months of gestation. After that, the differentiation of HSCs in the bone marrow becomes the major factor in hematopoiesis, and by birth there is little or no  A hematopoietic stem cell is said to be a multipotent, or pluripotent o erythrocytes, o granulocytes, o monocytes, o mast cells, o lymphocytes, and o megakaryocytes. These stem cells are few, normally fewer than one HSC per 5 x104 cells in the bone marrow. Early in hematopoiesis, a multipotent stem cell differentiates along one of two pathways, giving rise to either a common lymphoid progenitor cell or a common myeloid progenitor cell. The types and amounts of growth factors in the microenvironment of a particular stem cell or progenitor cell control its differentiation. During the development of the lymphoid and myeloid lineages, stem cells differentiate into progenitor cells, which have lost the capacity for self-renewal and are committed to a particular cell lineage.  Stromal Cells & The Microenvironment In bone marrow, HSCs grow and mature on a m e s h w o r k o f s t ro m a l c e l l s , w h i c h a r e nonhematopoietic cells that support the growth and differentiation of HSCs. Stromal cells include fat cells, endothelial cells, fibroblasts, and macrophages. Stromal cells inf luence the differentiation of HSCs by providing a hematopoietic-inducing micro-environment (HIM) consisting of a cellular matrix and factors that promote growth and differentiation.  Many of these hematopoietic growth factors are soluble agents that arrive at their target cells by diffusion, others are membrane-bound molecules on the surface of stromal cells that require cell-to-cell contact between the responding cells and the stromal cells. During infection, hematopoiesis is stimulated by the production of hematopoietic growth factors by activated macrophages and T cells.  Hematopoiesis Is Regulated at the Genetic Level T he d ev e l op m e nt of p l uri p ote nt HS Cs i nto different cell types requires the expression of different sets of lineage-determining and lineage- specif ic genes at appropriate times and in the correct order. The proteins specif ied by these genes are critical components of regulatory networks that direct the differentiation of the stem cell and its descendants. Targeted disruption and other approaches have identif ie d a number of transcription factors that play important roles in hematopoiesis; GATA2: lym phoid, erythroid, and m yeloid lineages. Ikaros: cells of the lymphoid lineage.  Hematopoietic Homeostasis  Steady-state regulation of hematopoiesis is accomplished in various ways, which include:  Control of the levels and types of cytokines produced by bone-marrow stromal cells.  The produc tion of c ytokines with hematopoietic activity by other cell types, such as activated T cells and macrophages.  T he re g ul a t i o n o f t he e x p re ssi o n o f receptors for hematopoietically active cytokines in stem cells and progenitor cells.  The removal of some cells by the controlled induction of cell death.  Homeostatic Mechanism Programmed cell death, an induced and ordered process in which the cell actively participates in bringing about its own demise. Cells undergoing programmed cell death often exhibit distinc tive m orphologic c hanges, collectively referred to as apoptosis. These changes include; a pronounced decrease in cell volume, modif ic ation of the cytoskeleton results in membrane blebbing, a condensation of the chromatin, and d e g ra d a t i o n o f t he DN A i nto sm a l l e r fragments.  Following these morphologic changes, an apoptotic cell sheds tiny membrane-bounded apoptotic bodies containing intact organelles. Macrophages quickly phagocytose apoptotic bodies and cells in the advanced stages of apoptosis. This ensures that their intracellular contents, including proteolytic and other lytic enzymes, cationic proteins, and oxidizing molecules are not released into the surrounding tissue. In this way, apoptosis does not induce a local inf la mmatory response. Apoptosis differs m arked ly f rom nec rosis, the c hang es associated with cell death arising from injury. In necrosis the injured cell swells and bursts, releasing its contents and possibly triggering a damaging inflammatory response.  Leukocytes White blood cells that provide either innate or specif ic adaptive immunity. Myeloid Cells: First line of defense, non-specific innate immunity - Neutrophils - Eosinophils - Basophils/Mast cells - Monocytes/Macrophages/Dendritic Cells  Lymphoid Cells: o non-specific immunity - Natural Killer Cells o Humoral and Cell Mediated specific immunity - B Lymphocytes - T Lymphocytes (Helper and Cytolytic)  Of these cells, only the lymphocytes possess the attributes of diversity, specif ic ity, memory, and self/nonself recognition, the hallmarks of an adaptive immune response. All the other cells play accessory roles in a d a p t i v e i m m u n i t y, s e r v i n g t o a c t i v a t e lymphocytes, to increase the effectiveness of antigen clearance by phagocytosis, or to secrete various immune-effector molecules.  Neutrophils Neutrophils are produced in the bone marrow from myeloblast-type stem cells, and are often called polymorphonuclear cells (PMN's). It is main role is in inf lammation. They are the f irst cells to arrive at the site of inf lammation by leaving the blood vessels (extravasation). Attracted by chemotactic factors that include complement proteins, clotting proteins (stimulated by tissue damage) and T cell derived cytokines. In the tissues, neutrophils are active phagocytes. Eosinophil Granulocytes stain intensely with 'eosin’; bilobed nucleus. Contain basic crystal granules in cytoplasm, which mediate toxic reactions to large parasites. Involved in asthma. Eosinophil are motile, sometimes phagocytic, and are particularly active in parasitic infection. Basophil Found in low numbers in the blood. Act like mast cells. Involved in Type I hypersensitivity responses. Have high affinity Fc receptors for IgE on their surface. Cross-linking of the IgE causes the basophils t o re l e a se p h a rm a c o l o g i c a l l y a c t i v e mediators (histamine, prostaglandins, leukotrienes).  Mast Cells Formed in the tissue from undifferentiated bone marrow precursor cells released into the blood. Similar importance in allergic reactions to those of basophils, but are only found in tissues. Contain granules with preformed mediators to be released after stimulation (histamine, prostaglandins and leukotrienes). Stimulation of mast cells occurs by the anaphylatoxins (complement proteins C3a and C5a) or by cross-linking of surface immunoglobulin (IgE).  Cells of the Reticuloendothelial System The “phagocytic system” of the body, including f ix ed macrophages of tissues. Ce lls o f t he RE S p rov id e nat ural im m unit y ag ainst microorganisms. Phagocytosis and intracellular killing Cell Recruitment via cytokine production. Presentation of peptide antigens to lymphocytes (APCs). Cells of the RES include: - circulating monocytes, and - resident macrophages in the liver, spleen, lymph nodes, thymus, submucosal tissues of the respiratory and alimentary tracts, bone marrow, and connective tissues macrophage-like cells including dendritic cells in lymph nodes, Langerhans cells in skin, and glial cells in the central nervous system.  Monocytes/Macrophages Circulate in the blood after leaving the bone marrow. Survive only a day or so before they enter the tissue to mature into macrophages. Involved in phagocytosis and intracellular killing of microorganisms. Ge ne rati on of tox i c m e tab ol i te s throug h respiratory burst. Production of nitric oxide, hydrogen peroxide, superoxide anion. Monoc ytes/ Mac rop hag es are antig en processing and presenting cells.  Mac rop hag e - l i ke c e l l s se rv e d i f fe re nt functions in different tissues and are named according to their tissue location: o Alveolar macrophages in the lung o Histiocytes in connective tissues Kupffer cells in the liver Mesangial cells in the kidney o Microglial cells in the brain o Osteoclasts in bone  Macrophages When monocytes enter the tissues and become macrophages: Enlarge and increase production of intracellular lysozymes. Greater phagocytosis. Can live for years in tissue; highly motile. Activation of these cells occurs by phagocytosis of antigens, or in response to T cell derived cytokines.  Activated macrophages recognize and remove unwanted particulate matter including products of inf la mmation and invading organisms, antigens and toxins. After activation, these cells secrete cytokines, chemokines, lysosymes and other factors to upregulate immune response. I n c h r o n i c i n f la m m a t i o n , m a c r o p h a g e scavengers can become “giant cells” or “foamy macrophages”.  Dendritic Cells (DCs) Specialized phagocytic cells. Abundant at interfaces between the external and internal env ironm ents ( skin, lining of the gastrointestinal tract). Found in most tissues. Actively motile; continuously sample surroundings by endocytic processes. DCs are very efficient at activation of T cells. Fo ur typ e s o f d e nd ri ti c c e l l s are kno w n: Langerhans cells, interstitial dendritic cells, myeloid dendritic cells, and lymphoid dendritic cells.  The Follicular Dendritic Cell Does not arise in bone marrow. Do not express class II MHC molecules. Found in the lymph node follicles. Express high levels of membrane receptors for antibody, which allows the binding of antigen- antibody complexes. The interaction of B cells with this bound antigen can have important effects on B cell responses.  Lymphoid Leukocytes B cells, T cells, and natural killer cells B and T lymphocytes that have not interacted with antigen— referred to as naive, or unprimed—are resting cells in the G0 phase of the cell cycle and have a short life span. Interaction with antigen, in the presence of certain cytokines, induces cells to enter the cell cycle by progressing from G0 into G1 and subsequently into S, G2, and M. As they p rog re ss throug h the c e l l c yc l e , lymphocytes enlarge into blast cells, called lymphoblasts; these cells have a higher cytoplasm: nucleus ratio and more organellar complexity than small lymphocytes.  Lymphoblasts proliferate and eventually differentiate into effector cells or into memory cells. Effector cells function in various ways to eliminate antigen. These cells have short life spans, generally ranging from a few days to a few weeks.  Natural Killer (NK) Cells Representing an innate population that kill viral infected or tumor target cells. constitute 5%–10% of lymphocytes. do not express the membrane molecules and receptors that distinguish T- and B-cell lineages. Target recognition occurs by: Killer Inhibitory Receptor, KIR, recognizes reduction in the display of class I MHC molecules and the unusual antigens displayed by some tumor cells and cells infected by some viruses. C D 1 6 ( l o w - a f fin i t y Fc ϒ I I I ) re c o g n i z e s membrane- bound immune-complex (ADDC). B Lymphocytes Develop from stem cells in the bone marrow. Produce antibodies with specif ic ity for antigens. Plasma cells = Activated B cells. Upon activation, a B cell can switch to produce a different class of antibody, with the same antigen specificity. Activation of B Lymphocytes Activation into antibody secreting cells is antigen-dependent. Antigen binding to surfac e I g m olec ules triggers differentiation into plasma cells. B cells are the most ef ficient presenting cell in the body. Interaction with T cell secreted factors triggers isotype (class) switching.  Cluster Of Differentiation (CD) Unique cell surface molecules. Molecules given number designations. The acronym CD describes the cluster of unique determinant; the number describes the order in which it was discovered. CD-specif ic markers (antibodies) have been useful for: - Determining the functions of CD proteins. - Identifying the distribution of CD proteins in d i f fe re nt c e l l p op ul ati ons i n norm al individuals. - Surface Molecules of B Lymphocytes. Surface Molecules of B Lymphocytes Ig H+L, B cell receptor for antigen. Ig , signal transduction molecules. H L A - D, c l a s s I I r e s t r i c t e d m a j o r histocompatibility marker. CR21 and CD35, complement receptors. CD19, B-cell co-receptor subunit. CD20, CD5, signal transduction molecules. CD40, co-stimulatory. CD5, co-stimulator-activator. CD32, Fc RII. CD45, leukocyte common antigen.  T Lymphocytes T lymphocytes regulate immune responses. Integral in cell mediated immunity. Critical in B cell-antibody production. Mature T cells display either CD4 or CD8. Develop in the thymus. Cells with a CD4 marker are called helper T cells (Th cells). CD8 marker positive cells are cytotoxic T cells (Tc cells). Each T cell has a TCR to recognize antigen: a transmembrane heterodimer composed of two polypeptide chains.  Surface Molecules of T Lymphocytes TCR, T cell receptor. CD3, TCR signaling complex. Thy-1, mouse T cell marker. CD45RO, Leukocyte common antigen for memory T cells. CD45RA, Leukocyte common antigen for naive T cells. CD2, LFA-3 adhesion molecule. CD28, co-stimulatory molecule that binds B7. CD5 co-stimulatory molecule. CD7, signal transduction.  T Helper Cells (Th) All express the CD4 molecule. Aid effector T lymphocytes in cell-mediated immunity. Aid antigen-stimulated subsets of B cells to proliferate and differentiate toward antibody- producing cells. Regulatory role for tolerization events.  T Cytotoxic Cells (CTLs) T cytotoxic cells are cytotoxic against tumor cells and host cells infected with intracellular pathogens. These cells express CD8. T Suppressor/Regulatory Cells T suppressor cells suppress the T and B cell responses. Misconception: Commonly thought these cells were a subpopulation of CD8+ cytotoxic cells. - R e c e n t d a t a s u g g e s t s t h e s e a re a s u b - population of T helper cells (CD4 + CD25 + ; Foxp3+). - Serve as regulators of T cell responses.  Natural Killer T Cells (NK1-T) Has characteristics of both T cells and NK cells. Like T cells, NK1-T cells have T cell receptors (TCRs). The TCRs of NK1-T cells interact with MHC-like molecules called CD1 rather than with MHCI or MHCII. Like NK cells, they have variable levels of CD16 and other receptors typical of NK cells, and they can kill cells. Triggered NK1-T cells rapidly secrete large amounts of the cytokines to support Abs production by B cells as well as inf lammation and the development and expansion of cytotoxic T cells. Antigen Presenting Cells APCs are found primarily in the skin, lymph nodes, spleen and thymus. Their main role is present antigens to antigen sensitive lymphocytes. APCs are classif ied according to their ability to phagocytose antigens, location in the body, and expression of MHC related molecules. Critical Molecules in Antigen Presentation LFA-3/LFA-1, adhesion molecules. CD28, co-stimulatory molecule that bind B7 -1 or B7-2. ICAM, intracellular adhesion molecule 1 (needed for migration). Cl ass I and I I MH C m o l e c ul e s ( Maj o r HistoCompatability). Organs of immune System  Primary (Central) Lymphoid Organs: - Foetal Liver - Adult Bone Marrow - Thymus Gland  Immature lymphocytes generated in h e m a t o p o i e s i s m a t u re a n d b e c o m e c o m m i t t e d to a p a r t i c ul a r a nt i g e ni c specif ic ity within the primary lymphoid organs.  Only after a lymphocyte has matured within a primary lymphoid organ is the cell immunocompetent (capable of mounting an immune re- sponse).  Secondary Lymphoid Organs: - Spleen - Lymph Nodes - Tonsils - Appendix - Peyer’s patches - Aggregates of cells in lamina propria (GALT, BALT, MALT). Thymus  Both the cortex and medulla of the thymus are criss- crossed by a three-dimensional stromal- cell network composed of epithelial cells, dendritic cells, and macrophages, which make up the framework of the organ and contribute to the growth and maturation of thymocytes. Many of these stromal cells interact physically with the developing thymocytes. Some thymic epithelial cells in the outer cortex, c al l e d nurse c e l l s, hav e l o ng m e m b rane e x te nsi o ns that surro und as m any as 5 0 t hym o c yt e s, f o rm i ng l arg e m ul t i c e l l ul ar complexes.  The function of the thymus is to generate and select a repertoire of T cells that will protect the body from infection. More than 95% of all thymocytes die by apoptosis in the thymus without ever reaching maturity. T hym oc ytes are educ ated to b ec om e T lymphocytes. Expression of specific receptors. T cells learn to recognize self as self. Secondary : Spleen  The spleen is a filter for blood. White pulp = lymphoid tissue. Red pulp = splenic cord and sinuses (RBCs). The white pulp contains the lymphoid tissue, arranged around a central arteriole as a periarteriolar lymphoid sheath (PALS). PALS c om p ose d of a Ge rm i nal Ce nte r surrounded by a Mantle and Marginal Zones.  Central Artery Periarterial Lymphatic Sheath Follicle/Germinal Center Mantle Zone (B cells) Marginal Zone (B and T cells) The lymph nodes  The Role of Lymphatic Te r m i n a l Ly m p h a t i c s a re b l i n d - e n d e d , endothelium-lined tubes present in most tissues in similar numbers to capillaries. Lymphatics drain into collecting Lymph Nodes. In acute inf lammation, the lymphatic channels b e c o m e d i l a t e d a n d d r a i n a w a y f lu i d (inflammatory exudate); this limits the extent of tissue edema. Antigens are carried to the regional lymph nodes for processing by APCs and further recognition by lymphocytes. Lymphoid Tissue  Remember: MALT, GALT, BALT(aggregates of cells in the lamina propria of musoca-, gut- bronchus). Peyer’s Patch M Cells Thank you