Cells and Organs of the Immune System Lecture 3 PDF

Cells and organs of the immune system Zahraa A Mohammed 2024 Lecture 3(undergraduate) ( Hematipoiesis The blood cells are derived from the stem cells in the bone marrow in a process termed as Haematopoiesis. Hematopoietic stem cell (HSC) differ...

Cells and organs of the immune system Zahraa A Mohammed 2024 Lecture 3(undergraduate) ( Hematipoiesis The blood cells are derived from the stem cells in the bone marrow in a process termed as Haematopoiesis. Hematopoietic stem cell (HSC) differentiates and gives rise to all red and white blood cell types therefore it is also referred to as pluripotent stem cell. These stem cells are self- renewing but their study is difficult due to struggle in- vitro culture and their scarcity (one HSC per 5 × 104 cells in bone marrow.  The process starts with the differentiation of pluripotent HSC to the lymphoid and myeloid progenitor cells. Progenitor cells are committed to develop into specific cell lineages and have lost the property of self-renewal.. In brief, lymphoid lineage differentiates into three types of cells namely B lymphocytes, T lymphocytes (commonly referred to as B and T cells) and natural killer (NK) cells. NK cells are innate immune cells. Myeloid lineage mostly gives rise to cells of the innate immunity like macrophages, granulocytes (neutrophils, eosinophils, basophils), dendritic cells and mast cells.  Erythrocytes and platelets are also formed from erythroid progenitor and megakaryocyte (myeloid progenitor lineage) but they are of no concern in immunity. The lineage of cells differentiating into either lymphoid or myeloid stem cells is determined by the Type and amount of cytokines which are required for proliferation,differentiation and maturation of different blood cell types as well as renewal of HSC. Among these cytokines known to be involved in haematopoiesis are stem-cell factors (SCFs) and erythropoietin (EPO). Haematopoiesis is a genetically regulated process, specific genes and transcription factors control the differentiation of specific lineages. Some of the major transcription factors are as follows:  GATA-2: Transcription factor GATA-2 (GATA-2 gene) influences multiple lineages. It is necessary for the formation of myeloid, erythroid and lymphoid lineages. GATA-1: it regulates only erythroid lineage i.e., development of red blood cells. Ikaros: it regulates only lymphoid lineage i.e., B and T cells and NK cells Cells of the immune system The immune system is composed of many interdependent cell types that collectively protect the body from microbial infections and the growth of tumor cells. The cells of the immune system can engulf bacteria, kill parasites or tumor cells, and destroy viral-infected cells. The only cells that are capable of specifically recognizing and eliciting specific immune responses are lymphocytes. The other types of white blood cells play an important role in nonspecific immune response, antigen presentation and cytokine production. Lymphoid Lineage CeLLs Lymphocytes (B and T cells) are differentiated from lymphoid progenitor mainly in bone marrow in mammals but maturation takes place at different sites. Natural killer (NK) cells are also produced in lymphoid lineage. B-lymphocytes The development and maturation of B cells take place in the bone marrow of long bones in most adult mammals and prenatally in the foetal liver. In birds, the site of B cell maturation is the bursa of fabricius. B lymphocytes are the major cells of adaptive immunity responsible for antibody (immunoglobulins Ig) production against antigens (pathogens). Mature B cells display of membrane-bound immunoglobulin (antibody) molecules, which serve as receptor for Ag (BCR). The binding of the Ag to the Ab causes the cell to divide rapidly; its progeny differentiate into : 1. Effector cells called Plasma cells ,which produce the Ab in a form that can be secreted and have little or no membrane-bound Ab. They are end- stage cells and do not divide. 2.Memory B cells, which have a longer life span than naïve cells, and they express the same membrane-bound Ab as their parent B cell.  T lymphocytes are also derived from a lymphoid progenitor in bone marrow but unlike B cells, lymphoblasts committed to differentiate into T cells migrate to a bilobed organ thymus for maturation. Immature T lymphocytes in the thymus are known as thymocytes. During the maturation, these thymocytes first develop receptors on their cell surface known as T cell receptors (TCR) and then undergo thymic selection. These T cells are then positively selected (chosen) for self-MHC recognition and negatively selected (deleted) for receptors that are reactive to other self- antigens. This means that thymocyte are unable to recognize self MHC or that do have a high affinity for self-antigen bound on self-MHC are eliminated by apoptosis. T cells cannot recognize antigen alone rather they recognize antigen complexed with MHC molecules presented by an APC. Along with TCR, certain markers are also present on T cell surface that differentiate them into three subtypes:  T helper cells express CD4 (Cluster of differentiation) marker and can only recognize antigens complexed with MHC II molecules expressed on the surface of APCs. The main function is to augment immune response by the secretion of cytokines that activate the other cells of immune system to fight infection. T cytotoxic cells have increased number of cytoplasmic granules whose contents include the protein perforin that lyses the target cells and are important in directly killing certain tumor cells, viral- infected cells and sometimes parasites. This type of cells express CD8 membrane glycoproteins on their surfaces.  The ratio of T H to T C is about 2:1 in normal human peripheral blood, but it may be significantly altered by immunodeficiency diseases, autoimmune diseases, and other disorders. Treg cells: Regulatory T cells have CD4 and CD25 markers. Their exact role is not well understood. But they are involved in regulating immune responses and tolerance Natural killer cells They are large granular cells capable of killing target cells which constitute 5%–10% of lymphocytes in human peripheral blood.These are derived from a common lymphoid progenitor but unlike lymphocytes, NK cells don’t possess antigen-specific receptors. These cells are best known for control-ling tumors and viral infections as a first line of defense. They can kill cells without any activation naturally hence named so. But they possess activation and inhibition receptors on their surface that recognize altered host cells (cancerous or virus infected). Further, they also secrete cytokines (IFN-γ and TNF-α) that activate dendritic cells and macrophages to come into play. NK cells differentiate between tumor, or virus-infected cells, and normal cells in two main ways. One involves KIR and the other involves Fc receptors (CD16) present on the cell surface  The infection of cells by some viruses (such as Herpesvirus) or tumor cells reduces the expression of class I MHC molecules on the cell surface. the KIR receptor cannot bind class I MHC molecules. Moreover, the absence of class I molecules activates the receptor NKG2D to induce the killing of the infected cells by the NK cells NK cells are also able to kill target cells coated with lgG antibodies via their receptors for IgG (FcγRIII; CD16). NK cells attach to the Fc region of antibodies bound on the virus- infected or tumour cells and subsequently lyse the target cells by degranulation. This property is referred to as antibody-dependent cellular cytotoxicity (ADCC) NK cell (KIR) Normal cell (MHC I) No lysis  NK cell (KIR) virus-infected or tumor lysis Myloid lineage Mononuclear Phagocytes The mononuclear phagocytic system consists of monocytes circulating in the blood and macrophages in the tissues. * Phagocytosis of particulate antigens serves as an initial activating stimulus. * macrophage activity can be further enhanced by cytokines secreted by activated TH cells, by mediators of the inflammatory response, and by components of bacterial cell walls. * One of the most potent activators of macrophages is interferon gamma(IFN-γ) secreted by activated TH cells. Activated macrophages also express higher levels of class II MHC molecules, allowing them to function more effectively as antigen-presenting cells. Thus, macrophages and TH cells facilitate each other’s activation during the immune response. activated macrophages secrete: 1. a collection of cytokines, such as interleukin 1 (IL-1), TNF-α and interleukin 6 (IL-6), that promote inflammatory responses. 2. Complement proteins. 3. The hydrolytic enzymes contained within the lysosomes of macrophages. 4. TNF-α, that can kill a variety of cells. Macrophages are dispersed throughout the body. Some take up residence in particular tissues, becoming fixed macrophages, whereas others remain motile and are called free, or wandering, macrophages. Free macrophages travel by amoeboid movement throughout the tissues. Macrophage-like cells serve different functions in different tissues and are named according to their tissue location: 1. Alveolar macrophages in the lung. 2. Histiocytes in connective tissues. 3. Kupffer cells in the liver. 4. Mesangial cells in the kidney. 5. Microglial cells in the brain. 6. Osteoclasts in bone. myeLoid Lineage Neutrophils are usually the first cells to migrate and arrive at the site of infection. They have multilobed nucleus (polymorphonuclear leukocytes(PMN) and specialize in phagocytosis of pathogens like bacteria and fungi. Both acid and basic dyes can be used for staining of neutrophils. In response to many types of infections, the bone marrow releases more than the usual number of neutrophils and these cells generally are the first to arrive at a site of inflammation. The resulting transient increase in the number of circulating neutrophils, called leukocytosis, is used medically as an indication of infection. Movement of circulating neutrophils into tissues, called extravasation, takes several steps: 1. the cell first adheres to the vascular endothelium. 2. then penetrates the gap between adjacent endothelial cells lining the vessel wall. 3. and finally penetrates the vascular basement membrane, moving out into the tissue spaces. A number of substances generated in an inflammatory reaction serve as chemotactic factors that promote accumulation of neutrophils at an inflammatory site. As for example complement components. Like macrophages, neutrophils are active phagocytic cells. Phagocytosis by neutrophils is similar to that described for macrophages, except that the lytic enzymes and bactericidal substances in neutrophils are contained within primary and secondary granules. Neutrophils are in fact much more likely than macrophages to kill ingested microorganisms. Neutrophils exhibit a larger respiratory burst than macrophages and consequently are able to generate more reactive oxygen intermediates and reactive nitrogen intermediates. Eosinophils. These cells comprise about 5 per cent of the total leukocyte population. Eosinophils have bilobed nuclei and many cytoplasmic granules that stain red with acid dye. Eosinophils are motile,weak phagocytes that migrate from the blood into the tissue spaces. Their phagocytic role is less important than that of neutrophils. Eosinophils are often produced in very large numbers in persons with parasitic infections such as schistosomiasis. Basophils are nonphagocytic granulocytes that express high affinity receptors for IgE antibodies and function by releasing pharmacologically active substances from their cytoplasmic granules. These substances play a principal role in certain allergic reactions and some delayed hypersensitivity states. Mast-cell Mast-cell precursors, which are formed in the bone marrow by hematopoiesis are released into the blood as undifferentiated cells; they do not differentiate until they leave the blood and enter the tissues. It plays an important role in the development of allergies. Dendritic cell (DC) acquired its name because it is covered with - long membrane extensions. There are many types of dendritic cells, although most mature dendritic cells have the same major function, the presentation of antigen to TH cells. Four types of dendritic cells are known: 1. Langerhans cells. 2.Interstitial dendritic cells. 3. Myeloid cells. 4. Lymphoid dendritic cells. Each arises from hematopoietic stem cells via different pathways and in different locations. They all constitutively express high levels of both class II MHC molecules and members of the co-stimulatory B7 family. For this reason, they are more potent antigen- presenting cells than macrophages and B cells, both of which need to be activated before they can function as antigen-presenting cells (APCs). Another type of dendritic cell, the follicular dendritic cell, does not arise in bone marrow and has a different function from the antigen-presenting dendritic cells. Follicular dendritic cells do not express class II MHC molecules and therefore do not function as APCs for TH-cell activation. It express high levels of membrane receptors for antibody, which allows the binding of Ag-Ab complexes. The interaction of B cells with this bound antigen can have important effects on B cell responses. Organ of the immune system Organs of the Immune System These can be distinguished by function as the primary and secondary lymphoid organs. * The thymus and bone marrow are the primary (or central) lymphoid organs, where maturation of lymphocytes takes place. * The lymph nodes, spleen, and various mucosal associated lymphoid tissues (MALT) such as gut-associated lymphoid tissue (GALT) are the secondary (or peripheral) lymphoid organs, which trap antigen and provide sites for mature lymphocytes to interact with that antigen. * In addition, tertiary lymphoid tissues, which normally contain fewer lymphoid cells than secondary lymphoid organs, can import lymphoid cells during an inflammatory response. Most prominent of these are cutaneous - associated lymphoid tissues (CALT). Once mature lymphocytes have been generated in the primary lymphoid organs, they circulate in the blood and lymphatic system (a network of vessels that collect fluid that has escaped into the tissues from capillaries of the circulatory system and ultimately return it to the blood). The human lymphoid system. Adenoids Tonsil Thymus Lymph nodes Spleen Payer's patches Bone marrow Tissue lymphatics