MACROPHAGE "MONOCYTES" SURFACE RECEPTORS

Transcription

1 LECTURE: 13 Title: MACROPHAGE "MONOCYTES" SURFACE RECEPTORS LEARNING OBJECTIVES: The student should be able to: Describe the blood monocytes (size, and shape of nucleus). Enumerate some of the monocytes lysosomes (e.g., perodiase, and acid hydrolases). Define the two main functions of the mononuclear phagocytic cells: 1. Professional phagocytic macrophage. 2. Antigen-presenting cells (APCs), give examples. Describe how the monocyte adheres to, and ingest the pathogens. Enumerate some of the monocyte/ macrophage major cell surface receptors. - Mannosyl-Fucosyl receptors MFR (binds to sugars on pathogens, and aged cells). - Phosphatidyl serine receptors (binds to apoptotic cells). - Lipopolysaccharide binding proteins (LBP), also called CD14. - IgG receptors: 1. High affinity FcγRI (CD64). 2. Medium affinity FcγRII (CD32). 3. Low affinity FcγRIII (CD16). - Complement receptors 1. CR1 (C3b receptor, CD35). 2. CR3 (CD11b, MAC-1, fir C3bi, involved in adhesion and activation) in active macrophages. 3. CR4 (CD11c p150, 95 ) in active macrophages. - Major histocompatibility MHC II molecules. - Low affinity receptor for IgE Fc εrii (CD23) in active macrophages. - B7 (on macrophage) binds to CD28 (on Th lymphocytes) for co-stimulatory signals. LECTURE REFRENCE: 1. TEXTBOOK: ROITT, BROSTOFF, MALE IMMUNOLOGY. 6 th edition. Chapter 2. pp. 3, 6, 15-17, 106,

2 MACROPHAGE "MONOCYTES" SURFACE RECEPTORS INTRODUCTION All haemopoietic cells are derived from pluripotent stem cells which give rise to two main lineages; one for lymphoid cells and the other for myeloid cells. The common lymphoid progenitor has the capacity to differentiate into either T cells or B cells depending on the microenvironment to which it homes. In mammals, T cells develop in the thymus while B cells develop in the fetal liver and bone marrow. The precise origin of some antigen presenting cells (APC) is uncertain, although they do develop ultimately from the haemopoietic stem cells. NK cells also derive form the common lymphoid progenitor cell. The myeloid cells differentiate into the collective mane granulocytes is used for eosinophils, neutrophils, and basophils. Myeloid lineage produces as well monocytes, and macrophages. The phagocytes are of two basic kinds; monocytes/macrophages and polymophonuclear granulocytes. The latter have a distinctive lobed, irregularly shaped (polymorphic) nucleus. They divided into neutrophils, basophils, and eosinophils, the basis of how the cytoplasmic granules respond to different dyes. The three cells each have different distinct function. The most numerous are the neutrophils, also called PMNs (polymophonuclear neutrophils), which constitute the majority of leukocytes in the blood stream. The myeloid progenitor cells in the bone marrow differentiate into promonocytes and then into blood monocytes. These cells migrate into the various organs and tissues to become macrophages. The human blood monocytes are large (10-18 μm in diameter) relative to the lymphocyte. It is usually has a horseshoeshape nucleus and often contains faint azurophilic granules. It has ruffled membranes. a well-developed Golgi complex and many intracytoplasmic lysosomes. These lysosomes contain peroxidase and several acid hydrolase which are important in killing of micro-organisms. Adherence and ingestion by monocytes occurs when the cells bind the microorganism through specialized receptors. The receptors may bind to certain carbohydrates of the microbial cell wall or to IgG and complement with which the microorganism has become coated. Mononuclear phagocytes are derived from the myeloid lineage, and have two main functions, performed by two different types of bone-marrow derived cells The network of phagocytic tissue macrophages, together with endothelial cells and polymorphs, was previously termed the reticuloendothelial system (RES). The mononuclear phagocyte system has two main functions, performed by two different types of bone-marrow derived cells: A. Professional phagocytic macrophages, whose predominant role to remove particular antigen. B. Antigen-presenting cells (APC), whose role is to take up, process and present antigen to T cells. These phagocytic tissues macrophages are found in many organs such as: Some examples of phagocytic cells are; - Circulating blood monocytes - Kupffer cells in liver - Intraglomerular measngium of the kidney - Alveolar macrophages in lung - Brain microglia - Spleen sinus macrophages - Lymph node sinus macrophages PHAGOCYTIC MACROPHAGES 2

3 Myeloid progenitor cells in the bone marrow differentiate into promonocytes and then into blood monocytes (larger than lymphocytes μm in diameter, has a horseshoe-shaped nucleus, and faint azurophilic granules. Ultrastructurally, the monocyte possesses ruffled membrane, a well-developed Golgi complex). Cells from this circulating pool migrate through the blood vessel walls into the various organs and tissue system to become phagocytic macrophages such as: 1. Liver, where the phagocytic cells are called Kupffer cells. 2. Kidney, where they are called intraglomerular Mesangial cell. 3. Lung, where phagocytic cells are called alveolar macrophages. 4. Brain, where the phagocytic cells are called microgial cells. 5. Lymph node sinus macrophages. 6. Circulating blood macrophages are called monocytes. A. Alveolar and serosal (e.g., peritoneal) macrophages are example of wandering macrophages. B. Brain microglia is cells which enter the brain around the time of birth and differentiate into fixed cells. Both monocytes and macrophages enhance their binding to the pathogens through specialized receptors. The receptors may bind the microbe carbohydrates on the microbial cell wall or to IgG and complement protein (e.g., C3b) which coat (opsonization) the microbe cell wall. Human and murine monocyte / macrophages: 1. Mannosyl-fucosyl receptors (MER) which bind to the sugars on the surface of microorganisms and of effete body cells (aged lymphocytes). 2. Phosphatidyl serine receptors (PSR), they remove the apoptotic cells. 3. CD14, a receptor for Lipopolysaccharide-binding protein (LBP) which is normally present in serum and which coats Gram-negative bacteria. 4. Three distinct Fc receptors: a. FcγRI (CD64) on human cells has a high affinity for IgG. b. FcγRII (CD32) is of medium affinity. c. FcγRIII (CD16) is of low affinity. Fc receptors probably have different functions A. Triggering of extracellular killing. B. Opsonization. C. Phagocytosis. 5. Complement receptor 1 (CR1, CD35, C3b receptor). 6. Molecules involved mainly in adhesion and activation include : A. Complement receptor 3 (C3bi receptors, CD11b, MAC-1), present especially on activated macrophages. B. Leukocyte function antigen LFA-1 (CD11a). C. p150, 95 (CD11c). Both CD11b and CD11c are found in intracytoplasmic vesicles of macrophages and are rapidly expressed following activation. 7. Class II MHC antigen is present on some monocytes / macrophages and is important in presentation of antigens to T cells. 8. A low affinity receptor for the Fc of IgE (FcεRII; CD23) is also present on activated macrophages. Molecules found on human macrophages include: 3

4 I. CD13, CD15, CD68 and VLA-4 (CD29/CD49d) II. The IL-2, IL-4, IFN-γ, and migration inhibition factor. The functions of monocytes and macrophages can therefore be enhanced by T-cell derived cytokines through these receptors (markers). Such activated monocytes / macrophages also generate cytokines them selves including IFNs, IL-1, and TNFα. Complement components and prostaglandins are also produced. NONE OF THE ABOVE MENTIONED MARKERS ARE LINEAGE SPECIFIC, ALTHOUGH FcγR IS A PARTICULARLY USEFUL MARKER. ANTIGEN-PRESENTING CELLS APCs are a heterogeneous population of leukocytes with exquisite immunostimulatory capacity. Cells other than leukocytes, such as endothelial or epithelial cells, can also acquire the ability to present antigens when stimulated by cytokines. These presenting cells are primarily found in the skin, lymph node, spleen, and thymus. They are rich in class II MHC molecules, which are important for presenting antigen to T helper cells. Follicular dendritic cells are specialized APC are found in the secondary follicles of the B cell areas of the lymph nodes and spleen. They present antigen to B cells and lack class II MHC molecules, but insted express high levels of Fcγ R and the complement receptors CR1 (CD35) and CR2 (CD21) for interaction with immune complex. APCs have actions on several different targets such as: A. Some APCs have pivotal role in the induction of functional activity of TH cells. B. Other APCs communicate with other leukocytes. The main APCs are: 1. Langerhans cells in the skin. These cells migrate as veiled cells via the afferent lymphatics into the lymph node paracortex of the draining lymph nodes. Within the paracortex the cells interdigitate with many T cells. This migration provides an efficient mechanism for carrying antigen from the skin to the TH cells located in the lymph nodes. 2. Follicular dendritic cells are found in the secondary follicles of the B cell areas of the lymph nodes and spleen. They present antigen to B cells and lack class II MHC molecules, but instead express high levels of FcγR and the complement receptors CR1 (CD35) and CR2 (CD21) for interaction with immune complexes. 3. Interdigitating cells in the thymus are especially abundant in the medulla. They are rich in self antigens, including class II MHC antigens. The thymus is of crucial importance in the development and maturation of T cells, and it appears that the interdigitating cells play a role in deleting T cells that react against self antigens (negative selection). 4. B lymphocyte is APCs which is rich in class II MHC molecules (especially after activation) and are thus able to process and present antigen, especially when the B cell is specific for the antigen being presented. 5. Somatic cells other than immune cells do not normally express class II MHC molecules, but cytokines such as IFNγ and TNFα can induce these molecules on some cell types and thus allow them to present antigen. This induction of inappropriate class II MHC molecules expression might contribute to the pathogenesis of autoimmune diseases and to prolonged inflammation. Phagocytes can be monocytes, macrophages, or polymorphonuclear granulocyte 4

5 The phagocytic cells can be of two types: A. Monocytes/ Macrophages. B. Polymorphonuclear granulocytes (PMNs). These cells have lobed, irregular shaped (polymorphic) nucleus. On the basis of how their cytoplasmic granules react with several types of staining agents, these cells can be divided into neutrophils, basophils, and eosinophils. The most numerous immune white cells in the blood stream are the neutrophils also called (PMN) Accessory cells In addition to lymphocytes and phagocytes there are some other cells are also involved in the immune system, these are: A. Antigen presenting cells (APCs) Expose antigen to T cells. B. Platelets are involved in blood clotting and inflammation. C. Mast cells have structural and functional similarities to basophil polymorphs. D. Endothelial cells express surface molecules capable of recognizing certain lymphocytes but not others, and then control lymphocytes traffic and distribution. Dr. Mustafa Hasan Linjawi 5