Immunology Lecture two | Includes autoimmune

Immunology Lecture two | Includes autoimmune

1. Immune System Cells And organs Lecture #2 G.Shengelidze M.D

2. Phagocytes Phagocytes, including neutrophils and macrophages, are cells whose primary function is to ingest and destroy microbes and remove damaged tissues Recruitment of the cells to the sites of infection Recognition of and activation by microbes Ingestion of the microbes by the process of phagocytosis Destruction of ingested microbes Through direct contact and by secreting cytokines , phagocytes communicate with other cells in ways that promote or regulate immune responses

3. Distinguishing Properties of Neutrophils and Macrophages

4. Neutrophils • Circulating phagocytes • Short lived • Rapid response, not prolonged defense Monocytes/Macrophages • Monocytes circulate in the blood, become macrophages in the tissues • Provide a prolonged defense • Produce cytokines that initiate and regulate inflammation • Phagocytose pathogens • Clear dead tissue and initiate tissue repair • Macophages will develop along one of 2 different pathways

5. Neutrophils Neutrophils are the most abundant population of circulating white blood cells and the principal cell type in acute inflammatory reactions Production of neutrophils is stimulated by: Granulocyte colony-stimulating factor (G-CSF) Granulocyte-macrophage colony-stimulating factor (GM-CSF) Neutrophils may migrate to sites of infection rapidly after the entry of microbes. After entering tissues, neutrophils function for only 1 to 2 days and most of them then die. The cytoplasm contains two types of membrane-bound granules: Specific granules, are filled with enzymes, such as lysozyme, collagenase, and elastase Azurophilic contain enzymes (e.g., myeloperoxidase) and microbicidal substances, including defensins and cathelicidins

6. Function of neutrophils is to phagocytose microbes: Especially opsonized microbes Products of necrotic cells In addition, neutrophils may secrete granule contents and also extrude their nuclear contents, forming neutrophil extracellular traps (NETs), which serve to immobilize and kill extracellular microbes but also may damage healthy tissues .

7. Mononuclear Phagocytes The mononuclear phagocyte system includes circulating bone marrow–derived cells called monocytes , many of which become macrophages when they migrate into tissues, and tissue-resident macrophages, which are initially derived from yolk sac or hematopoietic precursors during fetal life.

8. Development of Macrophages and Monocytes After birth , cells of the monocyte-macrophage lineage arise from committed precursor cells in the bone marrow, driven by a cytokine called monocyte (or macrophage) colony-stimulating factor (MCSF). These precursors mature into monocytes, which enter and circulate in the blood where they have a short life span of approximately 1 to 7 days. Most macrophages at sites of inflammation are monocyte-derived Most long-lived tissue-resident macrophages are derived not from the bone marrow but from yolk sac or fetal liver precursors during fetal development. These cells have self-renewal capacity , so they can maintain stable numbers.

9. Monocytes are 10 to 15 μ m in diameter, and they have bean-shaped nuclei and finely granular cytoplasm containing lysosomes, phagocytic vacuoles, and cytoskeletal filaments. All human monocytes express class II major histocompatibility complex (MHC) molecules

10. Macrophage polarization Classical activation ------ Alternative activation

11. Macrophage functions

12. Macrophages promote the repair of damaged tissues by stimulating new blood vessel growth (angiogenesis) and synthesis of collagen-rich extracellular matrix (fibrosis, thickening or scarring of the tissue). These functions are mediated by cytokines secreted by the macrophages that act on various tissue cells.

13. Neutrophil Mast cell Basophil Eosinophil Granulocytes

14. Dendritic Cells (DCs) DCs are tissue-resident and circulating cells that detect the presence of microbes and initiate innate immune defense reactions, and they capture microbial proteins for display to T cells to initiate adaptive immune responses . Subsets of DCs can be defined on the basis of different cell surface markers, transcription factors, development from different precursor cells, tissue localization, and functions.

15. Classical DCs (also called conventional DCs [ cDCs ]) are the major type of DC involved in capturing protein antigens of microbes that enter through epithelial barriers and presenting them to T cells. Plasmacytoid DCs ( pDCs ) produce the antiviral cytokine type I interferon (IFN) in response to viruses and may capture blood borne microbes and carry their antigens to the spleen for presentation to T cells. Monocyte-derived DCs ( MoDCs ) include cells with functions similar to those of cDCs but are derived from monocytes that were recruited into tissue inflammatory sites. Langerhans cells are DCs found in the epidermis that share functions with cDCs but are developmentally related to tissue-resident macrophages, arising from embryonic fetal liver and yolk sac precursors. Dendritic Cell Subsets

16. Another population of cells called follicular dendritic cells (FDCs) have a dendritic morphology but are not derived from bone marrow precursors, do not present protein antigens to T cells , and should not be confused with DCs. FDCs are involved in B cell activation in the germinal centers of secondary lymphoid organs.

17. Maturation of lymphocytes

18. life of lymphocytes Naive lymphocytes typically live for 1 to 3 months. Their survival requires signals from antigen receptors and cytokines.

19. ANTIGEN RECOGNITION MOLECULES OF LYMPHOCYTES Each cell of the lymphoid lineage is clinically identified by the characteristic surface molecules that it possesses. The mature, naive B lymphocyte, in its mature ready-to-respond form, expresses 2 isotypes of antibody or immunoglobulin called IgM and IgD within its surface membrane. • The mature, naive T cell expresses a single genetically related molecule, called the T-cell receptor (TCR) , on its surface.

20. Antigen Receptors of Mature Lymphocytes

21. The antigen receptor of the B lymphocyte, or membrane-bound immunoglobulin , is a 4-chain glycoprotein molecule that serves as the basic monomeric unit for each of the distinct antibody molecules destined to circulate freely in the serum. flex bility of movement is permitted between the halves by disulfide bonds forming a hinge region . This monomer has 2 identical halves, each composed of a heavy chain and a light chain .

22. The unique structure of the antigen binding site is called the idiotype of the molecule. Although 2 classes (isotypes) of membrane immunoglobulin ( IgM and IgD ) are coexpressed on the surface of a mature, naive B lymphocyte, only one idiotype or antigenic specificity is expressed per cell (although in multiple copies). Each individual is capable of producing hundreds of millions of unique idiotypes.

23. B-Lymphocyte Antigen Recognition Molecule (Membrane-Bound Immunoglobulin)

24. The antigen receptor of the T lymphocyte is composed of 2 glycoprotein chains, a beta and alpha chain that are similar in length. Antigen-binding site is formed between the 2 chains, whose 3-dimensional shape will accommodate the binding of a small antigenic peptide complexed to an MHC molecule presented on the surface of an antigen-presenting cell. There is no hinge region present in this molecule, and thus its conformation is quite rigid.

25. The membrane receptors of B lymphocytes are designed to bind unprocessed antigens of almost any chemical composition, i.e., polysaccharides, proteins, lipids, whereas the TCR is designed to bind only peptides complexed to MHC . Also, although the B-cell receptor is ultimately modified to be secreted antibody , the TCR is never released from its membrane-bound location.

26. when a lymphocyte binds to an antigen complementary to its idiotype, a cascade of messages transferred through its signal transduction complex will culminate in intracytoplasmic phosphorylation events leading to activation of the cell.

27. B- versus T-Lymphocyte Antigen Receptors

28. The innate immune system includes several developmentally related subsets of bone marrow–derived cells with lymphoid morphology and effector functions similar to those of T cells but lacking T cell antigen receptors. Natural killer (NK ) cells have cytotoxic activity similar to that of CD8+ CTLs. They circulate in the blood and are present in various lymphoid tissues.

29. Lymph Nodes and Spleen

30. Lymph Interstitial fluid from tissues Drains into lymphatic system Eventually drains into subclavian veins

31. Lymphoid Organs • Primary lymphoid organs Sites of lymphocyte formation Bone marrow, Thymus Create B and T cells • Secondary lymphoid organs B cells and T cells proliferate Lymph nodes Spleen Peyer’s patches Tonsils

32. Lymph Nodes Follicle Cortex Paracortex Efferent Lymph Vessel Artery/Vein Medulla (sinus) Medulla (cords) Afferent Lymph Vessel

33. Lymph Nodes • Lymph fluid drains from site of infection Dendritic cells activated Express MHC I, MHC II, B7 Enter lymph carrying processed antigens Free antigens also carried with lymph • Lymph enters nodes - Many B and T cells waiting for matching antigen Dendritic cells present to T cells APCs in lymph nodes to process antigen B cells react to antigen Result: Generation of adaptive immune response

34. • Found in cortex of lymph nodes • Site of B-cell activation • Contain follicular dendritic cells Different from tissue dendritic cells Permanent cells of lymph nodes Surface receptors bind complement-antigen complexes Allows easy crosslinking of B cell receptors • Special note: FDCs important reservoir for HIV Early after infection large amounts HIV particles in FDCs Lymphoid Follicles

35. Lymphoid Follicles • Primary follicles Inactive follicles Follicular dendritic cells and B cells • Secondary follicles “Germinal center” B cell growth and differentiation, class switching Nearby helper T cells can bind → more growth

36. Lymphoid Follicles

37. Paracortex • Two key features: #1: Contain T cells activated by dendritic cells and antigen #2: Contain high endothelial venules - Vessels that allow B/T cell entry into node • Engorged in immune response (swollen nodes) • Underdeveloped in rare T-cell deficiency disorders DiGeorge syndrome

38. Medulla • Medullary sinuses (cavities) Contain macrophages Filters lymph → phagocytosis • Medullary chords (tissue between cavities) Contain plasma cells secreting antibodies

39. • Filters blood (no lymph) • All blood elements can enter No high endothelial venules No selective entry T and B cells Spleen

40. Spleen Sinusoids Marginal Zone PALS Follicle Artery

41. Spleen • White pulp Exposure to B and T cells Exposure to macrophages • Red pulp Filters blood in sinusoids Removes old RBCs (red) Stores many platelets

42. White Pulp • Marginal zone Macrophages Remove debris Dendritic cells process antigen • Follicles B cells • Periarteriolar lymphocyte sheath (PALS) T cells

43. Sinusoids of Spleen • Red pulp lined by vascular “sinusoids” • Open endothelium → cells pass in/out • Exit into splenic cords • Cords contain macrophages (filtration)

44. Splenic Dysfunction • Increased risk from encapsulated organisms • Loss of marginal zone macrophages → ↓ phagocytosis • Also loss of opsonization : ↓ IgM and IgG against capsules (splenic B cells) Loss of IgG opsonization ↓ complement against encapsulated bacteria ↓ C3b opsonization