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Immunology Faculty of Medicine University Of Jordan DIL-1 18 Sep 2012

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1 Immunology Faculty of Medicine University Of Jordan DIL-1 18 Sep 2012
Mohammed El-Khateeb

2 Outline Short History The Origin of Immune Concept
Overview of Immunity to Microbes Features Components Organs Cells Molecules Adaptive Immunity Innate Immunity

3 Historical Perspectives
In ancient times, many serious infection diseases, such as smallpox, plague and cholera etc, caused inumerable people dead.

4 A Short History of Immunology
~ 430 B.C: Thucydides describes plague – the ones who had recovered from the disease could nurse the sick without getting the disease a second time 15th centurry: Chinese and Turks use dried crusts of smallpox as ”vaccine” 1798: Edward Jenner – smallpox vaccine In 1670, Chinese medical practitioners : variolation

5 The Origin of Immune Concept-I
The term “Immunity” Latin word “Immunitas” => Protection from legal prosecution (Roman senators) Biological definition => Protection from infectious diseases 2. The concept of immunity existed in ancient Greek & Chinese => the experienced view The medical view of immunity => Edward Jenner (1796) Observation => Milkmaids generally get No Smallpox Hypothesis => Pus from vaccinia (cowpox) => Protect milkmaids from smallpox Test Inoculate materials from cowpox pus Protect a young boy from smallpox (Protective immunity) Vaccinia Vaccination (also called Immunization)

6 The first vaccination against smallpox
Table 1-2. Features of Innate and Adaptive Immunity Table 1-2. Features of Innate and Adaptive Immunity The first vaccination against smallpox Exudate from a cowpox pustule on the hand of milkmaid Nelmes was injected into scratches on the arms of 8 years old Sarah James Phipps, May 14, Follwed by exposure to smallpox This table lists the major characteristics and components of innate and adaptive immune responses. Innate immunity is discussed in much more detail in Chapter 2. Adopted from

7 Historical Events in Immunology
1881-Loius Pasteur (vaccines) 1884-Elie Metchnikoff (phagocytes) 1890-Emil von Behring* (antibodies) 1895-Jules Bordet* (complement) 1906-August Wasserman (syphilis) 1945-Owen found natural immune tolerance 1953-Medawar set up animal model of acquired immune tolerance in newborn period.

8 Historical Events in Immunology (cont’d)
1959-Rodney Porter Gerald Edelman* (antibodies) 1960-F McFarlane Burnet* (tolerance) 1975-Cesar Milstein*(monoclonal Ab) Jean Dauset immunogenetics 1987-Susumu Tonegawa* (genetics) 1996-Peter Doherty Rolf Zinkernagel* (MHC)

9 The Origin of Immune Concept-II
4. The concept of “Immunity” developed gradually over time through many scientific findings: => Robert Koch (1905 Nobel Laureate) => Infectious diseases caused by microorganisms => Louis Pasteur => Vaccines against cholera & rabies => These clinical successes => The search of underlying mechanism of “Protection of Infectious Diseases” => The development of “Immunology” Advances in technology (e.g., Cell culture, Monoclonal Ab, Flow cytometry, Genetic engineering…etc) have facilitated our understanding of the immune system and its functions. “Descriptive Science” => “Experimental Science”

10 Eradication of smallpox
Edward Jenner

11 Humoral Or Cellular Immunity?
Pasteur Did Not Know How Vaccination Worked Behring and Kitasato (1890) Proposed Serum Was Responsible For Immunity Elvin Kabat (1930), gamma-globulin, Antibody Antibodies Were Present in Body Fluids=Humor Therefore: Humoral Immunity

12 Immunology History Since 1901 there have been 19 Nobel Prizes for immunological research. Examples: Discovery of human blood groups (1930) and Transplantation immunology(1991)

13 Key concepts about immunity-I
1. The immune system has evolved to (1) Protect against the invading pathogens (or foreign substances) and to (2) Maintain tissue homeostasis (damaged cells or cancer). Meanwhile, microbes (outside) and tumors (inside) have evolved to survive in the host. 2. The immune system (in vertebrates) consists of (1) Innate immunity and (2) Adaptive immunity => An integrated system of host defense => Cells & molecules function cooperatively Antigen-presenting cells => Lymphocytes => Effector cells 3. Innate immunity is evolutionally the more conserved host defense system: - Existed in both Invertebrates & Vertebrates - Provides the first line of defenses against infections - “Activates” and “Programs” adaptive immune responses

14 Key concepts about immunity-II
5. Adaptive immunity evolved later: - Existed only in Vertebrates - Provides the more potent and diverse defenses against infections - Develops as a response to infection and adapts to the infection 6. The immune system may fail => Immunodeficiency, Hypersensitivity, & Autoimmune diseases. 7. Normal immune responses can be obstacles in medical cases, e.g., organ transplantation Better Understanding of Immunology Help manipulate immune responses Solve the medical problems

15 THE IMMUNE SYSTEM The immune system includes: Tissues, Cells Molecules

16 Organs of the Immune System

17 The lymph system and sites of lymphoid tissue

18 Lymphoid System Primary lymphoid organs Secondary lymphoid organs
Bone marrow Thymus Generation & Development Secondary lymphoid organs Organized Lymph nodes Spleen Less organized; MALT: GALT&BALT Initiation of the adaptive immune response Primary role is generation of specific immune responses. All connected to blood and lymph circulation. All have defined structure (B cell zones, T cell zones...)

19 Bone marrow Structure Function Microscopic Hematopoiesis
Less well defined than thymus Role of stromal cells Function Hematopoiesis B cell maturation B cell selection Puts out mature, naive B cells

20 B cell development Stem cell  B cell in Bone marrow (fetal liver)
Delete self reactive B cells generated by accident. Stem cell  B cell in Bone marrow (fetal liver) +5-15% of the circulating lymphoid pool +Defined by the presence of surface immunoglobulin (BCR). +BCR associated with two accessory molecules CD79a and CD79b.

21 Thymus Structure Gross Microscopic Bi-lobed Lies above heart Capsular
Lobules with outer cortex and inner medulla

22 THYMUS

23 T-CELL DEVELOPMENT +Stem cell  T cell in Thymus
+Delete self reactive TcR generated by accident. +TCR ab (90-95%)or gd (5-15%) T helper (CD4)>>>Th1 or Th2 (cytokine profiles) T cytotoxic Tc (CD8) Most of circulating gd T cells are double negative CD4-8-

24 Thymus Function Takes in immature T cells and puts out mature (immunocompetent) T cells Increased diversity of T cells T cell selection

25 Thymus T cell selection Athymic condition
Based on MHC/Ag complex recognition Recognize MHC/Non self AG complexes Recognize MHC/Self Ag complexes Do not recognize MHC/Ag complexes Athymic condition Natural Other

26 Lymph Nodes Structure Gross Bean-shaped structures
Drains major segments of lymphatic system

27

28 Lymph Nodes Structure Microscopic Major cell types Lymphocytes
Macrophages Dendritic cells Cortex/paracortex/medulla Follicles Primary Secondary

29 Lymph node 4. Germinal centre (site of intense B cell proliferation)
5. Medullary cords (Macrophage & plasma cell area) 3. Secondary lymphoid follicle 6. Efferent lymphatic vessel 2. Primary Lymphoid follicle (B cell area) Artery Paracortical (T cell) area Vein Medullary sinus 1. Afferent lymphatic vessel. Lymph, Ag, & cells with captured Ag drained from tissues enters here

30 Lymphoid follicle /nodule
Subcapsular zone Marginal zone Lymphoid follicle /nodule Germinal centre Cortex Paracortex

31 High Endothelial Venules
HEV Blood enters lymph node via the artery Post capillary venules in the paracortex have cuboidal endothelial cells HIGH ENDOTHELIAL VENULES - specialised properties to allow lymphocytes and nothing else into the lymph node

32 Recirculation Non-lymphoid cells Lymphoid cells
Pass through the blood vessels in the lymph node and continue arterio-venous circulation HEV Lymphoid cells Adhere to and squeeze between High Endothelial Venules (HEV), then percolate through the lymph node and exit via the efferent lymphatic vessel HEV

33 Lymphocyte recirculation
NAÏVE CELLS MEMORY CELLS Cells & antigens from a site of infection are trapped in draining lymph node. Cells proliferate and re-enter the RECIRCULATING LYMPHOCYTE POOL to re-seed the peripheral lymphoid organs Cells enter blood, are seeded to the peripheral lymphoid organs via arterial circulation and return via lymphatics

34 Lymph Nodes Function 1st line of response to antigens
Secondary follicle (Germinal center) is site of B cell proliferation, differentiation Specificity is high >90% of B cells die through apoptosis After Ag stimualtion lymphocyte numbers up by 50X in efferent lymphatic vessel Lymphadenopathy

35 Tonsils Follicular structure
Contains lymphocytes, macrophages, mast cells Germinal centers appear in response to Ag Protective role in URI

36 Appendix Associated with intestines Responds to Ag
Role in GI immune response

37 MALT Lymphoid tissues below epithelium Presence of B cells
Ag presented through unique cell (M cell) Preferentially responds with IgA antibody Villi GC

38 Spleen Structure Gross Microscopic
Ovoid organ in upper left quadrant of abdomen Microscopic Compartmentalized Red pulp White pulp Periarticualr lymphoid sheath Site of Ag presentation Major cell types Lymphocytes Macrophages Dendritic cells RBCs

39 Spleen Primary follicle Central arteriole Red pulp Periarteriolar
lymphocytic sheath Germinal centre Marginal zone Secondary follicle Trabecular artery

40 Central arteriole Periarteriolar lymphocytic sheath Marginal zone Venous sinus Trabeculae Germinal centre

41

42 Spleen Function Splenectomy Filters out older RBCs
Responds to Ag in circulatory system Produces activated B cells Splenectomy

43 Cells of the Immune System

44

45 Myeloid Lineage Granulocytes Eosinophils Basophils Megakaryocytes
Erythrocytes Dendritic cells

46 Lymphoid Lineage T Lymphocytes B Lymphocytes Natural Killer Cells

47 Neutrophils 60-70% of WBCs Multi-lobed nucleus Granulated cytoplasm
Life span is 2-3days Prominent in inflammatory response Leukocytosis is marker for infectious process Actively phagocytic

48 Eosinophils ~2% of WBCs Bi-lobed nucleus Granulated cytoplasm
Stains with acid dye (eosin) Prominent in response to parasitic infections Phagocytic

49 Basophils <1% of WBCs Lobed nucleus Heavily granulated cytoplasm
Stains with basic dye Prominent in allergic responses Non-phagocytic

50 Monocytes and Macrophages
Large WBCs Monocytes are circulating precursors Macrophages Phagocytic “Fixed” throughout the body, e.g. Liver (Kupffer) Activated by cytokines and gamma interferon APC Secretes numerous immune response factors

51 Macrophage Different names in different tissues Monocyte (blood)
Kupffer cells (liver) Mesangial cells (kidney glomerulus) Microglia (brain) Alveolar macrophages (lung) Histiocyte (connective tissue)

52 Some Factors Secreted by Activated Macrophages

53 Mast Cells Found in many different tissues
Contains granules which release histamine Play role in allergic reactions

54 Dendritic Cells Have long “dendrites” Major role as APC
Stimulated by innate response Have co-stimulatory molecules constitutively Have constitutive MHC II expression Phagocytic and endocytic

55

56 Lymphocytes ~30-40% of WBCs T Lymphocytes Mature in thymus Have TCRs
Recognize Ag on cells only Two subpopulations: Helper/Inducer (CD4) Suppressor (CD8)

57 Lymphocytes B Lymphocytes Mature in bone marrow
Have membrane-bound Ab(~10,000 per cell) Go from “naive” to activated. Plasma cells are Ab secretors ~1-2 week life span

58 Natural Killer Cells Detected for anti-tumor activity
Lack T and B cell markers Lack Ag receptors Involved with Ab-dependent cell-mediated cytotoxicity

59 How do you tell different cell types apart?
Physical appearance: Lymphocytes small, granulocyte larger with granules that stain in different ways with dyes used in lab. (Differential cell count) CD Ag system: over 250 cell surface proteins distinguished with Abs used as a diagnostic tool. Allows us to positively identify different cell types, function, state of activation.

60 Key CD Ags to remember CD3 on all T cells, NO B cells.
CD1 present on developing thymocytes but not on T cells Among T cells there are two main sub-groups: CD4 “helper T cell” CD8 cytotoxic T cell CD19 and 20 are on B cells but not T cells. CD56 is on NK cells but not other types of lymphocytes.

61 Molecules of The Immune System

62 T-Cell Products, B- Cell Products Macrophage Productes Interleukines,
Lymphokines Interferons B- Cell Products Antobodies (imunoglobulines) Macrophage Productes

63 MP ACQUIRED IMMUNITY INNATE IMMUNITY Skin, mucous membrane enzymes
PHYSICAL BARRIERS Skin, mucous membrane CHEMICAL BARRIERS pH, lipids, enzymes CELLS granulocytes, monocytes, macrophages ACQUIRED IMMUNITY HUMORAL B cells antibodies CELL MEDIATED T cells lymphokines MP


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