Immunology FACULTY OF MEDICINE UNIVERSITY OF JORDAN DIL-1 18 SEP 2012 MOHAMMED EL-KHATEEB.
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Transcript of Immunology FACULTY OF MEDICINE UNIVERSITY OF JORDAN DIL-1 18 SEP 2012 MOHAMMED EL-KHATEEB.
Immunology
FACULTY OF MEDICINEUNIVERSITY OF JORDAN
DIL-118 SEP 2012
MOHAMMED EL-KHATEEB
OutlineOutline
Short History The Origin of Immune Concept Overview of Immunity to Microbes Features
• Components • Organs
• Cells
• Molecules
• Adaptive Immunity
• Innate Immunity
Historical Perspectives
In ancient times, many serious infection diseases, such as
smallpox, plague and cholera etc, caused inumerable people dead.
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 medicalpractitioners : variolation
The Origin of Immune Concept-I
1. 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
3. The medical view of immunity => Edward Jenner (1796)Observation => Milkmaids generally get No SmallpoxHypothesis => 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)
The first vaccination against smallpox
Adopted from www.ebinrushed.com/history/images/history_7.jpg
• 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, 1796. Follwed by exposure to smallpox
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
tolerance1953-Medawar set up animal model of
acquired immune tolerance in newborn period.
Historical Events in Immunology(cont’d)
1959-Rodney Porter Gerald Edelman* (antibodies)
1960-F McFarlane Burnet* (tolerance)1975-Cesar Milstein*(monoclonal Ab)1980 - Jean Dauset immunogenetics1987-Susumu Tonegawa* (genetics)1996-Peter Doherty Rolf Zinkernagel* (MHC)
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”
5. 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”
Edward Jenner
Eradication of smallpox
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
Immunology History
Since 1901 there have been 19 Nobel Prizes for immunological research.
Examples: Discovery of human blood groups (1930) and Transplantation immunology(1991)
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
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
THE IMMUNE SYSTEM
The immune system includes:
Tissues, Cells Molecules
Organs of the Immune System
The lymph system and sites of
lymphoid tissue
Lymphoid System
Primary lymphoid organs Bone marrow ThymusGeneration & Development
Secondary lymphoid organs Organized
Lymph nodes Spleen
Less organized; MALT: GALT&BALTInitiation 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...)
Bone marrow
Structure Microscopic
Less well defined than thymus Role of stromal cells
Function Hematopoiesis B cell maturation B cell selection Puts out mature, naive B cells
Stem cell B cell in Bone marrow (fetal liver)
B cell development
Delete self reactive B cells generated by accident.
+5-15% of the circulating lymphoid pool
+Defined by the presence of surface immunoglobulin (BCR).
+BCR associated with two accessory molecules CD79a and CD79b.
Thymus
Structure Gross
Bi-lobed Lies above heart
Microscopic Capsular Lobules with outer cortex and inner medulla
THYMUS
+Delete self reactive TcR generated by accident.
T-CELL DEVELOPMENT
+Stem cell T cell in Thymus
+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-
Thymus
Function Takes in immature T cells and puts out mature
(immunocompetent) T cells Increased diversity of T cells T cell selection
Thymus
T cell selection 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
Lymph Nodes
Structure Gross
Bean-shaped structures Drains major segments of lymphatic system
Lymph Nodes
Structure Microscopic
Major cell types Lymphocytes Macrophages Dendritic cells
Cortex/paracortex/medulla Follicles
Primary Secondary
5. Medullary cords (Macrophage & plasma cell area)
Medullary sinus
6. Efferent lymphatic vessel
Artery
Vein
4. Germinal centre (site of intense B cell proliferation)
3. Secondary lymphoid follicle
Paracortical(T cell) area
2. Primary Lymphoid follicle (B cell area)
1. Afferent lymphatic vessel. Lymph, Ag, & cells with captured Ag drained
from tissues enters here
Lymph node
ParacortexCortex
Germinalcentre
Marginal zone
Subcapsular zone
Lymphoid follicle /nodule
HEV
Blood enters lymph node via the arteryPost capillary venules in the paracortex have cuboidal endothelial cells
HIGH ENDOTHELIAL VENULES - specialised properties to allow lymphocytes and nothing else into the lymph node
High Endothelial Venules
Non-lymphoid cells
Pass through the blood vessels in the lymph node and continue arterio-venous circulation
Recirculation
HEV
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
Lymphocyte recirculation
Cells enter blood, are seeded to the peripheral lymphoid organs via
arterial circulationand return via lymphatics
Cells & antigens from a site of infectionare trapped in draining lymph node.
Cells proliferate and re-enter the RECIRCULATING LYMPHOCYTE POOL
to re-seed the peripheral lymphoid organs
NAÏVE CELLS MEMORY CELLS
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
Tonsils
Follicular structureContains lymphocytes, macrophages, mast
cellsGerminal centers appear in response to AgProtective role in URI
Appendix
Associated with intestinesResponds to AgRole in GI immune response
MALT
Lymphoid tissues below epitheliumPresence of B cellsAg presented through unique cell (M cell)Preferentially responds with IgA antibody
GC
Villi
Spleen
Structure Gross
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
Spleen
Red pulp
Primary follicle
Central arteriole
Periarteriolarlymphocytic sheath
Germinal centre
Marginal zoneSecondary follicle
Trabecularartery
Central arteriole Periarteriolarlymphocytic sheath
Germinal centre
Trabeculae
Venous sinusMarginal zone
Spleen
Function Filters out older RBCs Responds to Ag in circulatory system Produces activated B cells
Splenectomy
Cells of the Immune System
Myeloid Lineage
GranulocytesEosinophilsBasophilsMegakaryocytesErythrocytesDendritic cells
Lymphoid Lineage
T LymphocytesB LymphocytesNatural Killer Cells
Neutrophils
60-70% of WBCsMulti-lobed nucleusGranulated cytoplasmLife span is 2-3daysProminent in inflammatory responseLeukocytosis is marker for infectious
processActively phagocytic
Eosinophils
~2% of WBCsBi-lobed nucleusGranulated cytoplasmStains with acid dye (eosin)Prominent in response to parasitic
infections Phagocytic
Basophils
<1% of WBCsLobed nucleusHeavily granulated cytoplasmStains with basic dye Prominent in allergic responsesNon-phagocytic
Monocytes and Macrophages
Large WBCsMonocytes are circulating precursorsMacrophages
Phagocytic “Fixed” throughout the body, e.g. Liver (Kupffer) Activated by cytokines and gamma interferon APC Secretes numerous immune response factors
MacrophageDifferent names in different tissues
Monocyte (blood)Kupffer cells (liver)Mesangial cells (kidney glomerulus)Microglia (brain)Alveolar macrophages (lung) Histiocyte (connective tissue)
Some Factors Secreted by
Activated Macrophages
Mast Cells
Found in many different tissuesContains granules which release histaminePlay role in allergic reactions
Dendritic Cells
Have long “dendrites”Major role as APCStimulated by innate responseHave co-stimulatory molecules
constitutivelyHave constitutive MHC II expressionPhagocytic and endocytic
Lymphocytes
~30-40% of WBCs
T Lymphocytes Mature in thymus Have TCRs Recognize Ag on cells only Two subpopulations:
Helper/Inducer (CD4)Suppressor (CD8)
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
Natural Killer Cells
Detected for anti-tumor activityLack T and B cell markersLack Ag receptorsInvolved with Ab-dependent cell-mediated
cytotoxicity
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.
How do you tell different cell types apart?
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.
Key CD Ags to remember
MOLECULES OF THE IMMUNE
SYSTEM
T-Cell Products, Interleukines, Lymphokines Interferons
B- Cell Products Antobodies (imunoglobulines)
Macrophage Productes
INNATE IMMUNITY
PHYSICAL BARRIERS
Skin, mucous membrane
CELLS granulocytes,
monocytes, macrophages
CHEMICAL BARRIERS pH, lipids,
enzymes
ACQUIRED IMMUNITY
HUMORAL
B cells
antibodies
CELL MEDIATED
T cells
lymphokinesMP