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