Cells, Tissues, and Cells, Tissues, and Organs of the Immune Organs of the Immune

SystemSystem

IntroductionIntroductionKnowledge of the structural and ultrastructural details Knowledge of the structural and ultrastructural details of the immune system is necessary to understand its of the immune system is necessary to understand its functions.functions.

Distinct compartments that are interconnected by the Distinct compartments that are interconnected by the blood and lymphatic system.blood and lymphatic system.

The immune response is coordinated at a system level The immune response is coordinated at a system level and complex series of physiologic events interact in and complex series of physiologic events interact in vivo to influence the outcome of immune response.vivo to influence the outcome of immune response.

The immune system is integrated with other systems; The immune system is integrated with other systems; namely the neural and endocrine systems which can namely the neural and endocrine systems which can influence the immune response.influence the immune response.

HematopoiesisHematopoiesis

The process of blood cellThe process of blood cell

–Proliferation, Proliferation,

–Differentiation, andDifferentiation, and

–MaturationMaturation

Sites of hematopoeisisSites of hematopoeisis

–Bone marrow in adults Bone marrow in adults

–Spleen and liver of fetus Spleen and liver of fetus

Yolk Sac

Fetal Liver Spleen Bone Marrow

?

Fetus Neonate Adult

Developmental Sites of Developmental Sites of HematopoiesisHematopoiesis

Hematopoietic TissueHematopoietic TissueBones:Bones:

– Containing hematopoietic marrow (red Containing hematopoietic marrow (red

marrow)marrow)

Flat bones of pelvisFlat bones of pelvis

Vertebrae Vertebrae

Skull Skull

Ribs and sternumRibs and sternum

The Process of HematopoiesisThe Process of HematopoiesisHematopoiesis begins with the stem cell Hematopoiesis begins with the stem cell (precursor cells)(precursor cells)

–Totipotent stem cellTotipotent stem cell

Primitive cellPrimitive cell

Potential to turn into any blood cellPotential to turn into any blood cell

Differentiation follows along 2 cell lines Differentiation follows along 2 cell lines (pathways)(pathways)– MyeloidMyeloid

– LymphoidLymphoid

Myeloid Cell LineMyeloid Cell Line

Granulocytes (4,000 - 6,000/µl)Granulocytes (4,000 - 6,000/µl)

–Neutrophils 50 - 70% of WBCsNeutrophils 50 - 70% of WBCs

SegmentsSegments = mature cells = mature cells

BandsBands = immature cells = immature cells

–Eosinophils: 1 - 4%Eosinophils: 1 - 4%

Increase during parasitic infectionsIncrease during parasitic infections

–Basophils: < 1 % Basophils: < 1 %

Involved in allergic reactionsInvolved in allergic reactions

50-70% of all leukocytes, circulate inthe blood, phagocytic, take up neutral dye

NeutrophilNeutrophil

1.5% of leukocytes, release destructiveenzymes to destroy invaders, stained with eosin

EosinophilEosinophil

Take up basic dye, release histamine,circulate in the blood

BasophilBasophil

Myeloid Cell LineMyeloid Cell Line

Monocytes /macrophagesMonocytes /macrophages

–2-8% of WBCs in blood2-8% of WBCs in blood

Platelets:Platelets: 150,0000 - 400,000/µl 150,0000 - 400,000/µl

Red blood cells (RBC): Red blood cells (RBC): erythrocyteserythrocytes: :

–4.2 - 6.2 million/µl4.2 - 6.2 million/µl

5% of leukocytes, circulates in the blood for a few hours, then crawls into tissues, enlarges and differentiates into...

MonocyteMonocyte

Phagocytic, very long-lived, some migratethroughout the body, others are resident in

tissues (especially lymph nodes)

Macrophage (“big eater”)Macrophage (“big eater”)

The Lymphatic SystemThe Lymphatic System

Two main functions:

1) Return tissue fluid to circulation

2) Fights infection - both specific and non-

specific resistance.

Lymph- fluid carried by lymphatic vessels

Adult Lymphoid OrgansAdult Lymphoid Organs

Lymphocyte DistributionLymphocyte Distribution

Lymphocytes lodge in secondary lymphoid Lymphocytes lodge in secondary lymphoid organs where they expand clonally upon organs where they expand clonally upon contact with specific antigens.contact with specific antigens.

Lymphocytes recirculate between secondary Lymphocytes recirculate between secondary organs via blood and lymphatic systemsorgans via blood and lymphatic systems

(trafficking).(trafficking).

With the exception of some sites, lymphocytes With the exception of some sites, lymphocytes are widely dispersed in the body.are widely dispersed in the body.

Lymphoid CellsLymphoid Cells

Lymphocytes (25-35% of WBCs)Lymphocytes (25-35% of WBCs)

–T-cellsT-cells: 70% of lymphocytes : 70% of lymphocytes

Cell mediated immunity Cell mediated immunity

–B-cellsB-cells: 20-25% of lymphocytes: 20-25% of lymphocytes

Humoral immunityHumoral immunity

T Cell

B CellT cell

B cells and T cells look alike but have important differences

Mature lymphocytes have antigen-specific receptors

T CELLST CELLS

B CELLSB CELLS

Origin: Bone marrowOrigin: Bone marrow

Maturation: ThymusMaturation: Thymus

Long-livedLong-lived

Highly mobileHighly mobile

No complement receptorsNo complement receptors

No surface IgNo surface Ig

No antibody synthesisNo antibody synthesis

Effector: cellular & humoralEffector: cellular & humoral

Bone marrow. Bone marrow.

Bone marrow; Bursa in birdsBone marrow; Bursa in birds

Short-lived/long-livedShort-lived/long-lived

Fairly mobile/stationaryFairly mobile/stationary

Complement receptorsComplement receptors

Surface immunoglobulinsSurface immunoglobulins

Antibody synthesisAntibody synthesis

humoral onlyhumoral only

COMPARISON BETWEEN T AND B CELLS

How does the bone marrow know which cell to How does the bone marrow know which cell to make?make?

Mechanisms of Regulation of Mechanisms of Regulation of HematopoiesisHematopoiesis

Control of cytokine production by stromal cells Control of cytokine production by stromal cells (altering the microenvironment)(altering the microenvironment)

Movement of developing cells from one Movement of developing cells from one microenvironment to anothermicroenvironment to another

Production of cytokines by non- stromal cellsProduction of cytokines by non- stromal cells

Up- or down-regulation of cytokine receptor Up- or down-regulation of cytokine receptor expression by developing cellsexpression by developing cells

Removal of developing (and developed) cells Removal of developing (and developed) cells by apoptosisby apoptosis

Critical Cytokines in HematopoiesisCritical Cytokines in Hematopoiesis

Interleukin 3 (IL-3)Interleukin 3 (IL-3)– Produced by T cells (Th1 and Th2)Produced by T cells (Th1 and Th2)– Binds to IL-3 Receptors on progenitorsBinds to IL-3 Receptors on progenitors– Maintains stem cells and early progenitorsMaintains stem cells and early progenitors– Induces proliferationInduces proliferation– Does not appear to induce differentiationDoes not appear to induce differentiation

Critical Cytokines in HematopoiesisCritical Cytokines in Hematopoiesis

Stem Cell FactorStem Cell Factor– AKA: Steel Factor, Mast Cell Growth Factor, c-kit AKA: Steel Factor, Mast Cell Growth Factor, c-kit

ligandligand– Produced by stromal cellsProduced by stromal cells– Binds to c-kit on progenitorsBinds to c-kit on progenitors– Maintains stem cells and early progenitorsMaintains stem cells and early progenitors– Induces proliferationInduces proliferation– Does not appear to induce differentiationDoes not appear to induce differentiation

Critical Cytokines in HematopoiesisCritical Cytokines in HematopoiesisFactors important for late progenitorsFactors important for late progenitors– Erythropoietin (EPO)Erythropoietin (EPO)

needed for red blood cell developmentneeded for red blood cell development– GM-CSF (Colony Stimulating Factor)GM-CSF (Colony Stimulating Factor)

works on common granulocyte/ monocyte works on common granulocyte/ monocyte precursorprecursor

– G-CSFG-CSFworks on granulocyte-committed progenitorsworks on granulocyte-committed progenitors

– M-CSFM-CSFworks on monocyte /macrophage progenitorsworks on monocyte /macrophage progenitors

StromalCell

StemCell Response

No Response

No Response

StromalCell

StromalCell

StemCell

StemCell

Growth Factor

Growth Factor Receptor

Bone marrowBone marrowThe major hematopoietic organ in humans. The major hematopoietic organ in humans.

Hematopoiesis is facilitated by a mixture of cells and Hematopoiesis is facilitated by a mixture of cells and extracellular matrix components.extracellular matrix components.

All blood cell types except mature T cells are found in All blood cell types except mature T cells are found in its cavities.its cavities.

B cell generation and development occurs in a radial B cell generation and development occurs in a radial direction towards the center of the bone.direction towards the center of the bone.

Growth factors, cytokines, and reticular stroma are all Growth factors, cytokines, and reticular stroma are all important in B cell development.important in B cell development.

ThymusThymus

Bilobed organ in the anterior mediastinum.Bilobed organ in the anterior mediastinum.Grows until puberty then it progressively involutes.Grows until puberty then it progressively involutes.Removal of thymus after birth?Removal of thymus after birth?Two types of epithelial cells (endoderm and ectoderm)Two types of epithelial cells (endoderm and ectoderm)Lobes are divided by trabeculae into lobules.Lobes are divided by trabeculae into lobules.Primary site of T cell development.Primary site of T cell development.Composed of three areas:Composed of three areas:

- - Subcapsular zoneSubcapsular zone→ earliest progenitor cell.→ earliest progenitor cell. - - CortexCortex→ Developing T cells undergoing selection.→ Developing T cells undergoing selection. - - MedullaMedulla→ mature T cells.→ mature T cells.

>95% of T cell progenitors die in the thymus.>95% of T cell progenitors die in the thymus.

SpleenSpleenLocated in left upper abdominal quadrant.Located in left upper abdominal quadrant.

Functions to filter blood from microbes and dead Functions to filter blood from microbes and dead RBCs.RBCs.

Main site for response to blood-borne antigens and T-Main site for response to blood-borne antigens and T-independent antigens.independent antigens.

Composed of red pulp (RBCs and macrophages) and Composed of red pulp (RBCs and macrophages) and white pulp (lymphocytes)white pulp (lymphocytes)

It lodges 25% of the total lymphocytes of the body.It lodges 25% of the total lymphocytes of the body.

T Cells: Periarteriolar lymphoid sheaths (PALS).T Cells: Periarteriolar lymphoid sheaths (PALS).

B cells: Primary (resting) and secondary (activated) B cells: Primary (resting) and secondary (activated)

follicles.follicles.

Marginal zones: T cells, B cells, and macrophages.Marginal zones: T cells, B cells, and macrophages.

SpleenSpleen

Lymph NodesLymph Nodes

Bean shaped, usually clustered in groups.Bean shaped, usually clustered in groups.Strategically located throughout the body.Strategically located throughout the body.Function to concentrate lymph-borne antigens for Function to concentrate lymph-borne antigens for presentation to T cells.presentation to T cells.StructureStructure: :

- - CortexCortex (B cells) (B cells) - - ParacortexParacortex (T cells) (T cells) - - MedullaMedulla( B cells, T cells, and macrophages).( B cells, T cells, and macrophages).

Circulating lymphocytes enter lymph nodes via Circulating lymphocytes enter lymph nodes via specialized high endothelial venules (HEVs).specialized high endothelial venules (HEVs).Lymphadenopathy: proliferation in response to Lymphadenopathy: proliferation in response to infection.infection.

Mucosa-associated lymphoid tissue Mucosa-associated lymphoid tissue (MALT)(MALT)

Respiratory and Gastrointestinal tract(NALT Respiratory and Gastrointestinal tract(NALT and GALT).and GALT).

Contain a specialized epithelial cell type (M Contain a specialized epithelial cell type (M cell) which engulfs antigens.cell) which engulfs antigens.

Rich in IgA producing plasma cells.Rich in IgA producing plasma cells.

Involved in the establishment of oral tolerance.Involved in the establishment of oral tolerance.

Intraepithelial lymphocytesIntraepithelial lymphocytes

The mucosa of gastrointestinal, respiratory, and The mucosa of gastrointestinal, respiratory, and reproductive tracts contain large number of reproductive tracts contain large number of lymphocytes.lymphocytes.

>90% T lymphocytes, 50% CD8+ of >90% T lymphocytes, 50% CD8+ of γδγδ type. type.

Develop without the influence of the thymus?Develop without the influence of the thymus?

Direct Ag recognition, no need for MHC.Direct Ag recognition, no need for MHC.

Secrete cytokines that cause immune Secrete cytokines that cause immune suppression at the mucosa.suppression at the mucosa.

Oral tolerance.Oral tolerance.

Skin (cutaneous Immune system)Skin (cutaneous Immune system)

The major physical barrier.The major physical barrier.

Dendritic cells.Dendritic cells.

Epidermis has many Langerhan’s cells.Epidermis has many Langerhan’s cells.

T cells (intraepidermal) mainly CD8+ of T cells (intraepidermal) mainly CD8+ of γδγδ type. type.

Dermis full of macrophages and T cells.Dermis full of macrophages and T cells.

Lymphocyte Recirculation (Trafficking) Lymphocyte Recirculation (Trafficking) and Homingand Homing

Moving of lymphocytes via blood and lymphatics from Moving of lymphocytes via blood and lymphatics from one lymphoid tissue to another.one lymphoid tissue to another.

A lymphocyte makes a tour of the body (Blood→ A lymphocyte makes a tour of the body (Blood→ Tissue→ Lymphatic system → Blood) once or twice Tissue→ Lymphatic system → Blood) once or twice daily ensuring antigen contact.daily ensuring antigen contact.

Mostly T cells. Naive T cells circulate until they find an Mostly T cells. Naive T cells circulate until they find an Ag or they will die.Ag or they will die.

B cells have less requirement to recirculate.B cells have less requirement to recirculate.

Recirculation and homing are regulated by receptor- Recirculation and homing are regulated by receptor- ligand interactions (selectins, addressins, integrins).ligand interactions (selectins, addressins, integrins).

Lymphocyte extravasationLymphocyte extravasation

Lymphocyte transport out of the blood stream Lymphocyte transport out of the blood stream into tissues.into tissues.

Four steps:Four steps:

- Primary adhesion to endothelium.- Primary adhesion to endothelium.

- Lymphocyte activation.- Lymphocyte activation.

- Secondary adhesion (arrest).- Secondary adhesion (arrest).

- Transmigration/ chemotaxis.- Transmigration/ chemotaxis.