Tissues of the immune system

Blood Leukocytes white blood cells Spleen Lymphatic system Lymph nodes Lymphatic vessels Mucosa-associated lymphoid tissues (MALT) Tonsils Peyers patches Etc

Blood
Hematopoiesis production of red and white blood cells.
Occurs at different locations depending on age

All blood cells (both erythrocytes and leukocytes) arise from pluripotent hematopoietic stem cells

Hematopoiesis
Bone Marrow

Blood

Tissues

Regulation of blood cell number

RATE of cell genesis
Hours

ATP-dependent process REQUIRES EFFORT AND ENERGY!

RATE of cell death

Cell injury

Programmed cell death

=
Memory B cells can last decades!

Induces inflammatory response and damages surrounding tissue.

Months, then phagocytized by macrophages in the spleen

Phagocytosis prevents lytic enzymes, cationic proteins and oxidants from being released in to surrounding tissue does NOT induce local inflammatory response!

Surface appearance of apoptotic T cell

Signals ATP

Normal

Apoptotic

Notice the blebbing of apoptotic bodies

Blood
Hematopoiesis
No longer self-renawable Lymphoid progenitor cells will become lymphocytes: B-cells T-cells Natural Killer (NK) cells Lymphoid dendritic cells Myeloid progenitor cells will become: Erythrocytes Platelets Granulocytes Macrophages Mast cells Myeloid dendritic cells

Pluripotent hematopoietic stem cell goes one of two ways

Myeloid progenitor derivatives

Macrophages and Dendritic Cells
Agranulocytes. Constantly phagocytize material and present it on the cell surface. May be stationary or mobile. Dendritic cells are often found in tissues and organs with external contact and migrate to lymph nodes after ingesting foreign material.

Myeloid progenitor derivatives

Monocytes become macrophages

Migrate from blood to tissue

Monocytes
Found in blood! Phagocytize pathogens and present their antigens to T cells. Can migrate out of the blood to form tissue macrophages. Relative percentage among leukocytes: 2-8% Diameter: 14-17 m Nucleus: kidney shaped Granules: none (abundant cytoplasm)

Macrophages
Monocytes that have left the blood stream and differentiated. Phagocytize pathogens and present antigens to T cells.

Diameter: 21 m Nucleus: single, unfragmented and unlobed Granules: none

Mononuclear phagocytes
Monocytes in the blood: Macrophages in tissue:

PROMONOCYTES IN MARROW

Circulate for 8 hours Enlarge

Tissue macrophage types: Intestinal macrophages GI tract Alveolar macrophages lung Histiocytes connective tissue Kupffer cells liver Mesangial cells kidneys Microglial cells brain Osteoclasts bone

5 to 10 x larger. Organelles increase in size and complexity. Acquire phagocytic capacity. Produce hydrolytic enzymes. Secrete soluble cytokines.

Stationary

Migrating

Dendritic Cells

Discovered by Paul Langerhans in 1868 (first immune cells discovered) 4 major categories: Langerhans DCs epidermal skin layers Interstitial DCs all organs except brain Monocyte-derived DCs migrate from blood to tissue Plasmacytoid-derived DCs innate immunity and antigen presentation

All display: class I and class II MHCs CD40 influence T cell behavior
Function:
Originate in bone marrow outside lymph nodes, immature DCs monitor for infection and phagocytize pathogens (1. engulf by phagocytosis, 2. internalize by receptor-mediated endocytosis or 3. imbibe by pinocytosis*) migrate to the lymph nodes and mature to present antigens to T cells on class II MHCs
* Pinocytose 1000 to 1500 m3 per hour (equals DCs volume)

Follicular DCs:
Present native antigens (not processed) - may not express MHC II (maybe they do?). Do not arise in bone marrow! Reside in lymph follicles and play a role in B cell maturation and diversification.

Myeloid progenitor derivatives

Granulocytes a.k.a. Polymorphonuclear Leukocytes (PMNs or PMLs)
Part of the innate immune system. Circulate freely in the blood stream. Leukocytes with lobed nuclei and granules in the cytoplasm. Granules contain compounds that kill infectious agents.

Neutrophils
1. 2. Phagocytize against bacteria and fungi. Degranulate to release toxic compounds in the vicinity of infectious agents. Examples: Defensins Lactoferrins Bactericidal/permeability increasing protein

Relative percentage among leukocytes: 54-62% Diameter: 10-12 m Nucleus: multilobed Granules: fine, faintly pink Their rapid proliferation and death contributes to pus formation.

Myeloid progenitor derivatives

Granulocytes a.k.a. Polymorphonuclear Leukocytes (PMNs or PMLs)
Part of the innate immune system. Circulate freely in the blood stream. Leukocytes with lobed nuclei and granules in the cytoplasm. Granules contain compounds that are released from the cell to fight off infectious agents.

Eosinophils
1. 2. Play a role in allergic reactions. Release chemicals that stimulate inflammation. Active against multicellular parasites (worms, arthropods, etc...) that are opsonized by antibodies. Degranulate to release toxic compounds. May play a role against viruses. Granules contain RNAses

3.

Relative percentage among leukocytes: 1-6% Diameter: 10-12 m Nucleus: bilobed Granules: very dense, stain red/pink/orange

Myeloid progenitor derivatives

Granulocytes a.k.a. Polymorphonuclear Leukocytes (PMNs or PMLs)
Part of the innate immune system. Circulate freely in the blood stream. Leukocytes with lobed nuclei and granules in the cytoplasm. Granules contain compounds that are released from the cell to fight off infectious agents.

Basophils
1. Release histamine to initiate the inflammation response. Also play a role in allergic reactions. Relative percentage among leukocytes: <1% Diameter: 9-10 m Nucleus: bi- or trilobed (may be obscured by granules) Granules: very dense, coarse blue

Myeloid progenitor derivatives

Mast Cells
Very similar to basophils, but found only in tissue. Cytoplasm jam packed with granules that contain histamine and heparin.
Histamine initiates the inflammatory response. Heparin inhibits blood coagulation.

Play a role allergies.

Granulocytic Cells - Overview

Collagenase, lactoferrin and lysozyme

Peroxidase, lysozyme and hydrolytic enzymes

50 to 70% of leukocytes
Marrow
Circulation 7 to 10 hrs extravasation Tissue 2 or 3 days Chemotax to site of inflammation. Phagocytize material and pathogens.

1 to 3% of leukocytes
Extravasate. Less phagocytic. Secrete contents of eosinophilic granules into extracellular space to disrupt parasite membranes.

Leukocytosis transient increase in neutrophils during an infection

<1% of leukocytes
Release pharmacologically active substances. Play a role in inflammation and the allergy response

Mast cells found in tissue; secrete histamine from granules

Lymphoid progenitor derivatives

Memory B-cell B-cell progenitor Hematopoietic stem cell Plasma B-cell Natural killer (NK) cell

Lymphoid progenitor Lymphoid dendritic cell

Lymphocytes: B cells
Plasma B cells Memory B cells

TH helper cell T-cell progenitor

TC cytotoxic T cell

Memory T cell

T cells
Cytotoxic T cells Memory T cells Helper T cells

Antigen interaction and clonal selection

Natural Killer (NK) cells

Lymphoid progenitor derivatives

Are responsible for the immune systems diversity, specificity and memory. Account for 20 to 40 % of all leukocytes. 99% of cells in lymph. 1011 lymphocytes in the human body at any given time. Circulate continuously through blood and lymph and can enter tissues and lymphoid organs. Typically more abundant in lymph than in blood.

Three classes:
Natural Killer cells

B cells

T cells

Part of the innate immune system. Large, granular cells that are part of the innate immune system. Do NOT express the surface markers found on other lymphocytes. Kill viral-infected cells and transformed self cells.

Mediate humoral adaptive immunity Each cell has 1.5 x 105 identical antibodies on its surface that can directly bind antigen. Plasma cells Secrete hundreds or thousands per second! Memory cells mediate subsequent immune responses.

Mediate cellular adaptive immunity. Antigen binding mediated by MHC glycoproteins Secrete cytokines (TH) Destroy infected self cells (CTL) TH:TC ratio 2:1 in blood

Lymphoid progenitor derivatives

Lymphocytes: Natural Killer (NK) Cells
Unlike B and T cells, NK cells are lymphocytes that are part of the innate immune system! Degranulate to kill viral-infected host cells or transformed host cells.

Natural Killer (NK) cells Large, granular cells that display cytotoxic
activity against tumor and cells infected by some viruses. Make up 5 to 10% of lymphocytes. No antigen specific receptors!!! part of innate immunity: 1. Recognize abnormal host cell surface proteins. 2. Cells with too many, or too little MHCI surface receptors. 3. Antibodies attached to surface-displayed antigens. Antibody-dependent cell-mediated cytotoxicity (ADCC) Utilizes a surface receptor (CD16) that binds to the antibodies

NKT cells (a special case?) Has characteristics of NK and T cells!

Exact role in the immune system is unknown! Can secrete large amounts of cytokine that supports B cell antibody production, inflammation and cytotoxic T cell proliferation. Has T cell receptors!!! However, NKT TCRs interact with a CD1 antigen presentation complex rather than an MHC. Also has CD16 antibody binding receptors.

Baby lymphocytes get all growed up

For T cells: TH cells Cytotoxic T lymphocytes

Small (6 m) Inactive Very little cytoplasm

Dense chromatin Few mitochondria Immature Golgi and ER

Nave lymphocyte

MITOTIC CYCLE
A ton of Gogi and ER membranes

Short lived Remains in G0

ANTIGEN EXPOSURE

Larger (15 m) More organelle activity Greater cytoplasm to nucleus ratio

Lymphocyte production & maturation

Lymphocytes are produced in the primary lymphoid organs: Bone marrow
B and T cell production Location of B cell maturation*

Thymus
T cell precursors migrate to and mature in the thymus

Nave lymphocytes are maintained and mature in the secondary lymphoid organs: Lymphatic vessels Lymph nodes Spleen Mucosal lymphoid tissues

*B lymphocytes derive their name from the avian bursa of Fabricius (near the cloaca), where they were originally discovered.

Secondary lymph organs and infection - Lymph nodes

Fibrous capsule that contains a collection of B and T cell lymphocytes, as well as macrophages and dendritic cells. Plays an important role in tissue infection first to encounter antigen that has entered the hosts tissue. Lymph filters through a cellular network of phagocytic cells that can present antigen to lymphocytes. Three distinct regions: 1. Cortex outermost layer that contains lymphocytes (primarily B cells), macrophages and dendritic cells arranged in primary follicles. 2. Paracortex inside the cortex; contains a large number of T cells and dendritic cells that migrate in from tissue. These dendritic cells express a high level of MHC II complexes. 3. Medulla center of node; sparsely populated; contains antibody-secreting plasma cells.

Secondary lymph organs and infection - Lymph nodes

Fibrous capsule that contains a collection of B and T cell lymphocytes, as well as macrophages and dendritic cells. Plays an important role in tissue infection first to encounter antigen that has entered the hosts tissue. Lymph filters through a cellular network of phagocytic cells that can present antigen to lymphocytes. Three distinct regions: B cells must pass 1. Cortex outermost layer that contains lymphocytes (primarily B cells), macrophages and dendritic cells arranged in primary follicles. through T-cell rich 2. Paracortex inside the cortex;paracortex to number of T cells and dendritic cells that migrate in contains a large interact from tissue. These dendritic cells express a high level of MHC II complexes. with antigen 3. Medulla center of node; sparsely populated; contains antibody-secreting plasma cells.

presenting cells

Antigenpresenting dendritic cells and M enter via afferent vessels

B cells and other lymphocytes enter via the node artery

Secondary lymph organs and infection

Secondary lymphoid organs contain Lymphoid Follicles

Lymphoid tissues that are found along lymphatic vessels Lymph nodes and the spleen are the most highly organized secondary immune organs

Lymph nodes

Spleen

Mucosa-associated lymphoid tissue (MALT)

germinal center

Contain lymphoid follicles: Primary follicle

Not yet activated by antigen. Contains follicular dendritic cells and small, resting B cells.

Secondary follicle
After antigen contact. Enlarges and organizes into a mantle of concentrically packed B cells surrounding a germinal center proliferating and mature, non-dividing B cells, TH cells interspersed with macrophages and follicular dendritic cells.

mantle

Secondary lymph organs and infection

Interaction of the circulatory and lymphatic systems

Fluid circulatory system capillary Plasma Interstitial fluid

Tissue

Lymph

lymphatic system
Lymphocytes, dendritic cells, macrophages and other cells can also pass through the entothelial lining of the primary lymphatic vessels

Foreign material and antigen that is introduced into tissue is typically picked up by the lymphatic system and transported to secondary organs

Secondary lymph organs and infection

Interaction of the circulatory and lymphatic systems

Route by which things are delivered to the lymph nodes.

Nave lymphocytes via blood vessels.

Lymph node

Antigens from the site of infection are delivered via the lymphatic vessels.

Secondary lymph organs and infection

Interaction of the circulatory and lymphatic systems

Following antigen interaction, lymphocytes undergo clonal selection and begin to leave the lymph nodes and enter the blood stream

THIS PROCESS TAKES 4 TO 6 DAYS!!!

1 WEEK OF OUCHIE THE FIRST TIME YOU ENCOUNTER AN ANTIGEN!

Secondary lymph organs and infection - Spleen

Large secondary lymphoid organ situated high left in the abdominal cavity.
Plays an important role when antigens enter the blood responds to systemic infection Blood (NOT lymph), with antigens and lymphocytes enters the spleen via the splenic artery and leaves via the splenic vein more recirculating lymphocytes pass through the spleen every day than all lymph nodes combined! Capsule with trabecular extensions contains two compartmentalized tissue types: 1. Red Pulp contains high number of macrophages and few lymphocytes. Site where old and defective blood cells (particularly erythrocytes) are destroyed and removed. 2. White Pulp surrounds the branches of the splenic artery to form the periarteriolar lymphoid sheath (PALS) that is heavily populated by T lymphocytes. Contains primary lymphoid follicles that are rich in B cells. Surrounded by a marginal zone that is populated by lymphocytes and macrophages.

Splenic

Splenic

Hilus

Secondary lymph organs and infection - Spleen

Secondary lymph organs and infection Mucosa-Associated

Lymphoid Tissue (MALT)

Situated in the lining of the digestive, respiratory and urogenital tracts.
Protects mucosal tissue from infection total area of 400 m2 May be: 1. a loose, unorganized collections of lymphoid cells. 2. highly organized structures such as the Peyers patches of the intestines, the tonsils and the appendix. Very high number of plasma cells more antibody-secreting cells than in the spleen, lymph nodes and marrow combined! Mucosa layers: 1. Epithelial layer Intraepithelial lymphocytes: mostly T cells that scavenge for antigen. M cells deliver foreign antigen from the lumen to the underlying MALT. 2. Lamina propria Loose clusters of activated TH cells, B cells, plasma cells and macrophages. Lymphoid follicles, including Peyers patches. No microvilli Delivers antigen to a pronounced pocket containing TH cells, B cells and macrophages

Secondary lymph organs and infection - MALT

Peyers patches are found in the digestive tract mucosa

Secondary lymph organs and infection Mucosa-Associated

Lymphoid Tissue (MALT)

MALT may be sub-classified based on location:

SALT - skin-associated lymphoid tissue GALT - gut-associated lymphoid tissue Includes Peyer's patches
BALT - bronchus-associated lymphoid tissue NALT - nasal-associated lymphoid tissue LALT - larynx-associated lymphoid tissue VALT - vascular-associated lymphoid tissue

CALT - conjunctiva-associated lymphoid tissue