Immunology 146:474

• Tu, Fri 1st period (8:40-10:00 AM)• SRC 118• Dr. Lori Covey• Dept. of Cell Biology & Neuroscience

Nelson Hall, B314

• covey@biology.rutgers.edu• Class web site:

http://lifesci.rutgers.edu/~covey/Immuno/index.htm

Concepts to be covered today

• Properties of innate and adaptive immunity

• Different cell types involved in each type of immunity

• Lymphoid tissues• Function of each lymphoid tissue

Types of immunity“The state of

protection from infectious disease”

• Innate– Derived from primordial immune responses

– First line of protection

– Immediate– No memory

• Adaptive– Antigen-specific– Delayed– Development of immunological memory

– 2 functional arms• Humoral Ab-mediated

• Cell-mediated-primarily CD8+ T cells

Innate Immunity

• Components present before onset of infection

• Disease-resistance mechanisms that are not specific to a particular pathogen

• Pathogens must first breach barriers that protect hosts

Pattern Recognition

• Many of the molecules involved in innate immunity have property of pattern recognition

• Patterns unique to microbes not found in multicellular organisms

• May be soluble molecules (lysozyme or complement proteins) or cell-associated receptors (Toll-like receptors (TLRs)

Natural Barriers to infections

• Skin• Mucosal membranes• Acidity of the stomach & perspiration

• Lysozyme in tears

• Barrier loss occurs in response to bites by animals, insects, burns, cuts, etc…

Innate Immunity

• Provides the first line of defense right after exposure

• Most microorganisms are readily cleared within a few days by innate immune system before adaptive immune system is activated.

Adaptive Immunity

• Comes into play after there is a recognized antigenic challenge to the organism

• Not the same in all members of a species but are reactions to specific antigenic challenges

• 4 characteristic attributes– Antigenic specificity– Diversity– Immunological Memory– Self-non-self recognition

Adaptive Immunity• Humoral Immune responses

mediated by serum antibodies produced by B lymphocytes, I.e. the effector molecule is the antibody molecule

• Cell-Mediated Responses depends on the function of T cells– Depends on both T helper (TH) and cytotoxic T lymphocytes (CTLs) serve as effector cells

Stem Cells

• Differentiate into all other cell types

• Self-renewing, maintaining their population level by cell division

• In humans, begins in embryonic yolk sac during first weeks of development

• By 3rd month, stem cells have migrated from ys to fetal liver and then colonize the spleen (hematopoesis from 3-7 months)

Hematopoiesis

Figure 1-3 part 1 of 4The Hematopoietic system develops in the bone

Marrow

CLPCMP

Ability for self-renewalGive rise to all classes of cells

Figure 1-3 part 2 of 4

Figure 1-3 part 3 of 4

Purification of Bone marrow stem cells

Take bone marrow

Stem cells <0.05% of cells

DifferentiationAntigen-Stem cell antigen 1 or

Sca-1

Stem cell

Bone marrow reconstitutionReconstitute

Irradiated mouse with

Bone marrow fromGenetically identical

(syngeneic) Mouse. The

Complete Hematopoietic

system isrestored.Take bone marrow or

Sca1+ cells

Take spleen

Mononuclear phagocytes

Monocytes (blood)--> migrate to tissues and differentiate, Cell enlarges 5-10-fold

Acquires increased phagocytic ability

Specific tissue macrophageIntestinal macrophage (gut)aveolar macrophages (lungs)histiocytes (connective tissues)Kupffer cells (liver)Mesangial cells (kidney)Microglial cells (brain)Osteoclasts (bone)

Dendritic cells

Extensions that resemble DendritesFour Major Categories

Langerhans DCs epidermal layers of skinInterstitial DCs interstitial spaces of all

tissues except brainMonocyte-derived DCsmigrated from blood to tissuesPlasmacytoid-derived DCs

arise from plasmacytoid cells

Figure 1-4 part 1 of 3

Granulocytic Cells• Neutrophils-ciruculate 7-10 h before migrating into the tissues (short life span approx. 2 days), Usually first cells to arrive at site of infections-are phagocytes

• Eosinophils-motile phagocytic cells, defense of parasitic organisms

• Basophils-non-phagocytic granulocytes

Figure 1-4 part 2 of 3

Granulocytic Cells…Basophils-non-phagocytic granulocytes, release pharmacologically active substances from their cytoplasmic granules-Allergy

Mast Cells-precursors are formed in the Bone Marrow, released into the blood as undifferentiated cells

Differentiate when they leave the blood and enter the tissuesLarge nos. of cytoplasmic granules that contain histamine and other pharmacologically active substances, play important role in allergy

Figure 1-4 part 3 of 3

B lymphocytes

• Display membrane-bound immunoglobulin or antibody-serve as receptors for antigen (ag)

• Once ag is encountered, B cells differentiate into plasma cells or memory B cells; plasma cells produce lg amounts of Ab but have a short life span-end stage cell.

B lymphocytes…

• Memory B cells, very long-lived, express same membrane-bound Ig as parent cell.

T lymphocytes (T cells)

• Mature in the thymus• Expresses a membrane-bound receptor called T cell receptor (TCR)

• Two well-defined subpopulations– T helper (TH)

– T cytotoxic (TC)

Recent subpop. Termed T regulatory (Treg)

T lymphocytes (T cells)…

• TH cells generally express CD4• TC cells generally express CD8• Ratio in human blood of CD4:CD8 is approx. 2:1

• Primary function of TH cells is to help other cells produce an immune response suggest as B cells, macrophage, Tc cells.

T lymphocytes (T cells)…

• TC cells kill virally infected cells

• Tregs, suppress immune responses

• Once activated, T cells become either effector cells or memory cells

Resting T or B lymphocyte

Figure 1-6

• Lymphoid organs are separated into primary and secondary organs

– Primary--> bone marrow, thymus

– Secondary or peripheral--> lymphnodes, spleen, mucosal lymphoid tissues (GALT, MALT), provide sites for mature lymphocytes to interact with antigen

Maturation of the immune response

Figure 1-7

Ti

Different organs of the immune system

• Microenvironment for differentiation of stem cells

• Site of origin of B and T lymphocytes, all other cells of the immune response

• “Antigen-independent” maturation of B cells.

• Site for mature re-circulating lymphocyte populations

The role of bone marrow in immune maturation

• Cells move out of Bone Marrow into blood

• The bursa in the bird plays the same role for B cell maturation; appendix in rabbit

Bone Marrow

The thymus is the site of T cell differentiation

• Primary immune tissue• Located in the thorax• Sequestered from antigen

• Two lobes, surrounded by a thin capsule of connective epithelium

• Involutes with Age- maximal size at puberty and then atrophies

Thymus-structure/function

• Thymic stroma--> network of epithelia-contains T cell precursors.

• Dendritic cells, macrophage and medullary epithelial cells in thymic medulla

• Sub-capsular epithelium underlying capsule-acts as barrier

cortex

m

tr

HC

Lymphatic System

• Blood circulates under pressure, fluid component (plasma) seeps through capillaries into surrounding tissues– Called interstitial fluid– An adult-3 liters or more per day– Returned to blood through walls of the venules (prevents edema)

– Remainder of fluid enter lymphatic system

Lymphatic System…

• Porous architecture of lymphatic vessels (allows fluids and cells to enter)

• Thoracic duct = largest lymphatic vessel– Empties into L. subclavian vein (lymph from all the body except r. arm and r. side of head)

• Ensures steady-state levels of fluid within the circulatory system

Lymphatic System…

• Heart does not pump lymph

• Lymph flow is achieved by movements of the body’s muscles

• Series of one-way valves produces one-way movement through vessels

• Foreign antigen is picked up by the lymphatic system and carried to lymph nodes

Circulation of lymphocytes in response to infection

Peripheral or Secondary lymphoid tissues

• Trap antigen-bearing dendritic cells

• Initiation of adaptive immune response

• Provide signals that sustain recirculating lymphocytes

Lymph Nodes• Sites of Immune responses• Encapsulated bean-shaped structures, reticular network, full of lymphocytes, macrophages, and dendritic cells.

• First organized lymphoid structure to encounter antigens-reticular structures trap antigen

• Morphologically divided– Cortex– Paracortex– medulla

Lymph Nodes

• Cortex– Contains mostly B cells, macrophages and follicular dendritic cells

• Paracortex– Primarily T lymphocytes, and dendritic cells

• Medulla– Sparsely populated with lymphoid lineage cells (mostly plasma cells)

Figure 1-8 part 1 of 2Structure/function of the Lymph Node

Figure 1-8 part 2 of 2Structure/function of the Lymph Node

Med. sinus

GC

Paracortical

capsule

Germinal center fociReach maximumSize within 4 to 6 days of antigen challenge.

Spleen

• Major role in mounting immune responses to antigens in the bloodstream– Filters blood and traps antigens

• Not supplied with lymphatic vesicles– Splenic artery carries antigens and lymphocytes

Structure of the Spleen

• Surrounded by a capsule from which a number of trabeculae extend into interior (compartmentalized structure)

Structure of the Spleen

• Spenic red pulp consists of a network of sinusoids– Populated by macrophages, RBCs, and a few lymphocytes

– Site where old and defective RBCs are destroyed and removed

– Macrophage engulf RBCs

Structure of the Spleen…

• Spenic white pulp surrounds the branches of the splenic artery– Forms periarteriolar lymphoid sheath (PALS), populated primarily by T cells.

– Primary lymphoid follicles are attached to the PALS, are rich in B cells and some contain germinal centers

– Marginal zone, peripheral to the PALS, is populated by lymphocytes and macrophages

Organization of the White Pulp in the Spleen

Organization of a germinal center in the

spleen• PFZ-perifollicular zone

• PALS-periarticular lymphoid sheath

• Co-follicular B-cell corona

• MZ-marginal zone• RP-red pulp

Loss of spleen (splenectomy)

• Severity depends on age• In children, splenectomy often leads to increased incidence of bacterial sepsis

• Few adverse effects in adults, can lead to some increase in blood-borne bacterial infections (bacteremia)

MALT or Mucosa-assoc. Lymphoid Tissue

• Mucous membranes lining digestive, respiratory and urogenital system are the major sites of entry for most pathogens.

BALT -Bronchus-associated (respiratory)

GALT-gut-associated (digestive tract)

MALT…

• Have different organizations.– Peyer’s patches in intestinal lining well organized

– Barely organized clusters of lymphoid cells in lamina propria of intestinal villi

– Tonsils– appendix

• Large nos. of plasma cells (more than in the spleen and lymph Nodes)

Figure 1-10 part 1 of 2

Gut luminepithelium

dome

follicle

T-cell area

GC

dome

follicleGC

Antigen transport carried out by specialized cells called M Cells. Flattened epithelial cells laccing microvilliM cells have deep invagination which is filled with B, T cellsAnd Macrophage.

M Cells. Have a deep invagination or pocket, in the basolateral plasmamembrane, which is filled with a cluster of B cells, T cells andMacrophage.

Antigens in intestinal lumen are endocytosed into vesicles andTransported from the luminal membrane to underlying pocketMembrane

Vesicles fuse with the pocket membrane, delivering antigensTo lymphocytes and macrophage

Epithelial surfaces-largest barrier to infectionSkinEpithelial surfaces of the: Gastronintestinal tractUrogenital tractRespiratory tract

Cutaneous-Associated Lymphoid Tissues. Skin-anatomic barrier to the external environment.

Surface-kertinocytes-secrete cytokines that set up local inflam-Matory reactions

Langerhans cells-type of Dendritic cell-antigens are phago-cytosed

Migrate from skin to lymphnodes

Intraepidermal lymphocytes-mostly T cells

Dermal layer also contains scattered T cells and macrophage