Lymphoid Organs

Hematopoiesis
the formation of red and white blood cells

Occurs via pluripotent hematopoietic stem cells (HSCs)

Self renewing

Yolk sac --> Liver --> Spleen -- (adulthood) --> Bone

Marrow (BM) Present at low concentrations in BM (less than 1-in5x104) High proliferative capacity HSCs differentiate towards a myeloid or lymphoid lineage Stem cells differentiate into committed progenitor cells (which do not self-renew)

Generation of Leukocytes, Platelets and Erythrocytes from HSCs

Fig. 2-1

Growth and Death of HSCs

In the BM, HSCs require stromal cells

(stroma) to grow Growth of HSCs is dependent on hematopoietic growth factors and cytokines
IL-3 M-CSF, G-CSF, GM-CSF

Erythropoietin (EPO)

Differentiation is regulated by hematopoiesis

genes Cell number is limited by programmed cell death (apoptosis)

 Primary Lymphoid Organs - sites

of lymphocyte maturation; include the BM and thymus

Secondary

Lymphoid Organs sites where antigen is trapped, and brought into contact with lymphocytes (differentiation)
Lymphatic System network of

vessels which collect fluid component of blood after it has drained to tissues; collects antigen from tissues and brings it to secondary lymphoid organs

Thymus
Bi-lobed organ sits

above the heart Site of maturation and selection of T cells Thymocytes which cannot recognize self MHC proteins, or which bind self antigen, are deleted by apoptosis Medulla contains mature T cells Cortex contains mainly of immature cells Atrophies with age (thymic involution)

T Cell Development and Thymic Maturation

TCR

Thymocyte

Thymus
TCR TCR

CD4 T Cell
(Helper T Cell)

CD4

CD8

CD8 T Cell
(Cytotoxic (killer) T Cell)

TCR

TCR

CD4

Approximately 90 - 95% of all thymocytes die in the thymus!!!

CD8

 Site of generation,

Bone Marrow

maturation and selection of B cells B cells interact directly with stromal cells during selection Mature, immunocompetent B cells exit BM and migrate to secondary lymphoid organs (only ~ 10%) Site of generation of T progenitor cells

Secondary Lymphoid Organs

Consist of lymph nodes (LN), spleen, and

mucosal-associated lymphoid tissue (MALT) which include tonsils, Peyers patches and appendix
Antigen in tissues is transported by lymphatic

system to secondary lymphoid organs where it is trapped

Newly-developed, immunocompetent lymphocytes

(T and B) migrate to secondary lymphoid organs where they interact with antigen, become activated, differentiate and mutate, divide and multiply

Lymph Node

Spleen

Spleen
Largest secondary lymphoid organ

Major organ in the body in which antibodies

are synthesized and from which they are released into the circulation Function: filters blood and traps bloodborne antigens; can respond to systemic infection Consists of white and red pulp 50% of cells are B cells, 30 40% are T cells and the remaining population are plasma cells and macrophages

Lymph Nodes
located along lymphatic ducts and serve as central

collecting joints for lymph fluid from adjacent tissues main function is filtration; ideal site for phagocytosis Medulla consist mainly of plasma cells while the cortex contains T cells and macrophages where the blast transformation of B cells take place (germinal center) plasma cells, memory cells are also present in the germinal center its primary function is the generation of B cell memory contains immobile B lymphocytes

Other Lymphoid Tissues

Includes GUT-associated lymphoid tissues and MALT At MALT macrophages and lymphocytes are localized at some of the main portals of entry for foreign organisms Peyers patches specialized type of MALT, located at the lower ileum of the intestinal tract

Other Lymphoid Tissues

Tonsils small masses of lymphoid tissue found in the mucous membrane lining of the oral and pharyngeal cavities Appendix also considered MALT

Lymphoid Cells
Approximately 1011 lymphocytes in the

human body Three main types of lymphocytes:

B Cells T Cells

Null Cells (Large granular lymphocytes (LGLs)

or Natural Killer (NK) Cells)

Transition through cell cycle from small

lymphocytes (nave) --> lymphoblasts --> effector cells or memory cells

Fig. 2-7

Clonal Selection of B Cells is Caused by Antigenic Stimulation

Humoral Response to T Dependent Antigens

B Lymphocytes First identified in the Bursa of Fabricius in

birds In humans, B cells develop in the Bone Marrow Primary effectors of humoral immunity, via antibody production Can be divided into memory and plasma B cells Recognize antigen by means of surfaceexpressed antigen receptor Distinguishing cell-surface markers include: B220 (CD45), MHC Class II, CD80 (B7-1) and CD86 (B7-2), CD40, CD19, CD21, etc.
Bursa of fabricius

T Lymphocytes
70% T cells (5 10% B cells and 10 15% are nulls cells)
T cells derive from stem cells in the bone marrow, mature in the thymus, and then are released into the periphery
Primary effectors of cellular immunity Can be divided (broadly) into helper T cells (Th) and cytotoxic T cells (Tc), usually found in a 2:1 ratio Similarities between T and B cells:
Antigen receptor on surface (T cell receptor or TCR) Recognize single, specific antigen Expand through clonal selection Some T cells exist as long-lived memory cells

Distinguishing cell-surface markers include TCR, CD3, CD2, CD4 or CD8, CD28, and CD45

T lymphocytes

have the ability to bind sheep erythrocytes, the clumps of cells formed are called E-rosettes (E+ cells) progenitor T cells appear in fetus as early as 8 weeks of gestation surface characteristics:
ability to bind to certain lectins ability to interact with the measles virus exhibit receptors for FC portion of IgM and IgG

Unlike B cells, T cells cannot recognize free antigen; it must be:

Processed (digested) in to smaller fragments within special antigen presenting cells (APCs) Presented on the surface of APCs in the context of MHC (major histocompatibility complex) proteins

Antigen Processing and Presentation

TCR

T Cell

APC

APC

APC
MHC + Ag

CD - Cluster of Differentiation

Table 2-4

T cell subsets
Activator T cells (Ta)
amplify killer to cell differentiation

Helper T cell (Th)

helps the B cell to produce antibody in response to

antigen activation of B cell and their differentiation into antibody-secreting plasma cells

Suppressor T cells (Ts)

inhibits initiation or expression of the response of T and

B cells to antigen

Cytotoxic T cells (Tc) or killer cells

causes death of the cell and destroy the inciting antigen

against which they specifically sensitized

Delayed type of hypersensitivity (Td or Tdth)

responsible for delayed type of hypersensitivity reaction

Helper T Cells
Helper T cells (CD4 T cells) produce proteins (cytokines) which act on B cells, stimulating them to produce antibodies

T Helper (TH) Cells: Central role in immune response.

Most are CD4+ Recognize antigen on the surface of antigen presenting cells (e.g.: macrophage). Activate macrophages Induce formation of cytotoxic T cells Stimulate B cells to produce antibodies.

Central Role of Helper T Cells

Helper T cell Role

Cytotoxic (Killer) T Cells

Cytotoxic T cells (CD8 T cells) attack their target cells (e.g. virally-infected cells) and kill them directly..

Cytotoxic (Killer) T Cells

Cytotoxic T (Tc) Cells: Destroy target cells. Most are CD4 negative (CD4 -). Recognize antigens on the surface of all cells: Kill host cells that are infected with viruses or bacteria. Recognize and kill cancer cells. Recognize and destroy transplanted tissue. Release protein called perforin which forms a pore in target cell, causing lysis of infected cells. Undergo apoptosis when stimulating antigen is gone.

Cytotoxic T Cells Lyse Infected Cells

Null Cells
Referred to as Null cells because they are

lymphocytes, but lack typical B cell or T cell markers on their surface Also known as large granular lymphocytes (LGLs) or natural killer (NK) cells Demonstrate cytotoxicity against tumor cells and some virus-infected cells most effect as killer cells in antibody-independent Cytotoxic reactions Not specific. Dont require antigen stimulation. Not phagocytic, but must contact cell in order to lyse it. NK1-T cell - Recently identified subset displaying some T cell markers (e.g. TCR), functions

Other Cells
Plasma cells (Plasmocyte)
known as mature antibody-producing cells contain large includsion bodies called Russel

bodies derived from B lymphocytes

Monocytes (peripheral blood)/Macrophage

(tissues)

formed in bone marrow, spleen and tissues of

RES function in amoeboid movement and phagocytosis (immune response)

Granulocytes
Neutrophils important in the bodys defense
(phagocytosis & destruction of microorganisms) process facilitated by complement and antibody

Basophils and Mast cells

contain heparin important in immediate hypersensitivity

reactions found in large numbers in some cell.-mediated delayed reactions: skin graft or tumor reject, hypersensitivity

Granulocytes
Eosinophils has a specialized role in immunity to helminth infections found in tissues at sites of immune response or reaction that have been triggered by IgE antibodies activated when antigen triggers IgE coated mast cells to release an eosinophil chemotactic factor of anaphylaxis attracted to antigen-antibody complex and can phagocytize them contain a number of enzymes that can degrade mediators of immediate hypersensitivity

Histamine slow reacting substance of anaphylaxis PAF (Platelet Aggregating Factor) control or diminish such hypersensitivity

Mast Cells
Found in a wide variety of tissues,

including:
skin
connective tissues

mucosal epithelial tissues of the respiratory,

genitourinary and digestive tracts

Heavily granulated

Granules contain histamine; degranulation

of mast cells results in histamine release, allergic/inflammatory response

Generation of Leukocytes, Platelets and Erythrocytes from HSCs

Fig. 2-1

Mononuclear Cells
Consist of monocytes (in blood) and

macrophages (in tissues) Macrophages (ms) are larger, more complex, and produce more hydrolytic enzymes There are multiple types of macrophages, defined by location:

Alveolar macrophages (lungs) Histiocytes (connective tissues) Kupffer cells (liver) Mesangial cells (kidney) Microglial cells (brain) Osteoclasts (bone) Splenic macrophages (spleen) Peritoneal macrophages (peritoneal fluid) Dendritic cells (lymph nodes) Langerhans cells (dendritic cells in the skin)

Functions of Macrophages
Phagocytosis
Chemotaxis
Formation of pseudopodia Opsonization (by antibody)

Antimicrobial and cytotoxic

activities Antigen processing and presentation Protein secretion

Interleukin 1 (IL-1) IL-6

Complement proteins
TNF-a

Dendritic Cells

Lineage/origin is not

entirely understood Express high levels of MHC class II and B7 molecules, making them extremely potent APCs Multiple different types, based on location (similar to m) Langerhans cells found in skin and mucous membranes