Marrow (BM) Present at low concentrations in BM (less than 1-in5x104) High proliferative capacity HSC’s 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 HSC’s
Fig. 2-1
Growth and Death of HSC’s
In the BM, HSC’s require stromal cells
(stroma) to grow Growth of HSC’s 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, Peyer’s 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 Peyer’s 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 (LGL’s)
or Natural Killer (NK) Cells)
Transition through cell cycle from small
lymphocytes (naïve) --> 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” (APC’s) • Presented on the surface of APC’s 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 (LGL’s) 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. Don’t 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 body’s 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 HSC’s
Fig. 2-1
Mononuclear Cells
Consist of monocytes (in blood) and
macrophages (in tissues) Macrophages (m’s) are larger, more complex, and produce more hydrolytic enzymes There are multiple types of macrophages, defined by location:
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 APC’s Multiple different types, based on location (similar to m) Langerhans cells found in skin and mucous membranes