Key concepts from last lecture
• • • • • • • • • • Pathogen Antigen Antibody? B cells (Plasma cells) T cells (Th&Tc) Innate immunity Adaptive immunity Passive immunity Active immunity History • • • • • • Overview of immune response Cell mediated immunity Humoral immunity Phases of immune response Adaptive immunity has memory Primary and secondary response • What happens on immunization
Today’s Objectives
1. What are the main cell types of the immune response? 2. Where are they, where do they come from, what do they look like, what are their major functions?
3. How does this package fit together to give you a circulating immune system? 4. Describe the overall physical organization of the immune system and the different roles played by primary and secondary lymphoid organs.
Blood composition
– 55% Plasma (fluid matrix of water, salts, hormones, proteins, Ab, metabolites, etc.) – 45% Cellular elements: Red Blood Cells (RBCs): 5-6 million RBCs/ml of blood. Contain hemoglobin which transport oxygen and CO2. White Blood Cells (WBCs also called leukocytes): 5,000-10,000 WBCs/ml of blood. Play an essential role in immunity and defense. Include: Lymphocytes: T cells, B cells and NK cells Macrophages (phagocytes) Granulocytes: Neutrophils, basophils, and eosinophils. Platelets/Thrombocytes: Cellular fragments. 250,000400,000/ml of blood. Important in blood clotting, release growth factors/cell differentiation/proliferation/blood cells/blood vessel/healing properties.
Name two types of fluid that circulate in our body?
1. Blood 2. Lymph: • • • • • •
Tissue fluid/interstitial fluid/intercellular fluid Colorless, composition similar to blood serum. Collected from tissue into lymph vessels by diffusion Along with it are collected Antigens (pathogens/toxins) Added to blood in the heart
Where are they (immune components)?
Blood
Serum Proteins
White Blood Cells (Leucocytes)
•Immunoglobulins •Complement •Clotting factors • Growth factors • Many others
Lymphocytes (T cells, B cells & NK cells)
Phagocytic/den dritic cells (macrophages, dendritic cells, NK cells etc)
Where are they?
Eosinophil
Neutrophil
Macrophage Lymphocytes
15-40%
Basophil
Hematopoiesis
• The process of
– proliferation – differentiation & – maturation of blood cell
Hematopoiesis
• Mostly in bone marrow from stem cells • Regulated by cytokines & growth factors
Routes for hematopoietic stem cell (HSC)
HSC
HSC
Self renewing
Differentiation and Maturation
Blood Cell (RBCs and WBCs)
Stromal cells
Non-hematopoietic cells found in bone marrow
Form a meshwork for HSC growth
Provide microenvironment consisting of cellular matrix + hematopoietic growth factors
(these proteins/Growth factors induce differentiation and maturation)
Thus stromal cells support HSC differentiation and maturation
When infection occurs: Activated T cell and macrophages produce hematopoitic growth factors stimulate hematopoiesis
Development of immune cells
HSC
Dendritic cell Myeloid Progenitor Macrophage Monocyte
Granulocyte monocyte progenitor
Lymphoid Progenitor
Natural killer (NK) cell
Neutrophil
T cell Progenitor
TH cell
Eosinsophil progenitor
TC cell B cell Progenitor
Eosinophil
Basophil progenitor
B cell
Basophil
Megakaryocyte
Platelets
RBC
Erythroid progenitor
Dendritic cell
Where do they come from?
Where do they come from?
Cytokines and Growth factors
IL = Interleukins
In Vitro Hematopoiesis
Adherent layer of stromal cells Bone marrow cells added (HSCs)
Cell culture in semisolid agar Growth of bone marrow cell colonies
Used for detection and identification of HGFs
Eg. Cytokine called colony stimulating factors (CSFs) • Acidic glycoproteins • Induce the formation of hematopoitic cell lines Eg. Cytokine Erythropoietin (EPO) • Glycoprotein involved in terminal development of RBCs
Cells of the Immune System
Immune System
Bone marrow lymph
Myeloid Cells
Lymphoid Cells
Granulocytic
Monocytic
T cells
B cells
NK cells
Neutrophils Basophils Eosinophils
Macrophages Dendritic cells
Helper cells Plasma cells Cytotoxic cells
Lymphocytes
• • • • • • •
Group of WBC (20 - 40%) 99% cells in lymph Three classes of lymphocytes Morphologically similar Each has distinct function Circulate in blood and lymph Migrate to tissue spaces and lymphoid organs
Lymphocytes Classes
Class B Lymphocytes T lymphocytes a) Helper T cell Function Antibody production
b)
-Stimuli for B-cell growth and activation - Release cytokines for macrophage activation Cytolytic T cell - Phagocytic, Lysis of pathogen infected cells - Lysis of pathogen infected cells, virus infected cells, tumor cells etc
Natural Killer cells
Lymphocyte subsets
CLP Common Lymphoid Progenitor
Naive T cell Naive B cell
Antigen activation
Antigen activation
TC cell CYTOTOXIC T LYMPHOCYTES Kill pathogen infected cells
TH cell
T HELPER CELLS Activate B cells and macrophages Secrete cytokines
B cell PLASMA CELLS Produce antibodies
Adaptive immunity
Naive Lymphocyte
Antigen activation
Effector cells • Short life (days to weeks) • Eliminate antigen
Memory cells • Long lived years • Give life long immunity against a particular antigen
TC cell CYTOTOXIC T LYMPHOCYTES
B cell T HELPER CELLS PLASMA CELLS
TH cell
Name and Maturation
B cell mature in bone marrow Called B cell (not true)
B cells got their name because B cell differentiation was first demonstrated in the bursa of Fabricius of chicken embryos.
T cell mature in thymus therefore called T cell
B cell
• Membrane bound Immunoglobulins (Ig)/Antibodies (Ab) on surface • These are receptors for Ag: recognize free Ag • ~1.5 x 105 Ab on B-cell surface • Other molecules on B-cell surface are CD40 (interaction with TH cell), MHCII (APC), (Major histocompatibility complex) CR1 and CR2 (receptor for complement products) • B cell Ab binds to Ag and also interacts with TH/macrophages • Activation of naïve B-cell • B cell divides and differentiate • Plasma cells + Memory cells • Plasma cells secrete Ab and die in 1-2 weeks
T cell
• Membrane bound T cell receptor (TCR) on surface • TCR receptor for Ag • Does not recognize free Ag • Recognizes Ag bound to MHC molecules on self-cells • TH cells express CD4 = CD4+T-cell • TC cells express CD8 = CD8+T-cell • CD4+T-cell recognize Ag bound to MHC II • CD8+T-cell recognize Ag bound to MHC I • CD4+T-cell: CD8+T-cell/TH:TC = 2:1 TH cells Ag on MHCII Activated Effector cells Secrete cytokines Cytokines activate Bcell, Tcell and macrophages Tc cells Ag on MHCI Interaction + Cytokines =Activated Effector cells= cytotoxic Tcell (CTL) Recognize and eliminate infected cells
Regulatory T cells (Treg)
CD4+CD25+Foxp3+ regulatory T cells, or "Tregs" Also known suppressor T cells (Ts) • The immune system must discriminate between self and non-self. • When self/non-self discrimination fails, the immune system destroys cells and tissues of the body and as a result causes autoimmune diseases (AID). • Autoimmunity against hematopoietic stem cell causes Aplastic anemia • Bone marrow transplant /Stem cell transplant • Regulatory T cells actively suppress activation of the immune system and prevent pathological self-reactivity, i.e. autoimmune disease. • The critical role regulatory T cells play within the immune system is evidenced by the severe autoimmune syndrome that results from a genetic deficiency in regulatory T cells.
Functions of T reg cells
1. Prevention of autoimmune diseases by establishing and maintaining immunologic self-tolerance . 2. Suppression of allergy and asthma. 3. Induction of tolerance against dietary antigens, i.e. oral tolerance. 4. Induction of maternal tolerance to the fetus .
Still research is ongoing?
A third kind of lymphocytes
Release lytic granules that kill Virus infected cells + Tumor cells
•Granules contain porins and granzyme (serine) proteases •Cause lysis or apoptosis of infected/tumor cells
Natural Killer cells
NK cells recognize potential target cells by the following ways
Tumor cells and virus infected cells display Ags on surface Antibodies (produced against these Ags by immune system) bind to theses Ags on the surface of infected cells CD16 receptor on NK cells recognizes antibodies (Fc) Destroys the target cell Process is called Antibody dependent cell mediated cytotoxicity (ADCC)
NK cells also recognize abnormalities on infected or tumor cells • Reduction in display of MHCI on surface • Unusual profile of surface Ags
The cells of the immune system
White Blood Cells
Lymphocytes
Other WBCs
B, T, NK
Phagocytic APC
Phagocytic
Secretory
Dendritic Macrophages
Neutrophil Eosinophil
Basophil Mast cell
Big in size Fix or moving Professional APC Secrete hydrolytic Enz. Innate immunity
Professional APC Present to TH cells
Most abundant WBCs Migrate to infection sites kill the invader
Non-phagocytic MC Precursor in Bone marrow Migrate blood tissue Differentiate in tissue Role in allergic reactions
The cells of the immune system
White Blood Cells
Lymphocytes
Other WBCs
B, T, NK
Phagocytic APC
Phagocytic
Secretory
Dendritic Macrophages
Neutrophil Eosinophil
Basophil Mast cell
Organs of the immune system
Lymphatic system: It is a network of lymph vessels that collects the fluid and lymphocytes that escape into the tissues from blood capillaries and returns these back to the circulating system. Lymph organs + lymph
Based on Function:
MALT: Mucosal associated lymphoid tissue:
(less organized compared to lymph nodes, includes: small Intestine – Peyer’s Patches, tonsil, appendix,)
The tertiary lymphoid tissue
• Far fewer lymphocytes • Assumes an immune role only when challenged with antigens • Generally result in inflammation. • It achieves this by importing the lymphocytes from blood and lymph
CALT (Cutaneous Associated Lymphoid Tissues)
Thymus
Thymus: • Site for Tcell dev and maturation • Flat • Bilobed organ • Situated above the heart • Each lobe has two compartments Cortex: outer Medulla: inner • Cortex: densely packed with immature T cells called thymocytes • Medulla: few thymocytes
Thymus
•Cortex+Medulla has stromal cell network • Stromal cell network help in differentiation and maturation of T cells • Composed of epithelial cells, dendritic and macrophages • Thymic epithelial cells called Nurse cells Nurse cells form membrane extensions surround many thymocytes form multicellular complexes
Selection process in thymus • Only 5% of T cells recognize Ag on MHC complex of APC • Rest 95% die (these cannot recognize Ag/or recognize self Ag)
Thymus does not work, No T cells, no cell mediated immunity, infectious diseases inc.
Age and Thymus
With age cell content of thymus decreases Size decreases Fat content increases Decline in thymic function Leads to decline in immune function
Birds (Bursa), primates+ rodents (primary lymphiod organ), cattle+sheep (spleen) different site of B cell maturation
Largest lymphatic vessel in the body. Collects most of the lymph in the body Empties it into left subclavian vein
•Blood flowing with pressure •Plasma seeps through the walls of capillaries • This fluid is called interstitial fluid • Most of it returns back to blood • Rest of this interstitial fluid is called lymph • Lymph collected by lymphatic capillaries network • Flows to large lymph vessels • Largest lymph vessel called Thoracic duct empties it in heart vein • Flow in the lymph achieved by muscles in the body •Ag is picked by lymph syst and carries to secondary lymphoid organs: lymph nodes and traped there • Lymph system also transports immune components to various sites
• Bean shaped structure • divided into three regions • Outer most: Cortex Contains lymphocytes ( B-cells mostly), Mac + dendritic cells = Primary follicle (PF) Ag challange PFs enlarges to Secondary follicles (SFs) Each SF has a germinal centre (GC) GC where B cell proliferate • Paracortex Contains ( T-cells mostly + dendritic cells APC:MHCII) to Th cells • Medulla Few cells mostly Plasma cells secreting Ab
•Afferent vessel carries lymph containing pathogens to lymph nodes into Cortex, paracortex medulla. •Macrophages/dendritic cells of lymph attack and present Ag by MHC molecules. •Activate B cells and T cells
•Efferent vessel carries lymph away from the lymph nodes •Lymph leaving the lymph node is rich in Abs secreted by Plasma cells in medulla and other activaed lyphocytes
Spleen
• Mounts immune response in blood • Large ovoid secondary lymphoid organ • traps blood born Ag • not connected with lymphatic vessles • Ag supplied by splenic artery • It has a capsule • Projection from capsule goes to the interior of spleen • compartments are formed • Two compartments •Red pulp (old RBCs removed here) •White pulp •Red pulp: Mac+RBCs • White pulp: mostly T cells, DC and few B cells, forms PALS • Marginal zone Primary follicles + GC
Self-reading
MALT intestine Mucosal membrane of gastrointestinal tract (stomach+intestine)
•Loose clusters: B cells, Plasma cells Th cells Macrophages •Ab are secreted in the lumen
M-cells Epithelial cells specialized for Ag transport
M cells
M cells lie above Inductive site:
Self-reading
Evolution and lymphoid cells and organs
• Innate immunity found in invert. + plants • Addaptive immunity mediated by Ab+Tcells found in vertebrates • All lyphoid tissues are not present in all vert. • With evolution new lymphid organs were added • Retains the old ones • Eg B and T cells not present in jaw less fish (Lamprey = GALT gut associated) • Shark is has jaws and it also has B and T cells