Cell and organs of immune system

Chapter 2 Kuby

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

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.

Today’s Objectives

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. 250,000- 400,000/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. Blood2. 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

BloodBlood

Serum ProteinsSerum Proteins White Blood White Blood CellsCells

(Leucocytes)(Leucocytes)

•ImmunoglobulinsImmunoglobulins•ComplementComplement•Clotting factorsClotting factors• Growth factorsGrowth factors• Many othersMany others

Phagocytic/Phagocytic/dendritic cells dendritic cells (macrophages, (macrophages, dendritic cells, dendritic cells, NK cells etc)NK cells etc)

Lymphocytes (T Lymphocytes (T cells, B cells & cells, B cells & NK cells)NK cells)

Where are they (immune components)?

Where are they?

Lymphocytes15-40%

Neutrophil

Eosinophil

Basophil

Macrophage

                                                                                                                                 

               

Hematopoiesis

• The process of– proliferation – differentiation &– maturationof blood cell

• Mostly in bone marrow from stem cells• Regulated by cytokines & growth factors

Hematopoiesis

                                                                                                                                 

               

Blood Cell (RBCs and WBCs)

Self renewing

Differentiation and Maturation

Routes for hematopoietic stem cell (HSC)

HSC HSC

Stromal cells

Non-hematopoietic cells found in bone marrowForm a meshwork for HSC growthProvide microenvironment consisting of

cellular matrix + hematopoietic growth factors (these proteins/Growth factors induce differentiation and maturation)

Thus stromal cells support HSC differentiation

and maturationWhen infection occurs: Activated T cell and macrophages produce hematopoitic

growth factors stimulate hematopoiesis

MyeloidProgenitor

LymphoidProgenitor

HSC

Development of immune cells

B cellProgenitor

T cellProgenitor

B cell

TC cell

TH cell

Dendritic cell

Natural killer(NK) cell

Dendritic cell

Macrophage

Monocyte

Neutrophil

Eosinophil

Basophil

Platelets

RBC Erythroid progenitor

Megakaryocyte

Basophil progenitor

Eosinsophil progenitor

Granulocytemonocyte progenitor

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

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

Growth of bone marrow cell colonies

Cells of the Immune System

Immune System

Myeloid Cells

Lymphoid Cells

Granulocytic Monocytic T cells B cells

NeutrophilsBasophils

Eosinophils

Macrophages

Dendritic cells

Helper cells

Cytotoxic cellsPlasma cells

NK cells

Bone marrow lymph

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 ClassesClass Function

B Lymphocytes Antibody productionT lymphocytes a) Helper T cell

b) Cytolytic T cell

-Stimuli for B-cell growth and activation- Release cytokines for macrophage activation- Phagocytic, Lysis of pathogen infected cells

Natural Killer cells - Lysis of pathogen infected cells, virus infected cells, tumor cells etc

Lymphocyte subsetsCLP

CommonLymphoidProgenitor

NaiveT cell

TC cellCYTOTOXIC T

LYMPHOCYTESKill pathogeninfected cells

TH cellT HELPER CELLSActivate B cellsand macrophagesSecrete cytokines

NaiveB cell

B cellPLASMA CELLS

Produce antibodies

Antigen activation Antigen activation

TC cellCYTOTOXIC T

LYMPHOCYTESTH cell

T HELPER CELLSB cell

PLASMA CELLS

Adaptive immunityNaive Lymphocyte

Antigen activation

Effector cells Memory cells• Short life (days to weeks)• Eliminate antigen

• Long lived years• Give life long immunity against a particular antigen

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 cellsAg on MHCIIActivatedEffector cells Secrete cytokinesCytokines activate Bcell, Tcell and macrophages

Tc cellsAg on MHCIInteraction + Cytokines =ActivatedEffector cells= cytotoxic Tcell (CTL)Recognize and eliminate infected cells

• 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.

Regulatory T cells (Treg)

Also known suppressor T cells (Ts)

CD4+CD25+Foxp3+ regulatory T cells, or "Tregs"

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 .

Functions of T reg cells

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

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

NK cells recognize potential target cells by the following ways

White Blood CellsWhite Blood Cells

Other WBCsOther WBCsLymphocytesLymphocytes

The cells of the immune system

PhagocyticPhagocyticPhagocytic Phagocytic APCAPC SecretorySecretoryB, T, NKB, T, NK

Dendritic Dendritic MacrophagesMacrophages

NeutrophilNeutrophil EosinophilEosinophil

Basophil Basophil Mast cellMast cell

Most abundant WBCsMigrate to infection siteskill the invader

Big in sizeFix or movingProfessional APCSecrete hydrolytic Enz.Innate immunity

Professional APCPresent to TH cells

Phago = “eating”Cyte = “cell”

Phagocytic

Read from Kuby

Non-phagocyticAllergic responsesHeparin (stop blood coagulation)+Histmine (allergic reaction)

PhagocyticMotileDamage parasite memb

Non-phagocyticMC Precursor in Bone marrowMigrate blood tissueDifferentiate in tissueRole in allergic reactions

White Blood CellsWhite Blood Cells

Other WBCsOther WBCsLymphocytesLymphocytes

The cells of the immune system

PhagocyticPhagocyticPhagocytic Phagocytic APCAPC SecretorySecretoryB, T, NKB, T, NK

Dendritic Dendritic MacrophagesMacrophages

NeutrophilNeutrophil EosinophilEosinophil

Basophil Basophil Mast cellMast 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,)

• 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

The tertiary lymphoid tissue

CALT (Cutaneous Associated Lymphoid Tissues)

Thymus:

• Site for Tcell dev and maturation• Flat• Bilobed organ• Situated above the heart• Each lobe has two compartments

Cortex: outerMedulla: 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.

Thymus

With age cell content of thymus decreases Size decreases Fat content increases Decline in thymic function Leads to decline in immune function

Age and Thymus

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

• ParacortexContains ( T-cells mostly + dendritic cells APC:MHCII) to Th cells

• MedullaFew 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 intestineMucosal membrane of gastrointestinal tract (stomach+intestine)

•Loose clusters:B cells,Plasma cellsTh cellsMacrophages

•Ab are secreted in the lumen

M-cellsEpithelial cells specialized for Ag transport

M cells

M cells lie aboveInductive site:

Self-reading

• 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

Evolution and lymphoid cells and organs

Break

Clotting factors in serum