Lecture 2: Cells, Tissues, and Organs of the Immune System part 1

Cells of the immune system:

 most of which originate from hematopoietic stem cells in the fetal liver and in the postnatal
bone marrow
 functions including:
 phagocytosis
 antigen presentation
 lysis of virus-infected cells
 Secretion of specific antibodies.
Cells of the innate immune system include monocytes/macrophages, polymorphonuclear
granulocytes, NK cells, mast cells, and platelets

 belong to the myeloid lineage and include:

 the monocytes: circulating blood cells
 the macrophages: differentiated from monocytes and residing in tissues
 The polymorphonuclear granulocytes (polymorphonuclear neutrophils [PMNs],
basophils, and eosinophils): circulating blood cells.
 All phagocytic cells are mainly involved in defense from extracellular microbes.
 Microbes express molecules called pathogen-associated molecular patterns (PAMPs).
 Cells of the innate system recognize microbes through their receptors to PAMPs called
pattern recognition receptors (PRR).

Antigen-presenting cells (APCs) link the innate and adaptive immune systems:

 Antigen-presenting cells (APCs) link the innate and adaptive immune systems by taking up
and processing antigens so they can be recognized by T cells, and by producing cytokines.
 They enhance innate immune cell function and they are essential for activation of T cells.

Adaptive immune system cells are lymphocytes:

 The lymphoid organs where the lymphocytes differentiate and mature from stem cells are
termed the primary lymphoid organs and include:
 The thymus – the site of T cell development.
 The fetal liver and postnatal bone marrow – the sites of B cell development.
 Cells of the T and B cell lineages migrate from the primary lymphoid organs to function in
the secondary lymphoid organ:
 encapsulated organs – the spleen and lymph nodes
 Non-encapsulated tissues, e.g. mucosa-associated lymphoid tissues (MALT).
 In the secondary lymphoid organs and tissues, lymphocytes undergo their final
differentiation steps, which occur in the presence of antigen
 As the cells of the immune system develop, they acquire molecules that are important for
their function called ‘lineage markers’
 Myeloid cells – polymorphs and monocytes; lymphoid cells – T and B cells.
 Other molecules include those involved in regulating cell differentiation
(maturation, development), and those involved in regulating the number of cells
participating in the immune response. Some of these are called ‘death receptors’
and mediate the programmed cell death (apoptosis)
Myeloid cells:

 Phagocytes belong to two major lineages that differentiate from myeloid precursors:
 Mononuclear phagocytes : monocytes/macrophages
o differentiate from monocytes and reside in a variety of organs (e.g. spleen,
liver, lungs, kidneys)
o in the lung as alveolar macrophages, in kidney as glomerular mesangial cells,
and in the liver as Kupffer cells
o Function: to remove particulate matter of ‘foreign’ origin (e.g. microbes) or
self-origin (e.g. aged erythrocytes).
o Myeloid progenitors in the bone marrow differentiate into pro-monocytes and
then into circulating monocytes, which migrate through the blood vessel walls
into organs to become macrophages.
o has a horseshoe-shaped nucleus, contains primary azurophilic (blue-staining)
granules; and has ruffled membranes, a well-developed Golgi complex, and
many intracytoplasmic lysosomes
o lysosomes contain peroxidase and several acid hydrolases, which are
important for killing phagocytosed microorganisms
 Polymorphonuclear granulocytes:
o Have a lobed, irregularly shaped (polymorphic) nucleus.
o classified into: neutrophils, basophils and eosinophils
o neutrophils also called polymorphonuclear neutrophils (PMNs),
 are most numerous & are released from the bone marrow & are short
lived
 They (adhere to endothelial cells lining the blood vessels) and
extravasate by squeezing between the endothelial cells to leave the
circulation to reach the site of infection in tissues. This process is
known as diapedesis.
 Adhesion is mediated by receptors on the granulocytes and ligands
on the endothelial cells, and is promoted by chemo-attractants
(chemokines) such as interleukin-8 (IL-8)
 Chemotactic agents attracting neutrophils to the site of infection
include: protein fragments released when complement is activated
(e.g. C5a); & factors derived from the fibrinolytic and kinin systems &
the products of other leukocytes and platelets; and the products of
certain bacteria
 Have two main types of granule:
1. The primary (azurophilic) granules: are lysosomes containing
acid hydrolases, myeloperoxidase, and muramidase
(lysozyme); antimicrobial proteins including defensins,
seprocidins, cathelicidins, and bacterial permeability inducing
(BPI) protein.
2. The secondary granules (specific to neutrophils) contain
lactoferrin and lysozyme
o the primary actions of eosinophils and basophils, which can both function as
phagocytes, involve granule release
Granulocytes and mononuclear phagocytes develop from a common precursor:

 Progenitor of Myeloid lineage(CFU-GEMM): give rise to which PMNs, monocytes and

megakaryocytes but monocytes and neutrophils arise from CFU-granular macrophage (CFU-
GMs).
 CFU-GEMMs differentiation is based on factors like colonies stimulating factor (CSFs) and
interleukin 3. Which is produced by mature lymphoid and myeloid cells, or from stromal
cells(connective tissue) in the bone marrow. Transforming growth factor b(TGFB)
downregulate hemopeiosis.

Monocytes express CD14 and significant levels of MHC class II molecules:

 Markers can be lost in differentiation e.g Non differentiated hematopeiotic stem cells
contain CD34 but they’re lost by differentiation. Or MHC-2 can be found in CSF-GMs but only
monocyte continue to express it.
 Mononuclear phagocytes express CD14 which is part of the receptor complex for the
lipopolysaccharide of Gram-negative bacteria).
 Mononuclear also acquire molecules found on mature neutrophils like CD11a and b and Fc
receptors that recognise antibodies e.g FcyR1, and FcyR11. igG)

Neutrophils express adhesion molecules and receptors involved in phagocytosis:

 Myeloblasts develop into promyelocytes and myelocytes, which mature and are released
into the circulation as neutrophils.
 Surface differentiation markers disappear or are expressed on the cells as they develop into
granulocytes. For example, MHC class II molecules are expressed on the CFU-GM, but not on
mature neutrophils
 Surface molecule that are acquired during differentiation include: adhesion molecules like
integrin like Lfa1 (CD11a,b,c ) and Receptors involved in phagocytosis are complement and
Fc receptors for antigen (E.g FcyR3, FcYR2 and FcYR1 when activated)

Eosinophils, basophils, mast cells and platelets in inflammation:

 Eosinophils:
 have a bilobed nucleus and many cytoplasmic granules, which stain with acidic dyes
such as eosin
 Granules have crystallised core containing major basic protein(MBP) complex which
is potent toxin for worms and helminths, activator of neutrophils and platelets,
release histamine from mast cells and provokes bronchospasm. Activated by il-5
 Other granule proteins with similar mechanism: eosinophilic neurotoxin(EDN) and
eosinophilic catatonic protein(ECP). For large pathogens it releases the granules.
 Basophils, mast cells:
 Their stimulus is an allergen usually an antigen binding to IgE by FcER1. Causing
degranulation of primary granule and mediators like histamine and heparin.

In blood Maturation site Life span IL-4 and IL-13 FcER1

Basophil Yes Bone marrow days Yes Yes

Mast cells No Connective T weeks-months Yes Yes

  Platelets:
 have a role in clotting and inflammation
 cellular fragments released from megakaryocytes in bone marrow.
 They contain MHC-1 product receptors and (2)Gp2b/Gp3a complex(CD41) which
binds to fibrinogen, fibronectin and vWF. (3)Receptors for coagulation factor e.g
Factor 13. (4)IgG (FcyR1) receptor.
 Damage in endothelium cause platelets to attach on endothelium and release their
granules that contains serotonin and endocytosed fibrinogen resulting in vascular
permeability, activation of complement and clotting.

NK cells:

 Derived from the bone marrow, and have the appearance of large granular lymphocytes
 they have no T or B antigen receptors.
 Functional NK cells are found in the spleen, and cells found in lymph nodes that express
CD56 but not CD16 which might represent immature NK cells
 CD16 can be found on Macrophage, neutrophils and gammaG T cells. But on neutrophils its
linked to GPI while in macro and T cell is transmembrane form.
 Resting NK cells also express the b chain of the IL-2 receptor, and the signal transducing
common g chain of IL-2 and other cytokine receptors. Therefore, direct stimulation with IL-2
activates NK cells
 Function of NK cells is to recognize and kill virus Infected cells and certain tumor cells
 MHC-1 present on all body cells inhibit NK cells receptors. Down regulation of MHC-1 Makes
cell susceptible to NK killing.
 Antibody dependent cellular toxicity (ADCC): NK Cells has FcYR3(for IgG) so anything coated
with IgG will be targeted.
 NK cells releases IF-y and IL-1, GM-CSF when activated it regulates hemopeiosis.

Antigen presenting cells:

 Professional APCs include (dendritic cells, macrophages and B cells).

 Non-professional like fibroblasts, vascular endothelial cells , glial cells, pancreatic b cells,
thymic epithelial cells, thyroid epithelial they all express MHC II for short periods of time.
 Somatic cells that doesn’t contain MHC-2 usually release TNF or interferon Y activating MHC-
II on other cells.

Dendritic cells:

 are divided into:

 ‘classical’ dendritic cells (DCs): process and present foreign protein antigens to T
cells
 follicular dendritic cells (FDCs): presents antigen in the form of immune complexes
to B cells in lymphoid follicles
 DCs derive from one of two precursors:
 a myeloid progenitor (DC1) that gives rise to myeloid DCs, otherwise called bone-
marrow derived or bm-DCs
 a lymphoid progenitor (DC2) that develops into plasmacytoid DCs (pDCs)
 Myeloid DC is divided into: Langerhans (Lc), interstitial or dermal (IDC, DDC), and blood
monocyte derived DC(moDC).
  Myeloid DC express CD1a and CD208, whilst DDC-IDC and moDC express also CD11b.
Langerhans’ cells have so called Birbeck granules containing Langerin
 Bm-DC receptors: C type lectin receptors e.g for mannose macrophage receptor(MMR)
family. Fc receptors igG and IgE. Heat shock receptors. Apoptotic corpses receptors.
Scavenger receptor for lipid and sugars. TLR.
 Immature DC(not activated) express CCR1, CCR5, CCR6 which is chemokine receptors that
attract them to site of infection.
 Activation will down regulate these CCR’s and upregulate CCR7 which allow it to travel to
lymphatics where CCR7 interact with chemokine SLC(CCL21) .
 Location of DC’s can be found in skin, nodes, underneath mucosal epithelia ,and thymus
where it present antigens to developing T cells or they can travel to lymph organ paracortex
and activate present to T cells.
 Langerhans’ cells in the epidermis migrate via the afferent lymphatics into the paracortex of
the draining lymph nodes they interact with T cells and are termed interdigitating cells
(IDCs). which are rich in class II MHC molecules.
 FDC lack MHC-2 and activate B cells found in primary and secondary lymph nodes. They
contain receptors for complement proteins complexes (CD21 and CD35). They express Fc
receptor, they are not bone marrow derived. but are of mesenchymal origin

Lymphocytes:

 Two distinct morphological types of lymphocyte are seen in the circulation:

 small, is typically agranular and has a high nuclear to cytoplasmic (N:C) ratio
 larger, has a lower N:C ratio, contains cytoplasmic azurophilic granules, and is known
as the large granular lymphocyte (LGL).
 Lymphocytes express a variety of cell surface molecules that belong to different families
 Major families include: the immunoglobulin superfamily; the integrin family; selectins;
proteoglycans.
 The immunoglobulin superfamily: includes CD2, CD3, CD4, CD8, CD28, MHC class I and II
 Integrin:
 Consist 2 molecules alpha and beta chain.
 Beta chain is same in each subfamily but each has unique alpha chain.
 B2 integrins uses CD18 as b chain and associated with CD11a, CD11c, or ad- which
makes LFA-1, MAC-1, p150, 95, and adb2.
 B1 integrins: CD29 as beta chain and is associated with other peptides and includes
the VLA (very late activation)
 Selectin: expressed on leukocytes or activated endothelial cells and platelets, have lectin-like
specificity for a sugars expressed on heavily glycosylated membrane glycoproteins (e.g.
CD43).
 Proteoglycans: typically CD44, have glycosaminoglycan (GAG) binding sites (e.g. for
chondroitin sulfate), and bind to extracellular matrix components (typically, hyaluronic acid).
 Other families include
 the tumor necrosis factor (TNF) and nerve growth factor (NGF) receptor
 the C-type lectin superfamily
 the family of receptors with seven transmembrane segments (tm7)
 the tetraspanins, a superfamily with four membrane spanning segments (tm4), for
example CD20.
T cells:

 T cell receptor(TCR) are found in all T cells but have 2 different receptor structures
 Alpha-beta T cells (most abundant in blood)
 y(g) T cells
 both are associated with polypeptides-CD3 and together the form TCR complex
 Three subpopulations of ab T cells
 Helper T cells (TH) that express the CD4 marker (CD4+ T cells), divided into two main
subsets (TH1 and TH2).
 Regulatory T cells (Tregs) that express the CD4 marker (CD4+T cells)
 Cytotoxic T cells (TC) that express the CD8 marker (CD8+ T cells) – also called
cytotoxic T lymphocytes (CTLs).
 CD4+ T cells recognize antigens in association with MHC class II molecules
 CD8+ T cells recognize antigens in association with MHC class I molecules
 Double negative T cells: small proportion of them are Ab T cells while majority of double
negative are circulating yg but most yg in cells express CD8
 T helper cells: are divided based on the cytokines they produce.
 TH1 produce IL-2 and IFNy.
 TH2 produced IL-4, IL-5, IL-6 and IL-10.
 TH1 help T cytotoxic cells to develop into cells that’s able to kill virally infected cells or
activate macrophages infected with intercellular pathogens by induction of IFNy.
 Some TH1 cells help B cells to produce antibodies.
 TH17 arise from Th0 by TGFB or IL-21 . They produce il-22 and IL-17 to attract neutrophils.
 TH2 activate b cells to produce IgG and IgE to defend against extracellular pathogens.
 Yg T cells are mainly found on mucosal surface. Its TCRs is biased to work against
viral/bacterial super antigens. (They recognize antigens directly (i.e. with no need for MHC
molecule-mediated presentation) also they display LGL characteristics
 NKT cells:
 have both T and NK cells markers- express CD3 and unique abTCR.
 They recognise molecules presented by CD1d not MHC. They are able to activate T
cells in response to non peptide antigen that’s why they are between adaptive and
innate.
 They Produce IFNy and IL-4. And regulate immune response by producing IL-10.

B CELLS:

 defined by the presence of surface immunoglobulin

 B cells recognize antigens using B cell receptor complex(BCR).
 Most human B cells in peripheral blood express IgM and IgD
 Fewer than 10% express in circulation express IgG, IgA, or IgE, but they are expressed more
on specific location in the body (Ex intestinal mucosa)
 BCR: is made of an immunoglobulin plus accessory molecules:
 IgAlpha (CD79a) or IgBeta (CD79b).
 Intercellular domains of CD79a is associated with immunorecpetor tyrosine based
activation motifs(ITAM). So activation it causes activated related gene expression.
 B cell receptors include MHC 2. Complement receptors for C3b(CD35) or C3d(CD21). And
chemokine receptors. Fc receptors: for IgG(FyR3, CD32).
 Main B cells markers are CD19 and CD20
 Other human B cell markers are CD22 and CD72 to CD78.
 CD40 is important for interactions between B cells and T cells expressing CD40 ligand.
Activated B cells upregulate expression of B7.1 (CD80) and B7.2 (CD86) molecules that
interact with their CD28 expressed by T cells. This provides a co-stimulatory signal for T/B
cognate interactions
 CD5 B-1 cell are first B cells that appear in baby’s. found in the peritoneal cavity, They
express natural antibodies IgM mainly then IgA or IgG.
 B1 cells function
 Respond to Thymus independent(TI) antigens which stimulate B cells without T cells
help.
 processing and presenting antigen to T cells
 Tolerance and antibody production.
 Antibodies function: first line of defense against pathogens. Clearance of damage
components, regulatory interactions within immune system.
 Natural antibodies react against DNA, Fc of IgG, Phospholipids and cytoskeletal components.
 Marginal zone b Cells found in marginal zone of spleen. Like B cells they respond to thymus
independent antigens. Thought to be primary line of defense against polysaccharides
antigens. They also produce natural antibodies.
 After B cell activation, many B cell blasts mature into antibody-forming cells (AFCs), and the
differentiate to plasma to produce antibodies or remain in periphery as memory cells
 B cell blasts that dont develop rough endoplasmic reticulum cisternae are found in germinal
centers and are named follicle center cells or centrocytes.
 Plasma cells are rarely seen in blood mainly seen in secondary lymphoid organs or bone
marrow. They don’t respond to antigens. Doesn’t have MHC-2 or BCR.
 Antibodies produced by single plasma are specific (idiotype) and Ig Class(allotype).