An integrated and brief overview of the function of Human Immune System.

1. First Pathogen must cross the physical barriers (e.g.: skin, stomach and vagina; all has an acidic pH) and chemical barrier (e.g.: sweat, mucus, tears, and saliva; all
contain enzymes that kill pathogens). Once pathogens cross all those barrier, they may go to blood circulation, reside at intracellular space or infect cells/tissues.
Microbial pathogens express PAMP (Pathogen associated
molecular patter) and Necrotic/dying cells produce DAMP
(Danger associated molecular pattern). PAMP include LPS
(pipopolysaccharide), PGN (peptidoglycan), bacterial DNA, viral
dsRNA etc. PAMP is recognized by PRR (Pattern recognition
receptor) on the sentinel cells (body’s first line of defense cells),
such as: Macrophage Dendritic cell , Mast cell
Macrophage (specialized monocyte) in tissue becomes
activated by various factor. Macrophage can present antigen
and produce cytokine. It has different names based on
location (Kupffer cells - in the liver, Langerhans cells - in the
skin and mucosa, Alveolar macrophages - in the lungs,
Microglia – in the brain). It has mainly 2 subtype for function:
M1 (Killer type, activated by LPS & IFNγ, release IL-12),
M2 (Tissue Repair, elevated by IL-4, produce IL-10 & TGFβ )
Already infected cells secrete Type-I interferons (eg- IFNα and IFNβ which interfere
with viral replication), and also cause down regulation of MHC-I molecules.
Antigen Presenting Cells like- Macrophage (Mφ), Neutrophil
or Dendritic cell (DC) displays antigen. APC displays antigen
using MHC Class I or Class II molecule. DC can be of 2 type
(myeloid DC & plasmacytoid DC). APC travels to lymph node.
Activated macrophage cause production of inflammatory
cytokines (eg. IL-1, IL-6, IL-12, TNF, CXCL8). A chemokine,
CXCLB, causes a conformational change in the
ICAM/integrin adhesion, trigger activation of Integrin.
Granulated Basophil cells (circulate) and Mast cells
(resident in tissues) discharge their granules
releasing Heparin and Histamin to reduce blood
viscosity and encourage vasodilation. This increases
blood flow and therefore flow of leucocytes to the
area of infection (Inflammatory response).
T helper cell (Th) binds with MHC II on APC and upregulates
expression of CD40L (activation). CD40L binds with CD40 on APC,
leading to more expression of MHC & greater activation of Th cell.
Cytokines are broad category of small proteins that are
important in cell signaling. Cytokines may include
chemokines, interferons, interleukins, lymphokines, and tumor
necrosis factors; but generally not hormones or growth factors.
Other effects of cytokines involve: Activation of Complement
system, cause Fever and Vasodilation.
Endothelial cells overexpress P and E-selectin, ICAM-1 etc; and
bind to integrins (e.g. LFA-1) on the neutrophils. Neutrophils
squeeze between neighboring endothelial cells and cross the
basement membrane by secreting proteases to break it down.
NK cell also release granules containing Perforin and Granzymes. Perforin
perforates membrane of target cell & Granzymes enter, induce apoptosis
Prostaglandins convert into Prostacyclin which inhibits platelet activation and acts
as an effective vasodilator. Prostaglandins can also synthesize Thromboxane
which play role as platelet aggregation.
Recognition of ‘missing self’ by Natural Killer cell, activate them, secrete
Type II interferon (eg- IFNγ, which play role in activation of Macrophage )
Infection along with other stress cause cell membrane injury, which activate
Platelet activating factor found in the lipid bilayer. Arachidonic acids in
Phospholipid bilayer converted into Prostaglandins (by cyclooxygenase enzyme)
and Leukotriene (by Lipooxygenase enzyme)
Mast cell activation also attracts Eosinophils
which combat parasitic worms (if present) and
neutralize/ control inflammatory response
Complement system: It can start in three way-
i) Classical pathway (immune complex)
ii) Lectin pathway (microbes, mannose)
iii) Alternative pathway (spontaneous, microbes)
Molecules that play role in the complement cascade are:
Classical (C1q,C1r, C1s, C2, C4 ), Lectin (MBL, MASP, C2, C4),
Alternative (C3b, factor B, factor D), C3 (C3a, C3b), C5 (C5a, C5b)
Finally, C5b C6 C7 & C9 together form a membrane attack
complex, then target cell swells and bursts
Histamin acts on vascular walls of smooth
muscle cell, cause vasodilation that leads
to heat and redness. Histamin receptors
on nerve ending lead to pain (Dolor).
Histamin on blood vessel endothelium cause
overexpression of P-selectin and Shrinking of
endothelial cells, which leads to increase in
vascular permeability.
Both increased vascular permeability &
vasodilation leads to movement of proteins and
leukocytes from blood into tissue fluid space.
Cytotoxic T cell (Tc) binds with MHC I on Dendritic cell and
upregulates expression of CD40L, which binds with CD40 on APC,
leading to greater expression of MHCI & activation of Tc cell.
Infected cell displays fragments of virus on surface using
MHC class I molecules. Tc cells identifies, activates and
destroys infected cells by apoptosis. Tc cells also support NK T
lymphocytes to destroy early cancers.
It results formation of inflammatory Exudate, which
leads to Swelling (Tumor) and Pain.
Also happen Chemotaxis ie, all leukocytes are
stimulated to migrate towards the infected area.
Activated T cells (CD25) then mature
into two types of T cell: i) Effector T
cell: Coordinate immune response, by
becoming helper or cytotoxic T cell
ii) Memory T cell: Remain inactive
until future infection. Its subtypes
are- Central MT (CD45RO, CCR7
CD44), Effector MT (CD45RO, CD44),
Tissue Resident MT, & Virtual MT
T cells are produced in bone
marrow (Stem cell, CD34) and
travel to thymus for maturation.
There they meet Antigens.
After naïve T cell (CD45RA)
encounters an antigen it becomes
activated and begins to proliferate.
T cells which fail to bind with MHC
or have an over affinity for MHC &
self-antigen undergo negative
selection. Those T cell that can bind
with self-MHC, survive.
Activated Tc cells create a large clone of cell-surface receptors
(called TCR) which are specific to antigens. Tc cells leave lymph
node and travels to area of infection.
Th cells coordinate immune response by stimulating response of
other cells including B cells. Th cell subtype and functions are:
i) Th1 (Activated by IL-12; produce IFNγ, IL-2 & TNFα; Acts on
intracellular pathogen, Cell mediated immunity and inflammation)
ii) Th2 (Activated by IL-4; Produce IL-4, IL-5, IL-6, IL-10 & IL-13; Acts
on Antibody mediated immunity, Allergic response)
iii) Th17 (Activated by TGFβ, IL-6, IL-23; Produce IL-17, IL-21, IL-22;
Fights fungal infections, Extracellular bacteria, Autoimmunity)
iv) Regulatory T cell (Activated by TGFβ, IL-12; Produce TGFβ, IL-10,
IL-35; Prevents overactive immune response)
v) Follicular helper T cell (Tfh) (Trigger the formation of Germinal
Centers by expressing CD40 Ligand & by the secretion of IL-21, IL-4)
Immature B cell leaves bone marrow
and circulates through blood and
lymphoid tissue. As it leaves bone
marrow it begins displaying IgD as
well as IgM on surface.
Surviving Centrocytes progress to Apical light
zone and present an antigen via MHC II to Th
cells. Those that are recognized receive signal to
differentiate into two type of cells:
Memory B cell (detector, keeps sp. memory)
& Plasma cells (Antibody production house)
Activated B cells travel to dark zone of germinal
centers in secondary follicles, express less Ig and
undergo Clonal Expansion (proliferation) and
Somatic hypermutation (expression of varying
affinity Ig). Now the cells are known as
centroblasts.
Antibodies secreted by plasma
cells bind with respective
antigens or pathogens; opsonize
pathogen , or neutralize viruses.
Centroblasts proceed to
Basal Light zone and
become Centrocytes. Here
they are exposed to antigen
presented by FDCs. Those
with low affinity to antigen
are destroyed.
Every plasma cell is essentially a factory for
producing an antibody. Each of the plasma cells
manufactures millions of identical antibody
molecules and pours them into the bloodstream.
During proliferation B cells can also switch classes, if
stimulated by a cytokine, by changing Fc region.
The immunoglobulin superfamily (IgSF) is a
large group of cell surface and soluble
proteins that are involved in the recognition,
binding, or adhesion processes. The Fc part of
antibodies help to bind with different
receptors and perform different functions.
Immature B cell created from Stem
Cell in Bone Marrow (displays IgM
on surface, also contain CD34 as
distinctive marker)
Now a Naïve (aka virgin) B cell in primary follicles of
lymph nodes endocytoses and presents antigen. The
interaction of antigens with membrane antibodies on
naive B cells initiates B cell activation. They becomes
2nd signal from conjugate Th1 cell.
(B cells that do not bind to antigen die in 1 week)
Edited by: Hasan Al Banna immunitybd.wordpress.com
An integrated and brief overview of the HUMAN IMMUNE SYSTEM
Stimulation of TLR (Toll like receptor) by corresponding PAMP or DAMP
initiate signaling cascade leading to activation of transcription factors,
like- AP-1, NFκB, IRF. TLR subtypes (& associated PAMP)are:
TLR1 (LPS, PGN, Triacylated lipoprotein), TLR2 + TLR6 (Diacylated
lipoprotein), TLR3 (dsRNA, tRNA, siRNA), TLR4 (LPS, paclitaxel), TLR5
(Flagelin), TLR7 (ssRNA, Imidazoquinolon, Guanosin analog), TLR8
(ssRNA, Imidazoquinolin), TLR9 (CpG DNA, CpG ODNs), TLR10 (profilin-
like protein). Monocyte, Mφ and DC express TLR(1, 2,4,5,6,7,8,9,10), B
cell express TLR(1,2,6,7,9), T cell contain TLR(3,9), Mast cell has TLR(4,
8), NK cell has TLR3, Intestinal Epithelium express TLR(4,5)
Effector T cells are transported via blood vessels
to the lymph nodes and spleen & become
specialized. They bind with Class I or Class II MHC
present on the surface of Antigen-presenting cells
(APCs) in the Lymph node. Lymph gathers antigens
as it drains from tissues, are filtered through lymph
nodes, & captured by APCs. The spleen also houses
B and T cells, macrophages, dendritic cells, and NK
cells. The spleen is also the site where APCs can
communicate with lymphocytes.
Distinctive CD markers in some CD45+ve cells: T lymphocyte (CD3), Th cell (CD4),
Tc cell (CD8), Granulocyte (CD15), Monocyte (CD14), B cell (CD19), Treg (CD4,
CD25, FOXP3), Tfh (CD4, CXCR5), Thrombocyte (CD61), NK cell (CD56, CD16),
NKT(CD4, CD8, CD56, CD161)
Immunoglobulin types and function:
IgG (75-85%): secreted by Plasma cell, can cross placenta in fetus, can
activate phagocytosis, neutralizes antigen.
IgM (5-10%): First antibody produced in initial immune response,
activates complement, pentamar in structure.
IgA (10-15%): Found in mucous, saliva, tears and breast milk. Protects
against pathogen in entry points.
IgD (0.001%): Part of B cell receptor & trigger its activation. Activate
basophils & mast cells
IgE (0.002%): Remain as bound to the surface of mast cell and
basophils, responsible for allergic reactions, protect against parasites
Interleukin types and function:
IL-1: source Macrophage; cause activation of Th and B cell
IL-2: source Th1 cell; cause proliferation & activation of NK, Tc
IL-3: Th Tc & NK; proliferation of Hematopoietic & Mast cells
IL-4: Th2 Mast & NK cell; cause B cell class switch, inhibit Mφ
IL-5: source Th2 Mast cell; proliferation of Eosinophil
IL-6: source Mφ Th2; acts on B cell, Ab produced by Plasma cell
IL-8: Bone marrow Thymus; acts Neutrophils, Chemoattractant
IL-9: sourceTh2 cell; survival of Treg, accumulation of Mast cell
IL-10: Th2 cell; activate B cell, help APC, inhibit Mφ function
IL-12: Mφ, mDC & B cell; cause proliferation of Tc, NK cells
IL-13: Th cell; acts Mφ & B cell for regulation of inflammation
IL-17: Th17; activate of innate immunity, pro-inflammation
IL-22: source Th17; regulate autoantibody production
B cell development and corresponding CD Markers:
Stem cell (CD34) > Pro B cell (CD34, CD19) > Pre B cell (CD19, CD20) > Immature B cell (CD19, CD20,
IgM) > Naïve B cell (CD19, CD20, CD38) > GC B cell (CD19, CD20, CD38, IgM, IgD) > Memory B cell
(CD19, CD20, CD27, IgA, IgG, IgE) > Plasmablast (CD19, CD27, CD38) > Plasma cell (CD27, CD38, CD138)
If Plasma cell are triggered by Th2 and
produced against Allergen (displayed by APC to
Th2), they secrete IgE. IgE binds to Mast cells.
Mast cell release inflammatory molecules,
resulting in allergic response.