The Immune System
(Protection from infectious pathogens)
Responses of the
Immune System
1. Hypersensitivity Disorder:
exagerrated response that
may cause tissue injury.
2. Tumor Immunity: response
of the body against cancer
cells.
3. Rejection reaction on
Tissue Transplants:
response of the immune
system (T cells and
antibodies) against graft
antigens.
4. Autoimmunity: mistaken
response of the immune
system toward’s one’s
antigens— recognizes self
antigens as FOREIGN
Mechanisms of Immunity
Innate Immunity
Adaptive Immunity
CHARACTERISTICS
•Natural/ native/ intrinsic
(always present)
•1st line of defense
(immediate)
•Major Reaction:
INFLAMMATION
•Detects PAMPs
•No memory or fine
antigens
CHARACTERISTICS
•Acquired/Specific (silent
immunity)
•Delayed defense
mechanisms (may take
time to respond)
•Major Stimuli: Microbes
and Foreign Bodies
•Has memory (anamnestic
response) or fine
antigens
COMPONENTS
EPITHELIAL BARRIER
•Mechanical barrier
•Skin epithelium and mucosal membranes
PHAGOCYTES
•Phagocytosis in tissues
•From YOLK SAC or FETAL LIVER
•Macrophages (tissues):
-Monocytes (blood)
-Kupffer cells ( liver)
-Microglia (brain)
-Alveolar macrophages/ Dust cells
(lungs)
•Polymorphonuc lear cells (neutrophil s)
DENDRITIC CELLS
•ANTIGEN-PRESENTING CELL
-Presents only to T cells and are
not involved in the destruction of
microbes
•Present in: epithelium, lymphoid organs
(germinal center) and most tissues
•Activati on = cytokine secretion
INNATE LYMPHOID CELLS (ILC)
•Activate d by cytokines and facilitate
the production of more cytokines
•No T-cell antigen receptors— cannot
respond to antigens
•Present in: Lymphoid tissues (MALT)
•GROUPS (based on patterns of
cytokine production):
-ILC1: IFN-gamma
-ILC2: Type-2 cytokines
-ILC3: IL-22 and IL-17
NATURAL KILLER CELLS
•TYPE OF ILC (Phenotypic, developmental,
and functional properties overlap with ILC1
and ILC3)
•Early protection against viruses, tumor
cells, and intracellular bacteria
•Recognizes and kills pathogen that are IgG-
coated (has receptors for the Fc tail of IgG
EPITHELIAL AND ENDOTHELIAL CELLS
•Produce defensins (antimicrobial)
PLASMA PROTEINS
•Proteins of complement system
-Mannose binding lectin and CRP
-Alternative and lectin pathways
(involved in innate immunity)
-Classical Pathway (involved in
adaptive immunity and antigen-
antibody formation)
•END RESULT: Activation of Membrane
Attack Complex (MAC )
MAST CELLS
•Found in: TISSUES
•Basophil (circulation) counterpart
•Produces mediators for
inlammation (histamine)
LUNG SURFACTANTS
•Prevents alveolar collapse
(atelectasis) among newborns
•Protection against inhaled
microbes
COMPONENTS
Reactions of Innate
Immunity
•Inflammation (major)
-Produce cytokines
(interleukins) and
complement
products
-Signal repair of
damaged cells
-Recruits leukocytes
to destroy microbes
and ingest
damaged cells
•Antiviral Defense
-Produce Type I IFN
and antiviral
cytokines (NK
cells)
-Type I IFN: act on
infected and
uninfected cells
and activate
enzymes that
degrade viral
nucleic acid and
inhibits replication
•Stimulate Adaptive
Immune Response
-Initiates the more
powerful immune
response in case
the innate immunity
fails to eliminate
the antigen.
CELLULAR RECEPTORS
PATHOGEN ASSOCIATED MOLECULAR
PATTERNS (PAMPs)
•Found and shared among related microbes.
•Recognized by PRR-bearing cells and epithelial cells
DAMAGE ASSOCIATED MOLECULAR
PATTERNS (DAMPs)
•Released by injured and necrotic cells.
•Endogenous danger molecules
PATTERN RECOGNITION RECEPTORS (PRRS)
•Proteins capable of recognizing molecules found in pathogens
•Found in all cellular compartments where microbes may be
present.
•Classifications:
-Plasma membrane receptors: extracellular microbes
-Endosomal receptors: intracellular/ ingested microbes
-Cytosolic receptors: cytoplasmic microbes
C-TYPE LECTIN RECEPTORS (CLRs)
•Detect fungal glycans
RIG-LIKE RECEPTORS (RLRs)
•Stimulate production of antiviral cytokines
CYTOSOLIC RECEPTORS
•Detect microbial DNA (from viruses).
•Activate STING (stimulator of interferon genes)
pathways— production of IFN-ą (antiviral)
•INTERFERONOPATHIES = mutation/ increased IFN
production
PLASMA MEMBRANE G PROTEIN-COUPLED
RECEPTORS
•Chemotaxis
MANNOSE RECEPTORS
•Recognize microbial sugars
•Induce phagocytosis of microbes
TOLL-LIKE RECEPTORS (TLRs)
•LOCATION: PLASMA MEMBRANE AND ENDOSOME
•10 TLRs in mammals— each recognizes a different set of
molecules.
•1st recognized receptor in Drosophila
•Induces activation of transcription factors
-NF-KB (Nuclear Factor Kappa B):
-(1) synthesis and secretion of cytokines;
-(2) expression of adhesion molecules;
-(3) both leads to recruitment and activation
of leukocytes to the site of inflammation
-IRFs (Interferon Regulatory Factors): for
production of antiviral cytokines and Type I IFN
•“Loss of function” mutation: problems with antiviral and
antimicrobial functions of transcription factors
NOD-LIKE RECEPTORS (NLRs)
•LOCATION: CYTOSOL
•Recognizes:
-Necrotic cell products (uric acid and ATP)
-Ion disturbances (K+ loss)
-Microbial products
•Signals inflammasome
INFLAMMASOME
•LOCATION: CYTOSOL
•Cytosolic multiprotein complex
•Components:
-NLRP3: activates the inactive caspase-1
-Adapter
-Caspase-1: cleave precursor of IL-1
•IL-1: induces fever and further leukocyte recruitment
•NLR-Inflammasome Pathway
-Periodic Fever Sy ndrome/ Autoinflammatory Syndrome
•Not autoimmune; unregulated production of IL-1
•Causes: “Gain of function” (NLR mutation) and
“Loss of function” (Inflammasome mutation)
•Management: IL-1 antagonist
-Gout
-Obesity associated with T2DM and atherosclerosis
NATURAL KILLER CELLS
•5-10% of circulating lymphocytes
•Cell surface receptor: CD16
•Recognize microbia l glycolipids displayed by CD1
•Function: ADCC; production of IFN-gamma (activates
macrophages to destroy ingested microbes)
•Regulation:
-IL-2 and IL-15: Proliferation
-IL-12: Activation and secretion of IFN-gamma
Explanation of the picture:
•Normal cells: no ligand
expression ; inhibitory rec eptor
attached to MHC I = no
activation of NK cells
•Infected/tumor cells: expressed
ligands on the surface and
bound to activating receptor
(green color); inhibitory receptor
removed = activation of NK cells
and killing of infected cells
Lymphocytes and antibodies
from plasma cells (B cells)
LYMPHOCYTES
Naive/Immunologically
inexperienced
•Mature lymphocytes that haven’t
encountered an antigen YET.
•LOCATION: PERIPHERY of primary
lymphoid organs and primary
follicles (without germinal centers)
in lymph nodes
Effector Cells
•For elimination of microorganism
Memory Cells
•Undergone activation BEFORE
•Under the state of heightened
awareness (react rapidly and
strongly in cases of microbial
re-encounter)
B Lymphocyte
•Production of antibodies
(plasma cells)
•Neutralization of microbes
•Phagocytosis
•Complement activation
T Lymphocyte
•Major lymphocyte in splenic
periarteriolar sheaths and
lymph node interfollicular
zones
•Sense peptide fragments
bound by MHC ONLY.
Helper T Lymphocyte (CD4)
•Binds to MHC Class II (APC cells only)
•50-60% of T cells
•Releases cyt okines and induces in flammation
•Activat es macroph ages (phag ocytes)
•Activation (proliferation and differentiation) of T and B lymphocytes
Cytotoxic T Lymphocyte (CD8)
•Binds to MHC Class I (seen in all nucleated cells + platelets)
•40% of T cells
•Also secrete cytokines
•Direct killing and lysis of infected/tumor cells and microbes
Regulatory T Lymphocyte (CD4)
•SUPPRESSION of immune system
•Prevention of autoimmunity
Lymphocyte Diversity
•Lymphocytes express
receptors specific for different
types of antigens and are fully
matured prior to exposure to
antigen
•Clone: lymphocytes of the
SAME SPECIFICITY (express
the same antigen receptors)
•Clonal selection: process by
which a single lymphocyte
bearing a receptor specific to
a particular antigen is selected
to proliferate and form clones.
Antigen Receptor Diversity
•Recombination-activating genes
(RAG-1 and RAG-2): encode for
enzymes found in developing
lymphocytes (only contained by T and B
cell)
-Defects in RAG proteins = failure to
generate mature lymphocytes
•Recombined TCR or Ig genes: marker
to differentiate T- or B-cell lineage cells
•Lymphomas:
-Polyclonal (non-neoplastic or
reactive): combination of CD3 (T
cells) and CD20 (B cells)
-Monoclonal (neoplastic): entire
lymph node is composed of one cell
type only (CD3 OR CD20)
T Lymphocytes
Thymus-derived
•60-70% of circulating lymphocytes
•Located in T cell zones of
secondary lymphoid organs:
Paracortex (LN) and spleen
•Recognizes a specific antigen by
means of antigen-specific TCR
•CD4, CD8, CD28, and integrins:
expressed by T cells and assist the
TCR complex in functional
responses
•TCR COMPLEX: has 6 polypeptide
chains
-Alpha and beta chains
-Variable and constant regions
•Alpha-beta TCR: recognize peptide
antigens presented by MHC
molecules.
•CD3 complex: epsilon, gamma,
delta proteins
•Zeta chain dimer: involve in the
signal transduction into the T cell
once antigen binds to the TCR
•Gamma-delta TCR: recognizes
peptides, lipids, and small
molecules without requiring for
display by MHC proteins.
CD28
•Receptor for c o-stimulators
that are induced on APCs
B Lymphocytes
Bone marrow-derived
•10-20% of circulating lymphocytes
•Located in peripheral lymphoid
tissues such as lymph nodes,
spleen, and MALT
•Activation = differentiation into
plasma cells = secretion of
antibodies = mediation of humoral
immunity
5 Classes of Antibodies
-IgG (able to cross the placenta)
-IgM (largest— a pentamer)
-IgA (found in secretions and serum)
-IgE (mostly located in mast cells)
-IgD (found on B cell surface)
•BCR COMPLEX: antigen recognition
receptor for B cells.
•Comprised of:
•Membrane Immunoglobulin (IgM,
IgG, IgA): for antigen and signaling
proteins recognition
•Signaling proteins (Igą/CD79a, Igß/
CD79b): attached to BCR
•Type 2 complement receptor (CR2/
CD21): for B cell activation and
recognition of complement
breakdown products deposited on
microbes
-Helps EBV enter and infect the
cell
•CD40: receives signals from helper
T cells for activation of B cells.
TYPES OF ADAPTIVE
IMMUNITY
•HUMORAL
-Tar ge t s extracellular
pathogens and their toxins
-Mediated by antibodies
produced by B cells
•CELL-MEDIATED
-Tar ge t s intracellular
pathogens and tumor
infected cells
-Mediated by T cells
Antigen-Presenting
Cells
Dendritic Cells
Interdigitating DCs
•Most important APC for
initiating T-cell
responses
•Langerhans cells:
immature DC in
epidermis
•Brings antigen to
paracortex and follicular
area/germinal center of
lymphoid organs
•LOCATIONS: skin
epithelium and tissue
interstitium
•Receptors: TLRs and C-
type lectins
•Express high levels of
MHC
Cells with Dendritic-
Like Morphology
•Plasmacytoid DCs
-Has plasma cells
resemblance
-Major source of
Type I IFN
-Present in blood
and lymphoid
organs
•Follicular DCs
-Contains Fc
receptors for IgG
and C3b (traps
antigens bound to
them)
-Present in germinal
center of lymphoid
follicle in spleen
and LN.
