Basic immunology from the dermatologic point of view(innate)

Basic Immunology from the
Dermatologic point of view


 Protection from foreign macromolecules or invading
organisms (viruses, bacteria, protozoa or even larger
parasites).
 Tumor immunity
Against our own aberrant cells.
 Autoimmunity
immune responses against our own proteins.
The Immune System


 It uses the immune system for protection.
 Has the capacity to generate an immune response
through the SALTSALT (skin associated lymphoid
tissues).
 Establishment and integration of SALT rests with
keratinocytes, Langerhans cells, and
immunocompetent lymphocytes.
SKIN AS A PART OF THE
IMMUNE SYSTEM


 There are two types of immune reaction to invadors.
 A rapid more primitive reaction called the INNATEINNATE
IMMUNITY.IMMUNITY.
 A later highly specific more developed ADAPTIVEADAPTIVE
IMMUNE RESPONSE (SPECIFIC IMMUNITY).IMMUNE RESPONSE (SPECIFIC IMMUNITY).
 Both types of the immune response can be generated
in the skin
TYPES OF THE IMMUNE
REACTION

Invading
microbes
(pathogens)
External defenses -1ST
Line
Skin
Mucous membranes
Secretions
INNATE IMMUNITY
Rapid responses to a
broad range of microbes
ADAPTIVE IMMUNITY
Slower responses to
specific microbes
Internal defenses - 2nd
Line
Phagocytic cells
Inflammatory response
Humoral response
(antibodies)Antimicrobial peptides
Natural killer cells Cell-mediated response
(cytotoxic
lymphocytes)


 INNATE IMMUNITY:INNATE IMMUNITY:
Defense mechanisms used by the host immediately after
encountering a foreign ligand
Composed of hereditary components that provide an
immediate "first-line" of defense to continuously protect
against pathogens.
 ADAPTIVE (ACQUIRED) IMMUNITYADAPTIVE (ACQUIRED) IMMUNITY::
The body can develop a specific immunity Humoral or
cell-mediated to target particular pathogens.
This response takes days to develop, and so is not
effective at preventing an initial invasion, but it will
normally prevent any subsequentsubsequent infection, and also
aids in clearing up longer-lasting infections.
Immune system


 This is the immunity one is born with.
 Responds quickly.
 It is the only form of immunity in primitive
organisms.
Innate immunity


 The first line of defense
- It discriminates between self and non-self .
- Distinguish between pathogenic and non-
pathogenic microbes.
- It plays an important role in triggering the adaptive
immune response.
Innate immunity


INNATE: Two Intrinsic
Defense Systems
 Non specific and consists of:
A.A. EXTERNAL (SURFACE) DEFENSES -FIRST LINE OFEXTERNAL (SURFACE) DEFENSES -FIRST LINE OF
DEFENSE:DEFENSE:
prevent entry of microorganisms
(1) Skin(1) Skin
(2) Mucosa(2) Mucosa
And their secretionsAnd their secretions
B.B. INTERNAL DEFENSES -SECOND LINE OF DEFENSE:INTERNAL DEFENSES -SECOND LINE OF DEFENSE:
(1) Biochemical factors(1) Biochemical factors e.g. C, cytokinese.g. C, cytokines
(2) Cells,(2) Cells, phagocytes, and other cellsphagocytes, and other cells
 Inhibit spread of invaders throughout the body
 Inflammation is its hallmark and most important mechanism


Surface Barriers (First Line
of Defense)
 Skin, mucous membranes, and their secretions make
up the first line of defense
 Keratin in the skin:
 Presents a tough physical barrierphysical barrier to most
microorganisms
 Is resistant to weak acids and bases, bacterial
enzymes, and toxins
 Mucosa provide similar mechanical barriers


Epithelial Chemical
Barriers
 Epithelial membranes produce protective chemicals
that destroy microorganisms
 Skin acidity (pH of 3 to 5) inhibits bacterial growth
 Sebum contains chemicals toxic to bacteria St corneum
FFAFFA prevent colonization by bacteria as S aureus.
 Stomach mucosa secrete concentrated HCl and
protein-digesting enzymes
 Saliva and lacrimal fluid contain lysozyme
 Mucus traps microorganisms that enter the digestive
and respiratory systems


1. The identification and removal of foreign substances
present in organs, tissues, the blood and lymph, by
specialized cells.
2. Recruiting immune cells to sites of infection,
through the production of chemical factors,
including cytokines.
3. Activation of the complement cascade
4. Activation of the adaptive immune system through
antigen presentation.
The major functions of innate
immune system

1.1. ComplementComplement
2.2. Toll-Like Receptors (TLR)Toll-Like Receptors (TLR)
3.3. Antimicrobial peptidesAntimicrobial peptides
4.4. CytokinesCytokines
5.5. MacrophagesMacrophages
6.6. NeutrophilsNeutrophils
7.7. EosinophilsEosinophils
8.8. Basophils, mast cellsBasophils, mast cells
9.9. Natural killer cells (NK cells)Natural killer cells (NK cells)
10.10. InflammationInflammation
Internal Defenses (Second Line of
Defense) Mediated through


 A biochemical cascade of the immune system that helps, or
“completes”, the ability of antibodies to clear pathogens or
mark them for destruction by other cells.
 The cascade is composed of about 35 serum glycoproteins,
12 which are directly involved in the complement
pathways, while the rest have regulatory functions.
 Synthesized in the liver.
1. The Complement system


 Activated by three pathways:
1) Classical pathway: stimulated by antigen antibody
complex.
2) Alternative pathway: stimulated by polysaccharides
of microbial cell walls.
3) Lectin pathway: by the binding of the microbial
carbohydrates with mannose binding lectin (MBL).


 All three pathways lead to activation of the central
C3 component
 Innate immune response uses Alternative pathway
and Lectin pathway


Antibodies coat the antigen (opsonization) & alert the
phagocytes to destroy (eat) the antigen
N.B. Gk, opsonein, to supply food
opsonization


 C5a is a powerful attractant for neutrophils
 C3a, C4a and C5a, also called anaphylatoxins, induce
the release of inflammatory mediators from mast
cells  vascular permeability  enabling proteins
(e.g. antibodies) to enter the tissue.
 Assembly of the complement components C5b, C6,
C7, C8 and C9 forms the membrane attack complex
(MAC), which generates pores in cell membranes 
osmotic lysis  cell death


 TheThe proteins work together toproteins work together to:
1. Trigger the attraction of inflammatory cells,
2. "Tag" pathogens for destruction by other cells,
3. Enhances phagocytosis (opsonization)
4. Disrupt the plasma membrane of an infected cell by MAC.
5. Rid the body of neutralized antigen-antibody complexes.


 Normal cells are less susceptible to destruction by
complement as human cells express factors which
inhibit C3 convertase and thereby block progression
of the complement cascade.


 Clinical manifestations of complement deficiency:Clinical manifestations of complement deficiency:
1. Autoimmune diseases
2. Increased susceptibility to infection


 On the organism:
Pathogen associated molecular patterns (PAMPS),
 On the effector cells:
Pattern recognition receptors
(PRR).
Identification Of The InvaderIdentification Of The Invader
2. Toll-like receptors (TLR)


 Toll-like receptors (TLRs) are transmembrane
proteins that serve as a key part of the innate
immune system considered pattern recognition
receptors (PRRs), binding to pathogen-associated
molecular patterns (PAMPs). Their function is the
recognition of pathogens and the activation of
immune responses directed against those pathogens.


PATHOGEN-ASSOCIATED MOLECULAR
PATTERNS (PAMPS)
1. Must be shared by large groups of pathogens and thus
must represent general patterns & non-specific structures.
2. Must be conserved products of microbial metabolism
which are not subject to antigenic variability.
3. pathogens cannot "change" them because they are essential
for the survival or pathogenicity of the microorganisms.
Any attempts to change them could be lethal to the
microbe or render it nonpathogenic.
4. The recognized structures must be absolutely distinct from
self-antigens. The major consequence of this requirement
is the ability of the innate immune system to discriminate
between self and non-self.

GRAMGRAM
NEGATIVENEGATIVE
GRAM
POSITIVE

PAMPS recognized by the innate immune system:PAMPS recognized by the innate immune system:
Cell wall constituents or microbial nucleic acids
1. Lipopolysaccharide (LPS) from the gram -ve cell wall.
2. Peptidoglycan found abundantly in the gram-positive cell wall and to a
lesser degree in the gram-negative cell wall .
3. Lipoteichoic acids in the gram +ve bacterial cell walls
4. Lipoarabinomannum (LAM) in mycobacterial wall
5. Mannose-rich glycans (common in microbial glycoproteins and
glycolipids but rare in those of humans).
6. Flagellin found in bacterial flagella.
7. Pilin from bacterial pili.
8. Bacterial and viral nucleic acid. Bacterial and viral genomes contain a
high frequency of unmethylated cytosine-guanine dinucleotide
sequences (a cytosine lacking a methyl or CH3 group and located
adjacent to a guanine). Mammalian DNA has a low frequency of
cytosine-guanine dinucleotides and most are methylated.
9. Double-stranded RNA unique to most viruses.
10. Lipoteichoic acids, glycolipids, and zymosan from yeast cell walls.
PAMPS


To recognize microbial molecules,
various body defense cells have on
their surface a variety of receptors
called
Pattern-recognition Receptors
capable of binding specifically to
PAMPS
Pattern-recognition Receptors (PRR)


 Found on the surface of phagocytes and
promote the attachment of microorganisms
to phagocytes and their subsequent
engulfment and destruction.
ENDOCYTIC PRR


 Binding of microbial molecules to the
receptor promotes the synthesis and
secretion of intracellular regulatory
molecules such as cytokines that is crucial
to initiating innate immunity and adaptive
immunity.
1.1. Toll-like receptorsToll-like receptors
2.2. CD14.CD14.
3.3. NOD (nucleotide-binding oligomerizationNOD (nucleotide-binding oligomerization
domain proteins)domain proteins)
Signaling PRR


 Secreted pattern-recognition receptors. These
bind to microbial cell walls and enable them to
be recognized by the complement pathways
and phagocytes.
 E.g. mannose-binding lectin is synthesized by
the liver and released into the bloodstream. MBL
recognizes carbohydrate patterns, found on the
surface of a large number of pathogenic micro-
organisms, including bacteria, viruses, protozoa
and fungi.
Secreted PRR


 A series of Signaling PRR play a
major role in innate immunity and
the induction of adaptive immunity.


 Mammalian (homologues) TLRs owe their
name to a closely related receptor called
Toll receptor, first identified in Drosophila
in 1988.
 TOLL: german word of fantastical or
strange.
 They recognize and bind to PAMPS
THE TOLL


TLR Responding to Lipopolysaccharide (LPS)
from the Gram-Negative Cell Wall


 TLRs belong to the IL-1 receptor family.
 Linked to a signaling pathway that involves the
IL-1 receptor-associated kinase-4 (IRAK-4) 
transcription NF-κB .
 Upon binding of the extracellular ligand
recognition domain to PAMPs, changes in the
intracellular domain result in initiation of
signaling events leading to
 Inflammatory responses and/or
 Release of antimicrobial agents.
2. Toll like receptors (TLR)


TLRs are found both on the surface and within the
phagolysosomes of phagocytes.

PAMPs Binding to TLRs on Macrophage

The TLRs found in the membranes of the phagosomes
Recognizing Viral Double-Stranded RNA after phagocytosis

ROLE IN INNATE IMMUNITYROLE IN INNATE IMMUNITY
1.The binding of a microbial molecule to its TLR
transmits a signal to the cell's nucleus inducing the
expression of genes coding for the synthesis of
cytokines. Many of the TLRs, especially those that bind
to BACTERIAL AND FUNGALBACTERIAL AND FUNGAL cell wall components
stimulate IL -1, TNF-alpha, and IL-8. triggering innate
immune defenses such as inflammation, fever, and
phagocytosis in order to provide an immediate
response against the invading microorganism.
2.Most of the TLRs that bind to VIRALVIRAL components
trigger the synthesis of interferons via activation of
interferon regulatory factor 3 (IRF-3) that block viral
replication within infected host cells..

ROLE IN ADAPTIVE IMMUNITYROLE IN ADAPTIVE IMMUNITY
TLRs trigger various secondary signals needed for
- Humoral immunity (the production of antibodies).
- Cell-mediated immunity (the production of cytotoxic T-
lymphocytes and additional cytokines).
Dendritic cells express several types of TLRs. Upon activation
of these receptors by microbial components, the dendritic cells
mature and migrate to the lymph nodes, where they present
pathogen-derived antigens to
naive T cells differentiate into TH-1, TH-2 or T-reg
TLRs thereby bridge the gap between the innate and adaptive
immune systems
 Without innate immune responses there could be no adaptive
immunity.


 Secreted by the human epithelia including the
epidermis (KERATINOCYTES-all as well as AIRWAY
EPITHELIA) to exhibit the capacity of an innate
immunity.
 Expression of antimicrobial peptides can be induced
by bacteria, bacterial products or proinflammatory
cytokines via TLRs and other mechanisms.
3. Antimicrobial peptides (AMPs)


1.1. HumanHuman β-β-defensin hBD 1-4defensin hBD 1-4 attract immature dendritic
cells and memory T cells via the chemokine receptor
(CCR)-6
2.2. Antileukoproteases (ALP)Antileukoproteases (ALP)
3.3. Dramcidin (DCD)-1Dramcidin (DCD)-1 (SWEAT GLANDS)
4.4. LysosymeLysosyme
5.5. PsoriasinPsoriasin (SEBOCYTES) prevents E. coli infection
6.6. RNase7RNase7 ((ribonucleotidase)
7.7. LL-37 A.K.A Cathelicidin antimicrobial peptideLL-37 A.K.A Cathelicidin antimicrobial peptide
(CAMP)/hCAP18(CAMP)/hCAP18 (UROGENITAL TRACT) mediates
dendritic cell activation in psoriasis

Summary illustrating the function of epithelial AMPs.
Frew L , and Stock S J Reproduction 2011;141:725-735
© 2011 Society for Reproduction and Fertility


 Induced by bacterial and proinflammatory products
or cytokines as well as toll like receptor stimulation.


ACTIONSACTIONS
1.Broad spectrum anti bacterial and variable anti fungal and
antiviral activities.
2.Disrupting membranes, interfering with metabolism, and
targeting cytoplasmic components
3.Attract immature dendritic cells and memory T cells via CCR6
role in adaptive immunity


Cytokines are a large, heterogeneous family of low-molecular-
weight messenger proteins that play a crucial role in
intercellular communication among immune system cells and
between immune cells and those of other tissue types.
These chemicals are actively secreted by immune cells as well as
other cell types in response to external stimuli to produce certain
actions.
They may act in an autocrine, paracrine or endocrine manner.
4. Cytokines

 Cytokines influence the proliferation, differentiation and
activation of cells.
 Each cytokine exhibits multiple activities, a fact that
complicates strict categorization.
4. Cytokines

FAMILIES OF CYTOKINES:FAMILIES OF CYTOKINES:
1.Interleukins (ILs): (interinteraction bet. leukleukocytes), Cytokines produced by
leukocytes and exert effects preferentially on other WBCs.
2.Interferons (IFNs): interfeinterfere with viral replication.
3.Tumor necrosis factor (TNF)
4.CSFs (Colony stimulating factors) induce differentiation and
proliferation of hematopoietic progenitor cells.
5.Chemokines: Cytokines that have chemochemoattractant activity, and
they play a crucial role in leukocyte migration.
6.6.Inflammatory chemokines:Inflammatory chemokines: Chemokines that recruit leukocytes.
7.7.Lymphoid chemokines:Lymphoid chemokines: Chemokines that regulate trafficking within
lymphoid tissues.
4. Cytokines

CYTOKINES OF THE INNATE IMMUNE SYSTEMCYTOKINES OF THE INNATE IMMUNE SYSTEM
Mainly cytokines withMainly cytokines with
1.Inflammatory capacity (e.g. IL-1, IL-6, IL-18, tumor necrosis factor-α
[TNF-α], inflammatory chemokines)
2.Antiviral capacity (e.g. IFN-α, IFN-β).
CYTOKINES OF THE ADAPTIVE IMMUNITY:CYTOKINES OF THE ADAPTIVE IMMUNITY:
DependentDependent on cytokines withon cytokines with
Immunomodulatory capacities (e.g. IL-2, IL-4, IL-12, IL-13, IL-17, IL-
22, IL-23, IFN-γ).
However, since most of these mediators exhibit multiple and
sometimes overlapping activities, a strict separation into
inflammatory and immunomodulatory cytokines is not possible.
4. Cytokines

 Phagocytic cells derived from blood-borne monocytes.
 Expresses PRR to identify organisms.
 Receptors for antibodies and complement that enhances
phagocytosis.
 Destroy the organisms by toxic intracellular molecules as:
superoxide anionssuperoxide anions, hydroxyl radicalshydroxyl radicals, nitrous oxidenitrous oxide,
lysozymelysozyme.
 Antigen presenting capacity present processed antigens to
T and B cells. (much less than Langerhans cells)
 Releases G-CSF, & GM-CSF that stimulate the division
and release of neutrophils from the bone marrow.
5. Macrophages

 They enter the blood stream to enter the site of infection
through the complex effect of proinflammatory mediators, G-
CSF, GM-CSF, adhesion molecules chemoattractants and
chemokines
 Phagocytosis is enhanced by coating the organism by
antibodies and complement that bind to their receptors on the
neutrophils
 kills the organisms within phagolysosomes by:
a) Oxygen dependent mechanisms (e.g. H2O2 and hydroxyl
radicals)
b) Oxygen independent mechanisms (e.g. lysozyme).
6. Neutrophils

 Major function protective against parasites.
 Weak phagocytic activity.
 Important in allergic reactions.
 IgE antibodies coat the parasite  eosinophils bind to IgE
antibodies and become activated  Release toxic substances
to the parasite as:
 Major basic proteinMajor basic protein
 Eosinophilic cationic protein,Eosinophilic cationic protein,
 Eosinophil peroxidaseEosinophil peroxidase
 Eosinophil-derived neurotoxinEosinophil-derived neurotoxin,
which can kill parasites, together with prostaglandinsprostaglandins,
leukotrienesleukotrienes and various cytokinescytokines
7. Eosinophils

 Basophil in the blood and mast cell in the tissues have
similar functional and morphologic characteristics.
 Both express high-affinity receptors for IgE (FcεRI)
 Two populations of mast cells
1.1. Mucosal mast cellsMucosal mast cells: contain only trypsin,
2.2. Connective tissue mastConnective tissue mast: cells contain both trypsin an
chymotrypsin
 Mast cells are involved in TLR-mediated responses against
Gram-negative bacteria.
8. Basophils & mast cells

 When a specific antigen binds to mast cell-bound IgE, the
FcεRI becomes activated, which leads to degranulation and
release of preformed mediators, including:
1.1. HistamineHistamine
2.2. Serotonin.Serotonin.
3.3. ProstaglandinsProstaglandins
4.4. Leukotrienes (B4, C4, D4 and E4),Leukotrienes (B4, C4, D4 and E4),
5.5. Platelet activating factorPlatelet activating factor
 They enhance
i. vascular permeability
ii. bronchoconstriction
iii. induction of an inflammatory response
 Thus both play an important role in immediate allergic
reaction, urticaria and angioedema.
 Only cutaneous mast cells express receptors for the
anaphylatoxin C5 a so when activated by binding antigen
specific antibodies only a local reaction occur in the skin, but
8. Basophils & mast cells


 It’s major task to identify and eliminate virally infected
or malignant cells.
 Pattern recognition receptors (TLR 3,9)
 NK cells can recognize their targets in two ways:NK cells can recognize their targets in two ways:
1. Adhere and kill target cells coated with IgG as they carry
receptors for it (antibody dependent cellular cytotoxicity
ADCC).
2. Activation of killer activating receptors that recognize
the abnormal cells and kills them by secreting perforin
and injecting granzyme that kills the cells by inducing
apoptosis.
9. Natural killer cells


Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)
9. Natural killer cells


10. Inflammation
 The inflammatory response is triggered whenever
body tissues are injured, infected or irritated.
 physical barrier against the spread of infection
Prevents the spread of damaging agents to nearby
tissues
 Disposes of cell debris and pathogens
 Sets the stage for repair processes promote healing of
any damaged tissue following the clearance of
pathogens
 The 5 cardinal signs of acute inflammation are
redness, heat, swelling, tenderness and pain


10. Inflammation
 Begins with a flood of inflammatory chemicals released
into the extracellular fluid
INFLAMMATORYINFLAMMATORY MEDIATORSMEDIATORS ((CHEMICALSCHEMICALS) :) :
 Include histamine, bradykinins, serotonin, prostaglandins
(PGs), leukotrienes complement, and cytokines
 Are released by injured tissue, phagocytes, lymphocytes,
and mast cells
EFFECT OF INFLAMMATORY MEDIATORS:EFFECT OF INFLAMMATORY MEDIATORS:
 local small blood vessels to dilate,  permeability resulting
in hyperemia
 sensitize pain receptors,
 attract phagocytes, especially neutrophils


Neutrophils
enter blood
from bone
marrow
1
2
3
4
Margination
Diapedesis
Positive
chemotaxis
Capillary wall
Endothelium
Basal lamina
Inflammatory
chemicals
diffusing from
the inflamed
site act as
chemotactic
agents
Inflammatory Response: Phagocytic Mobilization

INNATE IMMUNITYINNATE IMMUNITY ADAPTIVE IMMUNITYADAPTIVE IMMUNITY
TriggerTrigger
PAMP
(Pathogen-associated
molecular pattern)
Specific antigensSpecific antigens
ActionAction Min to hours Days to weeksDays to weeks
ReceptorsReceptors
PRR (Pattern recognition
receptor) as TLR
TCR, BCRTCR, BCR
MemoryMemory No YesYes
CommunicationCommunication CytokinesCytokines
EffectorsEffectors
Complement
Antigen presentation
Phagocytosis
ComplementComplement
Antigen presentationAntigen presentation
AntibodiesAntibodies
CytotoxicityCytotoxicity


 Dr Samia Esmat Professor of Dermatology CairoDr Samia Esmat Professor of Dermatology Cairo
UniversityUniversity
 Bolognia: Dermatology, 2nd &3rd ed.Bolognia: Dermatology, 2nd &3rd ed.
 Immense Immunology InsightImmense Immunology Insight
 Immunity and the immune system Dr. Angelo SmithImmunity and the immune system Dr. Angelo Smith
WHPLWHPL
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