Basic Immunology from the Dermatologic point of view

Protection from foreign macromolecules or

invading organisms (viruses, bacteria, protozoa or even larger parasites).

Tumor immunityAgainst 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

INNATE IMMUNITY.INNATE IMMUNITY. A later highly specific more developed

ADAPTIVE IMMUNE RESPONSE (SPECIFIC ADAPTIVE IMMUNE RESPONSE (SPECIFIC IMMUNITY). IMMUNITY).

Both types of the immune response can be generated in the skin

TYPES OF THE IMMUNE REACTION

Invadingmicrobes

(pathogens)

External defenses -1ST Line

SkinMucous membranesSecretions

INNATE IMMUNITYRapid responses to a

broad range of microbes

ADAPTIVE IMMUNITYSlower responses to

specific microbes

Internal defenses - 2nd Line

Phagocytic cells

Inflammatory response

Humoral response(antibodies)Antimicrobial peptides

Natural killer cells Cell-mediated response(cytotoxiclymphocytes)

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 EXTERNAL (SURFACE) DEFENSES -FIRST LINE

OF DEFENSE:OF DEFENSE: prevent entry of microorganisms (1) Skin (1) Skin (2) Mucosa(2) MucosaAnd their secretionsAnd their secretionsB.B. INTERNAL DEFENSES -SECOND LINE OF INTERNAL DEFENSES -SECOND LINE OF

DEFENSE:DEFENSE: (1) Biochemical factors (1) Biochemical factors e.g. C, cytokines e.g. C, cytokines (2) Cells, (2) Cells, phagocytes, and other cells phagocytes, 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 barrier physical 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 cascade4. Activation of the adaptive immune system

through antigen presentation.

The major functions of innate immune system

1.1. ComplementComplement2.2. Toll-Like Receptors (TLR)Toll-Like Receptors (TLR)3.3. Antimicrobial peptidesAntimicrobial peptides4.4. CytokinesCytokines5.5. MacrophagesMacrophages6.6. NeutrophilsNeutrophils7.7. EosinophilsEosinophils8.8. Basophils, mast cellsBasophils, mast cells9.9. 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).

1. The Complement system

All three pathways lead to activation of the

central C3 component Innate immune response uses Alternative

pathway and Lectin pathway

1. The Complement system

Antibodies coat the antigen (opsonization) & alert the phagocytes to destroy (eat) the antigen

N.B. Gk, opsonein, to supply food

opsonization

1. The Complement system

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

1. The Complement system

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.

1. The Complement system

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.

1. The Complement system

Clinical manifestations of complement Clinical manifestations of complement

deficiency:deficiency:

1. Autoimmune diseases 2. Increased susceptibility to infection

1. The Complement system

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.

2. Toll-like receptors (TLR)

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.

GRAM GRAM NEGATIVENEGATIVE

GRAM POSITIVE

PAMPS recognized by the innate immune system:PAMPS recognized by the innate immune system: Cell wall constituents or microbial nucleic acids1. 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 walls4. Lipoarabinomannum (LAM) in mycobacterial wall5. 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)

CLASSIFICATION OF PRR

CLASSIFICATION OF PRR

Found on the surface of

phagocytes and promote the attachment of microorganisms to phagocytes and their subsequent engulfment and destruction.

ENDOCYTIC PRR

CLASSIFICATION OF 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 receptors2.2.CD14. CD14. 3.3.NOD (nucleotide-binding NOD (nucleotide-binding

oligomerization domain proteins)oligomerization domain proteins)

Signaling PRR

CLASSIFICATION OF 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.

2. Toll-like receptors (TLR)

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 IMMUNITY1.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 FUNGAL BACTERIAL 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..

2. Toll like receptors (TLR)

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 tonaive 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.

2. Toll like receptors (TLR)

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)

3. Antimicrobial peptides (AMPs)

1.1. Human Human β-β-defensin hBD 1-4 defensin 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)-1 Dramcidin (DCD)-1 (SWEAT GLANDS)4.4. LysosymeLysosyme5.5. PsoriasinPsoriasin (SEBOCYTES) prevents E. coli infection 6.6. RNase7 RNase7 ((ribonucleotidase)7.7. LL-37 A.K.A Cathelicidin antimicrobial peptide LL-37 A.K.A Cathelicidin antimicrobial peptide

(CAMP)/hCAP18 (CAMP)/hCAP18 (UROGENITAL TRACT) mediates dendritic cell activation in psoriasis

3. Antimicrobial peptides (AMPs)

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.

3. Antimicrobial peptides (AMPs)

ACTIONSACTIONS1.Broad spectrum anti bacterial and variable anti fungal and antiviral activities.2.Disrupting membranes, interfering with metabolism, and targeting cytoplasmic components3.Attract immature dendritic cells and memory T cells via CCR6 role in adaptive immunity

3. Antimicrobial peptides (AMPs)

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

4. Cytokines

Interferon (IFN)

CYTOKINES OF THE INNATE IMMUNE SYSTEM CYTOKINES OF THE INNATE IMMUNE SYSTEM Mainly cytokines with Mainly 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 with on 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 nitrous oxideoxide, 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

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 protein Major basic protein Eosinophilic cationic protein,Eosinophilic cationic protein, Eosinophil peroxidase Eosinophil 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 cells1.1. 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. Histamine Histamine 2.2. Serotonin. Serotonin. 3.3. ProstaglandinsProstaglandins4.4. Leukotrienes (B4, C4, D4 and E4), Leukotrienes (B4, C4, D4 and E4), 5.5. Platelet activating factorPlatelet activating factor They enhance i. vascular permeabilityii. bronchoconstrictioniii. 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 not systemic.

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 NK cells can recognize their targets in two

ways: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

Positivechemotaxis

Capillary wall EndotheliumBasal lamina

Inflammatory chemicals diffusing from the inflamed site act as chemotactic agents

Inflammatory Response: Phagocytic Mobilization

INNATE IMMUNITYINNATE IMMUNITY ADAPTIVE IMMUNITYADAPTIVE IMMUNITY

TriggerTriggerPAMP

(Pathogen-associated molecular

pattern) Specific antigensSpecific antigens

ActionAction Min to hours Days to weeksDays to weeks

ReceptorsReceptorsPRR (Pattern

recognition receptor) as TLR

TCR, BCRTCR, BCR

MemoryMemory No YesYes

CommunicationCommunication CytokinesCytokines

EffectorsEffectorsComplement

Antigen presentationPhagocytosis

Complement Complement Antigen presentationAntigen presentation

AntibodiesAntibodiesCytotoxicityCytotoxicity

Dr Samia Esmat Professor of Dermatology Dr Samia Esmat Professor of Dermatology

Cairo University Cairo University Bolognia: Dermatology, 2nd &3rd ed.Bolognia: Dermatology, 2nd &3rd ed. Immense Immunology Insight Immense Immunology Insight Immunity and the immune system Dr. Angelo Immunity and the immune system Dr. Angelo

Smith WHPLSmith WHPL

References