Basic Immunology from the Dermatological point of view. Introduction to the major components of adaptive immunity.

1. Basic Immunology from the
Dermatologic point of view
Cont.

2. 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)

4. 
 The innate immune system effectively prevent free
growth of bacteria within the body.
 however, many pathogens have evolved mechanisms
allowing them to bypass the innate immune system and
generates a threshold level of antigen which triggers the
adaptive immune system .
Adaptive immunity

5. 
1. The RECOGNITION of specific “non-self” antigens in the
presence of “self”, during the process of ANTIGEN
PRESENTATION.
2. The generation of TAILORED RESPONSES to eliminate
specific pathogens.
3. The development of IMMUNOLOGIC MEMORY in which
each pathogen is “remembered” by a signature antibody.
These memory cells can be called upon to quickly eliminate
a pathogen on subsequent infections due to enhancement
with each successive antigen encounter owing to the
accumulation of “memory” .
Functions of the adaptive
immune system

6. 
 The lymphocytes of the adaptive immune system
are:
• T cells mature in the thymus
• B cells mature in the bone marrow
 The process starts by antigen presentation.
Adaptive immune system

7. 
It has two separate but overlapping arms:
I. Humoral, or antibody-mediated (B Cell)
immunity
II. Cellular, or cell-mediated (T Cell) immunity
Adaptive immune
system

10. 
1. Foreign substances
 Mainly proteins, often microorganisms and their toxins
2. Human cells that have been transformed
 May be tumor cells, or cells infected with viruses
3. Human tissue
 Organ transplants, tissue grafts, incompatible blood
types during a transfusion
4. Autoimmune diseases
 Tissue from the person’s own body becomes an
antigen
Antigens

11. 
With the exception of non-nucleated cells all cells are capable
of presenting antigen and of activating the adaptive
response.
- depending on how and where the antigen first encounters
cells of the immune system.
- Some cells are specially equipped to present antigen, and
to prime naive T cells and are termed professional (APC).
 Dendritic cells: Langerhans cells (LCs) are key APCs.
 B-cells
 Macrophages
 Neutrophils
Antigen presenting
cells (APCs)

12. 
 Defined as professional APCs that display an
extraordinary capacity to stimulate naive T cells and
initiate a primary immune response.
Dendritic cells (DC)

13.  Dendritic Cells of the epidermis.
 Derived from the bone marrow
 EXPRESSES:
1. Birbeck granules
2. Langerin
3. MHC class II.
4. CD1, useful marker for LCs, since within the epidermis
(normal or inflamed) it is exclusively expressed on LCs.
5. S100 ptn
6. Vimentin
7. FcεRI
 Derived from the bone marrow from CD34 precursor cells.
LNGERHANS CELLS

14. 
 LCs cannot be identified in routinely fixed and stained
histologic sections; their recognition requires electron
microscopy or histochemical analysis.
Numbers of LCs are reduced in following:
1. The palms and soles, genitalia and buccal mucosa.
2. With age.
3. Chronically UV-exposed skin.
LNGERHANS CELLS

16. 
Langerhans cells can be visualized by staining using an
antibody against MHC class II molecules. Note the
dendritic shape of Langerhans cells.

17. Electron microscopic picture of a Langerhans cell. Arrows
indicate The Birbeck granules, rod-shaped organelles
specific for Langerhans cells. They are said to resemble
tennis rackets

18. 
 Resident Langerhans cell engulfs the exogenous
antigen or express the endogenous one
 Starts emigration to the lymph nodes to meet the T
cells.
 During this trip it develops some changes to become
similar to mature Dendritic cell.
LC: Antigen presentation

19. 
:
a) Molecules involved in antigen uptake as Birbeck
granules, Fc receptors
b) Molecules mediating the attachment to neighboring
keratinocytes ( E-Cadherins).
:
a) Expression of receptors involved in tissue homing at
the lymph nodes as CD44.
b) Surface molecules necessary for antigen presentation
and T cell priming as MHC class I, MHC class II,
CD40, CD54, CD58, CD80, CD86.
c) Type IV collagenase enable their penetration through
the basement membrane.
d) Their dendricity becomes more pronounced.
Changes of LCs during
migration

20. 
 APC to B cells and T cells is not the same.
 T cells only identify the antigen when processed into
peptides bound to specific surface molecules on
APC.
 B cells can identify the whole antigen by antibodies
on their surface
Ag Presentation to
T-Cells

21. 
 T-cells identify the processed antigen bound to MHC
on the surface of Dendritic cells.
 T helper CD4 T cells identify antigens bound to
MHC II while;
 Cytotoxic CD8 T cells identify antigen T cells bound
to MHC I
 Exogenous and endogenous antigen presentation.
Ag Presentation to
T-Cells

22. 

23. 
 The MHC complex is divided into three subgroups
called MHC class I, MHC class II and MHC class III.
 MHC class I is present on all nucleated cells (except
RBCs).
 MHC class II is present on antigen presenting cells.
MHC

24. 

25. 
1. Exogenous antigens:
are engulfed by the APC, processed and presented in
association with MHC II.
2. Endogenous antigens:
(VIRUS AND TUMOURS) are processed and presented
in association with MHC I
TYPES OF AP to T-
cells

27. lymphocytes
T cells undergo thymic education through positive and negative selection.
They are taught the difference between self and non-self molecules in
their school to achieve Immunologic tolerance.

28. T cells develop and mature in the Thymus after migration of the
stem cells from the bone marrow.
 At the thymus only T cells that can recognize foreign and
not self antigen in the MHC complex get a survival signal
(positive selection) and pass to the circulation and lymph
nodes.
 Those who fail have affinity to self antigens receive
signals for apoptosis (negative selection) thus no auto
attack.
Positive and negative selection allow the survival of just those T
cells that recognize foreign (but not “self”) peptides in the context
of “self” MHC molecules and thus are useful for immune defense
without causing auto-attack
T cells

29. 
1. Immature T cells:
Express both CD4 and CD8 molecules.
2. Mature T cells:
Later with the development of the T-cell receptor
(TCR), they either express:
a)CD4 and become T helper cell that binds
antigens in MHCII
b)CD8 molecule and becomes T cytotoxic cell that
binds antigens on MHCI.
Types of T cells

30. 
 It is the part responsible for recognition of the specific
antigen and the further T cell response.
 TCR are transmembrane molecules that are mainly of
the α/β type while only 10% are of the γ/δ type in body
and skin.
The T-CELL
RECEPTOR (TCR)

31. 
 Do not follow the classic way of antigen recognition .
 May play a role in innate immunity.
 Increase in the skin in leprosy and lieshmaniasis.
γ/δ T-cells

32. 
 Can recognize a huge number of antigens encoded
by more than 400 genes that are modified and
rearranged to cover an endless number of antigens
by recombination activation genes
 when defective ----combined immune deficiency.
TCR

33. 
CD3 is an important part of TCR responsible
for transmission of the signal to the cell that
encodes for the cytokine needed to stimulate
the required response for that particular
antigen.
TCR SIGNALLING

35.  Signaling through the TCR complex alone does not
suffice to activate T cells. The presence of costimulatory
signals is needed for T cells to undergo antigen-specific
clonal expansion.
 Development of a productive T-cell immune response
requires exposure of these cells to at least two types of
stimuli.
 The first signal is the interaction of the TCR with
peptide–MHC complexes presented by APCs, which
determines the specificity of the immune response.
 The second signal involves surface molecules and
cytokines, which determine the clonal expansion of
specific T cells and their differentiation into effector
and memory cells.
Costimulatory molecules

36. 
 B7 FAMILY e.g. B7-1 (CD80) and B7-2 (CD86)
induced by cytokines (TNF, IL-1) or by various TLR
ligands
 Cytokines, especially inflammatory mediators
like IL-1, IL-6 and TNF-α, also provide
costimulatory signals by themselves and, in
addition, upregulate costimulatory molecules.
 Are very important for completion of the T-cell
response other wise ANERGY (non-reactivity)
and failure of T-cell stimulation occurs.
Costimulatory molecules

38. 
After proper antigen presentation
and costimulation T cell
becomes activated division
occurs.
Memory T cells develop
CLONAL EXPANSION

39. 
 Majority are:
 In the dermis.
 CD4 OR CD8.
 α/β TCR.
 memory phenotype CD45RO+/CD45RA-
 Skin homing receptor CLA(cutaneous
lymphocyte associated antigen).
Criteria of Skin T cells

40. 
1. CENTRAL MEMORY T CELLS [TCM]:
express lymph node homing receptors and thus stay in the
lymph nodes. CD45RO+CD45RA- CCR7+ Have no
effector function. They stimulate dendritic cells to produce
IL-12 upon secondary stimulation and differentiate into
CCR7- cells.
2. EFFECTOR MEMORY T CELLS [TEM]:
CD45RO+CD45RA- CCR7- develop receptors to migrate
to the inflamed tissues (e.g. CLA in the skin). express
receptors for migration to inflamed tissues and have
immediate effector function.
Memory T cells

41. 
After recognition of the antigen
 CD4: T helper cells (Th):
activate the immune system to combat the antigen
including both T and B cells.
 CD8: T cytotoxic cells (Tc):
Antiviral and anti-tumor responses
Effector T cell function

42. 
 According to the type of antigen recognized by the
Th cells they secrete different cytokine patterns that
will further stimulate different parts of the immune
system.
 Pre-activated precursor Th cells (Th0) secretes a
wide variety if cytokines which then develops into:
Th1 or Th2 with more restricted type of cytokine
secretion.
T helper response

45. Th1 cells Th 2 cells
Differentiation from Th0
mediated by
IL-12 IL-4
Secretes
a) IL-2: stimulates both
Th and Tc
proliferation.
b) IFN GAMMA:
activates
macrophages and NK
cells and IL-12.
a) IL-4: Stimulates B cells
to produce IgE and
stimulates further Th 2
response and inhibits
Th1 response.
b) IL-5: promotes
eosinophil growth.
c) IL-10: inhibits Th1
response
Mediates
CELL MEDIATED
RESPONSE
HUMORAL IMMUNITY
Th1 cells versus Th2
cells

46. 

47. 
1. Depends mainly upon the type of antigen presented.
2. The cytokines it stimulates.
3. The Dendritic cells.
4. the toll like receptor.
5. Dose of antigen.
6. Genetic background of the host.
7. The APC and its cytokines.
8. The co-stimulatory molecules.
Th1/Th2 decision

48. 
Transforming growth factor B .
Helps IgA production.
Suppresses both Th1 and Th2 responses.
Th3 cells

49. 
CD4 + T cells.
Secretes large amounts of IL-10.
Suppressor effect on both immune
responses.
Produced by immature inactive dendritic
cells.
Important for TOLERANCE towards self
antigens and regulating inflammation.
Regulatory T cells (Tregs)

50. 
Function of regulatory T cells

52.  Direct killing of the organism or the abnormal or infected cells.
 TC1 and TC2 in cytokine patterns (functional roles still remain to
be determined. Even).
 Viral and anti-tumor activities.
 Cytotoxic T cells with CD8 surface protein are called CD8+ T cells.
 Three different pathways of killing:
a) Perforin which forms pores in the target cell's plasma
membrane this causes ions and water to flow into the target
cell, making it expand and eventually lyse then Granzyme
that can enter target cells via the perforin-formed pore and
induce apoptosis.
b) Tc cells activate the death receptor Fas on the target cell by
expressing the cognate death ligand FasL. The activated Fas
also triggers apoptosis.
c) Cytokines, including TNF-α and IFN-γ, which are released as
long as TCR stimulation continues. These mediators can
affect distant cells as well as the target cell
Cytotoxic T cells (CD8+ T
cells)

54. 
 B cells function to protect the host by producing
antibodies that identify unique antigen and neutralize
specific pathogens.
 B Cells are the major cells involved in the creation of
humoral immunity.
 Like the T cell receptor, B cells express a unique B
cell receptor (BCR), in this case, an immobilized
antibody molecule. The BCR recognizes and binds to
only one particular antigen.
 Differentiates into an effector cell, known as a
PLASMA CELL
The B lymphocyte (B cells)

55. B-cell
response

56. 
T cell B cell
Antigens
reorganization
Processed form
in the context of an
MHC
Native form
Activation signals Th1 Th2
B cell Vs. T cell
ACTIVATION

57. 
 Short lived cells (2-3 days) which secrete antibodies
that bind to antigens, making them easier targets for
phagocytes, and trigger the complement cascade.
 About 10% of plasma cells will survive to become
long-lived antigen specific memory B cells primed to
produce specific antibodies and respond quickly if
the same pathogen re-infects the host; while the host
experiences few, if any, symptoms.
Plasma cells

58. 
 Primary immune response – cellular differentiation
and proliferation, which occurs on the first exposure
to a specific antigen
 Lag period: 3 to 6 days after antigen challenge.
 Peak levels of plasma antibody are achieved in 10
days.
 Antibody levels then decline.
Immunological Memory

59. 
 Secondary immune response – re-exposure to the
same antigen
 Sensitized memory cells respond within hours.
 Antibody levels peak in 2 to 3 days at much higher
levels than in the primary response.
 Antibodies bind with greater affinity, and their levels in
the blood can remain high for weeks to months.
Immunological Memory

60. 
Primary and Secondary Humoral Responses

63. 
 Antibodies (or immunoglobulin, Ig), are large Y-
shaped proteins used by the immune system to
identify and neutralize foreign objects.
 In mammals there are five types of antibody: IgA,
IgD, IgE, IgG, and IgM, differing in biological
properties, each has evolved to handle different
kinds of antigens.
 Heavy chains: The heavy chains of a given antibody
molecule determine the class of that antibody: IgM(
μ), IgG(γ ), IgA(α ), IgD( δ), or IgE(ε ).
Antibodies

64.  IgG is monomer Ig & the most abundant
immunoglobulin, accounting for approximately 75%
of the total amount of serum immunoglobulin.
 The major immunoglobulin of the secondary immune
response.
 Four subclasses (IgG1, IgG2, IgG3, IgG4) are
defined by the amino acid sequences of their
constant region.
 Most of the autoimmune dermatoses caused by
autoantibodies are mediated by IgG, most often
IgG4.
 Crosses the placenta and confers passive immunity.
Immunoglobulin G

65. 
 The largest immunoglobulin.
 IgM molecules are pentamers that (in addition to light
and heavy chains) contain one J chain.
 IgM is the major immunoglobulin produced in the
primary immune response.
 Upon binding to its antigen, IgM induces
agglutination and activates the classical complement
pathway.
Immunoglobulin M

66. 
 IgA is the predominant immunoglobulin present in
mucosal surfaces prevent attachment of pathogens to
epithelial cell surfaces.
 IgA can activate the complement system via the
alternative (but not the classical) pathway.
 Two subclasses of IgA exist, IgA1 and IgA2. IgA
molecules can be joined by a J chain; this dimer form is
mostly found in secretions, while in the serum, IgA
circulates primarily as a monomer.
 IgA molecules can be involved in the pathogenesis of
bullous autoimmune diseases.
Immunoglobulin A

67. 
 IgE monomer is the classic anaphylactic antibody that
mediates most immediate allergic and anaphylactic
reactions.
 Mast cells and basophils express high-affinity receptors
for the Fc portion of IgE (FcεRI). Antigens, anti-IgE
antibodies or other substances that crosslink at least two
IgE molecules bound on mast cells induce the release of
mediators.
 Also LCs, dermal DCs and peripheral blood DCs as well
as monocytes from atopic individuals can bind monomeric
IgE via the high-affinity FcεRI.
 The second IgE receptor, FcεRII exhibits weaker binding
affinity and is expressed on macrophages, eosinophils,
platelets, and particular subtypes of T and B cells.
Immunoglobulin E

68. 
 The function of IgD still remains mysterious. Recent
evidence suggests that IgD participates in respiratory
immune defense.
 It binds to basophils and mast cells, stimulating their
production of antimicrobial factors.
 IgD may also exert proinflammatory functions, as
illustrated by the hyperimmunoglobulinemia D with
periodic fever syndrome (HIDS).
Immunoglobulin D

69. 
Mechanisms of Antibody Action

70. Functions of
antibodies

71. 

72. INNATE IMMUNITY ADAPTIVE IMMUNITY
Trigger
PAMP
(Pathogen-associated
molecular pattern)
Specific antigens
Action Min to hours Days to weeks
Receptors
PRR (Pattern recognition
receptor) as TLR
TCR, BCR
Memory No Yes
Communication Cytokines
Effectors
Complement
Antigen presentation
Phagocytosis
Complement
Antigen presentation
Antibodies
Cytotoxicity

74. Hypersensitivity
An allergic reaction.
An exaggerated response.
Tissue destruction occurs as a result
of the immune response.
Four main types.

75. 

76. Type I Hypersensitivity
Immediate (Anaphylactic type)
The reaction occurs within minutes after exposure
to an antigen.
Plasma cells produce IgE.
IgE causes mast cells to release histamine,
causing increased dilation and permeability of
blood vessels and constricting smooth muscle in
bronchioles of the lungs.
The reaction may range from hay fever to asthma
and life-threatening anaphylaxis.

77. 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. Histamine
2. Bradykinin
3. Serotonin.
4. Prostaglandins
5. Leukotrienes (B4, C4, D4 and E4),
6. Platelet activating factor
They enhance
i. vascular permeability
ii. bronchoconstriction
iii. induction of an inflammatory response
Type I Hypersensitivity

78. 
Acute Allergic Response

79. Type II Hypersensitivity
Cytotoxic type (Sub acute type)
Antibody combines with an antigen bound to the
surface of tissue cells, usually a circulating RBC.
Activated complement components, IgG and IgM
antibodies in blood, participate in this type of
hypersensitivity reaction.
This destroys the tissue that has the antigens on
the surface of its cells (e.g., Rh incompatibility).

80. Type III Hypersensitivity
Immune complex type (serum
sickness, SLE) (Also a Sub acute
type)
Immune complexes are formed between
microorganisms and antibody in circulating blood.
These complexes leave the blood and are
deposited in body tissues, where they cause an
acute inflammatory response.
Tissue destruction occurs following phagocytosis
by neutrophils.

81. Type IV Hypersensitivity
Cell-mediated type (delayed)
T lymphocytes that previously have been
introduced to an antigen cause damage
to tissue cells or recruit other cells.
Responsible for the rejection of tissue
grafts and transplanted organs
Allergic contact dermatitis.

82.  The body produces auto-antibodies and sensitized TC cells
that destroy its own tissues
 Examples include:
 systemic lupus erythematosus (SLE)
 Pemphigus
Autoimmune Diseases

83. 
 Dr Samia Esmat Professor of Dermatology Cairo
University
 Bolognia: Dermatology, 2nd &3rd ed.
 Immense Immunology Insight
 Immunity and the immune system Dr. Angelo Smith
WHPL
References

84. 