Basic Immunology from the Dermatological point of view. Introduction to the major components of adaptive immunity.
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Basic Immunology from the Dermatologic point of view Cont.
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)
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
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
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
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
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 persons own body
becomes an antigen Antigens
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)
Defined as professional APCs that display an extraordinary
capacity to stimulate naive T cells and initiate a primary immune
response. Dendritic cells (DC)
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. FcRI Derived from the bone marrow from CD34 precursor
cells. LNGERHANS CELLS
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
Langerhans cells can be visualized by staining using an
antibody against MHC class II molecules. Note the dendritic shape
of Langerhans cells.
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
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
: 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
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
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
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
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
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.
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
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
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 / type while only 10% are of the /
type in body and skin. The T-CELL RECEPTOR (TCR)
Do not follow the classic way of antigen recognition . May play
a role in innate immunity. Increase in the skin in leprosy and
lieshmaniasis. / T-cells
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
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
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 peptideMHC 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
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-, 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
After proper antigen presentation and costimulation T cell
becomes activated division occurs. Memory T cells develop CLONAL
EXPANSION
Majority are: In the dermis. CD4 OR CD8. / TCR. memory
phenotype CD45RO+/CD45RA- Skin homing receptor CLA(cutaneous
lymphocyte associated antigen). Criteria of Skin T cells
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
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
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
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
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
Transforming growth factor B . Helps IgA production. Suppresses
both Th1 and Th2 responses. Th3 cells
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)
Function of regulatory T cells
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- and IFN-, 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)
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)
B-cell response
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
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
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
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
Primary and Secondary Humoral Responses
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( ), IgG( ), IgA( ), IgD( ), or IgE( ).
Antibodies
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
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
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
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
(FcRI). 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 FcRI. The second IgE receptor, FcRII exhibits
weaker binding affinity and is expressed on macrophages,
eosinophils, platelets, and particular subtypes of T and B cells.
Immunoglobulin E
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
Mechanisms of Antibody Action
Functions of antibodies
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
Hypersensitivity An allergic reaction. An exaggerated response.
Tissue destruction occurs as a result of the immune response. Four
main types.
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.
When a specific antigen binds to mast cell-bound IgE, the FcRI
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
Acute Allergic Response
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).
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.
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.
The body produces auto-antibodies and sensitized TC cells that
destroy its own tissues Examples include: systemic lupus
erythematosus (SLE) Pemphigus Autoimmune Diseases
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