Transcript Mucosal immune system

Immune system
The main functions of the immune
system
Immune system belongs to the basic homeostatic
mechanisms
Defense - identification and protection against pathogenic
microorganisms and their toxins
Autotolerance – recognition of own tissues and keeping
tolerance to them
Immune surveillance - identifying and removing the old ,
damaged and otherwise changed cells
Antigen (immunogen)
* substance that the immune system recognizes and
responds to it
* usually proteins or polysaccharides (lipids and nucleic
acids only in the combination with proteins or
polysaccharides)
* Molecules <5 kDa can´t trigger an immune response,
the optimal size of the antigen molecules to initiate
immune response is about 40 kDa
* autoantigen - antigen derived from his own body
* exoantigen - alien substance from the external environment
allergen - exoantigen that in susceptible individuals may
cause pathological (allergic) immune response
Haptens
* small molecules, that are able to induce specific
immune response only after the establishment
to the macromolecular carrier
(separate haptens are not immunogenic)
* typically drugs (eg penicillin antibiotics, hydralazin)
Interaction antigen – antibody
* Binding site of antibody (paratop) form
non-covalent complexes with
the corresponding part on antigen
molecule (epitope)
* participation: the hydrogen bonds, electrostatic
and hydrophobic interactions, van der Waals forces
* antigen-antibody complex is reversible
Types of antigens according to antigen
presentation
1) thymus dependent antigens
* more frequently, mostly protein Ag
* for specific humoral immune response to antigen
is necessary to cooperate with TH lymphocytes
(or response isn´t enough effective)
* assistance implemented in the form of cytokines
produced by TH lymphocytes
Types of antigens according to antigen
presentation
2) thymus independent antigens
* in a small number of antigens can be induced antibodies
production directly without the participation of T lymphocytes
* this are mainly a bacterial polysaccharides,
lipopolysaccharides and polymer forms of proteins
(e.g. Haemophilus, Str.pneumoniae)
Superantigens
* proteins (microbial products) which have 2 binding sites,
one interacts with the epitope presented on all MHCgpII,
second interacts with other structures presented in many
different TCR molecules (connection of T lymphocyte with
APC)
* stimulate polyclonaly and massively
* massive activation of T lymphocytes can cause shock
* e.g. bacterial toxins (Staph.aureus, Str.pyogenes,
Pseud.aeruginosa)
Differcence between antigen and superantigen binding
Sequestered antigens
* autoantigens that are normally hidden to the immune
system and therefore unknow (e.g. the lens of the eye ,
testes)
* if they are "uncovered" by demage, may take the immune
system to respond (one of the theories of autoimmune
processes)
Components of the immune
system
Components of the immune system
* Lymphoid tissues and organs
* Cells of the immune systém
* Molecules of the immune system
Lymphoid tissues and organs
* are linked with the other organs and tissues by network
of lymphatic and blood vessels
Primary lymphoid tissues and organs
* bone marrow, thymus
* place of maturation and differentiation of immunocompetent
cells
* immature lymphocytes acquire here their antigenic specificity
Secondary lymphoid tissues and organs
* meeting place of immunocompetent cells with Ag
spleen - in contrast to the lymph nodes filter the blood and
captures presented antigens
lymph nodes and their organized clusters (tonsils,
appendix, Peyer patches in the intestine) - filter lymph and
capture present antigens
MALT (mucous associated lymphoid tissue) - diffuse
lymphatic tissue, the main role is capture of antigens that
penetrate through the mucous membrane
Cells of the immune system
* evolution of red and white blood cells begin at yolk sack,
then haematopoiesis travels to fetal liver and spleen
(3 to 7 month gestation), the main hematopoietic
function has bone marrow
* all blood cells arise from a pluripotent stem cell (CD 34)
* stem cells are modified and maintained throughout life
* haematopoiesis is regulated by cytokines that are
secreted by bone marrow stromal cells, activated TH cells
and macrophages
Surface molecules of leukocytes
* antigen-specific receptors (TCR, BCR)
* adhesion molecules (integrin, selectin, adhesion molecules
Ig family)
* Fc receptors
* complement receptors
* cytokine and chemokine receptors
* MHC gp
* receptors for components of microbial surfaces
CD nomenclature
* leukocyte surface molecules are called by CD-names
(cluster of differentiation)
* newly described molecules get the serial number
* many of them have alternative names (CD14 - LPS receptor;
CD16 - FcgRIII ...)
* TCR, BCR and MHC gp have no CD title
Molecules of the immune system
* antigen-specific receptors (TCR, BCR)
* antibodies
* MHCgp I and II class (HLA)
* Fc receptors
* adhesion and costimulating molecules
* cytokines and their receptors
* non-specific receptors for components of microbial
surfaces
* complement system
Immune mechanisms
Immune mechanisms
Nonspecific and specific immune mechanisms cooperate
with each other. The first in defense usually apply nonspecific mechanisms that recognize the chemical structures
present on the surface of many microorganisms (and
absent in their own cells). Some types of phagocytes are
essential for the initiation of antigen-specific mechanisms,
because they work as APC (antigen presenting cells)
for T lymphocytes.
Tolerance
Redundancy
Nonspecific immune mechanisms
* non-adaptive, innate
* evolutionarily older
* no immunological memory
* in the presence of pathogens react quickly, in minutes
(based on molecules and cells which are in the body
prepared in advance)
* component
cellular - phagocytes (some are APC), NK cells
humoral - complement, interferons, lectins
and other serum proteins
Natural non-immune protective
mechanisms
In protection the body against infection are important intact
mucous membranes and skin and nonimmune protective
mechanisms.
mechanical – movement of cilia, air flow in the airways,
or fluid flow in the urinary tract
chemicals – fatty acids on skin; lysozyme in saliva, tears
and sweat; antibacterial defensins, acid pH
in stomach and urine
microbial - non-pathogenic microflora
Specific immune mechanisms
* adaptive, antigen-specific
* evolutionarily younger
* have immunological memory
* development of a full-specific immune response takes
several days even weeks
* component cellular - T lymphocytes (TCR)
humoral - antibodies
Specific immune mechanisms
Clonal, anticipatory principle - the immune system is
able to predict (anticipate) meeting with any Ag, so that it is
prepared to advance a large number of T and B
lymphocytes, which differ in their antigen-binding sites of
specific receptors (TCR and BCR) and after contact with
certain Ag multiply relevant cells and create clones of cells
with the same specificity
Principle of the second signal - for the full activation of
lymphocytes is necessary costimulating signal, when it is
not present, and lymphocyte reaches only the first signal
(via the TCR, BCR), it leads to anergy or apoptosis
Mucosal and skin
immune system
Function and structure of the mucosal
and skin immune system
Mucous membranes and skin are in constant contact with
the outside environment, there is concentrated about
80% of immunocompetent cells.
Skin - barrier against mechanical, physical and chemical
damage, and against the penetration of microorganisms,
humans surface of about 1,5 m2
Mucosal immune system - prevents the penetration of
pathogenic microorganisms, preventing the development of
self-harm inflammatory immune responses against
pathogens and harmless antigens from the external
environment, mucosa with an area of about 400 m2
Mucosal immune system
Mucosa of mouth and nose, respiratory, gastrointestinal
and urogenital system, mucous membrane of eye and inner
ear, ducts of exocrine glands
Natural non-immune defense mechanisms
Movement of cilia, the flow of air and fluids, secrets of
exocrine glands with bactericidal effects (fatty acids ,
lysozyme, pepsin, defensins, acidic pH of the stomach and
urine)
Structure of mucosal immune system
MALT (mucous associated lymphoid tissue)
BALT (bronchus associated lymphoid tissue)
GALT (gut associated lymphoid tissue)
o-MALT (organized) – consists from lymphoid follicles in
the mucous membrane, tonsil and adenoids, appendix,
Peyer patches
d-MALT (diffuse) - is made up of leukocytes diffusely
distributed in the lamina propria (T and B lymphocytes,
macrophages, neutrophils, eosinophils and mast cells)
Intraepithelial T lymphocytes
* located predominantly in the villi of the small intestine
* mostly have TCRgd a coreceptor CD8
* produce TGFb (mucosal healing)
* suppression of adverse reactions to food allergens
Humoral immune mechanisms of the
mucous system
sIgA
*(secretory immunoglobulin A)
*
*
*
most significant mucosal immunoglobulin, in breast milk
transcytosis - IgA is transported across the epithelium
using transport Fc receptor (poly-Ig receptor), on luminal
side is IgA split off with the part of the receptor called
secretory component, which protects Ig against intestinal
proteases
neutralizing antigens on mucosal surfaces, don´t activate
complement, binds to Fc receptors on phagocytes, in
Peyerś patches may be immune complexes with IgA
captured and can induce immune response
sIgM
* secretory immunoglobulin M
* applied in newborns and in selective IgA deficiency
* more prone to intestinal protease degradation
* neutralizing antigens on mucosal surfaces
IgG
* get on the mucous membrane by diffusion
* applies particularly in the lower airways
Induction of mucosal immune response
Oral tolerance
* majority of antigens given orally causes suppression
of specific immunity (critical is also the size of the
antigenic particles)
* Tr lymphocytes (regulatory) - production of IL-10
Induction of mucosal immune response
* M cells - specialized enterocytes that provide transport of Ag
(endocyte Ag from the surroundings)
- are in close contact with lymphocytes and APC
* mucosal immunization leads to stimulation of TH2 and TH3
lymphocytes and IgA production
Immunological importance
of the breastfeeding
Breast milk contains:
* sIgA, IgG (neutralization of infectious microorganisms, their
products and potential allergens - before the full development
of the newborn mucosal immune system)
* CD 59 (protektin) - protect cells from the effects
of complement
* lysozyme, lactoferin, complement components, cytokines,
including interferons
* immunocompetent cells
Skin immune system
Epidermis
* keratinocytes - secretion of cytokines (IL-1,6,TNF,IL-10,TGFb)
- expression of MHCgpII → can serve as APC
* Langerhans cells - skin dendritic cells (APC)
* scattered intraepithelial lymphocytes
* melanocytes
Dermis
* fibroblasts - collagen production
- removal of apoptotic cells
* mast cells
* T lymphocytes (small amount)
* vessels, hair follicles, sweat and sebaceous glands
Immune mechanisms
of inflammation
(Local and systemic reactions)
Inflammation
* Is a summary of physiological responses to breach the
integrity of the organism, leading to protection against
infection of damaged sites, localization of damage and
healing.
* The first signals to the development of inflammatory
responses come from mast cells, phagocytes, and the
substances released from damaged cells and
extracellular components of matter.
Inflammation - acute (physiological defensive reactions,
usually subside without consequences,
damaged tissue heals completely)
- chronic (usually already pathological
reactions, occurs partial destruction
of tissue and compensation with
fibrous tissue)
Response of the organism - local
- system
Local body's response to inflammation
Manifestations - pain (dolor), heat (calor), redness (rubor), swelling
(tumor) and loss of function (funkcio laesa)
- increased permeability of blood vessels (vasoactive
amines, complement components C3a, C5a, leukotrienes
..., swelling at site of inflammation)
- increased expression of adhesion molecules on endothelia
- activation of coagulation, fibrinolytic, kinin and complement
system
- influence of local nerve endings (prostaglandins, pain)
- changes in temperature (IL-1, IL-6, TNF, prostaglandins)
Systemic response to inflammation
- depends on the extent of damage and duration of local
inflammation
- fever (proinflammatory cytokines TNF, IL-1, IFN g;
stimulate hypothalamic center of thermoregulation)
- mobilization of tissue metabolism
- induction of expression of Hsp (heat-shock-proteins;
function as chaperones)
- production of acute phase proteins(CRP, SAP, C4, C5;
opsonization and complement activation)
- increased hepatic synthesis of certain serum transport proteins
(ceruloplasmin, transferrin)
- increased synthesis of protease inhibitors ( macroglobulin)
- leukocytosis
Septic shock - the massive penetration of microorganisms
into the bloodstream (  TNF)
Anaphylactic shock - basophil degranulation and complement
activation with allergen
Repair of damaged tissue
- elimination of damaged cells with phagocytes
- activation of fibroplastic mechanisms
- activation of angiogenesis
- regeneration and tissue remodeling
Phagocytosis
Phagocytosis
= ability to absorb particles from the surroundings
Professional phagocytes
* cells, which provide defenses by mechanism of phagocytosis
* neutrophilic and eosinophilic granulocytes, monocytes
and macrophages
granulocytes - a defense against extracellular pathogens
- able to perform effector functions immediately
- neutrophils don´t express MHCgpII (not APC)
macrophages - the removal of own apoptotic cells,
defense against certain intracellular parasites
- fully functional after activating by cytokines
(IFNg, TNF)
The intersection of phagocytes
in damaged and infected tissues
7% of peripheral neutrophils and phagocytes
93% neutrophils and phagocytes in the bone marrow
* this ratio changes due to inflammatory cytokines
and bacterial products
* in place of damage are captured phagocytes
to endothelium (due to inflammatory cytokine expression
of adhesion molecules is higher)
* the first is interaction between selectins (adhesion
proteins of endothelial cells) and carbohydrate structures
on the surface of neutrophils - called roling, which slows
the movement of neutrophils
* then there is a stronger link between ICAM-1 (endothelial
cells) and leukocyte integrins (neutrophils) or VCAM-1
(endothelial cells) and b1-integrins (monocytes,
eosinophils) and subsequent penetration between
endothelial cells to the tissue - diapedesis , extravasation
* phagocytes are directed to the site of inflammation by
chemotactic active substances (IL-8, MIP-1 and b,
MCP-1, RANTES, C3a, C5a, bacterial products ...),
for which phagocytes have receptors
* in tissue phagocytes move so that they secret the
hydrolytic enzymes witch cleave components
of intercellular substance
Receptors of phagocytes
PAMPs - "pathogen associated molecular patterns„
- structures that are located on the surface of
microorganisms, but not on their own intact cells
* mannose receptor
* galactose receptor
* CD14 (binds bacterial LPS)
* receptors of TLR Group (binds bacterial lipoproteins,
lipopolysaccharides, bacterial DNA)
* scavenger receptors (bind phospholipids on the surface
of apoptotic cells)
Opsonization - process, which increases the efficiency
of foreign particles phagocytosis
- the establishment of opsonins (IgG, IgA,
C3b, MBL, fibronectin, fibrinogen, CRP,
SAP) on the surface of foreign particles
* Fc receptors on phagocytes (recognize antibodies linked
to surface of micro-organism)
* complement receptors (for binding C3b)
Liquidation of absorbed organism
* fusion of fagosome with lysosomes
lysosomes contains - bactericidal substances (defensins)
- hydrolytic enzymes (cathepsin, lysozyme)
- liquid with a pH of 4-5
* activation of membrane NADPH oxidase after activation
of Fc receptors and complement receptors, which leads
to respiratory (oxidative) flash, when arise reactive oxygen
intermediates (superoxid radical O2-, singlet oxygen, hydrogen
peroxide, hydroxyl radical), which damage the structure of
biopolymers, enzymes and DNA of microorganisms;
enzyme myeloperoxidase catalyses the reaction of H2O2 with Clto form chlornan anions (ClO-)
* creation of nitric oxide (NO), which produces NO synthase
of macrophages after activation with cytokines (IFNg, TNF) that are
produced by TH1 lymphocytes, NO liquidate intracellular parasites
of macrophages
Secretory products of phagocytes
* IL-1, 6, TNF (systemic response to inflammation)
* IL-8 (chemokine)
* IL-3, GM-CSF (control haematopoiesis)
* TGF, TGFb (helping healing of tissues)
* metabolic products of arachidonic acid (prostaglandins,
prostacyclin, leukotrienes and thromboxanes
Complement
Complement
* system of about 30 serum and membrane proteins
(humoral component of nonspecific immunity)
* complement components in serum are present in inactive form
* complement activation has cascade character
* complement proteins are synthesized in the liver, less by tissue
macrophages and fibroblasts
* the main complement components: C1-C9 (C3 is the central
component)
* other complement components: factor B, factor D, factor P
* regulatory proteins: C1 - inhibitor, factor I, factor H, DAF, MCP,
CR1, CD59 (protektin) inactivator of anafylatoxin
Function of complement
* Opsonization (C3b)
* Chemotactic (C3a, C5a)
* Osmotic lysis (MAC C5b-C9)
* Anafylatoxins (C3a, C4a, C5a)
Complement activation
* Alternative pathway
* Clasial pathway
* Lektin pathway
An alternative pathway
* C3 component of complement rarely spontaneously break
into C3b and C3a
* C3b can covalently bind on the surface of a particle (own
cell, microorganism) or reacts with water and inactivate
* to bound C3b join a factor B, which is cleaved by factor D
to Ba and Bb, resulting complex C3bBb is stabilized by
factor P and functions as an alternative C3 convertase
* C3 convertase cleaves C3 to C3a (chemotactic for
phagocytes) and C3b, which binds to the surface of the
particles (opsonization), or gives rise to other C3 convertases
* from some C3 convertases form C3bBbC3b that act as
an alternative C5 convertase, which cleaves C5 to C5a
(chemotaxis) and C5b (starts terminal lytic phase)
Classical pathway
* Can be initiated by antibodies (IgG, not by IgG4; IgM)
or so-called pentraxins (CRP, SAP - acute phase
proteins)
* after binding of antibodies to the bacteria surface, there is
a change in its conformation and C1 protein can bind
* C1 have to bind to the 2 molecules of antibodies, change
their conformation and get proteolytic activity - will cleave
proteins C4 and C2
* fragments C4b and C2a bind to the surface of organism
and create the classic C3 convertase (C4bC2a), which
cleaves C3 to C3a and C3b
* then creates a classic C5 convertase (C4bC2aC3b) that
cleaves C5 to C5a and C5b
Lektin pathway
* is initiated by serum mannose binding lectin (MBL)
* MBL binds to carbohydrate structures on the surface
of some microbes, after the bindins starts cleave C4
and C2
* this way is similar to the classical way
Terminal (lytic) phase of the
complement cascade
C5b fragments creates a complex with C6, C7 and C8, the
complex dive into the lipid membrane of the cell and attached
to it into a circle 13-18 molecules of C9, thus create in the
membrane pores and cell can lysis (G-bacteria, protozoans,
some viruses).
Most microorganisms is to this lytic effect of complement
resistant (protection by cell wall).
Regulation of complement and protection
of own cells
Activation of complement cascade is controlled by the plasma
and membrane inhibitors.
* C1 inhibitor
* DAF (decay-accelerating protein)-degradation of C3 convertase
* factor I, MCP (membrane cofactor protein), CR1, factor H –
C3b cleavage
* CD 59 (protectin) - prevents the polymerization of C9
* inactivator of anafylatoxin - inactivates anafylatoxins (C3a,
C4a, C5a)
Complement receptors
* Bind fragments of complement components
CR1 - on various cells
- removing of immunecomplexes
CR2 - on B lymphocytes and FDC
- activation of B cells
CR3, CR4 - on phagocytes
- participation in opsonization, adhesion