“Types of hypersensitivity.
Cell-type immune responses
(hypersensitivity of the delayed type of HRT). Clinical examples".
Cycle 1 – immunology.
Lesson No. 5 a

Allergy (ancient Greek ἄλλος - other, other, foreign + ἔργον - impact)

Allergy
(ancient Greek ἄλλος - other, different, alien + ἔργον -
impact)
1906 Austrian
pediatrician Clemens von
Pirquet suggested
the term "Allergy".
He noticed that
some symptoms in
patients are called
influence of external
agents (later
named
allergens).
Currently under
the term allergy
understand excessive
painful
immune reaction
directed against
exogenous substances
(allergens).

Atopia (Greek: Atopia – unusual, strange, alien)

In 1923 Coca and Cook
proposed the term
"atopy".
They described
hereditary
predisposition
to the development of eczema and
allergic reaction
Type I in response to
inhalation
allergens.
Currently under
the term "atopic"
diseases" unite
allergic diseases,
flowing through
hypersensitivity
immediate type –
allergic asthma,
allergic rhinitis,
atopic dermatitis
and etc.

Sensitization (lat. sensibilis - sensitive)

Specific
sensitivity
body to allergens,
which is based on
synthesis process
allergenspecific
kih IgE
followed by them
linking with
high affinity IgE receptors in obese
cells and basophils.

Anaphylaxis

French physiologist Charles
Richet (Nobel Prize
1913): anaphylaxis –
state of sharply increased
the body's sensitivity to
getting caught again
allergen organism
(medicines, food, poisons
insects, etc.), develops
by IgE-mediated
mechanism.
(Rich and Portier
first in 1902
applied
term
"anaphylaxis"
for description
systemic
reactions to
whey
a rabbit).

Hypersensitivity

Excessive or
inadequate
manifestation of reactions
acquired
immunity.
Hypersensitivity
does not appear when
first, and when
repeated hit
antigen into the body.
After the first hit
antigens develop
immune responses,
clinical manifestations
not available yet.
If hit again
antigen occur
effector
inflammatory reactions,
appearing
clinically (inflammation).

Types of hypersensitivity according to the classification of British immunologists Robin Coombs and Philip Gell 1963

Based on all types
hypersensitivity –
different types of immune
mechanisms leading to
tissue damage
body
(pathophysiological
classification).
CLASSIFICATION OF TYPES
HYPERSENSITIVITY
COOMBS and GELLA
1963
also used in
present time

4 types of hypersensitivity according to Coombs and Gell (Coombs and Gell)

Type 1 - reagin or
acute allergic
inflammation,
hypersensitivity
immediate type (GNT).
Type 2 – antibody dependent
cellular cytotoxicity
(AZKTS).
Type 3 –
immunocomplex
inflammation (IR).
Type 4 –
hypersensitivity
slow type
(HRT).

Type 1 hypersensitivity according to Coombs and Gell (Coombs and Gell)

Type 1 - reagin or spicy
allergic inflammation,
hypersensitivity
immediate type (GNT).
By the time of creation
classifications
immunoglobulin E has not yet been
open.
The answer was described as
"reaginic".
In GNT, the main role is played by
IgE synthesized against
soluble proteins
(allergens); the most
common examples
are pollen, wool
animals, pollen mites,
food products,
anthropogenic toxins.
Exposure to an allergen initiates
interaction on
membrane-bound IgE with obese
cells or basophils trigger
typical inflammatory reaction:
release of neurotransmitters
immediate response (eg
histamine)
formation of prostaglandins and
leukotrienes
synthesis of cytokines – IL-4,5,13, ​​which, in
in turn, strengthen this reaction.
Typical clinical examples of HNT:
allergic rhinitis, allergic
asthma, allergic urticaria,
anaphylactic shock.

Type 2 – antibody dependent
cellular cytotoxicity
(AZKTS) result of interaction
circulating antibodies
class G with surface
antigens.
Typically target antigens are
associated with red blood cells
antibiotics (penicillin),
cellular components
(for example, Rh D antigen,
components of the basal
membranes).
Such interaction
stimulates toxic
effects using
complement or
phagocytosis.
Examples – hemolytic
anemia, some forms
glomerulonephritis,
some forms
hives,
mediated
antibody formation
against Fcέ receptors.

Type 2 hypersensitivity according to Coombs and Gell (Coombs and Gell)

Diagnosis of type 2 reactions is difficult in
in vitro conditions.
Mechanisms of tissue destruction in type 2
reactions.
Antibody binds to antigens on
cell surface (Fab fragment), and
Fc fragment is capable of:
1. Activate NKs that have F receptors. Activated NKs lyse
target cells with which it connected
antibody.
2.Fc receptors are expressed on
cells of monocyte-macrophage
row. Macrophages destroy cells
which antieles are present – ​​that is, this
–antibody dependent cytotoxicity
(different types of singing - thrombocytopenia and
hemolytic anemia).
Thrombocytopenia more often
appear in the form
purpura on the skin (feet,
distal parts
shins) and on mucous membranes
shells (often on
hard palate).
Damage
represent
petechiae - small, with
pin head, no
disappearing when
clicking on them
red spots.

Type 3 – immunocomplex
inflammation (IR).
When antibodies to
soluble antigens
immune systems are formed
complexes in certain
concentrations.
Typical antigens
are:
whey proteins
antigens of bacteria, viruses
mold antigens.
Emerging immune
complexes can act
local, or spread
with blood flow.
Effector mechanism
inflammatory response in this
case includes system activation
complement via the classical pathway with
stimulation of granulocytes,
damage to tissues and blood vessels.
Examples are serum sickness or
local Arthus reactions to
serum injection; vasculitis,
including skin lesions,
kidneys and joints (for example, related
with a chronic form of viral
hepatitis), or, for example. exogenous
allergic alveolitis (EAA),
which, depending on the antigen,
called "farmer's lung"
(molds), pigeon breeder's lung,
easy wavy lovers
parrots (AG feathers, excrement

Type 3 hypersensitivity according to Coombs and Gell (Coombs and Gell)

Type 3 – immunocomplex
inflammation (IR).
Diagnosis of type 3 reactions
difficult in conditions
vitro. Distinctive feature
this type of reaction is
deposition of complexes
antigen-antibody along
basement membranes of small
vessels - for example, in
renal glomeruli and
skin. Launch
system activation
complement and attraction
cells – neutrophils and
others to the place of deposition
immune complexes
leads to development
immunocomplex
Skin manifestations
immune complex vasculitis is
palpable purpura that is detectable
like small hemorrhagic papules,
capable of uniting and forming
zone of necrosis (Arthus reaction).
More often this type occurs within one
organ (for example, exogenous
allergic alveolitis), but may
develop and generalized response
Common triggers for this reaction:
Bacterial infection
Reaction to drugs
(penicillin and its derivatives)
Reaction to mold spores
Within a few hours after
exposure to these antigens appears
symptoms: malaise, fever, pain in

Type 4 hypersensitivity according to Coombs and Gell (Coombs and Gell)

Type 4 – hypersensitivity
delayed type (DTH).–
delayed reactions,
mediated by antigen-specific T helper 1
type and cytotoxic T lymphocytes.
Possible causative
the agents are ions
metals or others
low molecular weight substances
(food preservatives),
called haptens, which
become full-fledged
antigens after
interaction with the protein carrier.
Mycobacterial proteins
often cause a reaction
HRT.
Inflammatory
cellular infiltrate –
characteristic feature
HRT.
Examples – contact
dermatitis, local
erythematous nodules,
detected by
positive
tuberculin reaction,
sarcoidosis, leprosy.

TYPE
TYPE I
TYPE II
TYPE III
TYPE I V
hypersensitive
flatness; time
manifestations
10-30 minutes
3-8 hours
3-8 hours
24-48 hours
Immune
reaction
Ig E
antibodies;
Th 2
Ig G
Ig G
Th 1
macrophages
Th 1
CD 8+
macrophages
Antigen (AG)
Dissolve
washed
AG
AG,
Related to
cells
or
matrix
Dissolve
washed
AG
Dissolve
washed
AG
AG,
Related to
cells
Effector
ny
mechanism
Activation
obese
cells
Complement
and cells with
Fc γR
(phagocytes and
NK)
Complement
and cells with
Fc γR
(phagocytes
and NK)
Activation
macropha
gov
Cytotoxic
ness
Allergies Hemolytics
cue rhinitis;
what kind of anemia
asthma;
anaphylactic
Immunreaktionen
der Haut
this
System
red
lupus
Reaction to
tuberka
lin
Contact
dermatitis
Examples
15

Immediate hypersensitivity (IHT)

this phenomenon is used in
Mechanism for the first time
currently as
diagnostic method
described in 1921
allergies in vivo - skin
(Praunitz, Kustner):
samples.
Blood serum
Kustner, who suffered
allergy to fish, introduced
subcutaneously to Praunitz.
Then subcutaneously
antigens were injected into the same place
fish. On the skin
Praunitz appeared
blisters.

Stages of HNT

The first contact of the allergen with
mucous membrane or skin
leads to the formation of IgE.
Locally produced IgE
first sensitize only
local mast cells
then penetrate into the blood and
bind to fat receptors
cells in any part of the body.
On the receptors
mast cells
IgE can
persist
some
months (and
blood - only
2-3 days).

Stages of HNT

If hit again
allergen into the body
interacts with IgE,
associated with receptors
mast cells.
Such interaction
leads to degranulation
mast cells and triggering
pathochemical and further pathophysiological stages
allergic inflammation.
Because obese
cells
presented
everywhere in
body,
degranulation of them
may happen
in various tissues
and organs - skin,
lungs, eyes,
gastrointestinal tract and
etc.

HNT effector cells

APC (antigen
representing
cells)
T – lymphocytes –
helper type 2
B - lymphocytes
plasma cells,
synthesizing IgE
B - memory cells
Obese
cells and
basophils
Eosinophils
Neutrophils

Type of polarization of the immune response during HNT

GNT is characterized by
response polarization
along the Th2 pathway.
In microenvironment
naive T
lymphocyte
IL-4 is present,
produced by DC
and mast cells.
T naive cell
differentiates
in Th2,
synthesizing:
IL-4
IL-5
IL-10
IL-13.

GNT effector cells: Th2 lymphocytes
Analysis of cytokines in bronchoalveolar lavage fluid
allergic patients bronchial asthma showed that T lymphocytes produce not only IL-5, but also IL-4 - that is
cytokine profile typical of Th2 cells:
IL-3
Growth of progenitor cells
GM-CSF
Myelopoiesis.
IL-4
IL-5
IL-6
IL-10
B cell growth and activation
Isotype switching to IgE.
Induction of MHC class II molecules.
Macrophage inhibition
Eosinophil growth
B – cell growth,
release of acute phase proteins
Inhibition of macrophage activity:
inhibition of Th1 cells
Th2

Stages of GNT: stage 1 - immunological

In response to a hit
allergen in the body
education occurs
allergen-specific
IgE,
IgE binds to IgE
-receptors on
fat surfaces
cells and basophils,
these cells become
sensitized.
Repeated hit
allergen leads to
its interaction with
Fab - fragment
IgE molecules, strong
bound by the F fragment to IgE –
fat receptor
cells and basophil,
begins
mast degranulation
cells and basophil.

Type I hypersensitivity

interaction of allergen with IgE R on the surface of fat
cells causes the release of inflammatory mediators
IgE binding to mast cell receptors
Mast cell
Granules with mediators

Hypersensitivity type I (HHT)

Immunological
stage
ends
degranulation
mast cells
or basophils -
begins
pathochemical
stage, since in
surrounding
space
are released
mediators
inflammation
Allergen
Obese
cell
Mediators
inflammation
Bound IgE

Mast cells and basophils

Paul Ehrlich – discovery of mast cells (P. Ehrlich 1878)

Mastzellen
Mast - “fattening”.
At first it was believed that mast cells
“feed” the cells adjacent to them.

Stages of HNT: 2. Pathochemical stage

Degranulation of obese
cells and basophils
Selection in
surrounding
space
pre-existing in
mediator granules
inflammation
De novo synthesis
mast cells and
basophils
mediators
inflammation and inflammation
chemoattractants for
eosinophils,
lymphocytes,
neutrophils

Immune mechanism of mast cell degranulation: the allergen interacts with two IgE molecules associated with IgE receptors on the surface of the mast cell

Immune mechanism of mast cell degranulation:
the allergen interacts with two IgE molecules,
associated with IgE receptors on the surface of mast cells
,

Stages of HNT: 3. Pathophysiological stage

Stage
manifestations
clinical
manifestations:
mediators
inflammation
Act on
substrates,
calling
response
reactions.
Clinical manifestations,
conditional
by the action of mediators
inflammation:
itching
hyperemia
edema
skin rashes
suffocation, etc.

GNT (IgE responses) - pathophysiology

Organeffector
Syndrome
Allergens
Path
Answer
Vessels
Anafi
laxia
Medicines
Serum
Poisons
Inside
ny
Edema; increased permeability
vessels; tracheal occlusion; collapse
vessels; death
Leather
Nettle
face down
Bee stings;
allergy specialist
You
Intrako
gentle
Local increase in blood flow and
vascular permeability.
Upper
respiratory
ways
Aller
gical
rhinitis
Pollen
plants
Home
dust
Ingala
tional
Swelling and inflammation in the nasal cavity
mucous membrane
Lower
respiratory
ways
Bronchial
asthma
Pollen
plants
Home
dust
Ingala
tional
Bronchospasm
Increased mucus production
Inflammation in the bronchi
Gastrointestinal tract
Food
allergy
Products
nutrition
Oral
ny
Nausea, vomiting, enterocolitis
30 characters
allergic
urticaria, anaphylaxis

Inflammation: history

External signs
inflammation (Cornelius
Celsus):
1. rubor (redness),
2. tumor (tumor in
in this case
swelling),
3. calor (heat),
4. dolor (pain).
(Claudius Galen 130 -
200 n. e.)
5. function laesa
(dysfunction).
Manifestations of allergic
inflammation

Manifestations of allergies

Quincke's edema

Manifestations of allergic inflammation

Early response from GNT

At an early stage
GNT (10-20 minutes)
is happening
tying
allergen with
specific
IgE associated
high affinity
fat receptor
cells and
basophils.
Happening
degranulation of mast cells and
basophils.
Contents of granules –
histamine, tryptase,
heparin, and
accumulated
metabolites
arachidonic acid
launch
inflammatory response
(swelling, redness, itching).
TC start
synthesize
chemoattractants for
eosinophils,
lymphocytes, monocytes.

Late response from GNT

If exposure
allergen (receipt into
organism) continues
then after 18-20 hours at
focus of inflammation from
peripheral blood
eosinophils migrate
lymphocytes, monocytes,
neutrophils –
cellular stage
infiltration.
Eosinophils
degranulate,
release
basic cationic
proteins are gaining
active compounds
oxygen.
Inflammation
intensifies.

Figure 12-16

Early reply
Late answer
Enter
tion
AG
30 minutes
watch

Pseudoallergy - (Greek pseudēs false)

Pathological
process, according to
clinical
manifestations
similar to GNT, but
not having
immunological
stages of development.
(“false allergy”)
The final stages of true
allergies coincide with
pseudoallergy:
pathochemical stage of release (and
de novo education)
mediators;
pathophysiological
stage –
implementation of clinical
symptoms

Non-immune mechanisms of mast cell degranulation are factors leading to destabilization of the mast cell membrane and to its degranulation (medicine

Non-immune mechanisms of mast cell degranulation –
factors leading to destabilization of the mast cell membrane and its
degranulation (medicines, nutritional supplements, stabilizers, etc.)

Comparison of HNT and HRT

1. GNT: Th0 (naive) migrate to the lymph nodes, where under
the influence of IL-4, synthesized by dendritic cells,
turn into Th 2 (T helper type 2), synthesizing IL-4
and promoting the synthesis of IgE.

Delayed-type hypersensitivity (DTH) - T h1-mediated response

Immune response mediated
CD4+Th1-type, previously
sensitized
antigen.
If this happens again
the same antigen, Th1 is synthesized
cytokines responsible for
development of inflammation during
24-48 hours.
Hypreactivated
interferon-gamma
macrophages destroy
own fabrics.
Activated
interleukin 2 and interferon gamma CD8+ T lymphocytes exhibit
its cytotoxic
properties.
Histology: under conditions
inflammations form
giant cells and special
formations - granulomas.
Example: tuberculosis,
sarcoidosis, contact
dermatitis, etc.

Comparison of HNT and HRT

2. HRT: Th0 (naive) migrate to the lymph nodes, where under the influence
IL-12, synthesized by dendritic cells, is converted into Th
1 (T helper type 1), synthesizing interferon-gamma and factor
tumor necrosis-alpha

Different types of immune responses

IL-21
IL-10
IL-6
IL-21
Th fn
IL21
Immunoglobulin synthesis
Humoral or
cell type
answer

HRT - T h1 – indirect response

At the source of infection
dendritic cells
absorb the pathogen and or its
fragments and transport
AG to the regional lymph node
– in T-dependent zones.
DCs synthesize chemokines,
attractive T naive
lymphocytes in lymph nodes
In T-dependent zones of the LU
migrate Th 0 (naive).
The cultural center is presented to them
antigenic peptide in
MHC class II molecules.
Under the influence of cytokines
(IL-12, 18,23,27 and IFN-γ)
Th 0 (naive)
differentiated at Th 1
type.
Type 1 Ths enter into
interaction
macrophages carrying
on its surface
MHC II molecules with
antigenic peptides.
Th type 1 are activated and
begin to synthesize
IFN-γ and TNF-α,
activating macrophages.

HRT - T h1-mediated response

Under the influence of gamma interferon in
genes are activated in macrophages
those responsible for activation
oxidative metabolism and genes
pro-inflammatory cytokines
Macrophages generate
oxygen radicals (nitric oxide
and etc.);
synthesize cytokines (TNF-α, IL-6,
IL-1,IFN-α).
Destruction occurs
intracellular pathogens (as well as
possible destruction of own
fabrics).
For possible
localization
inflammatory
and destructive
processes in
fabrics
is happening
process
granuloma-like
vania

Granulomas

For sarcoidosis
For tuberculosis (caseous)

Review: Types of Immune Response

Properties
Cell type response
Humoral type
answer
Cellular
cytotoxicity
Inflammatory
immune response
(hypersensitive
there is a slow
type -GZT)
Localization
antigen
In the cytosol, between
organelles
In phagocytic
vacuoles
Outside the cage
agro-industrial complex
dendritic cells
macrophages
dendritic cells
dendritic cells
In lymphocytes
Imagine
tion of AG
HLA I
HLA II
HLA II

GNT and HRT

Properties
T lymphocytes
Mediators
Cell type response
Special case
humoral
immune response Cellular
Inflammatory
GNT
cytotoxicity immune response
(IgE response)
(hypersensitive
ness
slow type
–HRT)
CD8+cytotoxic CD4+ T helper cells
cues
Transition Th 0
in Th 1
IL-2, TNF-, IFN-
IFN-,TNF-,
IL-2
CD4+ T helper cells
Transition Th 0
in Th 2
IL-4, IL-5,IL-10, IL13

GNT and HRT

Properties
Cell type response
Cellular
cytotoxic
awn
Inflammatory
immune response
(hypersensitivity
delayed type - HRT)
CellsClone
Macrophages, hyper
effectors are cytotoxic
activated
CD8+ positive interferon - ,
lymphocytes
synthesized
-(CTL)
T helper type 1
Special case
humoral
immune response - GNT
(IgE response)
B lymphocytes
turn into
plasmatic
some cells,
synthesizing IgE and in
Into the cells of memory

GNT and HRT

Property
va
Cell type response
Cellular
cytotoxicity
Special case
humoral
Inflammatory
immune response
immune response
- GNT
(hypersensitivity
(IgE response)
delayed type - HRT)
Effek
CTL:
Macrophages,
Short-lived
activated
plasmatic
perforin-granzyme
mechanism of target lysis;
which cells
new IFN- , form
we are Fas-mediated
synthesize
together with Th 1 granuloma.
antibodies class
cytolysis;
Macrophages synthesize
E, which
Cytokine mechanism
pro-inflammatory
cytotoxicity (synthesis of cytokines and release binding
high-affe
TNF-α cytotoxic
factors
nym
lymphocytes-apoptosis
bactericidal
receptors
targets)
mast cells
basophils

The role of reactions
hypersensitive
flatness in the cavity
mouth increases in
dental
some orthopedics –
at
use
foreign to
body
prosthetic
materials.
The materials themselves can cause
mechanical irritation
oral mucosa and
especially mast cells, their
degranulation (pseudoallergy).
Release of histamine and
synthesis of IL-4 and IL-5 by obese
cells can contribute
development of Th 2 type immune
answer
(IgE response and GNT may develop).

Main manifestations of allergies

Skin rashes.
Rashes and inflammation
on the mucous membrane
oral cavity.
Attacks of bronchial
asthma.
Inflammation of the parotid
salivary gland
(mumps).
Dry mouth.
Burning sensation on the tongue.

Hypersensitivity reactions in prosthetic dentistry

Using
dissimilar materials
(alloys) in the oral cavity in
liquid phase (saliva) can
create galvanic
effects,
which act as
stress factors on
commensal microorganisms,
cause a decrease
protective factors
innate immunity
Reduced resistance
oral mucosa
to pathogenic bacteria
leads to their
subsequent
colonization, in response
macrophages launch
inflammatory
process.
Pro-inflammatory
cytokines - IL-1, IL-6,
IL-8 in such cases
determined in saliva.

Hypersensitivity reactions in prosthetic dentistry

Chemical substances
prosthetic materials
may be haptens.
Haptens are not themselves
antigens. Antigens
they only become
after connecting them with
proteins of the host organism.
Conversion of haptens into
antigens, often
accompanied by
development of reactions
hypersensitivity.
More often in the mouth
HRT develops
(involving Th type 1,
hyperactivated
interferon - gamma
macrophages,
synthesizing
pro-inflammatory
cytokines,
supportive
inflammation, and - how
consequence - possible
rejection of prosthetics
designs.

Hypersensitivity reactions in prosthetic dentistry

Metals in the composition
alloys (haptens)
When combined with carrier proteins, they can
cause development
reactions
hypersensitivity.
In experiments on
guinea pigs
availability shown
varying degrees
sensitization to
metals:
chrome, nickel
cause
expressed
allergic
reaction.
cobalt and gold –
moderate reaction.
titanium and silver –
weak reaction.
aluminum is practically
does not cause
sensitization.

Hypersensitivity reactions in prosthetic dentistry

Diagnostics
possible allergies
oral mucosa (HRT) by
type of contact
dermatitis to
metals are carried out
before production
prosthetic
designs with
using
PATCH tests
Patch (from the English patch -
"patch").
According to the results of PATCH tests for severity
positive reaction
metals are distributed
in the following way:
cobalt ˃ tin ˃ zinc
˃ nickel ˃ palladium

Hypersensitivity reactions in prosthetic dentistry: PATCH tests

With a special patch for
skin surface tightly
glued plate with
applied to it in
certain places 16
commercially available
metals
Applied to skin
material is held in
within 48 hours, reaction
usually assessed through
24, 48 hours and after 1
a week
after removing the adhesive
patch.
Inflammation of the skin at the site
contact with a certain
metal reveals
hypersensitivity to
specific metal.
If this metal
use this
patient, he has a large
most likely
develop contact
dermatitis (DTH).
This method is not used
only in dentistry (others
allergens are also present
in PATCH tests).

Patch tests (patch tests) are used as a diagnostic method for contact dermatitis.

Patch tests (skin patch tests) are used
as a diagnostic method for contact dermatitis.

Reaction assessment: in the presence of sensitization to contact allergens, a local reaction is observed on areas of the skin in contact with them

Reaction assessment: in the presence of sensitization to contact
allergens, on areas of skin in contact with them,
local reaction of varying degrees is observed
severity (score in “crosses”)

Is it possible for such a patient to have a metal structure installed in the oral cavity with this metal?

Questions

1.
2.
3.
Define the term “hypersensitivity.”
What types of hypersensitivity do you know?
What principle underlies the classification of types
hypersensitivity.
4. Characterize HNT
5. Describe type I hypersensitivity.
6. Describe type I I I hypersensitivity.
7. Describe type IV hypersensitivity.
8. In the pathogenesis of what diseases is HRT based?
9. How does type IV hypersensitivity differ from all other types.
10. What cells are involved in type 4 hypersensitivity?

Test questions

The main types of hypersensitivity reactions according to Gell P.,
Coombs (1969), are:





Time course for the development of type I hypersensitivity reaction:
1. 10-30 minutes
2. 3-8 hours
3. 5-15 hours
4. 45-50 hours
5. 24-48 hours

Test questions

Term of development of type I hypersensitivity reaction:
1. 10-30 minutes
2. 3-8 hours
3. 5-15 hours
4. 45-50 hours
5. 24-48 hours
Duration of development of type IV hypersensitivity reaction:
1. 10-30 minutes
2. 3-8 hours
3. 5-15 hours
4. 45-50 hours
5. 24-48 hours

Test questions

The sequence of development of type I hypersensitivity reaction includes:
1. The presence of a genetic predisposition to an IgE response to an allergen.
2. The allergen induces the synthesis of IgE antibodies.
3. IgE antibodies are fixed on the surface receptors of mast cells and
basophils.
4. Interaction of a re-entered allergen with IgE antibodies
on the surface of mast cells and basophils leads to their degranulation.
5. Degranulation products cause a response that is inadequate
intensity.
The sequence of development of type I hypersensitivity reaction includes:
1. Immunological stage.
2. Pathochemical stage.
3. Pathophysiological stage.
4. Stage of activation of natural killer cells.
5. Stage of activation of type 1 helper T lymphocytes.

Test questions

The main effector cells of type IV hypersensitivity are:
1. Dendritic cells
2. Type 2 helper T lymphocytes
3. Type 1 helper T lymphocytes
4. Activated macrophages as effectors
5. Activated plasma cells
What types of hypersensitivity most often develop in the cavity?
mouth when using prosthetic materials?
1. Type I hypersensitivity
2. Type I hypersensitivity
3. Hypersensitivity I I I type
4. Type IV hypersensitivity
5. Type V hypersensitivity

Test questions

What in vitro laboratory diagnostic methods are used for
detection of immediate hypersensitivity reactions in
dentistry?
1. Determination of IgE antibodies to metals in the blood
2. Lymphocyte proliferative activity activation test
3. Determination of eosinophilic cationic protein in saliva
4. Determination of T-lymphocyte subpopulations
5. Determination of tryptase in saliva
Which metals used in dentistry have the most
pronounced “allergenic” properties?
1. Gold
2. Nickel
3. Cobalt
4. Aluminum
5. Titan

Immediate hypersensitivity.

Clinical manifestations of type I hypersensitivity. Clinical manifestations of type I hypersensitivity can occur against the background of atopy.

Atopy- hereditary predisposition to the development of HNT, due to increased production of IgE antibodies to the allergen, an increased number of Fc receptors for these antibodies on mast cells, characteristics of the distribution of mast cells and increased permeability of tissue barriers.

Anaphylactic shock- occurs acutely with the development of collapse, edema, spasm of smooth muscles; often ends in death.

Hives- vascular permeability increases, the skin turns red, blisters and itching appear.

Bronchial asthma- inflammation and bronchospasm develop, mucus secretion in the bronchi increases.

Types of transplants. Mechanisms of transplant rejection.

Organ and tissue transplantation (synonymous with organ and tissue transplantation).

Transplantation of organs and tissues within one organism is called autotransplantation , from one organism to another within the same species - homotransplantation , from an organism of one species to an organism of another species - heterotransplantation .

Transplantation of organs and tissues with subsequent engraftment of the graft is possible only with biological compatibility - the similarity of antigens that make up the tissue proteins of the donor and recipient. In its absence, the donor's tissue antigens cause the production of antibodies in the recipient's body. A special protective process occurs - a rejection reaction, followed by the death of the transplanted organ. Biological compatibility can only occur with autotransplantation. It is not present in homo- and heterotransplantation. Therefore, the main task when performing organ and tissue transplantation is to overcome the barrier of tissue incompatibility. If in the embryonic period the body is exposed to some antigen, then after birth this body no longer produces antibodies in response to repeated administration of the same antigen. Active tolerance (tolerance) to the foreign tissue protein occurs.

The rejection reaction can be reduced by various influences that suppress the functions of the systems that develop immunity against a foreign organ. For this purpose, so-called immunosuppressive substances are used - imuran, cortisone, antilymphocyte serum, as well as general x-ray irradiation. However, this suppresses the body’s defenses and the function of the hematopoietic system, which can lead to serious complications.

Autotransplantation - tissue transplantation within one organism is almost always successful. The ability of autografts to easily take root is used in the treatment of burns - one’s own skin is transplanted onto the affected areas of the body. Syngeneic transplants - tissues that are genetically closely related to the donor tissue (for example, obtained from identical twins or inbred animals) - almost always take root. Allogeneic grafts (allografts; tissue transplanted from one individual to another genetically foreign individual of the same species) and xenogeneic grafts (xenografts; tissue transplanted from an individual of another species) are usually subject to rejection.

Graft versus host disease (GVHD) is a complication that develops after a stem cell or bone marrow transplant as a result of the transplanted material beginning to attack the recipient's body.

Causes. The bone marrow produces various blood cells, including lymphocytes, which carry out the immune response. Normally, stem cells are found in the bone marrow. Since only identical twins have absolutely identical tissue types, the donor Bone marrow does not completely correspond to the recipient tissues. It is this difference that causes the donor's T-lymphocytes (a type of white blood cell) to perceive the recipient's body as foreign and attack it. Acute form GVHD usually develops within the first three months after surgery, and a chronic reaction occurs later and can last throughout the patient's life. The risk of GVHD when receiving a transplant from a related donor is 30-40%; with an unrelated transplant it increases to 60-80%. The lower the compatibility index between donor and recipient, the higher the latter's risk of developing GVHD. After surgery, the patient is forced to take drugs that suppress the immune system: this helps reduce the chances of the disease occurring and reduce its severity.

Transplant immunity is an immune reaction of a macroorganism directed against foreign tissue (graft) transplanted into it. Knowledge of the mechanisms of transplantation immunity is necessary to solve one of the most important problems of modern medicine - organ and tissue transplantation. Many years of experience have shown that the success of transplantation of foreign organs and tissues in the vast majority of cases depends on the immunological compatibility of the tissues of the donor and recipient.
The immune reaction to foreign cells and tissues is due to the fact that they contain antigens that are genetically foreign to the body. These antigens, called transplantation or histocompatibility antigens, are most fully represented on the CPM of cells.
A rejection reaction does not occur if full compatibility donor and recipient by histocompatibility antigens - this is only possible for identical twins. The severity of the rejection reaction largely depends on the degree of foreignness, the volume of transplanted material and the state of immunoreactivity of the recipient. Upon contact with foreign transplantation antigens, the body reacts with factors of the cellular and humoral immunity.

The main factor cellular transplantation immunity are T-killer cells. These cells, after sensitization by donor antigens, migrate into the graft tissue and exert antibody-independent cell-mediated cytotoxicity on them.

Specific antibodies that are formed against foreign antigens (hemagglutinins, hemolysins, leukotoxins, cytotoxins) have important in the formation of transplantation immunity. They trigger antibody-mediated cytolysis of the graft (complement-mediated and antibody-dependent cell-mediated cytotoxicity). Adoptive transfer of transplantation immunity is possible using activated lymphocytes or with specific antiserum from a sensitized individual to an intact macroorganism.
The mechanism of immune rejection of transplanted cells and tissues has two phases. In the first phase, an accumulation of immunocompetent cells (lymphoid infiltration), including T-killer cells, is observed around the graft and vessels. In the second phase, destruction of the transplant cells by T-killers occurs, the macrophage link, natural killer cells, and specific antibody genesis are activated. Immune inflammation, thrombosis of blood vessels occurs, the nutrition of the graft is disrupted and its death occurs. Destroyed tissues are utilized by phagocytes.
During the rejection reaction, a clone of immune memory T and B cells is formed. A repeated attempt to transplant the same organs and tissues causes a secondary immune response, which is very violent and quickly ends in transplant rejection.
From a clinical point of view, acute, hyperacute and delayed graft rejection are distinguished. They differ in the reaction time and individual mechanisms.

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Two types of immune complex damage are known: 1) when an exogenous antigen enters the body (foreign protein, bacteria, virus) and 2) when antibodies are formed against one’s own antigens (endogenous). Diseases, the development of which is caused by immune complexes, can be generalized, if immune complexes are formed in the blood and settle in many organs, or local, when immune complexes are localized in individual organs, such as the kidneys (glome nephritis), joints (arthritis) or small blood vessels to °G (local Arthus reaction).
Scheme 28. ReactionshypersensitivityIIItype- immunocomplexreactions

Scheme 30. Rejectiontransplant


T-lymphocyte-mediated reactions. Activated CD4+ T helper cells are involved in the activation of CD8+ CTLs. The development of T-lymphocyte-mediated reactions occurs when the recipient's lymphocytes meet the donor's HLA antigens. It is believed that the most important immunogens are dendritic cells in donor organs. Host T cells encounter dendritic cells in the transplanted organ and then migrate to regional lymph nodes. SS+CTL precursors (prekiller T cells), possessing receptors for class I HLA antigens, differentiate into mature CTLs. The differentiation process is complex and not entirely understood. It involves antigen presenting cells, T lymphocytes and the cytokines IL-2, IL-4 and IL-5. Mature CTLs lyse the transplanted tissue. In addition to specific CTLs, lymphokine-secreting CO4 + T-lymphocytes are formed, which play exclusively important role in transplant rejection. As in a delayed hypersensitivity reaction, activated CO4 + T lymphocytes release cytokines that cause increased vascular permeability and local accumulation of mononuclear cells (lymphocytes and macrophages). It is believed that HRT, manifested by microvascular damage, ischemia and tissue destruction, is the most important mechanism of graft destruction. It is more likely, however, that the relative importance of CD8 + T cell-associated cytotoxicity versus CO4 + T cell-mediated responses depends on the nature of the donor-recipient HLA mismatch.
Antibody-mediated reactions. These reactions can occur in two ways. Hyperacute rejection occurs when the recipient's blood contains antibodies against the donor. Such antibodies may occur in a recipient who has already had a transplant failure. Previous blood transfusions from HLA-unidentified donors can also lead to sensitization due to the fact that platelets and leukocytes are particularly rich in HLA antigens. In such cases, rejection develops immediately after transplantation, since circulating antibodies form immune complexes that settle in the vascular endothelium of the transplanted organ. Then complement fixation occurs and the Arthus reaction develops.
In recipients who have not been previously sensitized to transplant antigens, exposure to donor HLA class I and II antigens is accompanied by the formation of antibodies. Antibodies generated by recipients can cause damage through several mechanisms, including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytolysis, and shedding of antigen-antibody complexes. The original target for these antibodies is the graft vessels, so the phenomenon of antibody-dependent rejection (for example, in the kidney) is represented by vasculitis.

Lecture 17

REACTIONSHYPERSENSITIVITY

Hypersensitivity reactions can be classified based on the immunological mechanisms that cause them.

In type I hypersensitivity reactions, the immune response is accompanied by the release of vasoactive and spasmogenic substances that act on blood vessels and smooth muscles, thus disrupting their functions.

In type II hypersensitivity reactions, humoral antibodies are directly involved in cell damage, making them susceptible to phagocytosis or lysis.

In type III hypersensitivity reactions (immune complex diseases), humoral antibodies bind antigens and activate complement. Complement fractions then attract neutrophils, which cause tissue damage.

In type IV hypersensitivity reactions, tissue damage occurs, which is caused by the pathogenic effect of sensitized lymphocytes.

Type I hypersensitivity reactions - anaphylactic reactions

Type I hypersensitivity reactions can be systemic or local. A systemic reaction usually develops in response to intravenous administration of an antigen to which the host is already sensitized. In this case, a state of shock often develops after a few minutes, which can cause death. Local reactions depend on the site where the antigen enters and are in the nature of localized swelling of the skin (skin allergies, urticaria), discharge from the nose and conjunctiva (allergic rhinitis and conjunctivitis), hay fever, bronchial asthma or allergic gastroenteritis (food allergy). allergy).

Scheme25. ReactionshypersensitivityItype- anaphylacticreactions

It is known that type I hypersensitivity reactions undergo two phases in development (Scheme 25). The first phase of the initial response is characterized by vasodilation and an increase in their permeability, as well as, depending on the location, spasm of smooth muscles or glandular secretion. These signs appear 5-30 minutes after exposure to the allergen. In many cases, the second (late) phase develops after 2-8 hours, without further

additional antigen exposure and lasts several days. This late phase of the reaction is characterized by intense infiltration of eosinophils, neutrophils, basophils and monocytes, as well as tissue destruction in the form of damage to mucosal epithelial cells.

Mast cells and basophils play a major role in the development of type I hypersensitivity reactions; they are activated by cross-reacting high-affinity IgE receptors. In addition, mast cells are activated by complement components C5a and C3 (anaphylatoxins), as well as macrophage cytokines (interleukin-8), certain drugs (codeine and morphine) and physical influences (heat, cold, sunlight).

In humans, type I hypersensitivity reactions are caused by immunoglobulins of the IgE class. The allergen stimulates the production of IgE by B lymphocytes mainly in the mucous membranes at the site of antigen entry and in regional lymph nodes. IgE antibodies formed in response to an allergen attack mast cells and basophils, which have highly sensitive receptors for the Fc portion of IgE. After mast cells and basophils, attacked by cytophilic IgE antibodies, re-encounter a specific antigen, a series of reactions develops, leading to the release of a number of strong mediators responsible for the clinical manifestations of type I hypersensitivity.

First, the antigen (allergen) binds to IgE antibodies. In this case, multivalent antigens bind more than one IgE molecule and cause cross-linking of neighboring IgE antibodies. The binding of IgE molecules initiates the development of two independent processes: 1) degranulation of mast cells with the release of primary mediators; 2) de novo synthesis and release of secondary mediators, such as arachidonic acid metabolites. These mediators are directly responsible for initial symptoms type I hypersensitivity reactions. In addition, they include a chain of reactions that lead to the development of the second (late) phase of the initial response.

Primary mediators are contained in mast cell granules. They are divided into four categories. - Biogenic amines include histamine and adenosine. Histamine causes a pronounced spasm of the smooth muscles of the bronchi, increased vascular permeability, and intense secretion of the nasal, bronchial and gastric glands. Adenosine stimulates mast cells to release mediators that cause bronchospasm and inhibition of platelet aggregation.

- Chemotaxis mediators include eosinophilic chemotactic factor and neutrophilic chemotactic factor.

- Enzymes are contained in the granule matrix and include proteases (chymase, tryptase) and some acid hydrolases. Enzymes cause the formation of kinins and the activation of complement components (C3), affecting their precursors - Proteoglycan- heparin.

Secondary mediators include two classes of compounds; lipid mediators and cytokines. - Lipid mediators are formed due to sequential reactions occurring in the membranes of mast cells and leading to the activation of phospholipase A2. It affects membrane phospholipids, causing the appearance of arachidonic acid. Arachidonic acid, in turn, produces leukotrienes and prostaglandins.

Leukotrienes play an extremely important role in the pathogenesis of type I hypersensitivity reactions. Leukotrienes C4 and D4 are the most powerful vasoactive and spasmogenic agents known. They are several thousand times more active than histamine in increasing vascular permeability and contracting bronchial smooth muscle. Leukotriene B4 has a strong chemotactic effect on neutrophils, eosinophils and monocytes.

ProstaglandinD 2 is formed in mast cells and causes intense bronchospasm and increased mucus secretion.

Platelet activating factor(PAF) is a secondary mediator that causes platelet aggregation, histamine release, bronchospasm, increased vascular permeability and dilation of blood vessels. In addition, it has a pronounced pro-inflammatory effect. PAF has a toxic effect on neutrophils and eosinophils. In high concentrations, it activates cells involved in inflammation, causing them to aggregate and degranulate. - Cytokines play an important role in the pathogenesis of type I hypersensitivity reactions due to their ability to recruit and activate inflammatory cells. Mast cells are believed to produce a number of cytokines, including tumor necro-α factor α (TNF-α), interleukins (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Experimental models have shown that TNF-a is an important mediator of IgE-dependent skin reactions. TNF-α is considered a strong proinflammatory cytokine that can attract neutrophils and eosinophils, promoting their penetration through the walls of blood vessels and activating them in tissues. Finally, IL-4 is required for eosinophil recruitment. Inflammatory cells accumulating in places where a type I hypersensitivity reaction develops

pas, are an additional source of cytokines and gnetamine-releasing factors, which cause further degranulation of mast cells.

Thus, histamine and leukotrienes are rapidly released from sensitized mast cells and are responsible for the immediately developing reactions characterized by edema, mucus secretion, and smooth muscle spasm. Many other mediators are represented by leukotrienes, PAF and TNF-a. included in late phase response, recruiting an additional number of leukocytes - basophils, neutrophils and eosinophils.

Among the cells that appear in the late phase of the reaction, eosinophils are especially important. The set of mediators in them is as large as in mast cells. Thus, additionally recruited cells enhance and maintain the inflammatory response without additional antigen supply.

Regulation of hypersensitivity reactions of type I by cytokines. Firstly, IgE secreted by B lymphocytes in the presence of IL-4 plays a special role in the development of type I hypersensitivity reactions. YYA-5 and IL-6, and IL-4 is absolutely necessary for the transformation of IgE-producing B cells. The propensity of some antigens to cause allergic reactions is due in part to their ability to activate T helper 2 (Th-2) cells. On the contrary, some cytokines. formed by T helper-1 (Th-I), for example gamma interferon (INF-γ). reduce IgE synthesis. Secondly, a feature of type I sensitivity reactions is an increased content of mast cells in tissues, the growth and differentiation of which depend on certain CYTOKINES, including IL-3 and IL-4. Third, IL-5 secreted by Th-2 is critical for the formation of eosinophils from their precursors. It also activates mature eosinophils.

Allergy (from the Greek alios - different, ergon - acting) is a typical immunopathological process that develops upon contact with an antigen (hapten) and is accompanied by damage to the structure and function of one’s own cells, tissues and organs. Substances causing allergies are called allergens.

Sensitization

The basis of allergies is sensitization (or immunization) - the process of the body acquiring hypersensitivity to one or another allergen. Otherwise, sensitization is the process of producing allergen-specific antibodies or lymphocytes.

There are passive and active sensitization.

• Passive sensitization develops in a non-immunized recipient with the introduction of ready-made antibodies (serum) or lymphoid cells (during a lymphoid tissue transplant) from an actively sensitized donor.
• Active sensitization develops when an allergen enters the body due to

the formation of antibodies and immunocompetent lymphocytes upon activation of his own immune system.

Sensitization (immunization) itself does not cause disease - only repeated contact with the same allergen can lead to a damaging effect.

Thus, an allergy is a qualitatively altered (pathological) form of the body’s immunological reactivity.

Allergies and immunity have common properties:

1. Allergy, like immunity, is a form of species reactivity that contributes to the preservation of the species, although for an individual it has not only a positive, but also a negative meaning, since it can cause the development of a disease or (in some cases) death.
2. Allergies, like immunity, are protective in nature. The essence of this protection is localization, inactivation and elimination of the antigen (allergen).
3. Allergies are based on immune development mechanisms - the “antigen-antibody” reaction (AG+AT) or “antigen-sensitized lymphocyte” (“AG+ sensitized lymphocyte”).

Immune reactions

Typically, immune reactions unfold covertly, and they lead either to the complete destruction of the antigenic aggressor or to the partial suppression of its pathogenic action, providing the body with a state of immunity. However, under some circumstances, these reactions can develop unusually.

In some cases, when a foreign agent is introduced into the body, they are so intense that they lead to tissue damage and are accompanied by the phenomenon of inflammation: then they speak of a hypersensitivity reaction (or disease).

Sometimes, under certain conditions, the body's cells acquire antigenic properties or the body produces antibodies that can react with normal cell antigens. In these cases we talk about diseases due to autoimmunization or autoimmune diseases.

Finally, there are conditions in which, despite the arrival of antigenic material, immune reactions do not develop. Such conditions are referred to as immune failure or immunodeficiency.

Thus, the immune system, which is normally involved in maintaining homeostasis, can serve as a source pathological conditions caused by an excessive reaction or insufficient response to aggression, which are referred to as immunopathological processes.

Immune hypersensitivity

Hypersensitivity is a pathological overly strong immune reaction to a foreign agent, which leads to damage to body tissues. Four stand out various types hypersensitivity All forms, except type IV, have a humoral mechanism (that is, they are mediated by antibodies); Type IV hypersensitivity has a cellular mechanism. In all forms, the initial intake of a specific antigen (sensitizing dose) causes a primary immune response (sensitization). After a short period (1 week or more) during which the immune system is activated, a hypersensitive response occurs to any subsequent exposure to the same antigen (resolving dose).

Type I hypersensitivity (immediate) (atopy; anaphylaxis)

Development mechanism

The first arrival of an antigen (allergen) activates the immune system, which leads to the synthesis of antibodies - IgE (reagins), which have a specific reactivity against this antigen. They are then fixed on the surface membrane of tissue basophils and blood basophils due to the high affinity (affinity) of IgE for Fc receptors. The synthesis of antibodies in sufficient quantities for the development of hypersensitivity takes 1 or more weeks.

With subsequent administration of the same antigen, the antibody (IgE) interacts with the antigen on the surface of tissue or blood basophils, causing their degranulation. Vasoactive substances (histamine and various enzymes that are involved in the synthesis of bradykinin and leukotrienes) are released into the tissue from the cytoplasmic granules of tissue basophils, which cause vasodilation, increased vascular permeability and contraction of smooth muscles.

Tissue basophils also secrete factors that are chemotactic for neutrophils and eosinophils; When studying preparations from tissues where a type I hypersensitivity reaction occurred, a large number of eosinophils are determined, and an increase in the number of eosinophils is observed in the blood of patients. Eosinophils activate both blood coagulation and the complement system and promote further degranulation of blood basophils and tissue basophils. However, eosinophils also secrete arylsulfatase B and histaminase, which degrade leukotrienes and histamine, respectively; thus they weaken the allergic response. ====Disorders that occur with type I hypersensitivity====:

• Local manifestations - the local manifestation of type I hypersensitivity is called atopy. Atopy is an innate predisposition, which runs in families, to have an abnormal response against certain allergens. Atopic reactions are widespread and can occur in many organs.
  • Skin - when an allergen enters the skin, there is immediate redness, swelling (sometimes with blistering [urticaria]) and itching; in some cases, acute dermatitis or eczema develops. The antigen can come into contact with the skin directly, through injection (including insect bites) or orally into the body (with food and drug allergies).
  • Nasal mucosa - when allergens are inhaled (for example, plant pollen, animal hair), vasodilation and hypersecretion of mucus occurs in the nasal mucosa (allergic rhinitis).
  • Lungs - inhalation of allergens (pollen, dust) leads to contraction of bronchial smooth muscles and hypersecretion of mucus, which leads to acute obstruction respiratory tract and suffocation (allergic bronchial asthma).
  • Intestines - oral ingestion of an allergen (for example, nuts, shellfish, crabs) causes muscle contraction and fluid secretion, which manifests itself in the form of cramping abdominal pain and diarrhea (allergic gastroenteritis).

• Systemic manifestations - anaphylaxis - a rare but extremely life-threatening systemic type I hypersensitivity reaction. The entry of vasoactive amines into the bloodstream causes contraction of smooth muscle, widespread vasodilation and an increase in vascular permeability with the release of fluid from the vessels into the tissue.

The resulting peripheral vascular insufficiency and shock can lead to death within minutes (anaphylactic shock). In less severe cases, increased vascular permeability leads to allergic edema, which has its most dangerous manifestation in the larynx, since it can cause fatal asphyxia.

Systemic anaphylaxis usually occurs following injection of allergens (eg, penicillin, foreign serum, local anesthetics, X-ray contrast agents). Less commonly, anaphylaxis can occur when allergens are ingested orally (shellfish, crabs, eggs, berries) or when allergens enter the skin (bee and wasp stings).

In sensitized individuals, even small amounts of the allergen can trigger fatal anaphylaxis (eg, intradermal penicillin [penicillin hypersensitivity test]).

Type II hypersensitivity

Development mechanism

Type II hypersensitivity is characterized by the reaction of an antibody with an antigen on the surface of a host cell, which causes the destruction of that cell. The antigen involved may be self, but for some reason recognized immune system as foreign (an autoimmune disease occurs). The antigen can also be external and can accumulate on the surface of the cell (for example, a drug can be a hapten when it binds to a cell membrane protein and thus stimulates an immune response).

A specific antibody, usually IgG or IgM, produced against an antigen interacts with it on the cell surface and causes cell damage in several ways:

1. Cell lysis - activation of the complement cascade leads to the formation of the “membrane attack” complex C5b6789, which causes lysis of the cell membrane.
2. Phagocytosis - the antigen-bearing cell is engulfed by phagocytic macrophages, which have Fc or C3b receptors, which allows them to recognize antigen-antibody complexes on the cell.
3. Cellular cytotoxicity - the antigen-antibody complex is recognized by unsensitized "null" lymphocytes (K cells; see Immunity), which destroy the cell. This type of hypersensitivity is sometimes classified separately as type VI hypersensitivity.
4. Altering Cell Function - An antibody can react with cell surface molecules or receptors to cause either enhancement or inhibition of a specific metabolic response without causing cell necrosis (see Stimulation and Inhibition in Hypersensitivity, below). Some authors classify this phenomenon separately as type V hypersensitivity.

Manifestations of type II hypersensitivity reaction

Depends on the type of cell carrying the antigen. Note that blood transfusion reactions are actually normal immune responses against foreign cells. They are identical in the mechanism of type II hypersensitivity reactions and also adversely affect the patient, and therefore blood transfusion complications are often considered together with disorders that occur with hypersensitivity.

Reactions with destruction of red blood cells

• Post-transfusion reactions - antibodies in the patient's serum react with antigens on transfused red cells, causing either complement-mediated intravascular hemolysis or delayed hemolysis as a result of immune phagocytosis by splenic macrophages. There are a large number of erythrocyte antigens that can cause hemolytic reactions during transfusions (ABO, Rh, Kell, Kidd, Lewis). Also, hemolysis can occur when Rh+ blood is retransfused into an Rh- patient. In addition, transfused blood may directly contain antibodies that react against host cells, but due to the high dilution in the total blood volume, this reaction usually has little clinical consequence. To prevent these reactions, it is necessary to check blood compatibility.
• Hemolytic disease In newborns, it develops when maternal antibodies penetrate the placenta, which are active against fetal erythrocyte antigens (Rh and ABO) and destroy them. Hemolytic disease of the newborn is more common in Rh incompatibility, since anti-Rh antibodies in maternal plasma are usually IgG, which readily cross the placenta. Anti-A and anti-B antibodies are usually IgM, which normally cannot cross the placenta.
• Other hemolytic reactions - hemolysis can be caused by drugs that act as haptens in combination with red blood cell membrane proteins or it can develop when infectious diseases associated with the appearance of anti-erythrocyte antibodies, for example, in infectious mononucleosis, mycoplasma pneumonia.

Reactions with destruction of neutrophils

maternal antibodies to fetal neutrophil antigens can cause neonatal leukopenia if they cross the placenta. Sometimes post-transfusion reactions occur due to the activity of the host serum against the leukocyte HLA antigens of the donor.

Reactions with platelet destruction

posttransfusion febrile reactions and neonatal thrombocytopenia may result from the factors described above for leukocytes. Idiopathic thrombocytopenic purpura is a common autoimmune disease in which antibodies are formed against self-antigens of the platelet membrane.

Reactions on the basement membrane

antibodies against basement membrane antigens in the renal glomeruli and pulmonary alveoli occur in Goodpasture syndrome. Tissue damage occurs as a result of complement activation.

Stimulation and inhibition for hypersensitivity

• Stimulation - with the formation of antibodies (IgG) that bind to TSH receptors on follicular epithelial cells thyroid gland Graves' disease (primary hyperthyroidism) develops. This interaction leads to stimulation of the enzyme adenylate cyclase, which leads to an increase in cAMP levels and to the secretion of increased amounts of thyroid hormones.
• Inhibition - inhibitory antibodies play a key role in myasthenia gravis, a disease characterized by impaired neuromuscular transmission and the occurrence of muscle weakness. The disease is caused by antibodies (IgG) directed against acetylcholine receptors on the motor end plate. Antibodies compete with acetylcholine for the binding site on the receptor, thus blocking the transmission of nerve impulses.

The mechanism of inhibition also underlies pernicious anemia, in which antibodies bind to internal factor and inhibit the absorption of vitamin B12.

Hypersensitivity type III (immune complex damage)

Development mechanism

The interaction of antigen and antibody can lead to the formation of immune complexes, either locally at the site of damage, or generalized in the bloodstream. The accumulation of immune complexes in various parts of the body activates complement and causes acute inflammation and necrosis.

There are two types of immune complex damage:

• Reactions such as the Arthus phenomenon - in reactions such as the Arthus phenomenon, tissue necrosis occurs at the site of antigen injection. Repeated administration of the antigen leads to the accumulation of large amounts of precipitating antibodies in the serum. Subsequent administration of the same antigen leads to the formation of large antigen-antibody complexes, which are deposited locally in small blood vessels, where they activate complement, which is accompanied by the development of a severe local acute inflammatory reaction with hemorrhage and necrosis. This phenomenon is observed very rarely. It occurs in the skin after repeated administration of the antigen (for example, during rabies vaccination, when multiple injections of the vaccine are given). The severity of inflammation depends on the dose of antigen. Type III hypersensitivity is believed to be responsible for the occurrence of hypersensitivity pneumonitis, a lung disease that presents with cough, dyspnea, and fever 6–8 hours after inhalation of certain antigens (Table 11.2). If the supply of antigen is repeated, then chronic granulomatous inflammation occurs. Types I and IV hypersensitivity can coexist with type III.
• Serum sickness type reactions - serum sickness type reactions, also caused by immune complex damage, are more common than reactions like the Arthus phenomenon. The course of reactions depends on the dose of antigen. Re-arrival large dose antigen, for example, foreign serum proteins, drugs, viral and other microbial antigens, leads to the formation of immune complexes in the blood. In the presence of excess antigen, they remain small, soluble, and circulate in the bloodstream. They ultimately pass through the endothelial pores of small vessels and accumulate in the vessel wall, where they activate complement and lead to complement-mediated necrosis and acute inflammation of the vessel wall (necrotizing vasculitis).

Vasculitis can be generalized, affecting a large number of organs (for example, in serum sickness due to the introduction of foreign serum or in systemic lupus erythematosus, autoimmune disease) or may affect a separate organ (for example, with post-streptococcal glomerulonephritis).

Immune complex damage can occur in many diseases. In some of them, including serum sickness, systemic lupus erythematosus, and poststreptococcal glomerulonephritis, immune complex damage is responsible for the main clinical manifestations of the disease. For others, such as hepatitis B, infective endocarditis, malaria and some types malignant tumors, immune complex vasculitis occurs as a complication of the disease.

Diagnosis of immune complex diseases: a reliable diagnosis of an immune complex disease can be established by detecting immune complexes in tissues when electron microscopy. Rarely, large immune complexes may be visible by light microscopy (eg, in poststreptococcal glomerulonephritis). Immunological methods (immunofluorescence and immunoperoxidase method) use labeled anti-IgG, anti-IgM, anti-IgA or anti-complement antibodies that bind to immunoglobulins or complement in immune complexes. There are also methods for determining immune complexes circulating in the blood.

Hypersensitivity type IV (cellular)

Development mechanism

Unlike other hypersensitivity reactions, delayed-type hypersensitivity involves cells rather than antibodies. This type is mediated by sensitized T lymphocytes, which either directly exert cytotoxicity or through the secretion of lymphokines. Type IV hypersensitivity reactions usually occur 24 to 72 hours after administration of the antigen to a sensitized person, which distinguishes this type from type I hypersensitivity, which often develops within minutes.

Histological examination of tissues in which type IV hypersensitivity reaction occurs reveals cell necrosis and pronounced lymphocytic infiltration.

Direct cytotoxicity of T cells plays an important role in contact dermatitis, in the response against tumor cells, virus-infected cells, transplanted cells bearing foreign antigens, and in some autoimmune diseases.

T-cell hypersensitivity resulting from the action of various lymphokines also plays a role in granulomatous inflammation caused by mycobacteria and fungi. The manifestation of this type of hypersensitivity is the basis of skin tests used in the diagnosis of these infections (tuberculin, lepromin, histoplasmin and coccidioidin tests). In these tests, inactivated microbial or fungal antigens are injected intradermally. If the reaction is positive, granulomatous inflammation develops at the injection site after 24-72 hours, which manifests itself in the form of a papule. Positive test indicates the presence of delayed hypersensitivity against the administered antigen and is evidence that the body has previously encountered this antigen. ===Disorders that occur with type IV hypersensitivity===delayed type hypersensitivity has several manifestations:

• Infections - in infectious diseases caused by facultative intracellular microorganisms, for example, mycobacteria and fungi, morphological manifestations of delayed type hypersensitivity - epithelioid cell granuloma with caseous necrosis in the center.
• Autoimmune diseases - with Hashimoto's thyroiditis and autoimmune gastritis associated with pernicious anemia, the direct action of T cells against antigens on host cells (thyroid epithelial cells and parietal cells in the stomach) leads to the progressive destruction of these cells.
• Contact dermatitis - when an antigen comes into direct contact with the skin, a local hypersensitive response of type IV occurs, the area of ​​which exactly corresponds to the area of ​​contact. The most common antigens are nickel, drugs, and clothing dyes.

Morphological changes in organs with hypersensitivity

Morphologically, during antigenic stimulation (sensitization) of the body, the most pronounced changes are observed in the lymph nodes, primarily regional to the site of entry of the antigen.

• Lymph nodes are enlarged and full of blood. In types I-III of hypersensitivity, an abundance of plasmablasts and plasma cells is detected in the light centers of the follicles of the cortical and in the pulpal cords of the medulla. The number of T-lymphocytes is reduced. A large number of macrophages are noted in the sinuses. The degree of macrophage-plasmacytic transformation of lymphoid tissue reflects the intensity of immunogenesis and, above all, the level of production of antibodies (immunoglobulins) by plasmacytic cells. If, in response to antigenic stimulation, predominantly cellular immune reactions develop (type IV hypersensitivity), then in the lymph nodes in the paracortical zone, mainly sensitized lymphocytes proliferate, rather than plasmablasts and plasma cells. In this case, expansion of T-dependent zones occurs.
• The spleen enlarges and becomes full of blood. In types I-III of hypersensitivity, sharply enlarged large grayish-pinkish follicles are clearly visible on the section. Microscopically, hyperplasia and plasmatization of the red pulp and an abundance of macrophages are noted. In the white pulp, especially along the periphery of the follicles, there are also many plasmablasts and plasmacytes. In type IV hypersensitivity, the morphological changes are similar to the changes observed in the lymph nodes in the T-zones.

In addition, in the organs and tissues in which an immediate-type hypersensitivity reaction develops - HHT (types I, II, III), acute immune inflammation occurs. It is characterized by rapid development, the predominance of alterative and exudative changes. Alternative changes in the form of mucoid, fibrinoid swelling and fibrinoid necrosis are observed in the ground substance and fibrous structures of the connective tissue. In the focus of immune inflammation, plasmorrhagia is expressed, fibrin, neutrophils, and erythrocytes are detected.

In type IV hypersensitivity (delayed hypersensitivity reaction - DTH), lymphocytic and macrophage infiltration (sensitized lymphocytes and macrophages) at the site of immune conflict are an expression of chronic immune inflammation. To prove ownership morphological changes to the immune reaction, it is necessary to use the immunohistochemical method; in some cases, electron microscopic examination can help.

Literature

Pathophysiology: textbook: in 2 volumes / ed. V.V. Novitsky, E.D. Goldberg, O.I. Urazova. - 4th ed., revised. and additional - GEOTAR-Media, 2009. - T. 1. - 848 p. : ill.

Lecture by Prof. V.G.Shlopova