Transcript Diapositiva 1 - Tor Vergata

IPERSENSIBILTA’ e
I MISFATTI DELLA RISPOSTA IMMUNITARIA
• Risposta immunitaria diretta specificamente verso definite
strutture molecolari (antigeni)
• Risposta infiammatoria, processo aspecifico innescato da
“ogni tipo” di danno tessutale e varia poco a seconda del tipo
dell’agente scatenante
• Ipersensibilità è l’eccessiva o non necessaria risposta
immunitaria (anticorpale o dei linfociti T) che determina un
rischio maggiore dell’antigene che l’ha evocata.
• Classificazione secondo Coombs e Gell (1975)
RISPOSTA IMMUNITARIA
• INSUFFICIENTE
Immunodeficienze
• INADEGUATA
Autoimmunità
(rivolta contro il bersaglio sbagliato)
• ECCESSIVA
Ipersensibilità
Consequences of Defective or Excessive Inflammation
•
Defective inflammation typically results in increased susceptibility to infections and
delayed healing of wounds and tissue damage.
– reflects the fundamental role of the inflammatory response in host defense,
– Delayed repair is because the inflammatory response is essential for clearing damaged
tissues and debris, and provides the necessary stimulus to get the repair process started.
•
Excessive inflammation is the basis of many categories of human disease.
– allergies, in which individuals mount unregulated immune responses against commonly
encountered environmental antigens,
– autoimmune diseases, in which immune responses develop against normally tolerated selfantigens, are disorders in which the fundamental cause of tissue injury is inflammation.
– cancer, atherosclerosis and ischemic heart disease, and some neurodegenerative diseases
such as Alzheimer disease (not primarily disorders of the immune system).
– prolonged inflammation and the fibrosis that accompanies it are responsible for much of the
pathology in many chronic infectious, metabolic and other diseases.
Immune response
Adaptive immunity serves the important function of host defense against
microbial infections, but immune responses are also capable of
causing tissue injury and disease.
Disorders caused by immune responses are called hypersensitivity
diseases.
This term arose from the clinical definition of immunity as "sensitivity,"
which is based on the observation that an individual who has been
exposed to an antigen exhibits a detectable reaction, or is
"sensitive," to subsequent encounters with that antigen.
Normally, the immune response eradicates infecting organisms
without serious injury to host tissues. However, sometimes
these responses are inadequately controlled or inappropriately
targeted to host tissues, and in these situations, the normally
beneficial response is the cause of disease.
Immunologic tissue injury and immunopathology, and
some specific immunologic diseases
• Hypersensitivity reactions, which give rise to immunologic injury in a
variety of diseases, discussed throughout this book
• Autoimmune diseases, which are caused by immune reactions against self
• Immunologic deficiency syndromes, which result from genetically
determined or acquired defects in some components of the normal
immune system
• Amyloidosis,
association.
a
poorly
understood
disorder
having
immunologic
Immunologic tissue injury and immunopathology, and
some specific immunologic diseases
•
Contact with antigen leads not only to induction of a protective immune response,
but also to reactions that can be damaging to tissues
•
Exogenous antigens occur in dust, pollens, foods, drugs, microbiologic agents,
chemicals, and many blood products used in clinical practice.
•
The immune responses that may result from such exogenous antigens take a
variety of forms, ranging from annoying but trivial discomforts, such as itching of
the skin, to potentially fatal diseases, such as bronchial asthma.
•
The various reactions produced are called hypersensitivity reactions, and tissue
injury in these reactions may be caused by humoral or cell-mediated immune
mechanisms.
Immunologic tissue injury and immunopathology, and
some specific immunologic diseases
• Injurious immune reactions may be evoked not only by exogenous
environmental antigens, but also by endogenous tissue antigens
• Some of these immune reactions are triggered by homologous antigens
that differ among individuals with different genetic backgrounds.
• Transfusion reactions and graft rejection are examples of immunologic
disorders evoked by homologous antigens.
• Another category of disorders, those incited by self-, or autologous,
antigens, constitutes the important group of autoimmune diseases.
Hypersensitivity diseases can be classified on the basis of the
immunologic mechanism that mediates the disease
• In immediate hypersensitivity
(type I hypersensitivity), the
immune
response
releases
vasoactive and spasmogenic
substances that act on vessels
and smooth muscle and proinflammatory cytokines that recruit
inflammatory cells.
Immediate (typeI)
Hypersensitivity
Anaphylaxis; allergies;
bronchial asthma (atopic
forms)
Production of IgE antibody → immediate release
of vasoactive amines and other mediators from
mast cells; recruitment of inflammatory cells
(late-phase reaction)
Vascular dilation, edema, smooth muscle
contraction, mucus production, inflammation
Hypersensitivity diseases can be classified on the basis of the
immunologic mechanism that mediates the disease
• In antibody-mediated disorders
(type
II
hypersensitivity),
secreted antibodies participate
directly in injury to cells by
promoting their phagocytosis or
lysis and injury to tissues by
inducing inflammation. Antibodies
may also interfere with cellular
functions and cause disease
without tissue injury.
Hypersensitivity diseases can be classified on the basis of the
immunologic mechanism that mediates the disease
• In immune complex-mediated
disorders
(type
III
hypersensitivity),
antibodies
bind antigens and then induce
inflammation directly or by
activating
complement.
The
leukocytes that are recruited
(neutrophils
and
monocytes)
produce tissue damage by
release of lysosomal enzymes
and generation of toxic free
radicals.
Hypersensitivity diseases can be classified on the basis of the
immunologic mechanism that mediates the disease
• In cell-mediated immune disorders
(type
IV
hypersensitivity),
sensitized T lymphocytes are the
cause of the cellular and tissue
injury.
Ipersensibilità di tipo I: allergia
• Reazioni allergiche si manifestano quando un individuo che
ha già prodotto IgE in risposta ad un antigene innocuo
(allergene) viene successivamente in contatto con lo stesso
Ag
• IgE presenti principalmente nei tessuti si legano alla
superficie dei mastociti attraverso il recettore ad alta affinità
FceRI causando un cross-link dei recettori e stimolando la
secrezione di mediatori chimici
• FceRI sono presenti anche su basofili ed eosinofili attivati
•
Immediate (Type I) Hypersensitivity
Immediate, or type I, hypersensitivity is a rapidly developing immunologic reaction
occurring within minutes after the combination of an antigen with antibody bound to
mast cells in individuals previously sensitized to the antigen
The systemic reaction usually follows injection of an antigen to which the host has
become sensitized.
Many local type I hypersensitivity reactions have two well-defined phases:
•
The immediate, or initial, response is characterized by vasodilation, vascular leakage,
and depending on the location, smooth muscle spasm or glandular secretions. These
changes usually become evident within 5 to 30 minutes after exposure to an allergen
and tend to subside in 60 minutes.
•
In many instances (e.g., allergic rhinitis and bronchial asthma), a second, late-phase
reaction sets in 2 to 24 hours later without additional exposure to antigen and may last
for several days. This late-phase reaction is characterized by infiltration of tissues with
eosinophils, neutrophils, basophils, monocytes, and CD4+ T cells as well as tissue
destruction, typically in the form of mucosal epithelial cell damage.
Immediate hypersensitivity
Kinetics of the immediate and late-phase reactions. The immediate vascular and smooth muscle reaction to allergen
develops within minutes after challenge (allergen exposure in a previously sensitized individual), and the late-phase reaction
develops 2 to 24 hours later
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Morphology
The immediate reaction (B) is characterized by vasodilation, congestion, and edema, and the late
phase reaction (C) is characterized by an inflammatory infiltrate rich in eosinophils, neutrophils, and T
cells.
(Courtesy of Dr. Daniel Friend, Department of Pathology, Brigham and Women's Hospital, Boston, MA.)
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Allergic reactions can be divided into an immediate
response and a late-phase response.
direct effects on blood vessels and
smooth
muscle
of
rapidly
metabolized mediators such as
histamine released by mast cells.
The late-phase response is caused
by the effects of an influx of
inflammatory leukocytes attracted by
chemokines and other mediators
released by mast cells during and
after the immediate response
Photographs courtesy of A.B. Kay.
Pathogenesis of immediate (type I) hypersensitivity reaction. The late-phase
reaction is dominated by leukocyte infiltration and tissue injury.
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The differentiation of Th cells depends on the antigen source, the quantity of allergen, and the cytokines produced. Bacterial
antigens or a high dose of antigen will induce IL-12 from macrophages. In addition, the developing Th1 cells produce
IFNγ, which further enhances the production of Th1 cells. Low-dose antigen without adjuvant will induce Th2 cells,
which produce both IL-4 and IL-5. IL-4 plays a role in (i) enhancing the growth of Th2 cells; (ii) the expression of the gene for
IgE. In turn IgE binds to the high-affinity receptor for IgE on mast cells.
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(1) The serum concentration of IgE (which is around 100 IU/ml) is only approximately 0.001% that of IgG
(around 10 mg/ml) and comprises less than 0.001% of the total immunoglobulin. Levels in atopic patients
tend to be raised, and this is especially so in atopic eczema (1 IU = 2.4 ng). (2) The higher the level of IgE
the smaller the percentage of the population affected, but the greater the likelihood of atopy. Where the
level is greater than 450 IU/ml the majority of subjects are atopic.
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Activation of mast cells in immediate hypersensitivity
and release of their mediators.
ECF, eosinophil chemotactic factor; NCF, neutrophil chemotactic factor; PAF, platelet-activating factor.
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Primary Mediators
Primary mediators contained within mast-cell granules can be
divided into three categories:
•
Biogenic amines. The most important vasoactive amine is histamine. Histamine
causes intense smooth muscle contraction, increased vascular permeability, and
increased secretion by nasal, bronchial, and gastric glands.
•
Enzymes. These are contained in the granule matrix and include neutral
proteases (chymase, tryptase) and several acid hydrolases. The enzymes cause
tissue damage and lead to the generation of kinins and activated components of
complement (e.g., C3a) by acting on their precursor proteins.
•
Proteoglycans. These include heparin, a well-known anticoagulant, and
chondroitin sulfate. The proteoglycans serve to package and store the other
mediators in the granules.
Secondary Mediators
Secondary mediators include two classes of compounds (1) lipid
mediators and (2) cytokines
•
Leukotrienes. Leukotrienes C4 and D4 are the most potent vasoactive and
spasmogenic agents known. On a molar basis, they are several thousand times
more active than histamine in increasing vascular permeability and causing bronchial
smooth muscle contraction. Leukotriene B4 is highly chemotactic for neutrophils,
eosinophils, and monocytes.
•
Prostaglandin D2. This is the most abundant mediator derived by the
cyclooxygenase pathway in mast cells. It causes intense bronchospasm as well as
increased mucus secretion.
Secondary Mediators
Secondary mediators include two classes of compounds (1) lipid
mediators and (2) cytokines
•
•
•
•
•
•
•
•
Platelet-activating factor (PAF). PAF is produced by some mast-cell populations. It
causes
platelet aggregation,
release of histamine,
bronchospasm,
increased vascular permeability, and
vasodilation. In addition, it has important pro-inflammatory actions.
PAF is chemotactic for neutrophils and eosinophils.
At high concentrations, it activates the newly recruited inflammatory cells, causing
them to aggregate and degranulate. Because of its ability to recruit and activate
inflammatory cells, it is considered important in the initiation of the late-phase
response. Although the production of PAF is also triggered by the activation of
phospholipase A2, it is not a product of arachidonic acid metabolism.
Secondary Mediators
Secondary mediators include two classes of compounds (1) lipid
mediators and (2) cytokines
•
Cytokines. Mast cells are sources of many cytokines, which play an important role
in the late-phase reaction of immediate hypersensitivity because of their ability to
recruit and activate inflammatory cells. The cytokines include TNF, IL-1, IL-3, IL-4,
IL-5, IL-6, and GM-CSF, as well as chemokines, such as macrophage
inflammatory protein (MIP)-1α and MIP-1β. Mast cell-derived TNF and chemokines
are important mediators of the inflammatory response seen at the site of allergic
inflammation. Inflammatory cells that accumulate at the sites of type I
hypersensitivity reactions are additional sources of cytokines and of histaminereleasing factors that cause further mast-cell degranulation.
Normal larynx
Laryngeal oedema
MECCANISMI EFFETTORI: EFFETTO DELL’ATTIVAZIONE DEI
MASTOCITI IN DIVERSI TESSUTI
TRATTO GASTROINTESTINALE
Aumento della SECREZIONE FLUIDI
Aumento della PERISTALSI
ATTIVAZIONE DEI MASTOCITI
Espulsione contenuto del
tratto intestinale
(vomito diarrea)
VASI SANGUIGNI
Aumento del FLUSSO SANGUIGNO
Aumento della PERMEABILITA’
Aumento di fluidi nei tessuti
causa aumento di flusso
VIE AEREE
Aumento della SECREZIONE di MUCO
Diminuizione del DIAMETRO
Congestione e blocco delle
vie aeree (starnuti tosse e
muco)
Gonfiore e secrezione di
muco nel tratto nasale
linfonodi, aumento di cellule e
proteine nei tessuti,
Aumento di risposta effettrice
nei tessuti
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