hypersensitivity and autoimmunity
TRANSCRIPT
Hypersensitivity and Autoimmunity
Lecture’s outline• Hypersensitivity• Immunologic Tolerance • Autoimmunity
Hypersensitivity and its causes• Hypersensitivity :is the term used when an immune response
results in exaggerated or inappropriate reactions harmful to the host.
Hypersensitivity and its causes• 1.Autoimmunity:• normally we tolerate our own antigens(self-tolerance)• Self-tolerance failsautoimmunity• 2.Reaction against microbes:• Excessive reactions or persistent antigens,the formed
antibodies may bind to the microbial antigens to produce immune complexes that trigger inflamation in the tissues
• Ex: poststreptococcal glumerulonephritis
Cont’d• 3.Reactions against environmental antigens :• Pollens, animal danders,dust (20% of the population)
Types of hypersensitivity Diseases
Types of hypersensitivity Diseases
• 1.Immediate (type 1) hypersensitivity • Rapid immune reaction within minutes• Interaction of antigen and IgE antibody that is bound to the
mast cells in a sensitized host .• Induced by enviromantal antigens that stimulate strong Th2
responses and IgE production in genetically susceptible individuals
• Reaction starts by the entrance of an antigen (allergens to this individual)
1.Immediate (type 1) hypersensitivity
• Principle mediators: histamine, proteases prostaglandins, leukotrienes, cytokines immediate vascular and smooth muscle reactions , later phase inflammation .
• Allergens are harmless to normal individuals • Clinical manifestations local or systematic• Ex: seasonal rhinitis ,hay fever, asthma , fatal systemic
disorder anaphylaxis .
1.Immediate (type 1) hypersensitivity
Sequence of events in immediate hypersensitivity reaction
• IgE-triggered reaction has two well defined phases• 1. immediate response (vasodilatation,vascular leakage
smooth muscle spasm , 5-30 mins after exposure and subsiding by 60 mins .• 2. Late-phase reaction 2-8 hrs ,may last several days
inflamation ,tissue destruction .
Sequence of events in immediate hypersensitivity reaction
• Activation of Th2 cells and production of IgE ab . Th2 cells secrete several cytokines that are resposible to all rxns of immediate hypersensitivity • Sensitization of mast cells by IgE ab • Activation of mast cells and release
of mediators .• Late-phase reaction :
neutrophils,eosinophils,lymphocytes Th2
1.Immediate (type 1) hypersensitivity
three groups of mediators: 1. Vasoactive amines released from granule stores1.Histamine: vasodilation, increased vascular permeability, smooth muscle contraction ,increased secretion of mucus 2.Adinosine: broncoconstriction ,inhibit platelet aggrigation ,inhibit chemotactic factors in neutrophils and eosinophils 3.Proteases (tryptase) chemotactic and inflammatory factors
Cont’s• 2.newly synthesized lipid mediators(membrane phospholipids)• 1.Prostaglandins: by mast cells ,
PGD2 most abundant ,causes broncospasm ,increased mucus secretion • 2.leukotrienes (LTC4, LTD4) most potent vasoactive and
spasmogenic agents (> 1000 more potent from histamine in increasing vascular permeability ,bronchial smooth muscle contraction )
Cont’s• 3.Cytokines:• Important for late -phase reaction• TNF • Chemokines :recruit and activate leukocyte• IL-4,IL5 :amplify Th2
Types of hypersensitivity Diseases
• 2. Antibody-Mediated Diseases (Type II Hypersensitivity) • caused by antibodies directed against target
antigens on the surface of cells or other tissue• components. The antigens may be normal • molecules intrinsic to cell membranes or in the
extracellular matrix, or they may be adsorbed exogenous antigens (e.g., a drug metabolite).
Mechanisms of Antibody-Mediated Diseases• 1. Opsonization and phagocytosis• When circulating cells, such as erythrocytes or platelets,
are coated (opsonized) with autoantibodies, with or without complement proteins, the cells become targets for phagocytosis by neutrophils and macrophages .• Opsonized cells are usually eliminated in the spleen, and
this is why splenectomy is of clinical benefit in autoimmune thrombocytopenia and some forms of autoimmune hemolytic anemia.
Mechanisms of Antibody-Mediated Diseases• 2. Inflammation• Antibodies bound to cellular or tissue antigens activate the
complement system by the “classical” pathway.• Products of complement activation serve several functions
one of which is to recruit neutrophils and monocytes, triggering inflammation in tissues.
• Ex : Goodpasture syndrome and pemphigus vulgaris.
Mechanisms of Antibody-Mediated Diseases• 3. Antibody-mediated cellular dysfunction.• Antibodies directed against cell surface receptors impair or
dysregulate cellular function without causing cell injury or inflammation
• Ex : myasthenia gravis, antibodies against acetylcholine receptors in the motor end plates of skeletal muscles inhibit neuromuscular transmission, with resultant muscle weakness.
• Ex: Antibodies can also stimulate cellular responses excessively. In Graves disease, antibodies against the thyroid-stimulating hormone receptor stimulate thyroid epithelial cells to secrete thyroid hormones, resulting in hyperthyroidism
• Table examples of type 2
Types of hypersensitivity Diseases
• 3. Immune Complex Diseases (Type III Hypersensitivity• Antigen–antibody (immune) complexes that are formed in the
circulation may deposit in blood vessels, leading to complement activation and acute inflammation
• exogenous or endogenous antigens• The mere formation of immune complexes does not equate with
hypersensitivity disease; small amounts of antigen– antibody complexes may be produced during normal immune responses and are usually phagocytosed and destroyed. It is only when these complexes are produced in large amounts, persist, and are deposited in tissues that they are pathogenic.
• Immune complex–mediated injury is systemic when complexes are formed in the circulation and are deposited in several organs, or it may be localized to particular organs (e.g., kidneys, joints, or skin) if the complexes are formed and deposited in a specific site.
3. Immune Complex Diseases (Type III Hypersensitivity
• The pathogenesis of systemic immune complex disease can be divided into three phases:
• (1) formation of antigen– antibody complexes in the circulation
• (2) deposition of the immune complexes in various tissues, thereby initiating
• (3) an inflammatory reaction in various sites throughout the body
3. Immune Complex Diseases (Type III Hypersensitivity• Local Immune Complex Disease• Arthus reaction, in which an area of tissue necrosis appears as a
result of acute immune complex vasculitis.• The reaction is produced experimentally by injecting an antigen into
the skin of a previously immunized animal (i.e., pre-formed antibodies against the antigen are already present in the circulation).
• Because of the initial antibody excess, immune complexes are formed as the antigen diffuses into the vascular wall; these are precipitated at the site of injection and trigger the same inflammatory reaction and histologic appearance as in systemic immune complex disease. Arthus lesions evolve over a few hours and reach a peak 4 to 10 hours after injection, when the injection site develops visible edema with severe hemorrhage, occasionally followed by ulceration.
Types of hypersensitivity Diseases
• 4. T Cell–Mediated (Type IV) Hypersensitivity• Several autoimmune disorders, as well as pathologic
reactions to environmental chemicals and persistent microbes, are now known to be caused by T cells.
• The occurrence and significance of T lymphocyte–mediated tissue injury have been increasingly appreciated as the methods for detecting and purifying T cells from patients’ circulation and lesions have improved.
4. T Cell–Mediated (Type IV) Hypersensitivity
• Two types of T cell reactions are capable of causing tissue injury and disease:
• (1) cytokine-mediated inflammation• the cytokines are produced mainly by CD4+ T cells.
exemplified by the delayed-type hypersensitivity (DTH) • CD4+ T cells of the TH1 and TH17 subsets secrete
cytokines, which recruit and activate other cells, especially macrophages, and these are the major effector cells of injury
• (2) direct cell cytotoxicity, mediated by CD8+ T cells.• cytotoxic CD8+ T cells are responsible for tissue damage.
(1) Inflammatory Reactions Elicited by CD4+ T Cells EXAMPLES
• Contact dermatitis is an example of tissue injury resulting from T cell–mediated inflammation
• . It is evoked by contact with pentadecylcatechol (also known as urushiol, the active component of poison ivy and poison oak, which probably becomes antigenic by binding to a host protein
EXAMPLES• several systemic diseases, such as type 1 diabetes and multiple
sclerosis, are caused by TH1 and TH17 reactions against self antigens, and Crohn disease may be caused by uncontrolled reactions involving the same T cells but directed against intestinal bacteria. T cell–mediated inflammation also plays a role in the rejection of transplants
Delayed-Type Hypersensitivity • Delayed-Type Hypersensitivity DTH is a T cell–mediated
reaction that develops in response to antigen challenge in a previously sensitized individual.
• the DTH reaction is delayed for 12 to 48 hours, which is the time it takes for effector T cells to be recruited to the site of antigen challenge and to be activated to secrete cytokines
• On histologic examination, the DTH reaction is characterized
by perivascular accumulation (“cuffing”) of CD4+ helper T cells and macrophages
• . DTH reactions are mediated primarily by TH1 cells; the contribution of TH17 cells is unclear.
Delayed-Type Hypersensitivity• . Prolonged DTH reactions against persistent microbes or other
stimuli may result in a special morphologic pattern of reaction called granulomatous inflammation.
• The initial perivascular CD4+ T cell infiltrate is progressively replaced by macrophages over a period of 2 to 3 weeks. These accumulated macrophages typically exhibit morphologic evidence of activation; that is, they become large, flat, and eosinophilic, and are called epithelioid cells
• . The epithelioid cells occasionally fuse under the influence of cytokines (e.g., IFN-γ) to form multinucleate giant cells
• . A microscopic aggregate of epithelioid cells, typically surrounded by a collar of lymphocytes, is called a granuloma
The events that give rise to the formation of granulomas in
type IV hypersensitivity reactions.
(2) direct cell cytotoxicity, mediated by CD8+ T cells.
• T cell–mediated cytotoxicity: CD8+ CTLs specific for an antigen recognize cells expressing the target antigen and kill these cells. CD8+ T cells also secrete IFN-γ.
2) direct cell cytotoxicity, mediated by CD8+ T cells.
• T Cell–Mediated Cytotoxicity In this form of T cell–mediated tissue injury, CD8+ CTLs kill antigen-bearing target cells.
• The principal mechanism of killing by CTLs is dependent on the perforin–granzyme system.
• CTLs play an important role in the rejection of solid-organ transplants and may contribute to many immunologic diseases. • cytokine-mediated inflammation, but less so than CD4+
cells.
Immunological tolerance
Immunological tolerance
• Definition: • specific unresponsiveness to an antigen that is induced by
exposure of lymphocytes to that antigen (implies antigen specificity, in contrast to “non-specific immunosuppression”)
• a lack of immune responsiveness to one’s own tissue antigens .
• Significance:• All individuals are tolerant of their own antigens (self-
tolerance); breakdown of self-tolerance results in autoimmunity
• Therapeutic potential: Inducing tolerance may be exploited to prevent graft rejection, treat autoimmune and allergic diseases, and prevent immune responses in gene therapy, perhaps stem cell transplantation
Central and peripheral tolerance
• Central tolerance: Immature self-reactive lymphocytes that recognize self antigens in generative (“central”) lymphoid organs die by apoptosis; other fates (i.e., in the thymus for T cells and in the bone marrow for B cells).
• Peripheral tolerance: mature ,Self-reactive T cells that escape negative selection in the thymus , recognize self antigens in peripheral tissues are inactivated (anergy), killed (deletion) or suppressed.
Central and peripheral tolerance
• The principal fate of lymphocytes that recognize self antigens in the generative organs is death (deletion), BUT:
• Some B cells may change their specificity (called “receptor editing”)
• Some T cells may differentiate into regulatory (suppressor) T lymphocytes
Peripheral tolerance
• Anergy: refers to functional inactivation (rather than death) of lymphocytes induced by encounter with antigens under certain conditions.• Suppression by regulatory T cells: The responses of T
lymphocytes to self antigens may be actively suppressed by regulatory T cells. • Activation-induced cell death: Another mechanism of
peripheral tolerance involves apoptosis of mature lymphocytes as a result of self-antigen recognition.
Off signalsFunctionalunresponsivenessAnergy
TCR
Deletion
ActivatedT cell Apoptosis
(activation-inducedcell death)
RegulatoryT cell
Block inactivation
The immunological equilibrium: balancing lymphocyte activation and control
ActivationEffector T cells
ToleranceRegulatory T cells
Normal: reactions against pathogensPathologic: inflammatorydisease, e.g. caused by reactions against self
No response to selfControlled response to pathogens
Autoimmunity
• Definition: immune response against self (auto-) antigen, by implication pathologic
• General principles:• Pathogenesis: The development of autoimmunity reflects a
combination of susceptibility genes and environmental triggers (usually infections)
• Different autoimmune diseases may be systemic or organ-specific; may be caused by different types of immune reactions (antibody- or T cell-mediated)
• Table organ specific and systemic
Mechanisms of Autoimmunity • Unfortunately, the underlying causes of
most human autoimmune diseases remain to be determined. the breakdown of self-tolerance and development of autoimmunity result from a combination of : 1-Inherited susceptibility genes, which influence L ymphocyte tolerance 2- Environmental factors, such as infections or tissue injury, that may expose self-antigens and activate APCs and lymphocytes in the tissues.
Genetic Factors in Autoimmunity
• Autoimmune diseases have a tendency to run in families, and there is a greater incidence of the same disease in monozygotic than in dizygotic twins
• Several autoimmune diseases are linked with the HLA locus, especially class II alleles (HLA-DR, -DQ). The frequency of a disease in a person with a particular HLA allele, compared with that in people who do not inherit that allele, is called the odds ratio or relative risk. • Genome-wide association studies and linkage studies in families are revealing many genetic polymorphisms that are associated with different autoimmune diseases Some of these polymorphisms seem to be associated with several diseases, suggesting that the genes involved influence general mechanisms of self tolerance and immune regulation. Others are disease specific and may influence end-organ sensitivity or display of particular self antigens.
Environmental factors(infections or tissue injury) • A variety of microbes, including bacteria, mycoplasmas, and viruses,
have been implicated as triggers for autoimmunity, by several mechanisms:
• Viruses and other microbes may share cross-reacting epitopes with self antigens, such that responses may be induced by the microbe but may attack self tissues. This phenomenon is called molecular mimicry. Ex: rheumatic heart disease, in which an immune response against streptococci cross-reacts with cardiac antigens.
• Microbial infections with resultant tissue necrosis and inflammation can cause upregulation of costimulatory molecules on APCs in the tissue, thus favoring a breakdown of T cell anergy and subsequent T cell activation
Mechanisms by which infections may promote autoimmunity
Environmental factors
•environmental insults, not only infections.
• ultraviolet (UV) radiation causes cell death and may lead to the exposure of nuclear antigens, which elicit pathologic immune responses in lupus
• Smoking is a risk factor for RA, perhaps because it leads to chemical modification of self antigens. Local tissue injury for any reason may lead to the release of self antigens and autoimmune responses.
• a strong gender bias of autoimmunity• many of these diseases being more common in women than
in men.
Autoimmune Diseases • Systemic Lupus Erythematosus• Rheumatoid Arthritis• Sjögren Syndrome
SLE• (SLE) The fundamental defect in
SLE is a failure to maintain self tolerance, leading to the production of a large number of autoantibodies that can damage tissues either directly or in the form of immune complex deposits.
• Disease manifistaion include nephritis, skin lesions and arthritis (caused by the deposition of immune complexes), and hematologic and neurologic abnormalities
Any organ in the body; principally the skin, kidneys, serosal membranes, joints,
and heart.
SLE• Immunologically, autoantibodies, classically including
antinuclear antibodies (ANAs). • The diagnosis is established by demonstration of four or more
of the criteria during any interval of observation.• some studies estimate the prevalence to be as high as 0.2%
in certain groups• (approximately 9 : 1) female preponderance,• affects 1 in 700 women of childbearing age• SLE is more common and severe in black Americans
SLE-Etiology • The underlying cause of the breakdown in self-tolerance in SLE is
unknown; it may include excess or persistence of nuclear antigens,• Genetic Factors• Environmental Factors: UV radiation, cigarette smoking, drugs ,sex
hormones ( which results in cellular apoptosis and release of nuclear proteins).
Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease affecting many tissues but principally attacking the joints to produce a nonsuppurative proliferative synovitis that frequently progresses to destroy articular cartilage and underlying bone with resulting disabling arthritis.
Sjögren syndrome
• Sjögren syndrome is a clinicopathologic entity characterized by dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia), resulting from immune-mediated destruction of the lacrimal and salivary glands.
• (primary form), also known as the sicca syndrome, or more often in association with another autoimmune disease (secondary form).
• Among the associated disorders, RA is the most common(60%), but some patients have SLE, polymyositis, systemic sclerosis, vasculitis, or thyroiditis
• Approximately 90% of Sjögren syndrome cases occur in women between the ages of 35 and 45 years
Sjögren syndrome • • The disease is believed to be caused by an autoimmune T
cell reaction against one or more unknown self antigens expressed in these glands, or immune reactions against the antigens of a virus that infects the tissues
Symptoms