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MCB 2020 > 5.5 - 5.6 Immune Mediated Injury > Flashcards

5.5 - 5.6 Immune Mediated Injury Flashcards

1
Q

What is primary immunodeficiency?

A
  • Caused by inherited defect in the immune system
  • Innate host defenses (complement, phagocytes, NK-cells)
  • Adaptive immunity (humoral or cellular)
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2
Q

What is secondary immunodeficiency?

A
  • Caused by disease:
    • Infection
    • Malnutrition
    • Ageing
    • Immunosuppression
    • Chemotherapy
  • Manifests as increased susceptibility to infection and predisposition to some cancers.
  • E.g. Acquired Immunodeficiency Syndrome (AIDS) a disease caused by Human immunodeficiency virus I (HIV-I)
    • Infection and depletion of CD4+ T cells
    • Profound immunosuppression
      • Opportunistic infections
      • Secondary neoplasms
      • Neurologic manifestations
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3
Q

What are the mechanisms of CD4+ T cell loss mediated by HIV-1?

A
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4
Q

What is the clinical course of a HIV infection?

A
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5
Q

What is the role of tolerance in autoimmunity?

A
  • Immunological tolerance is when lymphocytes are unresponsive to antigen
  • Self-tolerance – the lack of an immune responsiveness to one’s own tissue antigen – is a fundamental property of the immune system
  • A breakdown in tolerance results in self-antigens becoming a target for the host immune response
  • This is the basis of autoimmune disease
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6
Q

Where does tolerance occur?

A
  • Central tolerance
    • Central lymphoid organs (thymus and bone marrow)
    • Immature lymphocytes that recognize self-antigen are killed or rendered harmless.
  • Peripheral tolerance
    • Occurs in periphery
    • Tissues and lymph nodes
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7
Q

What happens in central tolerance for T cell tolerance?

A
  • In developing T-cells, random somatic gene rearrangements generate diverse TCRs
  • APC present self-antigens present in thymus in conjunction with MHC to immature CD4/CD8 thymocytes
    • No signaling = apoptosis
    • Weak MHC-reactivity = survival and maturation
    • Strong MHC/self-peptide = Apoptosis
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8
Q

What is the role of tissue specific proteins AIRE in central T cell tolerance?

A
  • AIRE – autoimmune regulator
  • Transcription factor that induces expression of peripheral tissue antigens in the thymus
  • Mutations in aire give rise to autoimmune disease
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9
Q

What is the efficiency of central T cell tolerance?

A
  • Central Tolerance not 100% efficient
  • Despite the AIRE not all self-antigens are present in the thymus
  • Self reactive T cells can cause tissue injury unless they are deleted/suppressed in periphery
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10
Q

What are the four mechanisms of peripheral tolerance?

A
  • Anergy
  • Suppression
  • Deletion (activation-induced cell death)
  • Ignorance
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11
Q

What is anergy in T cell tolerance (peripheral tolerance)?

A
  • When the T cell cannot respond to antigen
  • T-cells require two signal for activation
    • Recognition of peptide antigen with self-MHC
    • Binding of CD28 to co-stimulatory molecule (B7)
  • T-cell encounters self-antigen
    • Co-stimulatory molecule not expressed on APC
    • T-cell inhibitory receptor (CTLA-4) competes for B7
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12
Q

What is suppression in T cell tolerance (peripheral tolerance)?

A
  • Tolerance due to regulatory lymphocytes (Treg)
  • Express CD25 and transcription factor FoxP3
  • Treg-cells recognize self antigen in the thymus and inhibit self reactive T cells that recognize the same antigen in the periphery
  • Secretion of cytokines that dampen T cell response
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13
Q

What is deletion in T cell tolerance (peripheral tolerance)?

A
  • Activation-induced cell death:
  • Strong or repeated self-antigen recognition
  • Engagement of death receptor Fas or expression of pro-apoptotic members of the Bcl family
  • Apoptosis of mature lymphocytes
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14
Q

What is ignoral in T cell tolerance (peripheral tolerance)?

A
  • Antigens are hidden from circulation (blood and lymph)
  • Immune privileged site
  • Some intracellular antigens
  • Eye or testes immune cells do not get into those organs. Could recognise testes antigen but would never see it
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15
Q

What is gene tolerance for B cell tolerance (central tolerance)?

A
  • B-cell encounters strongly cross- linking antigen in bone marrow
  • Autoreactive B-cell rescued by gene rearrangement
  • Receptor editing
  • Deletion of self-reactive light chain gene and replacement
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16
Q

What is deletion as a means of B cell tolerance for central tolerance?

A
  • B-cell encounters strongly cross-linking (multivalent) antigen in bone marrow
  • Rescue by gene rearrangement fails
  • Autoreactive B-cell eliminated by apoptosis
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17
Q

How is anergy seen in B cell tolerance (central tolerance)?

A
  • B-cell encounters weakly cross-linking antigen of low valence in bone marrow
  • Permanently unresponsive (anergic) even in the presence of T-cell help (tolerance)
  • Do not survive
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18
Q

How is ignorance seen in B cell tolerance (central tolerance)?

A
  • B-cells do not sense self-reactive antigen
    • Low access
    • Weak binding
    • Low concentration
  • Can react under certain conditions
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19
Q

Why is B cell tolerance less efficient than t cell tolerance?

A
  • B cell tolerance is less efficient than T cell tolerance
  • Relies upon efficient T cell tolerance
  • Relies on lack of T helper cells specific for self antigens
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20
Q

What are the two mechanisms of causing autoimmunity?

A
  • Inheritance of susceptibility genes
  • Environmental triggers that promote activation of self-reactive lymphocytes.
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21
Q

What are the genetic factors that predispose one to autoimmunity?

A
  • Disease runs in families
  • Affects monozygotic twins > dizygotic twins
  • Usually multiple genes, although can be caused by a single gene defect
  • Genes that affect self tolerance:
  • HLA genes
  • Non-MHC genes
    • Autoantigen availability and clearance (ie apoptosis)
    • Control of lymphocyte activation (ie IL-2R, CTLA-4)
    • Development – AIRE, responsible for presentation of peripheral tissue antigens in the thymus
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22
Q

What autoimmune diseases are linked to MHC genetic factors?

A
  • Human MHC genes (HLA) are highly polymorphic
  • Some autoimmune diseases are associated with HLA locus
  • Thought that MHC genotype determines ability of T cells to respond to antigen
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23
Q

What changes to tissues are seen in autoimmunity?

A
  • Inflammation
    • May activate anergic autoreactive bystanders cells
    • Secrete cytokines that impair regulatory T cells
  • Tissue injury
    • Tissue antigens may be altered by infection
    • Cryptic epitopes may be exposed by infection
  • Molecular mimicry
    • Microbial antigens with cross-reactivity with autoantigens
  • Drugs and toxins
    • Drugs and toxins can bind self antigens so that they are recognized as foreign
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24
Q

Does all autoimmunity lead to disease?

A
  • Not all autoimmunity leads to autoimmune disease
  • Transient anti-nuclear antibodies are produced after viral infections, with no outcome in most cases
  • Increase in the incidence of autoantibodies with increasing age - most show no evidence of autoimmunity
  • Experimental models of autoreactivity often need triggering events to develop disease
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25
Q

When does autoimmune disease occur?

A

Autoimmune disease occurs when immune response to specific self-antigens (autoimmunity) contribute to the ongoing tissue damage that occurs in that disease

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26
Q

What is the difference between organ specific and systemic autoimmune disease?

A
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27
Q

What are hypersensitivities directed against?

A
  • Pathogenic immune response directed against:
  • Host own antigen-autoimmunity
  • Microbe- immune response excessive or microbe persistent
    • Inflammation
    • Tissue damage
  • Environmental antigens
    • Immune response towards noninfectious and harmless antigens
28
Q

What are the four different types of hypersensitivities?

A
  • Type I – Immediate: IgE
  • Type II – Antibody-mediated: IgG and IgM antibodies directed to cellular antigens
  • Type III – Immune complex-mediated: Circulating IgG and IgM form complexes with antigen and are deposited
  • Type IV – T cell-mediated (type IV): CD4 and CD8 T-cells and macrophages
29
Q

What happens in type I hypersensitivity?

A
  • Production of antibody (IgE) to innocuous antigens
  • Allergic response
    • Exposure to antigen
    • Sensitization by production of IgE
    • Atopic individual often develop multiple types of allergic disease (eczema, rhinitis, asthma)
    • Non-atopic individuals may develop allergy to single antigen (penicillin, bee venom)
  • Inappropriate (pathological) triggering of a defensive immune response normally (physiological) directed to helminths (multicellular parasites)
  • Involves TH2 and B-cell class switch
30
Q

How does initial priming in response to antigen occur for Type I hypersensitivity?

A
  • APCs drive Th2 response
  • IL-4 induces class switching
  • IL-15 recruits and activates eosinophils
  • IL-13 acts on epithelial cells to stimulate mucous secretion
  • Th2 cells induce isotype switching to IgE
31
Q

How does sensitisation occur in type 1 hypersensitivity?

A
  • IgE opsonises local mast cells and basophils via FceRI
  • Contain preformed granules of inflammatory mediators
32
Q

What does repeat exposure do in type 1 hypersensitivity?

A
  • Repeat Exposure
  • Allergens bind IgE on mast cells
  • Initiates rapid degranulation of inflammatory mediators
  • Inflammatory mediators drive pathology
33
Q

What is the role of Th2 CD4+ T cells in type 1 hypersensitivity?

A
  • Activation and cytokine production:
    • IL-4 induces class switching to IgE which binds mast cells
    • IL-5 recruitment and activation of eosinophils
    • IL-13 acts on epithelial cells and stimulate mucous secretion
34
Q

What is the role of IgE in type 1 hypersensitivity?

A
  • Binds FCεRI (high affinity) on mast cells (tissues) and basophils (circulation)
  • Binds cells without antigen
  • IgE present in tissues
35
Q

What is the role of mast cells in type 1 hypersensitivity?

A
  • Location/properties
    • Mucosal and epithelial tissues, and connective tissue
    • Alert immune system to local infection
    • Have surface-bound IgE (via FcεR)
    • Contain pre-formed granules
  • Allergen-mediated IgE/ FcεR cross-linking causes granule exocytosis
    • synthesis of inflammatory lipid mediators & cytokines & chemokines
36
Q

What immune mediators do mast cells release in type 1 hypersensitivity?

A
  • Immune mediators - Immediate response:
  • 5-30min
  • Granule contents:
    • Histamines
    • Proteases
    • Chemotactic factors
  • Membrane phospholipids:
    • Platelet activating factor
    • Arachidonic acid (prostaglandin (D2), leukotrienes (B4, C4, D4)
  • Response:
    • Vasoldilation, vascular leakage, smooth muscle contraction, increased mucus secretion
37
Q

What immune mediators are released by mast cells in the late phase reaction?

A
  • 2-8hrs, lasting days
  • Cytokines:
    • TNF and chemokines – recruit and activate leukocytes
    • IL-4, IL-5 – Th2
    • IL-13 – mucous secretion
  • Response:
    • Leukocyte infiltration (neutrophils, eosinophils, lymphocytes
    • Epithelial damage
    • bronchospasm
38
Q

What are the tissue specific mechanisms of type 1 hypersensitivity?

39
Q

What are the type 1 hypersensitivity systemic symptoms?

A
  • Itching
    • Hives
    • Skin erythemia
  • Respiratory difficulty
    • Pulmonary bronchoconstriction
    • Hypersecretion of mucous
    • Laryngeal edema
  • Vomiting, abdominal cramps, diarrhea
    • Gastrointestinal contraction
  • Drop in blood pressure (anaphylactic shock)
    • Systemic vasodilation
40
Q

What genetic conditions give susceptibility to type 1 hypersensitivity?

A
  • Genome-wide linkage scans:
    • FCeRI
    • Cytokines that control Th2
    • Adam33 (tissue remodeling)
  • HLA molecules:
    • IgE production to certain allergens is associated with particular haplotypes
41
Q

What environmental conditions give rise to type I hypersensitivity?

A
  • Atopic allergic disease is increased in economically advanced regions of the world
  • Hygeiene hypothesis:
    • Early childhood exposuire to infection protects against allergy by skewing immune response away from Th2 and IgE
  • Counter regulation hypothesis:
    • Exposure to infection down-regulates both Th1 and Th2 through activation of Tregs
    • Less infection => less efficient Treg production
42
Q

What is type II hypersensitivity?

A
  • Antibody-Mediated Diseases
  • Directed to normal cell or tissue antigens or cell surface or tissue matrix molecules that have been modified by chemical or microbial proteins.
  • Antibodies (IgM and IgG) directed against tissue antigens
    • Cell death and tissue damage
      • Activation of the complement system
      • Targeting cells for phagocytosis
      • Inflammation
  • Interfere with normal function
    • Block or change the function of the antigen they have bound to
43
Q

What is the first step of type II hypersensitivity?

A

Activation of complement system

44
Q

What is the second step of type II hypersensitivity?

A
  • Cell death and tissue damage:
  • Phagocytosis by macrophages and neutrophils:
    • Antibodies recognized by Fc receptors
    • Complement recognized by C3b receptor
  • Neutrophils release enzymes and ROS which damage tissue
45
Q

What is the third and fourth step of type II hypersensitivity?

A
  • Cell death and tissue damage:
  • Tissue that’s too big for phagocytosis may be damaged by antibody-dependent cell- mediated cytotoxicity (ADCC)
46
Q

What is an example of type 2 hypersensitivity where normal funciton is blocked?

A
  • Block normal function
  • Myasthenia gravis
  • Antibodies directed against the acetylcholine receptors in motor end plates inhibit neuromuscular transmission and cause muscle weakness.
47
Q

What is an example of type 2 hypersensitvity where normal funciton is changed?

A
  • Change normal function
  • Graves disease
  • Autoantibodies against the thyroid stimulating hormone (TSH) receptor on thyroid epithelium mimic TSH to cause excessive production of thyroid hormone
48
Q

How is Rh disease of the newborn an example of type 2 hypersensitivity?

A
  • Rhesus negative woman carries a Rhesus positive fetus
  • Preformed maternal IgG antibody (previous pregnancy or transfusion) react with child’s RBC in utero
  • Removal of RBC via complement activation
  • Prevention; a Rh- woman carrying a Rh+ fetus is given anti-D (Rh antigen) antibodies, which attack and destroy the babies Rh+ cells before they can initiate the formation of antibodies by the mother
49
Q

How is rheumatic heart disease an example of type II hypersensitivity?

A
  • Acute, immune mediated, inflammatory disease
  • Occurs following group A streptococcal infection (pharyngitis)
  • Inflammation of the valves, myocardium, pericardium
  • Certain streptoccocal strains induce host antibodies that cross react with host antigens.
  • Damage host tissue
50
Q

What is type 3 hypersensitivity?

A
  • Immune complex disease
  • Immune complexes are formed between antibody and antigen
  • Exogenous antigen • Microbial protein
  • Endogenous protein • Nucleoprotein
  • Includes some of the most common immunologic diseases
51
Q

What happens to immune complexes under normal circumstances (not type 3 hypersensitivity)?

A
  • Under normal circumstances
  • Immune complexes are formed between antibody and antigen
  • Removed from circulation by the action of complement
    • Activation of complement => C3b deposited on immune complex
    • Binds to CR1 receptor on erythrocytes
    • Removed by CR1 and FcR bearing phagocytic cells in spleen and liver
52
Q

How do immune complexes cause disease in type 3 hypersensitivity?

A
  • Immune complexes cause disease when they are produced in large amounts – persistent infection, autoimmune disease, constant environmental exposure
  • inadequately cleared – limited Fc receptors
  • deposit in tissue (basement membranes of blood vessels, kidney, joints)
  • induce inflammatory reaction
  • Systemic: immune complexes formed in the circulation and deposited in many tissues Eg SLE
  • Localized: immune complexes are deposited in specific tissues
53
Q

What happens when complement is activated in type 3 hypersensitivity?

54
Q

What sort of pathological lesions are seen in type 3 hypersensitivity?

A
  • Vasculitis in blood vessels
    • Fibrinoid necrosis associated with vasculitis
    • Protein deposition in tissue as a result of the inflammatory reaction
  • Glomerulonephritis in renal glomeruli
  • Rheumatoid Arthritis with immune complexes causing inflammation of flexible joints
55
Q

How is arthus reaction an example of type 3 hypersensitivity (local)?

A
  • Pre-existing antibodies (through previous exposure to antigen)
  • Complex with antigen as it diffuses across the vascular wall
  • Induce inflammatory reaction
  • Edema, hemorrhage, occasionally ulceration
  • Rapid time course-4-10 hours
56
Q

How is acute post infection glomerulonephritis an example of type 3 local hypersensitivity?

A
  • Can occur following group A streptococcal infection of skin or pharynx
  • Immune complexes between streptococcal antigens and antibodies form in circulation and deposit in glomeruli or form in situ
  • Acute inflammation in glomeruli
57
Q

How is systemic lupus erythematosus and example of systemic type 3 hypersensitivity?

A
  • Multi-system autoimmune disease
  • Failure to maintain self-tolerance large array of autoantibody
  • Clinical manifestation
    • Unpredictable,
    • Remitting, Relapsing,
    • Acute, Insidious
  • Effects any organ through deposition of immune complexes in basement membrane
    • Skin, kidney, serosal membranes, joints, heart
58
Q

What is the mechanism of SLE in type 3 systemic hypersensitivity?

A
  • Increased generation/ defect in clearance of antigens (in particular nuclear antigens) released by apoptotic cells and the failure of T- and B-cell tolerance to these self antigens.
    • Antibodies
    • Nuclear proteins
    • Cytoplasmic proteins
    • Protein:Phospholipid complexes
    • Surface antigens of blood vessels
59
Q

What factors make one susceptible to type 3 hypersensitivity for SLE?

60
Q

What is type IV hypersensitivity triggered by?

A
  • AKA Delayed type hypersensitivity (DTH)
  • Due to persisting antigen specific T cells (CD4 or CD8)
  • Triggered by intracellular antigen
61
Q

What is the mechanism of type IV hypersensitivity that is CD4 T cell mediated?

A
  • TH1 CD4+ T-cells secrete cytokines
  • Recruitment of macrophages
  • When the organism, or stimulating agent persists, macrophages and T cells accumulate at the antigen site in large numbers and result in pathology
62
Q

How is the tuberculin reaction an example of type 4 hypersensitivity that is CD4 T cell mediated?

A
  • In individuals previously sensitized to tubercle bacillus: Vaccination or infection
  • Tuberculin (M. tuberculosis peptides and carb) injected intradermally.
  • Results in T cell-mediated inflammatory response
  • Morphology of tuberculin reaction
    • Local erythema (reddening) and induration (hardening)
    • Perivascular accumulation of CD4+ helper T cells and macrophages
    • Secretion of cytokines increased microvascular permeability
  • Edema and fibrin deposition
63
Q

How is Mtb granuloma formation an example of type IV hypersensitivity that is CD4 T cell mediated?

A
  • CD4+ infiltrate replaced by macrophages (2-3 weeks)
    • Macrophages activated–flat and eosinophilic
    • Fuse in presence of cytokines (giant cells)
  • Granuloma:
    • Giant cells
    • Surrounded by lymphocytes
    • Enclosing ring of fibroblasts
  • Tuberculosis
    • Inhaled and deposited in lung
    • Phagocytosed by alveolar macrophages
    • Resist killing
    • Present antigen to CD4 T cells
    • Initiate granuloma formation
64
Q

What do CD8+ T cells do in type IV hypersensitivity?

A

CD8+ T-cell mediated:
• CD8+ CTLs kill antigen-expressing target cells

65
Q

How is poison ivy an example of CD8 T cell mediated Type IV hypersensitivity?

A
  • CD8+ T-cell response to contact with pentadecacatechol
  • Chemical in poison ivy
  • Lipid soluble
  • Crosses cell membrane
  • Modifies intracellular proteins
  • Results in modified peptides presented by MHC I
  • CD8+ T-cell response which directly kill cells

MCB 2020 (38 decks)

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