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Molecular and Cellular Biomedicine > Module 34 - Immune-Mediated Injury > Flashcards

Module 34 - Immune-Mediated Injury Flashcards

1
Q

Define immunodeficiency

A

Immunodeficiency is a state in which the immune system’s ability to fight infectious disease and cancer is compromised or entirely absent.

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2
Q

Differ between primary and secondary immunodeficiency.

A

Primary: caused by an inherited defect in the immune system

Secondary: caused by disease, manifests as increased susceptibility to infection and predisposition to some cancers

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3
Q

Give an example of a secondary immunodeficiency mechanism.

A

HIV-1 mediated loss of CD4+ T cells, leads to:

  • opportunistic infections
  • secondary neoplasms
  • neurological manifestation
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4
Q

Define tolerance and autoimmunity.

A

Self-tolerance refers to the lack of immune responsiveness to one’s own tissue antigen (fundamental property of IS).

A breakdown on tolerance results in self-antigens becoming the target for the host immune response (the basis of autoimmunity)

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5
Q

Where does tolerance occur?

A

Central tolerance:

  • Central lymphoid organs (thymus and bone marrow)
  • Immature lymphocytes that recognize self-antigens are killed or rendered harmless.

Peripheral tolerance:

  • Occurs in periphery
  • Tissues and lymph nodes
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6
Q

What happens to T-cells in central tolerance?

A

In developing T-cells, random somatic gene rearrangements generate diverse TCRs.

APC present self-antigens present in the thymus in conjunction with MHC to immature CD4/CD8 thymocytes, with three outcomes.

  1. No signaling => non-functional => apoptosis
  2. Weak MHC-reactivity = survival and maturation
  3. Strong MHC/self-peptide Apoptosis
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7
Q

Explain the role of AIRE in Central Tolerance.

A

AIRE (Autoimmune Regulator) is a transcription factor expressed in the medulla of the thymus. It exposes T cells to normal, healthy proteins from all parts of the body (peripheral), and T cells that react to those self-antigens are destroyed.

However, not all self-antigens are expressed, hence peripheral tolerance is required.

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8
Q

Mention the mechanisms of peripheral tolerance of T cells.

A
  • Anergy
  • Suppression
  • Deletion (activation-induced cell death)
  • Ignorance
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9
Q

Describe the mechanisms of anergy of T cells.

A

Anergy: T cell can’t respond to antigen due to lack of binding between CD28 to the co-stimulatory molecule (B7) - which is one of the signals required for T cell activation

  • Co-stimulatory molecule (B7) not expressed on APC - can’t bind to CD28
  • CTLA-4 (inhibitory receptor) competes for B7 in APC
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10
Q

Describe the mechanism of suppression of T cells.

A
  • Tolerance due to regulatory lymphocytes (Treg)
  • Express CD25 and transcription factor FoxP3 (Bio-markers)
  • 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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11
Q

Describe the mechanism of deletion of T cells.

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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12
Q

Describe the mechanism of ignorance of T cells.

A
  • Antigens are hidden from circulation (blood and lymph)
  • Immune-privileged site
  • Some intracellular antigens
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13
Q

Mention the mechanisms of central tolerance for B cells.

A
  • Gene arrangement
  • Deletion
  • Anergy
  • Ignorance
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14
Q

Describe the mechanism of gene rearrangement of B cells.

A
  • B-cell encounters strongly crosslinking 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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15
Q

Describe the mechanism deletion of B cells in the bone marrow.

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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16
Q

Describe the mechanism of anergy of B cells in the bone marrow.

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
17
Q

Describe the mechanism of ignorance of B cells in the bone marrow.

A
  • B-cells do not sense self-reactive antigen
    • Low access
    • Weak binding
    • Low concentration
  • Can react under certain conditions
18
Q

How does T cell tolerance assist B cell tolerance?

A

Activation and differentiation of B cells are usually helped by activated T cells, specific to the same antigen. Hence, if the T cell tolerance is effective against self-antigens, no T-cells specific to that antigen would be present to help differentiate B cells.

19
Q

Explain why self-reactive lymphocytes do not always cause disease.

A

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

20
Q

Mention example of genes that affect self-tolerance.

A
  • HLA genes (Human MHC genes - highly polymorphic)
  • Non-MHC genes
    • Autoantigen availability and clearance (ie. apoptosis)
    • Control of lymphocyte activation (ie. IL-2R, CTLA-4)
    • Development –AIRE, responsible for the presentation of peripheral tissue antigens in the thymus
21
Q

Differ between organ-specific and systemic autoimmune disease.

A

Organ-Specific: Confined to specific organs/cell types

  • Graves Disease
  • Rheumatic Heart Disease
  • Type I Diabetes

Systemic: affects multiple organs and systems

  • rheumatoid arthritis
  • systemic lupus erythematosus (SLE)
22
Q

Describe the concept of hypersensitivity.

A
  • Pathogenic immune response directed against:
    • Host own antigen-autoimmunity
    • Microbe-immune response excessive or microbe persistent
    • Environmental antigens
  • ​​Difficult to control, chronic conditions
    • Stimuli difficult/ impossible to eliminate
    • Redundancy
    • Intrinsic positive feedback
23
Q

Mention the classes 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: CD4 and CD8 T-cells and macrophages
24
Q

Type I Hypersensitivity involves the misdirection of immune defences usually used against _________ are mainly found at the site of entry

A

multicellular parasites

25
Q

Describe the mechanism of Type I Hypersensitivity.

A
  1. Initial priming in response to allergen antigen
    • APCs drive TH2 response
      • IL-4 - induces isotype switching in B cells to IgE
      • IL-5 - recruits and activates eosinophils
      • IL-13 - stimulates epithelial mucous secretion
  2. Sensitisation
    • IgE opsonises local mast cells and basophils via Fc𝜀RI
    • Contain preformed granules of inflammatory mediators
  3. Repeat exposure
    • Allergens bind IgE on mast cells
    • Initiates rapid degranulation of inflammatory mediators
    • Inflammatory mediators drive pathology
26
Q

Mention the key players in Type I Hypersensitivity.

A
  • Allergens
  • TH2 cells
  • Mast cells and eosinophils
  • IgE (produced by B cells)
27
Q

Type I Hypersensitivity has two phases of immune reaction. Explain.

A

(1) the immediate response, which is

  • stimulated by mast cell granule contents and lipid mediators (AA)
  • characterized by vasodilation, vascular leakage, and smooth muscle spasm,
  • evident within 5 to 30 minutes after exposure to an allergen and subsiding by 60 minutes;

(2) late-phase reaction

  • stimulated mainly by cytokines,
  • sets in 2 to 8 hours later, may last for several days
  • characterized by inflammation as well as tissue destruction, such as mucosal epithelial cell damage
  • Neutrophils, eosinophils, and TH2 cells.
28
Q

Describe the mechanism of Type II Hypersensitivity.

A

It refers to antibody-mediated hypersensitivity. Directed to normal cell/tissue antigens or matrix molecules that have been modified by chemical or microbial proteins.

This leads to antibodies (IgM, IgG) being directed to the antigens, which leads to tissue damage and cell lysis through

  1. Complement cascade: opsonisation or direct lysis
    • Phagocytosis: by macrophage or PMNs - antibodies and complement recognized by Fc and C3b receptors respectively
  2. Tissue damage:
    • PMNs release enzymes and ROS
    • Antibody-Dependent Cell-mediated Cytotoxicity (ADCC): for tissues that are too big to phagocytose
  3. It may also interfere with normal function by blocking or changing the function of the antigen they have bound to
29
Q

Mention examples of Type II Hypersensitivity Diseases.

A
  • Myasthenia gravis: antibodies bind to ACh receptors => impair neuromuscular transmission
  • Graves disease: Antibody-mediated stimulation of TSH  receptors => hyperthyroidism
  • Rh disease of newborn: Rh- woman carries Rh+ fetus
30
Q

Describe the mechanism of Type III Hypersensitivity. Compare between normal and disease-causing circumstances.

A

Under normal circumstances, immune complexes are formed between antibody and antigen and are removed from circulation by the action of complement. C3b deposited on the complex, at which they’ll bind to the CR1 receptor in RBCs before being removed by FcR-bearing phagocytes in the spleen and river.

Immune complexes cause disease when they are:

  1. produced in large amounts (chronic infection, autoimmune disease, etc)
  2. not cleared (limited FcR)
  3. deposited in tissue
  4. induce inflammatory reaction
31
Q

Mention examples of Type III Hypersensitivity.

A
  • Arthus Reaction: pre-existing antibodies react with antigen => induce inflammatory reaction
  • SLE: multi-system autoimmune disease => deposition of immune complexes in basement membrane
32
Q

Differ between systemic and localized Type III Hypersensitivity.

A
  • Systemic: immune complexes formed in the circulation and deposited in many tissues (eg. SLE)
  • Localized: immune complexes are deposited in specific tissues
33
Q

Describe the mechanism of Type IV Hypersensitivity.

A
  • CD4+ T cell-mediated: In response to an intracellular antigen (presented by APC - MHC II), TH1 cells secrete cytokines (IFN-γ) which recruit macrophage. If stimulating agent persists, accumulation of macrophages and antigen-specific T cells will result in pathology.
  • CD8+ T cell-mediated: similar to above, however, APC recruits cytotoxic T cell, which kills antigen-expressing target cells.
34
Q

Mention the examples of Type IV Hypersensitivity diseases.

A
  • Poison Ivy: CD8+ T cell
  • Tuberculin Reaction
  • MTB granuloma formation

Molecular and Cellular Biomedicine (35 decks)

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