Module 34 - Immune-Mediated Injury Flashcards
Define immunodeficiency
Immunodeficiency is a state in which the immune system’s ability to fight infectious disease and cancer is compromised or entirely absent.
Differ between primary and secondary immunodeficiency.
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
Give an example of a secondary immunodeficiency mechanism.
HIV-1 mediated loss of CD4+ T cells, leads to:
- opportunistic infections
- secondary neoplasms
- neurological manifestation
Define tolerance and autoimmunity.
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)
Where does tolerance occur?
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
What happens to T-cells in central tolerance?
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.
- No signaling => non-functional => apoptosis
- Weak MHC-reactivity = survival and maturation
- Strong MHC/self-peptide Apoptosis
Explain the role of AIRE in Central Tolerance.
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.
Mention the mechanisms of peripheral tolerance of T cells.
- Anergy
- Suppression
- Deletion (activation-induced cell death)
- Ignorance
Describe the mechanisms of anergy of T cells.
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
Describe the mechanism of suppression of T cells.
- 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
Describe the mechanism of deletion of T cells.
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
Describe the mechanism of ignorance of T cells.
- Antigens are hidden from circulation (blood and lymph)
- Immune-privileged site
- Some intracellular antigens
Mention the mechanisms of central tolerance for B cells.
- Gene arrangement
- Deletion
- Anergy
- Ignorance
Describe the mechanism of gene rearrangement of B cells.
- 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
Describe the mechanism deletion of B cells in the bone marrow.
- B-cell encounters strongly cross-linking (multivalent) antigen in bone marrow
- Rescue by gene rearrangement fails
- Autoreactive B-cell eliminated by apoptosis
Describe the mechanism of anergy of B cells in the bone marrow.
- 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
Describe the mechanism of ignorance of B cells in the bone marrow.
- B-cells do not sense self-reactive antigen
- Low access
- Weak binding
- Low concentration
- Can react under certain conditions
How does T cell tolerance assist B cell tolerance?
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.
Explain why self-reactive lymphocytes do not always cause disease.
Autoimmune disease occurs when the immune response to specific self-antigens (autoimmunity) contribute to the ongoing tissue damage that occurs in that disease
Mention example of genes that affect self-tolerance.
- 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
Differ between organ-specific and systemic autoimmune disease.
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)
Describe the concept of hypersensitivity.
- 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
Mention the classes of hypersensitivities.
- 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
Type I Hypersensitivity involves the misdirection of immune defences usually used against _________ are mainly found at the site of entry
multicellular parasites
