What are the 3 professional antigen presenting cells?
- Dendritic cells (most effective)
- Macrophages (particulate antigens)
- B-cells (soluble antigens, toxins, and viruses)
How does a Dendritic Cell perform antigen uptake?
- Endocytosis
- Phagocytosis
- Pinocytosis
How does a Macrophage perform antigen uptake?
Phagocytosis
How does a B-cell perform antigen uptake?
Receptor-mediated endocytosis
How is activation of a Dendritic Cell achieved?
- Mediated by pattern recognition receptors (PRRs)
- TLRs
How is activation of a Macrophage achieved?
- Meditated by pattern recognition receptors
- TLRs
- Enhanced by T-cell help
How is activation of a B-cell achieved?
- Mediated by antigen recognition
- surface immunoglobulin
How does the MHC Class II expression of a Dendritic cell vary?
- Immature dendritic cells in the peripheral tissues
- Constitutively express low levels of Class II molecules.
- increases with activation
- Constitutively express low levels of Class II molecules.
- Mature dendritic cells in lymphoid tissues
- Constitutively express high levels of Class II molecules.
How does the MHC Class II expression of a Macrophage vary?
- Must be activated by phagocytosis and by cytokines to express Class II molecules.
- increased expression with activation
How does the MHC Class II expression of a B-cell vary?
- Constitutively expresses Class II MHC molecules (low levels)
- increased expression with activation
When/What co-stimulatory activity does a Dendritic Cell produce?
- Immature Dendritic Cell
- Constitutively express low levels of B7 (CD80/86) and other co-stimulatory molecules
- up-regulation of CD80/86 with activation
- Constitutively express low levels of B7 (CD80/86) and other co-stimulatory molecules
- Mature Dendritic Cell
- Constitutively express high levels of B7 (CD80/86)
When/What co-stimulatory activity does a Macrophage produce?
- Must be activated to express co-stimulatory molecules (induced)
- upregulation of CD80/86 with activation
When/What co-stimulatory activity does a B-Cell produce?
- Must be activated by antigen binding antibody before they express co-stimulatory molecules (induced)
- up-regulation of CD80/86 with activation
What are the T-cell activation properties of a Dendritic Cell?
- Activate:
- Naïve T-cells
- Effector T-cells
- Memory T-cells
What are the T-cell activation properties of a Macrophage?
- Activate:
- Effector T-cells
- Memory T-cells
What are the T-cell activation properties of a B-Cell?
- Activate:
- Effector T-cells
- Memory T-cells
What are the two processes of MHC molecule presentation?
- Cytosolic pathway:
- presentation of antigen on MHC Class I molecules
- requires intracellular protein synthesis of the endogenous antigen
- Endocytic pathway
- presentation of antigen on MHC Class II molecules
- requires the endocytic uptake of exogenous antigen
How are MHC Class I molecule produced?
(Hint: 5 steps)
- Endogenous antigen tagged with ubiquitin
- Tagged antigen enters proteasome
- IFN stimulates → switch of beta subunits of proteasome to make “Immunoproteasome”
- better at breaking down molecules for MHC molecule
- antigen broken down into peptides
- IFN stimulates → switch of beta subunits of proteasome to make “Immunoproteasome”
- Peptide binds to transporter protein heterodimer complex TAP 1 & TAP 2
- transports peptides to lumen of RER
- Calnexin prepares and stabilizes MHC Class I for loading
- Peptide loaded onto MHC Class I Molecules
- ERAAP helps peptide fit into peptide-loading complex
- once loaded the peptide-loading complex dissociates
How is a newly assembled peptide-bound MHC Class I molecule get to the cell surface for expression?
- Leaves RER packaged in a secretory vesicle
- Vessicle undergoes further processing at Golgi complex
- Exported from Golgi to outer cell membrane
How are MHC Class II molecules produced?
(Hint: 7-8 steps)
- Antigen internalized into APC via endocytosis or phagocytosis.
- use clathrin-coated vesicle
- Antigen degraded in phagolysosome or endosome.
- low pH for degradation
- MHC Class II receptor molecule assembled simultaneously in RER
- alpha and beta chain coupled with an invariant chain (CD74)
- blocks binding of endogenous antigen
- MHC complex routed through RER to Golgi
- Invariant chain is digested, leaving CLIP fragment
- MHC Class II molecule catalyzes exchange of CLIP for antigenic peptide
- HLA-DM mediates exchange
- HLA-DO regulates exchange
- Class II MHC-peptide is transported to plasma membrane
What is the age of onset of diseases associated with MHC Class I Deficiency vs. MHC Class II Deficiency?
- MHC Class I Deficiency
- older age of onset
- 3-18 yoa
- MHC Class II Deficiency
- younger age of onset
- failure to thrive during infancy
What is the disease susceptibility associated with MHC Class I Deficiency vs. MHC Class II Deficiency?
- Class I
- chronic respiratory infections
- ability to fight some viral infections
- deficiency does not directly decrease ability to fight off capsulated bacterial infections
- low CD8+ T-cell count, normal CD4+ T-cell count
- Class II
- increased susceptibility to pyogenic and opportunistic infections
- opportunistic pathogens like fungus
- failure of T-cells to respond to specific pathogens
- low CD4+ T-cell count, normal CD8+ T-cell count
- moderate to severe hypogammaglobulinemia
- increased susceptibility to pyogenic and opportunistic infections
What ratio of CD4+:CD8+ T-cells would you expect in a MHC class I deficiency and why? What ratio would you expect in a MHC class II deficiency and why?
- Normal ratio of CD4:CD8 = 2:1
- Class I deficiency = 9:1
- profound deficiency of CD8+
- Class II deficiency = 1:3
- profound deficiency of CD4+
What are some causes of MHC class I and MHC class II deficiencies?
- Class I
- autosomal recessive inheritance
- trafficking problem, trouble getting MHC Class I molecule to cell surface
- Class II
- autosomal recessive inheritance
- defect in regulation of expression of the MHC Class II genes
- transcription factors required to regulate their coordinated expression
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Biologic Antineoplastics - Fitz100
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Acute Leukemia Cases - Nikcevich13
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Chronic Lymphocytic Leukemia Cases - Daniel Nikcevich18
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Antigen Presentation and Processing - Diebel24
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B-cell and T-cell Maturation - Diebel36
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Cell Mediated Cytotoxicity - Diebel15
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CML Module - Krafts35
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Multiple Myeloma - Krafts & Johns13
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CML Module - Scott8
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Chronic Lymphoproliferative Disorders - Krafts23
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Non-Hodgkin Lymphoma - Krafts28
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Hodgkin Lymphoma - Krafts10
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Lymphoma Cases & Review - Kebbekus20
