The Humoral Immune Response - cgu.edu.twdmi.cgu.edu.tw/ezfiles/70/1070/img/920/168580991.pdf · The...
Transcript of The Humoral Immune Response - cgu.edu.twdmi.cgu.edu.tw/ezfiles/70/1070/img/920/168580991.pdf · The...
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The Humoral Immune Response
Outlines: 1. How do T cells provide help to antibody production? TD vs.
TI Ags.
2. B cells vs. Self antigens
3. How and where are B cells activated?
4. The functions of Ig isotypes: neutralization, opsonization, and complement activation.
5. The destruction of Ab-coated pathogens via Fc receptors: ADCC and resistant to parasite infection.
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The humoral immune response is mediated by Ab molecules that are secreted by plasma cells
Opsonization: coating the surface of a pathogen to enhance phagocytosis
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but naive
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Self Ags-binding in the BM can lead to the death of immature B cells
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A second signal is required for B-cell activation by either thymus-dependent or thymus-independent Ags
receptors in the innate immunor extensive cross-linking
B-cell activation by armed T cells
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(TI-1) (TI-2)
(mitogen, 裂殖素)
(cytokines)
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TI-1 Ags are polyclonal B cell activators at high concentrations, whereas at low concentrations they induce an Ag-specific Ab response
as mitogen
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B-cell activation by TI-2 Ags requires, or is greatly enhanced by, cytokines
TI-1 Ags: activate both immature and mature B cells
TI-2 Ags: activate only mature B cellsMostly bacterial capsular polysaccharidesMainly by B-1 (CD5) cells (young children)
or marginal zone B cells (adults)
DC
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Properties of different classes of Ags that elicit Ab responses
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With co-receptor, require 102 instead of 104 mIgM for B-cell activation.
TAPA: target of an anti-proliferative Ab
(Immunoreceptor tyrosine inhibitory motifs)
(p389)B-cell responses to Ag are enhanced by co-ligation of the B-cell co-receptor
(↑ CD40 expression)
ITAM
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B cells and helper T cells must recognize epitopes of the same molecular complex in order to interactLinked recognition- same molecule- not the same epitope
Hapten + carrier
Ensure tolerance to self antigens(pages 390-391)
Cognate T cells:T cells that see same Ag and provide help to B cells.
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Protein Ags attached to polysaccharide Ags allow T cells to help polysaccharide-specific B cellsVaccine against Haemophilus influenzae type b is a conjugate of bacterial polysaccharide and the tetanus toxoid protein.
Isotype switching requires the expression of CD40L by the helper T cells → hyper-IgM immunodeficiency (HIM-1 syndrome)
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(To remove T cells)
Cell-transfer experiments demonstrating that hapten-primed and carrier-primed cells are separate populations
(1)
(2)
(3)
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When an armed helper T cell encounters an Ag-binding B cell, it becomes polarized and secretes IL-4 and other cytokines as well as the cell-associated TNF family member CD40 ligand at the point of cell-cell contact
B T CD40 and CD40LCD30L and CD3041BBL and 41BBB7-RP and ICOSICAM-1 and LFA-1
MTOC: microtubule-organizing center
(cytoskeleton)
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Armed helper T cells stimulate the proliferation and then the differentiation of Ag-binding B cells
IL-4: B-cell stimulating factor 1 (BSF-1) or B-cell growth factor 1 (BCGF-1)IL-5: B-cell growth factor 2 (BCGF-2)IL-6: B-cell stimulating factor 2 (BSF-2) or B-cell differentiation factor 1 (BCDF)
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Different cytokines induce switching to different isotypes
Isotype switching requires the expression of CD40L by the helper T cells → hyper-IgM immunodeficiency (HIM-1 syndrome)TI-2 responses might induce IgG, when use signals through BAFF (B-cell-activating factor of the TNF family) on M and DCs.
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Isotype switching is preceded by transcriptional activation of heavy-chain C-region genes
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Meeting of Ag-binding B and T cells at the border between the T-cell and B-cell zones in the spleen
CCR 7+
CCR7+
(also called as marginal sinus bridging channels)
表現 CXCR5
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Plasma cells secrete Ab at a high rate but can no longer respond to Ag or helper T cells
(condensed chromatinprominent perinuclear Golgi apparatus)
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Opsonized Ags are captured and preserved by subcapsular sinus (SCS) macrophages
(FDC)
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Second phase of the primary B-cell immune response -activated B cells form germinal centers in lymphoid follicles
CCL19 and CCL21 to CCR7 on B cells
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Germinal centers are sites of intense cell proliferation and cell death
Green: Ki67 stained proliferating cells Red: FDC staining
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(immune-complex coating)
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*basal
apical
IL-1 + CD 23
large sizeexpanded cytoplasmdiffuse chromatinno surface Ig
small sizenon-dividingwith surface Ig
(secrete CXCL13 to CXCR5 on B cells)
CXCR4+ or CXCR5+
no CXCR4
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The structure of germinal centers
and CXCR5+
Proliferation(6-8 hrs each time, 3-4 times/day) mutation (1/103) selection
Affinity maturation
Cyclic reentry model (p399)
Remember AID?(p179-186)
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Activated B cells undergo rounds of mutation and selection for higher-affinity mutants in the germinal center, resulting in high-affinity Ab-secreting plasma cells and high-affinity memory B cells
BLIMP-1 (B-lymphocyte-induced maturation protein 1): an important regulatory protein that switches off genes required for B-cell proliferation and class switch in the GC. It also induces the formation of plasma cells, including CXCR5 and ↑CXCR4 and 4:1 integrins.
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Immune complexes bind to the surface of follicular dendritic cells
iccosomes: Immune complex-coated bodies
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Immune complexes bound to follicular dendritic cells form iccosomes, which are released and can be taken up by B cells in the germinal center
iccosomes: Immune complex-coated bodiesSource:live pathogensor vaccine Ags + adjuvant bind
taken up
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(self-Ag)
clonal anergy
Metallothionine promoterZinc control the expression
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(self-Ag)
clonal deletion
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The distribution and functions of Ig isotypes
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Each human Ig isotope has specialized functions and a unique distribution
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Transcytosis of IgA Ab across epithelia is mediated by the poly-Ig receptor
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FcRn binds to the Fc portion of IgG
FcRn: similar to MHC Ian IgG transport protein in placentabinds to IgG at C2/C3 2 FcRn for 1 IgG- also maintain the IgG level in plasma
FcRn IgG
2 : 1
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Ig isotypes are selectively distributed in the body
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Neutralization of toxin by IgG Abs protects cells from their damaging action
toxinbinding
Toxoids: modified toxins, lack of toxic activity but retain the receptor–binding sitePassive immunization: anti snake venom (antivenins)
IVIG (intravenous immune globulin)1018 molecules (107 different specificities)200-400 mg/Kg
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Viral infection of cells can be blocked by neutralizing Abs
Anti-hemagglutinin of influenza virus
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Abs can prevent the attachment of bacteria to cell surface
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The classical pathwayof C’ activation is initiated by the binding of C1q to Ab on a surface such as a bacterial surface
Ag bound
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Erythrocyte CR1 helps to clear immune complexes from the circulation
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The destruction of Ab-coated pathogens via Fc receptors
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Distinct receptors for the Fc region of the different Ig isotypes are expressed on different accessory cells
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Bound Ab is distinguishable from free Ig by its state of aggregation
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Fc and C’ receptors on phagocytes trigger the uptake and degradation of Ag-coated bacteria
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Ab-coated target cells can be killed by NK cells in Ab-dependent cell-mediated cyotoxicity (ADCC)
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IgE Ab-cross-linking on mast-cell surface leads to a rapid release of inflammatory mediators
Mast cells: important for the resistance to parasite infection.The accumulation of mast cells In the intestine, known as mastocytosis with helminth infection.