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.

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

but naive

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Self Ags-binding in the BM can lead to the death of immature B cells

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

(TI-1) (TI-2)

(mitogen, 裂殖素)

(cytokines)

TI-1 Ags are polyclonal B cell activators at high concentrations, whereas at low concentrations they induce an Ag-specific Ab response

as mitogen

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

Properties of different classes of Ags that elicit Ab responses

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

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.

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)

(To remove T cells)

Cell-transfer experiments demonstrating that hapten-primed and carrier-primed cells are separate populations

(1)

(2)

(3)

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)

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)

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.

Isotype switching is preceded by transcriptional activation of heavy-chain C-region genes

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

Plasma cells secrete Ab at a high rate but can no longer respond to Ag or helper T cells

(condensed chromatinprominent perinuclear Golgi apparatus)

Opsonized Ags are captured and preserved by subcapsular sinus (SCS) macrophages

(FDC)

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

Germinal centers are sites of intense cell proliferation and cell death

Green: Ki67 stained proliferating cells Red: FDC staining

*

(immune-complex coating)

*

*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

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)

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.

Immune complexes bind to the surface of follicular dendritic cells

iccosomes: Immune complex-coated bodies

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

(self-Ag)

clonal anergy

Metallothionine promoterZinc control the expression

(self-Ag)

clonal deletion

The distribution and functions of Ig isotypes

Each human Ig isotope has specialized functions and a unique distribution

Transcytosis of IgA Ab across epithelia is mediated by the poly-Ig receptor

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

Ig isotypes are selectively distributed in the body

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

Viral infection of cells can be blocked by neutralizing Abs

Anti-hemagglutinin of influenza virus

Abs can prevent the attachment of bacteria to cell surface

The classical pathwayof C’ activation is initiated by the binding of C1q to Ab on a surface such as a bacterial surface

Ag bound

Erythrocyte CR1 helps to clear immune complexes from the circulation

The destruction of Ab-coated pathogens via Fc receptors

Distinct receptors for the Fc region of the different Ig isotypes are expressed on different accessory cells

Bound Ab is distinguishable from free Ig by its state of aggregation

Fc and C’ receptors on phagocytes trigger the uptake and degradation of Ag-coated bacteria

Ab-coated target cells can be killed by NK cells in Ab-dependent cell-mediated cyotoxicity (ADCC)

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.