Antibodies and B cell-mediated Immunity (Chp 9)

Sections 9-1,2,3,4,11,12,13,14,15,16,17,19,21,22,23

A mature naive B cell that initiate the primary B-cell response have surface ____ as the antigen-binding component of their B-cell receptors.

IgM

B-cell receptors becomes physically _______ to each other, which draws them together at a localized area of B-cell contact with the microbe.

cross-linked

_____ and _____of B-cell receptors sends signals from the receptor complex to the inside of the cell

Clustering; aggregation

In many ways, signal transduction from the B-cell receptor complex _____ that from the T-cell receptor complex

resembles

Both B-cell and T-cell receptors are associated with cytoplasmic _______ _______ that are activated by receptor clustering and give rise to similar pathways of signal transduction.

tyrosine kinases (Blk, Fyn, Lyn)

The signaling components of the B-cell receptor:

Igalpha and Igbeta

Interactions of antigen with surface immunoglobulin are communicated to _____.

the interior of the B cell by IgAlpha and IgBeta.

Tyrosine kinases phosphorylates the ____ of IgAlpha and IgBeta.

ITAMs (Immunoreceptor Tyrosine Activation Motifs)

The phosphorylation of ITAMS allows another tyrosine kinase, Syk, to ______.

bind to the phosphorylated ITAMS on the IgBeta tails.

The cumulative effect of Syk molecules bound to the clustered B-cell receptors is to ____

Initiate a pathway of intracellular signaling that leads to changes in gene expression in B cells.

Cross-linking of the B-cell receptor by antigen generates a signal that is necessary, but ______

not sufficient to activate a naive B cell

The b-cell co-receptor three proteins:

CR2, CD19, CD81.

CD2 function

The receptor for complement fragments IC3b and C3d fixed on pathogen surfaces.

CD19 function

The signaling component of the co-receptor.

CD81 function

Binds to CD19 and brings it to the B-cell surface.

CR1 function

CR1 binds to its ligand, C3b, which facilitates its cleavage generating an unstable iC3b and stable C3d fragments.

The main role of CR1 mechanism

CR1 increases the abundance of ligands for the B-cell co receptor at the pathogen’s surface.

When the B-cell receptor binds to its specific antigen on the pathogen, the CR2 component of the B-cell co-receptor binds to a nearby C3d fragment, bringing _____

the B-cell receptor and co-receptor close together.

After CR2 brings B-cell receptor and co-receptor close together, the tyrosine kinase, Lyn, phosphorylates the ______.

cytoplasmic tail of CD19.

Interaction of phosphorylated CD19 with intracellular signaling components generates _____.

signals that synergize with those coming from the B-cell receptor.

Simultaneous ligation of the B-cell receptor and co-receptor increases the overall signal by 1000- to 10,000- fold, greatly _____

increasing the B cell’s sensitivity to antigen.

The importance of B-cell receptor and co-receptor is illustrated by people with a immunodeficiency who lack ______ because of their defective genes for CD19 and CD81.

the B-cell co-receptor

Thymus-independent antigens (TI antigens)

Antigens that are efficient enough to activate B-1 cells without the help from T cells.

The antigens that recognize IgM antibodies from B cells causes extensive cross linking of B-cell receptors, leading to _____.

clustering of numerous B-cell receptors and co-receptors, causing B-1 cells to be activated.

The B cells that respond to TI antigens are predominantly of the ______ lineage.

B-1

Follicular dendritic cells (FDCs)

The primary follicles of secondary lymphoid tissues that are critical for the maturation and survival of B cells.

A major purpose of FDCs is to ___.

Serve as a vast depository of intact antigens and present them to circulating B cell antigen receptors.

First feature of FDCs for function:

The extensive surface area of dendrites allow them to store large quantities of antigens.

Second feature of FDCs for function:

They lack phagocytic activity, which preserves intact antigens on the cell surface over a period of months to years.

The ingestion of small amounts of extracellular fluid is called ______.

Pinocytosis

FcRn

A receptor that protects IgG from pinocytosis, extending its half-life in the circulation and maintaining a high level of IgG in the extracellular fluids of connective tissues. Structurally similar to MHC class 1.

polymeric immunoglobulin receptor (poly-Ig receptor)

A receptor that plays a crucial role in the transport dimeric IgA and pentameric IgM, across epithelial cells, facilitating their secretion into mucosal surfaces.

Receptor-medicated transport of a macromolecule from one of a cell to the other is called _______.

Transcytosis

secretory component

the fragment of the poly-Ig receptor that is left attached to dimeric IgA that has been secreted across a mucosal epithelium.

The carbohydrate of the secretory piece is bound by glycoproteins in the mucus called

mucins.

By this mechanism, transcytosed IgA dimers and IgM pentamers are

retained at the mucosal surface, where they bind to microorganisms and facilitate expulsion.

FcεRI, or the high-affinity IgE receptor

A receptor present on the surface of mast cells, basophils, and activated eosinophils that binds free IgE with very high affinity. This receptor plays a key role in allergic responses.

When a pathogen binds to the IgE on mast-cell surface and cross-links FcεRI, the cell secretes mediators that activate smooth muscles, causing ….

violent reactions such as sneezing, coughing, vomiting, and diarrhea that forcibly eject pathogens from the respiratory and gastrointestinal tracts.

the cytoplasm of a resting mast cell is filled with large granules containing _____ and _____ .

histamine; inflammatory mediators

Mast cells are activated by antigen when the antigen cross-links two complexes of ____ and ____ at the mast-cell surface.

IgE and FcεRI

Having prepackaged granules and high-affinity FcεRI receptors loaded with IgE guarantees that the mast cell’s response to antigen is _____.

impressively fast

What anatomical sites are antibody classes are found enriched in?

A mother’s milk contains dimeric IgA, which contains antibodies against all the microorganisms to which the mother has made an IgA response. The antibodies are secreted into the gut of infants, providing immune protection.

High-affinity antibodies that bind to the microbial ligand and prevent the microbe’s attachment to human epithelium stop the infection before it can start are called ____.

neutralizing antibodies.

Neutralizing antibodies that develop during primary immune responses to influenza and other viruses are the most important aspect of subsequent immunity to these viruses. Such antibodies coat the virus ___

inhibiting its attachment to human cells, and thereby prevent infection.

Disease-causing bacterial infections at mucosal surfaces are ___

prevented by neutralizing antibodies by coating the bacteria and impairing protein F to bind to cilia or attach to the fibronectin in the extracellular matrix, keeping the bacterial population down.

High-affinity IgG and IgA antibodies neutralize microbial toxins and animal venoms by

Covering up the toxins binding site, thus preventing its attachment to human cells.

Binding of IgM to antigen on a pathogen’s surface activates complement by the classical pathway by…

complement activation. IgM adopts the “staple” form and its Fc region can attach to C1q. C1 then becomes activated then cleaves C2 and C4 to form C2a and C4b fragments. Those fragments form C3 convertase on the pathogen surface. C3 converts to C3b and C3b attaches to the pathogen surface and recruits neutrophil or macrophage and is efficiently phagocytosed.

Complement activation by IgG requires the participation of?

C1q to cross-link two or more IgG molecules, leading to the activation of the complement cascade.

Because the antigen-binding sites of IgG generally have higher affinity for antigen than those of IgM, they can form stable _____ with soluble multivalent antigens.

immune complexes

Erythrocytes (red blood cell) facilitate removal of immune complexes from the circulation by …

expressing the complement receptor CR1. Majority of them do and by this, tissue macrophages remove and degrade the immune complexes (antigen-antibody complex).

Fcγ receptors enable effector cells to bind IgG and be activated by IgG bound to pathogens because

The activating receptor FcγRI are specific to IgG and is constitutively expressed by monocytes, macrophages, and dendritic cells. At infected tissues, its expression is also induced in neutrophils and eosinophils.

The major function of FcγRI is

to facilitate the uptake and degradation of pathogens by phagocytes and professional antigen-presenting cells.

Antibody binds to bacterium. Antibody-coated bacterium binds Fc receptors on cell surface. Macrophage membrane surrounds bacterium and triggers ____

the uptake and breakdown of antibody-coated pathogens.

As an effector mechanism of adaptive immunity, antibody-mediated opsonization ____

enhances the phagocytic mechanisms of innate immunity by increasing the speed at which pathogens are detected and devoured.

Of the three FcγRII receptors, one is activation and two are inhibitory. FcγRIIA is an _____.

activating receptor that promotes the uptake and destruction of pathogens by a wife range of myeloid cells.

FcγRIIB2 and FcγRIIB1 are ____ receptors.

Inhibitory receptors. B2 are expressed on macrophages, neutrophils, and eosinophils and controls their inflammatory responses. B1 has a similar role in mast cells and B cells.

FcγRIIB1 and FcγRIIB2 receptors have _____.

immunoreceptor tyrosine-based inhibitory motifs (ITIMs), in their cytoplasmic tails, which associate with intracellular proteins to develop inhibitor signals.

FcγRIII is the only Fc receptor expressed by ____ cells.

NK cells. They recognize and kill human cells that have been coated with IgG1 or IgG3 antibodies that recognize cell-surface components.

Antibody-dependent cell-mediated cytotoxicity (ADCC)

the killing of antibody-coated target cells by NK cells having the receptor FcγRIII, which binds to the Fc region of IgG antibodies.

When the therapeutic antibody, anti-CD20, bind to CD20 antigen on tumor cells, the FcγRIII receptors on the NK cell bind to the Fc regions of the cell-bound IgG. Cross-linked Fc receptors signal NK cell to _____.

kill the tumor cell.