Objectives and Vocabulary for Week # 12 Flashcards
Affinity Maturation
The process by which B cells produce antibodies with a greater specificity for the antigen in question; T-dependent humoral process; the result of somatic mutation Ig genes;
T-dependent antigens
Antigens that must be uptaken by specific B cells, processed into peptides, and presented to CD4+ helper T lymphocytes, which then activate B cells.
Tfh
Follicular helper T cells. Responsible for generating germinal centers, where several aspects of T-dependent humoral immune responses occur.
T Independent Antigens
multivalent non-protein antigens with repeating determinants, such as polysaccharides, some lipids, and nucleic acids that do not require antigen specific helper T lymphocytes (only need the B cell receptor and other receptors on the B cells)
CXCL13
chemokine secreted by follicular dendritic cells; binds to CXCR5 the chemokine receptor on recirculating naive B cells
CXCR5
the chemokine receptor on recirculating naive B cells. Attracted to lymphoid follicles by CXCL13.
TLRs present on B cells.
TLR 5 (recognizes bacterial flagelin) TLR 7 (recognizes ssRNA, endosomal); TLR 9 ( recognizes unmethylated CpG rich DNA in endosomes)
Initial activation and migration of helper T cells and B cells (T-dependent activation)
1) Both naive B cell and T cell recognize the same antigen and are activated 2) Helper T cells down-regulate CCR7 and increase the expression of CXCR5 to leave the T cell zone and migrate toward the follicle; CXCL13 is the ligand for CXCR5 3) B cells respond by down-regulating CXCR5 and upregulates CCR7. Causing the migration from the follicle to the T cell zone CCL19 and CCL21 are the ligands for CCR7. Also, B cells express CD69, which causes retention in the lymph node. (This ensures attraction to each other). 4) T cell recognizes the antigen in the context of MHC II on the surface of the B cell. 5) T cell upregulates CD40L, interacts with CD40 (expressed always) on the surface of the B cells, leading to B cell interaction. 6) Subsequent activation of B cells either occurs with an extrafollicular focus or in the germinal centers of follicles.
How is the germinal center created?
Develops 4-7 days after the initiation of a T-dependent B cell response. The germinal center is generated by Activated B cells, that travel from the extrafollicular zone back into the the follicle and proliferate
Germinal Center reaction
The characteristic evens of helper T cell-dependent antibody responses, including affinity maturation, isotype switching , and generation of long-lived plasma cells and memory B cells, occur primarily in organized structures call germinal centers, that are created during T-dependent immune reactions.
FDCs
Follicular Dendritic Cells; not bone marrow derived; do not express MHC II; express CR1, CR2, and CR3 and Fc receptors; only present in follicles; display antigens for the selection of germinal center b cells.
Tfh
T- Follicular helper Cells; generated 4-7 days after antigen exposure; antigen specific B cells induce the differentiation of T cells to Tfh cells; have high levels of CXCR5, ICOS, PD-1, IL-21 (defining chemokine), and BCL-6.
Tfh differentiation
1) activation by DCs 2) Activation by B cells; Strong TCR recognition of antigen leads to expression of Bcl-6 and reduced expression of IL-2R, which causes the inability of the CD4+ cell to differentiate into Th1,2, or 17; ICOS on the surface of the T cell reacts with ICOSL on the surface of the activated B cell is the final straw.
P.251
figure 12-12
IgG
Induced by IFNg (IFNg induces IgG1 and IgG3) ; Fights against intracellular bacteria and viruses; block entry of microbes into host cells and promote phagocytosis by macrophages opsonization; complement activation; neonatal immunity Th1 subset related
IgE
induced by IL-4 (IL-4 induces IgE and IgG4); fights against helminthic parasites; eosinophil/mast cell elimination of helminths; also plays a role in allergies; Th2 subset related
IgM
Complement activation
IgA
induced by mucosal tissues; cytokines, TGF-B, APRIL, BAFF etc); mucosal immunity; transported through epithelia and mucosal secretions;
AID
Activation induced deaminase; The key enzyme required for isotype switching; activated by CD40 signals from Tfh cells; deaminates cytosines in single stranded DNA; C->U; UNG removes uracil residues; APE I endo nuclease creates nicks in DNA;
Somatic hypermutation of Ig genes
Occurs in the dark region of the germinal center; mutations occur in the Ig V genes; occurs 1000 time faster than mutations in other cell types; AID plays a role. It can cause the exchange of U’s for T’s leading to mutations. UNG can also cause mutations by excising U’s, which are then replaced by error repair mechanisms.
What degree of affinity does a B cell need in order to survive post somatic hypermutation?
B cells that recognize antigen, on FDCs, with high affinity survive. These cells bind antigen and present them to Tfh cells.
B cell Survival signals
1) antigen recognition causes production of anti-apoptotic proteins of the Bcl-2 family 2) high affinity B cells uptake and present antigen, interact with CD40L on the surface of Tfh cells, causing the production of survival signals.
T-independent response
the production of antibodies without the help of helper T cells; antigens are non-proteins (LPS, lipids, glycolipids, nucleic acids, etc.); antibodies are typically IgM and are generally low affinity antibodies.
Which type of B cells utilize T-independent responses?
Marginal zone B cells and B-1 b cells.
Where are IgM and IgG located?
Plasma
Where is IgE located?
beneath epithelial surfaces
Which immunoglobulin classes are located in the extracellular space?
IgG and monomeric IgA
Which immunoglobulin class is secreted across epithelial surfaces? Beneath?
1) Dimeric IgA 2) IgE
Which immunoglobulin never gets secreted
IgD; no effector functions
Which Ig classes are important in maternal transfer?
IgG1 and IgG3
Which Ig classes are important for the induction of complement?
IgM, IgG1, and IgG3
Which Ig class is important in opsonization.
IgG1
Which Ig activates mast cells to secrete granules?
IgE
FcgR1, What immunoglobulin classes is it specific for?
present on the surface of macrophages neutrophils, mast cells, etc,Binds to the Fc portion of the antibody, induces phagocytosis, IgG1 and IgG4
FcgRIII
Binds IgG bound to cell surface antigens, FcGRIII on NK cell signals the release of GrB (granzymes) and Perforin.
Classical pathway of Complement
IgM and IgG can bind complement; only when bound to antigen pathogen surface; soluble antibodies do not bind
Which immunoglobulins are important for the neutralization of viruses and bacterial toxins
IgG and IgA
Antibody dependent cellular cytotoxicity
ADCC; mediated by NK cells, release GrB and Perforin, NK cells have FcgRIII receptors that are responsible for recognizing Fc regions of antibodies.
What are the three functions of the complement pathway?
Opsonization, chemoattraction/inflammation, killing
What are the three pathways of complement activation?
Classical, lectin, and alternative pathways.
Classical pathway
Adaptive immunity; antbody binds directly to the microbial surface (IgG or IgM the initiating protein)
Alternative Pathway
Innate immunity; Requires Complement binds directly to the microbial surface
Lectin pathway
Innate immunity; MBL binds directly on the pathogen’s surface.
C3a
Complement protein responsible for inflammation
C3b
complement protein responsible for opsonization and phagocytosis
C5a
Complement protein responsible for inflammation
Complement Reaction Sequence by number
C1, 4, 2, 3, 5, 6, 7, 8 , 9
Classical Pathway Process
1) Antibody/Antigen interaction 2) C1 complex binds to IgG/M Fc portion 3) C4 binds to C1 cleaving C4 by C1r2s2 enzyme also cleaves C2
C3 convertase
C4b and 2a, which were formed by enzymatic cleavage by C1r2s2
Lectin Pathway Process
1) MBL binds to mannose or carbohydrates 2) MASP1 and MASP2 cleave C4 and C2.
MBL and MASP-2 deficiency
Leads to increased infections in early childhood.
How is the alternative pathway initiated?
It is initiated by the hydrolysis of C3; spontaneous; C3b must quickly bind to microbial surface, or it is inactivated
What kind of C3 convertase does the alternative pathway use?
C3bBb, still works to bring C5 to the surface.
Factor I
Complement cascade regulatory protein; deficiency leads to an inability to stop complement cascades; cleaves C3b and C4b.
MAC
Membrane Attack Complex; C5 convertase is cleaved; C6, C7, and C8 are recruited. C9 molecules are put together to form the pore in a pathogens cell wall. pore allows for the entry of enzymes, water and solutes.
How important is the MAC?
Only important for defense against a few pathogens; especially Neisseria; C3b however is incredibly important for other stages in host defense, opsonization C9 not that important, C3 is.
Where do complement proteins come from?
Complement proteins circulate in the plasma, and are only activated when cleaved.
