23 february, 2006
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Hyper IgM Syndrome
CD40L deficiency (on X chromosome, X-linked).
Patients do not have IgG, IgA. IgG is needed for opsonize capsulated bacteria. These patients are susceptible to infection by encapsulated bacteria.They can make IgM through TI-antigens.
They also have defect in cell-mediated immunity, which involves T cell activation of M.They also suffer from opportunistic infections (bacteria, virus, fungi that normally do notcause disease).
Missing in patients
Class switch to IgG, IgAMutation (cannot happen in patients)
IgM (not affected)
Defects in B cell activationAnd germinal center formation.
Defect is in T cell.
Hyper-IgM Syndrome
Activation-Induced Deaminase (AID) DeficiencyUDG deficiency
Patients are susceptible to bacterial infection, but not opportunistic infection.They have normal T cell function. The defect is limited to B cells.
B cells are activated and germinal centers are formed. But no class switchingand somatic hypermutation take place.
V(D)J 3 1 2b 2a
Germline transcription Germline transcription AID
V(D)J 3 1 2b 2a
C U C UCleavage at U (UDG, etc)
Class switch recombination
C U
Somatic hypermutation
Immune Response to Extracellular Bacteria
Extracellular Bacteria, toxin
complement NeutrophilsMacrophages
Lysis
APCsDendritic cells
CD4 T cell
TH2
B cell
B cell activation
antibodies
Neutralization
Complementactivation
Opsonizationfor phagocytosis
phagocytosis
inflammation Humoral immunity
Complements, phagocytosis, and antibodiesare critical immune effector functions to extracellular bacteria and toxins.
Immune response to intracellular bacteria
bacteria
complement phagocytes
neutrophils macrophages
Killing of bacteriaIntracellular bacteria can Survive in macrophage
Neutrophils
High bactericidal activity
Short-lived
Intracellular bacteria cannot establishInfection within neutrophils
inflammation
macrophage
Bactericidal activityDepends on activation status
Long-lived
Intracellular bacteria can establishInfection within macrophage
Many intracellular bacteria interfere with phagosome maturation
Phagocytosis
phagosomeH+
Vacuolar ATPaseProton pump acidifiesphagosome
pH<5.5
ROIRNI
lysosome
Lysosomal enzymes
phagolysosome
Mycobacterim tuberculosis exclude proton pump.Produce NH4+ to neutralize pH.
M. Tuberculosis expresses iron binding proteins such as siderophore to obtain iron
Many intracellular bacteria produce superoxide dismutase and catalase that detoxify ROI.
M leprae produces ROI scavenger. S. enterica exclude NADPH oxidase from the Phagosomal membrane and interfere with the release of ROI into the phagosome.
Listeria monocytogenes (listeriosis)Produces cytolysin to escape into the cytosol
Immune response to intracellular bacteria
Mycobacterium leprae: Leprosy, macrophage, Schwan cells, Nasopharyngeal mucosa
Listeria monocytogenes: Listeriosis, macrophage, hepatocytes
Rickettsia rickettsii: Rocky Mountain Spotted fever, endothelial cells, blood (tick bite)
Rickettsia typhi: Typhus, endothelial cells, blood (flea bite)
Intracellular bacteria may also infect nonphagocytic cells through receptor-mediated entry.These cells have little anti-bacterial activities and serve as hapitat.
Intracellular bacteria is not accessible to antibodies.Effective immune response require activation of Macrophage and eliminate infected cells.
Activation to increaseAnti-bacteria activity
Cell death
Accessible to immune attack
Natural Killer (NK) cells
Hematopoietic stem cell(HSC)
Myeloid pregenitor
Granulocyte-monocyte progenitor
monocyte
Bone marrow
Neutrophil1-6% 50-70%
Blood
Lymphoid progenitor
B cell progenitor
B cell
T cell progenitor
T cell
thymus
Lymphocyte (20-40%)
macrophage
Tissue
NK cell
Large granular lymphocytes(LGL)
(5-10%lymphocyte)
NK cells produce interferon (IFN-), whichactivates anti-bacterial activity of M.
NK cells can be activated by cytokines produced by Macrophages and dendritic cells.
bacteria
Macrophages
Dendritic cells
IL-12IL-18TNF-
NK cells IFN-
IFN activates the production of ROI (NAPDH oxidase) and RNI (iNOS, inducible nitrogenOxide synthetase).
IFN stimulates antigen presentation by class I MHC.
Increases the expression of class I MHC
Increases the expression of PA28
Proteasome degrades ubiquitinated proteins.Ubiquitinated proteins
peptides
4 heptamerrings
cap
cap
The proteasome for antigen processing contains LMP2, LMP7, and LMP10.
Such proteasome preferentially cleaves peptide bonds after hydrophobic or basic residues.
Proteasome activating molecule (PA28) is inducible by interferon .
PA28 increases the release of cleaved peptides.
NK-T cells
Express both TCR and NK markers.
TCR is composed on unique chain (V14-J281) and three chains.
May recognize CD1-presented mycobacterial phospholipids.
T cells
May recognize phospho-ligands from mycobacteria.
The recognition does require MHC or CD1. May recognize the ligands directly.
NK-T cells and T cells can also produce IFN-.
Innate-like lymphocytes
bacteriaPhagocytosis
Degradationproduct
Endocytosismacropinocytosis
DCs present antigens to T cells.
Class I MHC-antigen
Class II MHC-antigen
Dendritic cells can present exogenousantigen on both class I and class II MHC.
Cross-priming
Abundant MHC and B7 for T cell activation
Activation of CD4 T cells
Naïve CD4 T cells Activated T cellsAg-DC Immature effector
T cells (TH0)
TH2 cells remain in secondary lymphoid tissues and facilitate B cell activation.TH2 cells secrete IL4, IL5, IL10, TGF-.
TH1 cells express move to sites of infection.
TH1 cells produce IFN-, IL2, which is crucial for activating macrophages.
The response is generally dominated by either TH1 or TH2.
Secondary lympoid tissues TH1
TH2
IL10 IFN-
IL12
IL4
During intracellular infection, the production of IL12 by DCs favor the differentiationof TH1 cells.
What favors the production of TH2 cells in humoral immune response?
Naïve T cells
Activated TH1 cells cease the production of L-selectinAnd stops homing to secondary lymphoid tissues.
Activated TH1 cells home to inflammation sites.
TH1 cells express new integrin VLA-4..VLA-4 binds to VCAM-1, which is induced in inflamed endothelial cells.The interaction initiates the extravation of TH1 cells into the infection site.
TH1 cells express increased levels of LFA-1 to interact with ICAM-1 on endothelial cells.
TH1 cells activate macrophage.
TH1 cells interact with the antigen-MHC II and provide activation signals
Similar to B cell activation:
IFN-
CD40L
IL4
Activated macrophage exhibit increased anti-bacterial activities.
Macrophages that are chronically infected with intracellular bacteria lose the abilityto be activated by IFN-.
TH1 cells express Fas ligand and TGF- that induce the apoptosis of these macrophages.The bacteria are released and phagocytose by new macrophages.
Activated TH1 cells secrete IL2, which facilitate the proliferation of effector T cells.
TH1 cells secrete IL3 and GM-CSF (granulocyte macrophage colony stimulatory factor),which induces the production of more neutrophils and monocytes in the bone marrow.
TH1 cells secrete TNF- and TNF-which induce inflammation in the bood vessel to recruit more phagocytes. TH1 cells secrete CCL2 to facilitate the chemotaxis of macrophage to the site of Infection.
TH1 cells induce the apoptosis of chronically infected macrophages
TH1 cell is the central coordinator of immune response to intracellular infection.
The activation of CD8 T cells produce cytotoxic TLymphocytes (CTL).
Bacteria (L. monocytogenes) can produce cytolysins to escape into the cytosol.
Bacteria (L. monocytogenes) can also enter into nonphagocytic cells (hepatocytes), and reside in the cytoplasm.
Some phagosomal bacteria (S. enterica) possess a specific secretion apparatus that translocatesproteins into the cytosol of host cells.
Antigens from bacteria that persist in the phagosome may leak into the cytosolic compartment.
Bacteria induce apoptosis of host cells. These result in the formation of vesicles Containing antigenic cargo that can be shuttled to dendritic cells for cross-priming.
In general, the bacteria that stay in the cytosol are the most potent stimulators of CD8 T cellresponse, while those in phagosomes are primarily dependent on CD4 T cell/Macrophage activation.
CD8 T cells are activated by antigens derived from the cytoplasm in the context of class I MHC.
Activation of CD8 T cells
The most important activators of CD8 T cells are DCs.Activation of CD8 T cells require more co-stimulatory activities than CD4 T cells.
TH1 cells facilitate the activation of CD8 T cellsby secreting IL2.
Activated CD8 T cells (CTL) home to inflammation sites.
CTL turns of the expression of L-selectin.CTL expresses VLA-4 and increased level of LFA-1.
CTL kills infected cells.Conjugate formation
Recognition of antigenBy TCR activates LFA-1to form more stableInteraction with ICAM.
TCR-Ag/MHC-CD8Interaction also stabilizeThe interaction.
Activated CD8 T cells interact with target cellswithout the need of B7 constimulatory signal.
CTL reorients its cytoskeleton.
The clustering of TCR signalsthe reorientation of the cytoskeleton and focus therelease of effector moleculesat the site of contact with the target cell.
Greencytoskeleton
RedLytic granules
Outer ring (red): LFA-1:ICAM
Inner ring (green): TCR-coreceptor-Ag:MHC
Immunological synapse
Similar immunological synapse forms betweenTH2 cells and B cells during B cell activation.
The formation of immunological synapse ensures delivery of effector molecules to target cells without affecting bystanders.
It also ensures high local concentration of the effector molecules.
CTL releases cytotoxins from lytic granules.(T cell-mediated cytotoxicity)
Perforin polymerizes in target-cell membranes to form transmembrane pores.
The pore can cause lysis and facilitate the entry of other cytotoxins into target cell.
Granzymes induce apoptosis of target cells.
Caspase-activatedDeoxyribonuclease(CAD) Fragmentation of nuclear DNA
Perforin releases granzyme B from Endosome vesicles
tBid induces the release cytochrome C
Granzyme B and caspase also cleaves Bid to tBid.
Granzyme B Cleaves and Activate caspase 8
Perforin pore facilitatesThe entry of granzymes
Fas ligand (CTL, TH1) induces apoptosis.
FasL is a TNFFamily of membraneassociated cytokines.
(TNF-a, CD40L)
Fas is a TNFRFamily memberTNF-R, CD40
FADD is an Adaptor protein
Clustered pro-caspase 8 Transactivate by proteolytic cleavage.
Granulysin has potent bactericidal activity.
Granulysin may be critical for the killing mycobacteria.Perforin may facilitate the entry of the protein into phagosomal bacteria.
Why aren’t CTL killed?Protective membrane proteins binds to perforin or prevent pore formation?
May disrupt membranes.
CTL also secretes IFN-to activate Macrophage.
The apoptosis of infected cells release intracellular bacteria to be eliminated by other immune functions.
Immune response to intracellular bacteria lead to the formation of granuloma.
BacteriaComplementMast cellsMacrophagesDCs
inflammation
Macrophages
CD8 T cell activation
CD4 T cell activation Th1
CTL
Activated macrophage kill bacteria within the granuloma.
Encapsulation by fibrosis (promoted by TNF) and calcification.Necrosis (promoted by TNF) leading to reduced nutrient and oxygen supply.The granuloma contains the infection.
Frequently, bacteria are not completely eradicated. They enter into a dormant form.
NK, NK-T, T cells
Neutrophils
granuloma
The predominant cellis macrophage.
MP can be inactivated by bacterial components. Some of these factors can Induce the maturation of immature monocytes into epithelioid cells and multinucleatedGiant cells.
Mycobacterium leprae (leprosy)
Lepromatous leprosy: TH2 response (IL4, IL5, IL10)Cell-mediated immunity is depressed and M. leprae infected cells are abundant. Bacteria are widely disseminated.
Tuberculoid leprosy:TH1 response (IL2, IFN-, TNF)Cell-mediated immunity with macrophage activation controls the infection. Infection is contained within granuloma with local damage.
TH1 mediated immune response is critical for controlling intracellular bacteria.
Relevant parts in book
CTL: page 319-329
Chronic inflammation: page 352
TH1/TH2: page 288-291
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