Hyper IgM Syndrome

1
Hyper IgM Syndrome
CD40L deficiency (on X chromosome, X-linked).
Defect is in T cell.
Defects in B cell activation And germinal center
formation.
Missing in patients
IgM (not affected)
Class switch to IgG, IgA Mutation (cannot happen
in patients)
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 not cause disease).
2
Hyper-IgM Syndrome
Activation-Induced Deaminase (AID) Deficiency UDG
deficiency
V(D)J
?2a
??
?3
?1
?2b
??
?
?
Germline transcription
Germline transcription
AID
V(D)J
?2a
??
?3
?1
?2b
??
?
?
C
U
C
U
Cleavage at U (UDG, etc)
Somatic hypermutation
Class switch recombination
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 switching and
somatic hypermutation take place.
3
Immune Response to Extracellular Bacteria
Extracellular Bacteria, toxin
Humoral immunity
inflammation
APCs Dendritic cells
Neutrophils Macrophages
B cell
complement
Lysis
CD4 T cell
phagocytosis
B cell activation
TH2
antibodies
Complements, phagocytosis, and antibodies are
critical immune effector functions to
extracellular bacteria and toxins.
Neutralization
Opsonization for phagocytosis
Complement activation
4
Immune response to intracellular bacteria
bacteria
inflammation
phagocytes
complement
macrophages
neutrophils
Intracellular bacteria can Survive in macrophage
Killing of bacteria
Bactericidal activity Depends on activation status
High bactericidal activity
Neutrophils
macrophage
Short-lived
Long-lived
Intracellular bacteria cannot establish Infection
within neutrophils
Intracellular bacteria can establish Infection
within macrophage
5
Many intracellular bacteria interfere with
phagosome maturation
Phagocytosis
Vacuolar ATPase Proton pump acidifies phagosome
pHlt5.5
H
phagosome
lysosome
ROI RNI
phagolysosome
Lysosomal enzymes
6
Immune response to intracellular bacteria
Intracellular bacteria may also infect
nonphagocytic cells through receptor-mediated
entry. These cells have little anti-bacterial
activities and serve as hapitat.
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)
7
Intracellular bacteria is not accessible to
antibodies. Effective immune response require
activation of Macrophage and eliminate infected
cells.
Activation to increase Anti-bacteria activity
Cell death
Accessible to immune attack
8
Natural Killer (NK) cells
Bone marrow
Hematopoietic stem cell (HSC)
Lymphoid progenitor
Large granular lymphocytes (LGL)
Myeloid pregenitor
thymus
B cell progenitor
T cell progenitor
Granulocyte-monocyte progenitor
Blood
(5-10 lymphocyte)
monocyte
B cell
Neutrophil
NK cell
T cell
1-6
50-70
Lymphocyte (20-40)
Tissue
macrophage
9
NK cells produce interferon ? (IFN-?),
which activates anti-bacterial activity of M?.
NK cells can be activated by cytokines produced
by Macrophages and dendritic cells.
Macrophages
IL-12 IL-18 TNF-?
bacteria
NK cells
IFN-?
Dendritic cells
IFN? activates the production of ROI (NAPDH
oxidase) and RNI (iNOS, inducible nitrogen Oxide
synthetase).
Increases the expression of PA28
IFN? stimulates antigen presentation by class I
MHC.
Increases the expression of class I MHC
10
Proteasome degrades ubiquitinated proteins.
Ubiquitinated proteins
The proteasome for antigen processing contains
LMP2, LMP7, and LMP10.
cap
Such proteasome preferentially cleaves peptide
bonds after hydrophobic or basic residues.
4 heptamer rings
cap
Proteasome activating molecule (PA28) is
inducible by interferon ?.
PA28 increases the release of cleaved peptides.
peptides
11
NK-T cells and ?? T cells can also produce IFN-?.
Innate-like lymphocytes
NK-T cells Express both TCR and NK
markers. TCR is composed on unique ? chain
(V?14-J?281) 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.
12
DCs present antigens to T cells.
Class I MHC-antigen
Class II MHC-antigen
Phagocytosis
bacteria
Cross-priming
Dendritic cells can present exogenous antigen on
both class I and class II MHC.
Endocytosis macropinocytosis
Degradation product
Abundant MHC and B7 for T cell activation
13
Activation of CD4 T cells
Secondary lympoid tissues
TH1
IL12
Ag-DC
Immature effector T cells (TH0)
Naïve CD4 T cells
Activated T cells
TH2
IL4
During intracellular infection, the production of
IL12 by DCs favor the differentiation of TH1
cells.
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.
IFN-?
IL10
TH2 cells remain in secondary lymphoid tissues
and facilitate B cell activation. TH2 cells
secrete IL4, IL5, IL10, TGF-?.
What favors the production of TH2 cells in
humoral immune response?
14
Activated TH1 cells cease the production of
L-selectin And stops homing to secondary lymphoid
tissues.
Naïve T cells
15
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.
16
TH1 cells activate macrophage.
IFN-?
TH1 cells interact with the antigen-MHC II and
provide activation signals
CD40L
Similar to B cell activation
Activated macrophage exhibit increased
anti-bacterial activities.
17
TH1 cell is the central coordinator of immune
response to intracellular infection.
TH1 cells induce the apoptosis of chronically
infected macrophages
Macrophages that are chronically infected with
intracellular bacteria lose the ability to 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.
18
The activation of CD8 T cells produce cytotoxic
T Lymphocytes (CTL).
CD8 T cells are activated by antigens derived
from the cytoplasm in the context of class I MHC.
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 translocates proteins 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
cell response, while those in phagosomes are
primarily dependent on CD4 T cell/Macrophage
activation.
19
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
cells by secreting IL2.
20
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.
21
CTL kills infected cells.
Conjugate formation
Recognition of antigen By TCR activates LFA-1 to
form more stable Interaction with
ICAM. TCR-Ag/MHC-CD8 Interaction also
stabilize The interaction.
Activated CD8 T cells interact with target
cells without the need of B7 constimulatory
signal.
22
CTL reorients its cytoskeleton.
The clustering of TCR signals the reorientation
of the cytoskeleton and focus the release of
effector molecules at the site of contact with
the target cell.
Green cytoskeleton
Red Lytic granules
Immunological synapse
Outer ring (red) LFA-1ICAM
Inner ring (green) TCR-coreceptor-AgMHC
23
Similar immunological synapse forms between TH2
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.
24
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.
25
Granzymes induce apoptosis of target cells.
Granzyme B Cleaves and Activate caspase 8
26
Fas ligand (CTL, TH1) induces apoptosis.
FasL is a TNF Family of membrane associated
cytokines.
FADD is an Adaptor protein
Clustered pro-caspase 8 Transactivate by
proteolytic cleavage.
(TNF-a, CD40L)
Fas is a TNFR Family member TNF-?R, CD40
27
Granulysin has potent bactericidal activity.
May disrupt membranes.
Granulysin may be critical for the killing
mycobacteria. Perforin may facilitate the entry
of the protein into phagosomal bacteria.
CTL also secretes IFN-??to activate Macrophage.
The apoptosis of infected cells release
intracellular bacteria to be eliminated by other
immune functions.
Why arent CTL killed?
Protective membrane proteins binds to perforin or
prevent pore formation?
28
Immune response to intracellular bacteria lead to
the formation of granuloma.
Neutrophils
Macrophages
Complement Mast cells Macrophages DCs
Bacteria
inflammation
NK, NK-T, ?? T cells
granuloma
The predominant cell is macrophage.
CD4 T cell activation
Th1
CD8 T cell activation
CTL
Activated macrophage kill bacteria within the
granuloma.
MP can be inactivated by bacterial components.
Some of these factors can Induce the maturation
of immature monocytes into epithelioid cells and
multinucleated Giant cells.
Frequently, bacteria are not completely
eradicated. They enter into a dormant form.
Encapsulation by fibrosis (promoted by TNF) and
calcification. Necrosis (promoted by TNF) leading
to reduced nutrient and oxygen supply. The
granuloma contains the infection.
29
TH1 mediated immune response is critical for
controlling intracellular bacteria.
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.
30
Relevant parts in book
CTL page 319-329
TH1/TH2 page 288-291
Chronic inflammation page 352