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Tolerance
Specific negative immunity
Not the same as immunosuppression, which is non-specific
3 Tolerance mechanisms:
Clonal deletion: Loss of certain Ag-specific cells
Occurs in primary lympoid tissues
Clonal anergy: clone is present, but unable to respond
May be slowly reversible
Clonal suppression:
Response re-appears if suppression is removed
Clonal Deletion (negative selection)
For T cells, occurs in thymus
Irreversible loss of activity, since Ag-reactive cells are gone
Negative selection can be studied observing Vb17 T cell receptor model
Vb17 is never expressed on peripheral T cells in mice that have MHC II IE
Vb17 is expressed on cortical thymocytes
Lost on mature thymocytes due to negative selection
Cell Population:
Immature thymos (CD4 + 8+ )
Mature thymos
(CD4+)
(CD8+)
Periph T cells
% cells with V b17a:
SJL (IE -)
B10.BR (IE +)
2.9
2.6
2.4
0.4
13.9
0.06
0.01
0.09
Thymocytes expressing TCRs bearing Vb17 bind too strongly to a conserved region
of IEa or IEb. This causes inappropriate signaling, and cells are deleted
Where does negative selection occur?
Positive selection occurs on thymic epithelium
Tested cells responsible for negative selection using bone marrow chimeras
Bone marrow from various donors was transferred into irradiated recipients
Marrow d onor
Recipi ent
(thym e pith)
% periph T c ells
Vb17a+
IEIE+
IEIE-
13.6
IEIE+
IE+
16.2
IE+
0.08
0.1
Bone marrow cells from donor determine negative selection
Host DC die from irradiation
Replaced by DC from donor marrow
Positive selection is on host thymic epithelium
Negative selection occurs on donor-derived DC
How is Reactivity to non-Thymic Self Ags Prevented?
Clonal anergy
Suppression
Clonal Anergy
Ag signals T cell in an improper fashion
Cell is turned off rather than on
Seen when cell gets signal 1 (TCR) but not signal 2 (co-stimulation)
DBA/2 mouse: T cells with Vb6 TCR autoreact with IEd
During the first week of life, autoreactive T cells are released from thymus
As mouse ages, negative selection initiates, and this process stops
Neonatal thymectomy freezes the early situation, see Vb6 in periphery
Thymectomize
Normal Adult
V 6 gradually disappears
B
from LN, Spleen
Day 0-4
VB 6 moving out
to LN, Spleen
Adult w/day 3 thymectomy
freezes d.3 picture
V 6 remains in periph
B
NTx mouse
(as adul t)
Neonatal mouse:
Adul t mouse: (%V b6)
Cortex
Medulla
Periph
Cortex
Medulla
Periphery
Periphery
3.1
0.2
0.1
3.6
3.2
3.3
3.2
Adult medullary thymocytes
Day 3 medullary thymocytes
Adult peripheral T cells
Neo-thymectomized T cells
Measure: IL-2 production
Proliferation
IE
IEddAPCs
Plate
Cells:
Adult med
Day 3 med
Adult periph
NTx periph
Prolif
IL-2 prod
+/++++
+/+/-
+/++++
+/+/-
V b6 freqcy
0.2%
3.6%
0.2%
3.3%
neg s el'd; no
not neg s el'd; fn remains
neg s el'd
not neg s el'd; anergic!
Day 3 thymocytes can respond to IEd
however peripheral cells in the thymectomized mouse cannot
Peripheral cells have been anergized
fn left
CD28/B7 is the most common
Form of co-stimulation
IL-1 can Co-stimulate TH2 cells
CD28/B7 is most common
Stimulator for CD8 cells
Clonal deletion occurs in B cells
H-2
k
Tgenic mouse # 1
genes for H&L chains
b
ant i-K
Ab
1 . Normal level of B cells
in BM, L, Spleen
H-2
b
Tgenic mouse # 2
genes for H&L chains
b
ant i-K
Ab
1 . No B cells in Ln, BM, Spleen
2 . Clonal delet ion and t olerance
2 . > 9 5 % display Tgenic sIg
B cells eliminated if specific for cell surface self Ag seen in BM
Peripheral deletion of B cells
H-2
k
H-2
k
X
Tgenic mouse #3
b
gene for k
under liver promoter
Tgenic mouse #1
F-1
1. In adults- normal levels of B cells in BM
>95% display Tgenic sIg
2. almost no B cells in LN, Spleen
none display Tgenic sIg
3. Clonal deletion
(peripheral tolerance)
B cells also eliminated if see self cell surface marker in periphery
Not deleted in BM, deleted in periphery
This is linked to failure to activate CD4 help
CD40 on B cell must be ligated by CD40L on activated T cell, or B cell dies
B cell tolerance to soluble self Ag
Tgenic mouse #1
x
genes for H&L chains
of anti-HEL Ab
Tgenic mouse #2
gene for HEL
1. makes, secretes HEL
2. Tolerant to HEL
a. T cells
b. B cells
1. >95% B cells have Tgenic sIG
2. Normal B cell levels, LN, Spl
3. Normal mu, delta chains
F-1
Transfer B cells
to normal mouse
1. Makes, secretes HEL
2. Normal B cell levels- BM,LN,Spl
3. B cells are mu low, delta hi
>95% have Tgenic sIg
4. B cells are anergic
cannot respond to HEL
Normal Mouse
1. B cells home to LN, Spl
2. inject hi [HEL]: become anergic
Altered levels of mu, delta chains
High levels of soluble self Ag cause alterations of B cell phenotype
B cells are not deleted, become m low, d high…..Anergized
Suppression as a Tolerance Mechanism
Some CD4 T cells are now thought to suppress immune responses
These T regulatory cells are:
T regs may be involved in
CD25+ (High affinity IL-2 R)
Peripheral tolerance to a
CTLA4+
Variety of Ags
Express IL-10, TGF-b
CD4+ Treg Cells
APC
MHC /Peptide
CD80/CD86
TCR
CTLA-4
CD4+
CD25+
immunosuppressive
cytokines
IL-10
TGF-b
Activation of the Treg cell is Ag specific
Suppression by the Treg cell is non-specific
If Treg cells are removed, Ag-reactivity ensues
To Initiate a Proper Immune Response
3 signals are required:
1. TCR/Ag binding
2. Co-stimulatory signal
3. Trauma or stress (danger signal) from injured cells/tissues
Activates APCs
Initiates inflammation
Autoimmunity
Organ specific disease
Response targets a unique organ or gland
Direct cellular damage occurs
Function of tissue stimulated or blocked by Abs
Systemic disease
Response directed against a broad range of Ags
Involves multiple organs or tissues
Organ Specific Autoimmune Diseases
Hashimoto’s Thyroiditis
DTH response to thyroid Ags
Inflammatory response causes goiter (enlarged thyroid)
Pernicious Anemia
Abs to membrane-bound intestinal protein (intrinsic factor)
Block absorption of vitamin B12
Hematopoiesis altered
Autoimmune Hemolytic Anemia
AutoAb to RBC proteins
complement lyses RBC
Insulin-Dependent Diabetes Mellitis
DTH and autoAbs against b islet cells in pancreas
Cytokines and lytic enzymes from macrophages destroy islet cells
insulin production reduced
Graves Disease
AutoAbs to thyroid stimulating hormone R
mimics receptor signaling
thyroid hormones produced
Myesthenia Gravis
Blocking Abs to acetylcholine R
inhibits muscle activation
C’ mediated destruction of receptor
Systemic Autoimmune Diseases
Multiple Sclerosis
T cells reactive to myelin basic protein
Numerous neurologic malfunctions
Systemic Lupus Erythematosis (SLE)
Multiple autoAbs (DNA, histones, RBC, platelets, clotting factors
Immune complexes deposited, destroy blood vessel walls
RBCs lysed, kidney damage
Often see butterfly rash on face, sun sensitivity
Rheumatoid Arthritis
Chronic inflammation of joints
Hematologic, cardiovascular and respiratory systems affected
Rheumatoid factors (anti-IgG Fc) cause immune complexes
localize to joints, activate C’, inflammation
Ankylosing Spondylitis
Associated with HLA-B27
Destruction of large joints
Fusion of vertebrae
Clinical Manifestations
of
Rheumatologic Diseases
(Tolerance Gone Awry)
Rheumatoid Arthritis
Rheumatoid Arthritis
Juvenile Onset RA: Growth Deformities
RA left knee, increased bone length
14 YOA, 3’9”
SLE: Anti-Nuclear Ab
Systemic Lupus Erythematosis
Butterfly Rash
Light Hypersensitivity
SLE: Kidney Damage
Immune complexes (pink) deposits on
Basement membrane (black)
IgG deposits in glomerulus
Ankylosing Spondylitis
26 year time course
Involvement in hips and knees
Bi-lateral hip replacement in 1973