Immunosuppression & Immune Tolerance Report 3HMT - Carbungco & Enverga
Tolerance Specific negative immunity Not the same as immunosuppression, which is non-specific 3...
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Transcript of Tolerance Specific negative immunity Not the same as immunosuppression, which is non-specific 3...
Tolerance
Specific negative immunity
Not the same as immunosuppression, which is non-specific
3 Tolerance mechanisms:
Clonal deletion: Loss of certain Ag-specific cells
Clonal anergy: clone is present, but unable to respond
May be slowly reversible
Clonal suppression:
Response re-appears if suppression is removed
Occurs in primary lympoid tissues
Clonal Deletion (negative selection)
For T cells, occurs in thymusIrreversible loss of activity, since Ag-reactive cells are gone
Negative selection can be studied observing V17 T cell receptor model
V17 is never expressed on peripheral T cells in mice that have MHC II IE
V17 is expressed on cortical thymocytes
Lost on mature thymocytes due to negative selection
% cells with V17a:Cell Population: SJL (IE-) B10.BR (IE+)
Immature ( 4thymos CD+8+) 2.9 2.6 Maturethymos
( 4+)CD 2.4 0.06( 8+)CD 0.4 0.01
Periph T cells 13.9 0.09
Thymocytes expressing TCRs bearing V17 bind too strongly to a conserved regionof IEa or IE. 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 donor Recipient(thym epith)
% periph T cellsV17a+
IE- IE- 13.6
IE+ IE- 0.1
IE- IE+ 16.2
IE+ IE+ 0.08
Bone marrow cells from donor determine negative selection
Host DC die from irradiationReplaced 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 anergySuppression
Clonal Anergy
Ag signals T cell in an improper fashionCell is turned off rather than on
Seen when cell gets signal 1 (TCR) but not signal 2 (co-stimulation)
Neonatal thymectomy freezes the early situation, see V6 in periphery
During the first week of life, autoreactive T cells are released from thymus
As mouse ages, negative selection initiates, and this process stops
Thymectomize
Normal Adult
V
B
6 gradually disappears
from LN, Spleen
Day 0-4
B
V 6 moving out
to LN, Spleen
Adult w/day 3 thymectomy
freezes d.3 picture
V 6 remains in periph
B
DBA/2 mouse: T cells with Vb6 TCR autoreact with IEd
NTx mouseAdult mouse: (%V6) Neonatal mouse: (as adult)Cortex Medulla Periph Cortex Medulla Periphery Periphery
3.1 0.2 0.1 3.6 3.2 3.3 3.2
Cells: Prolif IL-2 prod V6 freqcy
Adult med +/- +/- 0.2% neg ; sel'd no fn left
3 Day med ++++ ++++ 3.6% not neg ; sel'd fn remains Adult periph +/- +/- 0.2% neg sel'd
NTx periph +/- +/- 3.3% not neg ; !sel'd anergic
Peripheral cells have been anergized
Day 3 thymocytes can respond to IEd however peripheral cells in the thymectomized mouse cannot
Adult medullary thymocytes
Day 3 medullary thymocytes
Adult peripheral T cells
Neo-thymectomized T cells
Measure: IL-2 production
Proliferation
IE Plate
d
IEd APCs
CD28/B7 is the most commonForm of co-stimulation
IL-1 can Co-stimulate TH2 cells
CD28/B7 is most commonStimulator for CD8 cells
Clonal deletion occurs in B cells
Tgenic mouse #1genes for H&L chains
anti-K Abb
Tgenic mouse #2genes for H&L chains
anti-K Abb
1. Normal level of B cellsin BM, L, Spleen
2. >95% display Tgenic sIg
1. No B cells in Ln, BM, Spleen
2. Clonal deletion and tolerance
H - 2b
H - 2k
B cells eliminated if specific for cell surface self Ag seen in BM
Peripheral deletion of B cells
H-2
k
H-2
k
Tgenic mouse #1 Tgenic mouse #3
X
F-1
gene for k
b
under liver promoter
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 peripheryNot deleted in BM, deleted in periphery
This is linked to failure to activate CD4 helpCD40 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
genes for H&L chains
of anti-HEL Ab
1. >95% B cells have Tgenic sIG
2. Normal B cell levels, LN, Spl
3. Normal mu, delta chains
x
Tgenic mouse #2
gene for HEL
1. makes, secretes HEL
2. Tolerant to HEL
a. T cells
b. B cells
F-1
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
Transfer B cells
to normal mouse
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 low, high…..Anergized
Suppression as a Tolerance Mechanism
Some CD4 T cells are now thought to suppress immune responsesThese T regulatory cells are:
CD25+ (High affinity IL-2 R)CTLA4+Express IL-10, TGF-
APC
CD4+CD25+
MHC/Peptide
CTLA-4CD80/CD86
immunosuppressivecytokinesIL-10TGF-
TCR
4+ CD Treg Cells
Activation of the Treg cell is Ag specificSuppression by the Treg cell is non-specificIf Treg cells are removed, Ag-reactivity ensues
T regs may be involved inPeripheral tolerance to a Variety of Ags
To Initiate a Proper Immune Response
3 signals are required:
1. TCR/Ag binding2. Co-stimulatory signal
3. Trauma or stress (danger signal) from injured cells/tissuesActivates APCsInitiates inflammation
Autoimmunity
Organ specific disease
Systemic disease
Response targets a unique organ or glandDirect cellular damage occursFunction of tissue stimulated or blocked by Abs
Response directed against a broad range of AgsInvolves multiple organs or tissues
Organ Specific Autoimmune Diseases
Hashimoto’s ThyroiditisDTH response to thyroid AgsInflammatory response causes goiter (enlarged thyroid)
Pernicious AnemiaAbs to membrane-bound intestinal protein (intrinsic factor) Block absorption of vitamin B12Hematopoiesis altered
Autoimmune Hemolytic Anemia
AutoAb to RBC proteins complement lyses RBC
Insulin-Dependent Diabetes Mellitis
DTH and autoAbs against islet cells in pancreasCytokines 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 SclerosisT cells reactive to myelin basic proteinNumerous neurologic malfunctions
Systemic Lupus Erythematosis (SLE)Multiple autoAbs (DNA, histones, RBC, platelets, clotting factorsImmune complexes deposited, destroy blood vessel wallsRBCs lysed, kidney damageOften see butterfly rash on face, sun sensitivity
Rheumatoid ArthritisChronic inflammation of jointsHematologic, cardiovascular and respiratory systems affectedRheumatoid factors (anti-IgG Fc) cause immune complexes localize to joints, activate C’, inflammation
Ankylosing SpondylitisAssociated with HLA-B27Destruction of large jointsFusion of vertebrae
Clinical Manifestations
of
Rheumatologic Diseases
(Tolerance Gone Awry)
Rheumatoid Arthritis
Rheumatoid Arthritis
Juvenile Onset RA: Growth Deformities
14 YOA, 3’9”RA left knee, increased bone length
SLE: Anti-Nuclear Ab
Systemic Lupus Erythematosis
Butterfly Rash Light Hypersensitivity
SLE: Kidney Damage
Immune complexes (pink) deposits onBasement membrane (black)
IgG deposits in glomerulus
Ankylosing Spondylitis
26 year time courseInvolvement in hips and knees
Bi-lateral hip replacement in 1973