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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 V 6 moving out B to LN, Spleen Adult w/day 3 thymectomy freezes d.3 picture VB6 remains in periph 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 d IE IEd APCs 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