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 thymus Irreversible loss of activity, since Ag-reactive cells are gone Negative selection can be studied observing V  17 T cell receptor model V  17 is never expressed on peripheral T cells in mice that have MHC II IE V  17 is expressed on cortical thymocytes Lost on mature thymocytes due to negative selection Thymocytes expressing TCRs bearing V  17 bind too strongly to a conserved region of IE  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 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) Neonatal thymectomy freezes the early situation, see V  6 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 DBA/2 mouse: T cells with V b 6 TCR autoreact with IE d

Peripheral cells have been anergized Day 3 thymocytes can respond to IE d however peripheral cells in the thymectomized mouse cannot IE d APCs

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 B cells eliminated if specific for cell surface self Ag seen in BM

Peripheral deletion of B cells 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 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 responses These T regulatory cells are: CD25+ (High affinity IL-2 R) CTLA4+ Express IL-10, TGF-  Activation of the Treg cell is Ag specific Suppression by the Treg cell is non-specific If Treg cells are removed, Ag-reactivity ensues T regs may be involved in Peripheral tolerance to a Variety of Ags

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 Systemic disease Response targets a unique organ or gland Direct cellular damage occurs Function of tissue stimulated or blocked by Abs 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  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

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 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