IMMUNOLOGIC TOLERANCE Flashcards
Immune Tolerance
• Failure to recognize or mount an immune response to self-antigens that can otherwise result in…
autoimmune disease
• Lack of response to self-antigens
Immune tolerance (self-recognition / self-tolerance)
• Horror autotoxicus (19th century):
• “Body attacking itself”
• Coined by…
Paul Ehrlich
• - clinical syndrome in which the immune system attacks self-tissues
Autoimmunity
Immunogen manner if administration
• Subcutaneous
• Intramuscular
Tolerogen
Manner of administration
• Oral (HCl in stomach)
• Intravenous (enzyme in blood)
IR according to age of individual
Immunogen vs Tolerogen
Children, Adults
Infants, Elderly
Dose (concentration)
Immunogen vs Tolerogen
Optimal dose
Below and/or above optimal dose
Source of Self- Antigens
• Healthy tissues and organs that shed low levels of component proteins
• Normal turnover process of cells (undergo apoptosis)
• Molecules circulating in the blood plasma (no infection or injury)
• Protein encoded by the AIRE gene
• Transcription factor expressed in the thymic medulla that controls thymic dendritic cells
• Regulates the exposure of T cells in the thymus to normal, healthy self-antigens from all parts of the body
AIRE (autoimmune regulator)
T cell Ontogeny
•_______
• Is T cell able to bind to self-MHC?
•_______
• Does T cell bind too strongly to self-
МНС?
Positive selection (survival signal):
Negative selection (apoptosis signal):
• Events that characterize the differentiation of B cells from hematopoietic stem cells to pro-B cells, pre-B cells, immature B cells, and finally to mature B cells
B cell Ontogeny
• Occurs in primary lymphoid organs (PLOs):
• Thymus - T cells
• Bone marrow - B cells
Central Tolerance
presents self-antigens in the PLO AKA generative lymphoid organs
• Central tolerance
Initiated during fetal development by the elimination of cells with the potential to react strongly with self-antigens
Central tolerance
• Mediated by mechanisms that both foster the destruction and elimination of selected self-reactive lymphocytes
Central tolerance
• Monitor weakly self-reactive clones that survive the “weeding out” process during central tolerance
Peripheral Tolerance
• Occurs mainly in the secondary lymphoid organs or at the tissue site where the relevant self-antigen is expressed leading to immunosuppression
Peripheral Tolerance
• Important to continue maintaining self-tolerance in the periphery
Peripheral Tolerance
• Contributing factors for weakly self-reactive cells:
• Not all self-antigens are expressed in PLOs
• Threshold requirement for affinity before apoptosis
Central T cell Tolerance
Mechanisms:
• Cell death
• Generation of CD4+ regulatory T cells
- if an immature lymphocyte interacts strongly with a self antigen, displayed as a peptide bound to self MHCs, the immature lymphocyte receives signals that trigger apoptosis, and the cell dies before it can complete its maturation
• Affects CD4+ (recognizing MHC class Il) and CD8+ (recognizing MHC class I) T cells
• Some autoreactive immature T cells that recognize self-antigens become_____
Negative selection
Tregs/Th3 instead
Mechanisms of T cell Central Tolerance
• Three pathways recognized:
- Clonal abortion
- Functional deletion
- T cell suppression
Mechanisms of T cell Central Tolerance
- inhibition of actions of other autoreactive T cell subsets
T cell suppression
Mechanisms of T cell Central Tolerance
- removal through apoptosis of autoreactive mature T cell
subsets
Functional deletion
Mechanisms of T cell Central Tolerance
- prevention of immunocompetence of autoreactive maturing cells
Clonal abortion
• responsible for deleting autoreactive T cells that have the potential to cause autoimmune disease once engaged with self-antigens
Thymus
• present antigens using major histocompatibility complex (MHC) in the lymphoid organs
Epithelial cells or dendritic cells
• Provides backup mechanisms for preventing autoimmunity in situations where central tolerance is incomplete
Peripheral T Cell Tolerance
•
• Induced when mature T cells recognize self- antigens in peripheral tissues
Peripheral T Cell Tolerance
• Antigen recognition without adequate co stimulation results in:
- T cell anergy
- T cell suppression
- T cell death
• T cells may preferentially engage one of the inhibitory receptors of the CD28 family:
T cell Anergy
• Long-lived functional inactivation that occurs when these cells recognize antigens without adequate levels of the costimulators that are needed for full T cell activation
T cell Anergy
• Anergic cells survive but are incapable of responding to the antigen
T cell Anergy
inhibitory receptors of the CD28 family:
• CTLA-4 or CD152 (cytotoxic T
lymphocyte- associated antigen 4)
• PD-1 (programmed death protein 1)
• FoxP3 (forkhead box P3) AKA scurfin
- mediates the change to Treg cells (clonal diversion)
Immune Suppression by Treg Cells
• Although can be CD8+, most Tregs are
CD4+, and express high levels of
CD25+
Immune Suppression by Treg Cells
• As regulatory T cells, they enter the periphery and block the activation of other potentially harmful lymphocytes
Immune Suppression by Treg Cells
• Produced in the thymus due to being able to weakly react to self-antigens
• “Salvaged” cells to be used as Tregs instead of being destroyed
Immune Suppression by Treg Cells
The Key Role of Regulatory T cells
• Treg cells can be CD4+ or CD8+ and typically express CD25, CTLA-4, plus the master regulator transcription factor, FoxP3 (they also release immunosuppressive cytokines IL-10,TGF-B, IL-35)
The Key Role of Regulatory T cells
• Treg cells act in secondary lymphoid tissues and at sites of inflammation dampening immune responses by inhibiting, decommissioning, or killing other immune cells recognizing self antigens
Deletion by Programmed Cell Death (Apoptosis)
• Apoptosis can be triggered:
• Death by deficiency of survival signals (20)
• Death by engagement of death receptors
• Relative deficiency of survival signals = death
Deletion by Programmed Cell Death (Apoptosis)
• This activates enzyme caspases to induce apoptosis that induce further degradation
Deletion by Programmed Cell Death (Apoptosis)
• These activate the cell’s mitochondrial pathway, triggering various mitochondrial proteins to leak out, known as “leaky mitochondria”
Deletion by Programmed Cell Death (Apoptosis)
• Recognition of self-antigens induces the production of pro-apoptotic proteins in T cells
Deletion by Programmed Cell Death (Apoptosis)
• Recognition of self-antigens may lead to co-expression of death receptors and their ligands
Deletion by Death Receptors (FAS + FAS Ligand)
• Death receptor pathway is activated, generating signals that trigger caspases:
• Fas (CD95) - expressed on T cells and others
• Fas ligand (FasL) - mainly on activated T cells
= induces death of both T and B cells exposed to self antigens
• Self antigens are present throughout life and may therefore cause prolonged or repeated TCR engagement, promoting anergy and apoptosis
• Fas + FasL
Mechanisms of B cell Tolerance
- Clonal abortion:
- Clonal exhaustion:
- Functional deletion:
- Antibody-forming cell blockade:
B cell tolerance
• caused by low concentration of multivalent antigen
• repeated antigen challenge with a T-independent antigen
• combined absence of T helper subsets and T-dependent antigen OR an excess of T-independent antigens
• excess of T-independent antigen interferes with the secretion of antibody by antibody forming cells (plasma cells)
- Clonal abortion:
- Clonal exhaustion:
- Functional deletion:
- Antibody-forming cell blockade:
CENTRAL B CELL TOLERANCE
• Occurs when immature B lymphocytes interact strongly with self antigens in the bone marrow:
Receptor editing
Negative selection
B cell anergy
• Re-expression of recombination
activating genes (RAGs) to resume light chain recombination and produce a new receptor that is no longer reactive
Receptor editing
• If receptor editing fails, immature B cells that recognize self antigens with high avidity (accumulated binding strength) receive death signals and die by apoptosis
Negative selection
• Recognition of self antigen with low avidity, B cells in the bone marrow survive but antigen-receptor expression is reduced, rendering B cell unresponsive
B cell anergy
• Mechanisms to ensure that mature B cells that encounter self antigens in the peripheral lymphoid tissues become incapable of responding to them
Peripheral B Cell Tolerance
Peripheral B Cell Tolerance
• B cell can become anergic:
- Recognizes self antigens but don’t receive T cell help
- Self-reactive B cells may leave the lymphoid follicles and are subsequently excluded from the follicles
- Excluded self-reactive B cells may die due to lack of receiving survival stimuli (follicular exclusion)
B cell Anergy
• B cells specific for T-dependent antigens require two signals to be activated:
• 1st signal = provided by the____
• 2nd signal = provided by the ____
antigen
T cells
B cell anergy
• Second signal is provided by the CD40
+ CD40L used in class switching
• If second signal is missing (self-antigen): B cell will be rendered unresponsive (anergic)
• Autoreactive T cells usually get deleted in the thymus and thus not available in the periphery to provide costimulatory help to autoreactive B cells
- immunogen activates all B cells leading to maturation of cells and transient antibody synthesis, thereby exhausting and diluting B cell response
B cell clonal exhaustion
- B cell is coated with excess antigen rendering it unresponsive as all receptors on the cell surface become blocked
B cell receptor blockade
• Silencing of self-reactive B cells can occur through follicular exclusion in the lymph nodes
• Anergic B cells cannot successfully compete for entry into B cell follicles in the spleen and lymph nodes
• Anergic B cells require higher concentrations of BAFF cytokine (B-cell activating factor of the tumor necrosis factor family) aka Blys for survival than naïve B cells
• Without BAFF, B cell undergoes cell death instead of entering follicles
Follicular Exclusion
