3 . Mechanisms Flashcards
What is lost by self-antigens in AI’s?
Tolerance to self-antigens
How does the immune system respond to self-tissues in healthy individuals?
It is tolerant of self-tissues
What are chronic adaptive immune responses directed to in AI disease?
Towards normal body components
What can happen to cells and tissues in AI disease?
Can be destroyed or have function altered.
What is the role of self-antigens? (autoantigen)
Antigenic component/amino acid sequence that provokes immune response by individuals OWN system.
What is an antigens role?
Molecules or molecular fragments that can be bound by an MHC molecule and presented to a T-cell receptor.
What humoral mechanisms can be involved in inappropriate AI response to self -antigens?
Humoral mechanisms via B-cells and antibodies.
What cell-mediated mechanisms can be involved in inappropriate AI response to self -antigens?
Via T-cells and cytokines.
How do T-cells function?
Diverse and interact with antigen often dictates fate.
What chain does a T-cell follow?
T-cell maturation. T lymphocyte activation. Clonal expansion into helper/memory/suppressor- T cell.
Steps of B cell function?
.Immunoglobulins on B cell surface attach to antigen.
.Fragment of antigen in B cell combines with HLA II.
.HLA II antigen-fragment-complex on surface of B cell.
.TH Cell receptor recognizes HLA complex. Cytokines activate B cell.
.Clonal expansion begins. Some become antibody producing plasma cells.
When was ‘Tolerance’ defined?
1953 by Medawar and Burnet
Define ‘Tolerance’?
“A state of indifference or non-reactivity towards a substance that would normally be expected to excite an immunological response.”
What does tolerance do?
Helps fight and ensure NO ai disease develops
How do we develop ability to tolerate self-antigens?
From exposure of self-antigens to autologous lymphocytes in early development (self)
What happens if tolerance fails?
Failure to tolerate self-antigens can trigger ai development.
What is Central Tolerance?
Regulation of B and T cells that proliferate in thymus and BM
How does central tolerance impact B and T cells in thymus/bm?
Makes them unreactive to self-antigens. Originally they are reactive but regulatory processes nullify this later on.
What do T-cell receptors gene rearrangements cause in immature T cells?
Randomly generate thousands of antigen specific TCRs
What does the thymus do in central tolerance?
Selects and eliminates auto-reactive T-cells
When does thymus select and eliminate autoreactive T Cells?
Early in life. Near heart.
What does the thymus POSITIVELY select in central tolerance?
Tcells with TCRs that bind to MHC associated antigens expressed by epithelial thymocytes
What does the thymus NEGATIVELY select in central tolerance?
Negatively selects and induces apoptosis in TCells with high avidity for self-antigens on epithelial thymocytes.
What do thymus macrophages phagocytose in central tolerance?
Apoptotic dead T-cells
What percentages of Tcells die in central tolerance?
98% due to being autoreactive
Where are thymocytes found?
Distinct parts of the thymus depending on stage of development.
List mechanism of central tolerance thymocytes in TCells?
.Cells enter thymus into subcapsular region of cortex.
.Proliferate and mature into double positive thymocytes.
.Migrate deep in thymic cortex.
.Medulla left with MATURE SINGLE POSITIVE T CELLS.
.Leave thymus and enter blood
Name the 2 ways ai TCells can be activated in central tolerance?
In a pathogen specific or non-specific manner
How are ai T cells pathogen-specifically activated by infection?
Specific pathogen antigens presented to T-cells via TCR and MHC interaction
How are ai T Cells activated in a non-specific manner?
Inflammation or reduced regulation by cytokines
What can Inappropriate class II MHC expression activate in central tolerance?
B or Cytotoxic T Cells
Examples of Inappropriate class II MHC expression in central tolerance?
Pancreatic B Cells express high Class II MHC in diabetes. Thyroid cells express high CLASS II MHC in Graves disease.
What can viruses promotes in central tolerance that increases class II MHC expression by cells that should not express it?
Viruses promote Interferon-g release by T-cells.
When are the majority of B cells clones generated and how?
During foetal development. Randomly generated by gene rearrangements. Many are autoreactive and tolerance eliminated.
Where do developing B Cells undergo +ive/-ive selection?
In Bone marrow an germinal centres of other lymphoid tissues. (most undergo apopotosis)
What enables Bcells to produce heavy and light chai immunoglobulin receptors and functional BCR?
Induction of RAG initiates VDJ recombination.
What are immature B cells subjected to in CT?
subjected to central tolerance mechanisms that eradicate autoreactive cells
What happens to B cells that express BCRs that bind self-antigen ?
Undergo receptor editing in an attempt to produce BCRs that are not autoreactive.
What happens to B cells that successfully pass these central tolerance checkpoints?
Leave the bone marrow and travel to the spleen where they are subjected to further tolerance mechanisms
Where do autoreactive B Cells migrate to when stimulated by autoantigen?
T cell area of secondary lymphoid tissues.
What is the effect between B and T cells in CT?
T cells allow B cells to survive and cause disease. Without they will die.
What virus can induce non-specific polyclonal BCell activation?
Epstein Barr and Cytomegalovirus
How do viruses and bacteria impact BCells?
Bcells produce IgM which combines with IgG to = immune complexes.
What is AIRE?
Autoimmune Regulator. Transcription factor.
What does AIRE do?
Promotes the ectopic transcriptional activity of a large number of chromosomal locations, thereby enhancing the expression by medullary epithelial cells (MECs) of genes that would normally only be expressed in specific tissues
Where is AIRE localised?
Thymus- medulla
What is AIRE involved in?
Negative selection
What is meant for AIRE by ‘immunological shadow’
Shadow of the peripheral self in MECs.
What happens to AIRE with differentiating T cells that recognize these antigens?
Removed primarily by apoptotic clonal deletion, although some may survive by adopting alternative fates that have regulatory rather than autoreactive properties.
What does the regulatory element of AIRE achieve?
These mechanisms thus prevent the autoimmune attack of peripheral organs.
What disease is AIRE linked to?
Autoimmune Polyendocrinopathy Syndrome
Type I
What is Autoimmune Polyendocrinopathy Syndrome
Type I?
Dysfunction of multiple endocrine glands.
What causes Autoimmune Polyendocrinopathy Syndrome
Type I?
AIRE gene mutations
Impact of Autoimmune Polyendocrinopathy Syndrome
Type I?
Tolerance less. Persistant mucosal fungal infections.
What gland does Autoimmune Polyendocrinopathy Syndrome Type I effect?
Parathyroid and adrenal.
What is FOXp3?
Forkhead box p3. Regulator master for T-Cell regulation. Transcriptional regulator. Essential for development and function.
What does FOXp3 do?
Predominantly acts to directly supress activation of target genes.
What phenotype isFOXp3 comitted to?
Treg phenotype from precursor cells.
Explain the regulatory elements of Tregs?
A regulatory T Cell that expresses CD4/CD25 and FOXp3/
.
What is FOXp3 essential for?
Immune supression
What does FOXp3 mutations cause?
Disease IPEX
What is supressed in FOXp3?
Activation/proliferation and cytokine production in CD4/CD8 TCells.
What is peripheral toleracne?
A redundancy mechanism within the immune system. Regulates cells in peripheral tissue and limits access to tissues when activated.
What circulates in peripheral tolerance?
Self-reactive B and T cells that survive toleracne
Define peripheral tolerance?
Tolerance to self antigens acquired by lymphocyte population outside thymus and BM .
What regulates peripheral tolerance?
CTLA-4. HLA-B7 co stimulator on APC membrane.
What supresses peripheral tolerance?
