Immunological Tolerance and Autoimmunity Flashcards
Immunological tolerance is specific unresponsiveness to an antigen. Self- toleranc: all individuals are tolerant to self-ags. What results from the breakdown of self-tolerance?
Autoimmunity
Central tolerance is induced in immature self-reactice llymphocytes in the primary lymphoid organs, ensuring mature lymphocytes are not reactive to self ags.. Peripheral tolerance is induced in mature self-reactive lymphocyes in perpheral sites which is needed to?
prevent activation of these potentially dangerous lymphocytes in the tissue
What are the outcomes for self reactive immature lymphocytes in central tolerance? (3)
They are either deleted, B cells can change BCR specificity, or they develop in to T regulatory cells
What are the outcomes for mature self-reactive lymphocytes in peripheral tissues? (3)
They are inactivated (anergy), deleted by apoptosis or suppressed by Treg cells
Central tolerance occurs in the thymus where thymocytes undergo maturation and selection process in which strongly self reactive thmyocyes are deleted by apoptosis or nonfunctional thymocytes with no affinity are also?
Deleted by apoptosis
Thymocytes which are activated by MHC self complexes below a certain threshold are positively selected to become Effector T cells and migrate to the periphery. A small percentage of cells from the thymus express FOXP3 and develop into?
natural CD4+CD25+CTLA4+ T regulatory cells
In peripheral tolerance inactivation of self reactive naive T cells occurs and it is called anergy (functional unresponsiveness). Anergy occurs by Ag recogonition without costimulation and the other way anergy occurs is when the T cell engages inhibitory receptors________ which block activation.
CTLA-4 and PD-1 (which are expressed after antigen recognition)
Sometimes cancer is treated with anti-CTLA4 and anti PD1 that block these receptors leading to?
enhanced antitumor response and tumor regression called CHECKPOINT BLOCKADE
What does checkpoint blockade develop due to inhibition of CTLA4 and PD1?
Leads to autoimmune reactions
Treg cells are developed in thymus and positively selected d/t strong TCR interactions with self-ags. Treg generation requires TGF-B. Treg cells express _____ and are _______ positive?
FOXP3 and are CD4+CD25+ positive
CTLA-4 is highly expressed in Treg and IL2 is critical for survival and function of Tregs. Tregs are long lived populations and prevent?
potential autoimmune reactions
Natural immature Tregs are made in the thymus while inducible Treg (iTreg) cells are produce by Ag recognition in LNs and GI tract. Naive (mature) T cells are activated by TGF-B, FoxP3 can be expressed on a CD4 T cell. iTregs are in close relationship with?
Th17 cells.
FoxP3 is expressed when CD4 gets TGF-B +IL2 from a DC, however, FoxP3 only is expressed in the absence of which cytokine?
IL6
In contrast, Ag recognition in the presence of TGF-B and IL6 prevents Foxp3 expression and induces transcription factor for _______ which induces ________ production.
RORyt and IL17 and Th17 cell differentiation
CD4+CD25+CTLA4+FOXP3+ T reg cells are key mediators of peripheral tolerance. They can inhibit what? (3)
T cell activation by APCs
T cell differentiation into CTLs
T cells from providing help to B cells
When an APC binds to a Treg, the Treg releases IL4, IL10, and TGFB to the APC. The APC then has a decrease in expression of CD40, CD80/86 and IL 12, and expresses what?
IL10, resulting in loss of ability to induce effectors
What are the four mechanisms by which a Treg cell can work?
- inhibitory cytokines IL10/TGFB
- cytolysis
- metabolic disruption
- trageting dendritic cells
Cytolysis includes granzyme A and granzyme B dependent and ________ depenedent killing mechanisms
perforin
Metabolic disruption by Treg cells includes CD25(IL2RA)-dependent cyotkine-deprivation-mediated apoptosis, cAMP mediated inhibition and _______ mediated immunosupression.
adenosine receptor 2A (A2AR) mediated supression
death due to cytokine deprivation
Targeting DC cells by inhibition of DC maturation and function includes CTLA4 -CD80/86 mediated inhibtion. and induction of ____________ which is an enzyme that degrades the essential amino acid trytophan
indoleamine 2,3-dioxygenase (IDO)
Cell death is caused when a mature T cell binds a self APC with self Ag. This reaction does not produce an IL2 due to no costimulation. This leads to ? (intrinsic)
Apoptosis. This occurs due to IL2 starvation, which leads to decreased expression of antiapoptotic gene BCL2, allowing apoptotic proteins to be released from the mT, activating caspase 9, which activates caspase 3 to CAD and degredation
Cell death is also cause when a mature T cell binds a self APC, activating its death receptors, such as? (extrinsic)
Fas receptor is expressed on T cell, binds to FasL on other T cell, causing extrinsic pathway apoptosis, Caspase 8 activated and activates Caspase 3 to CAD to degredation
Central B cell tolerance : Immature B cells that recognize self Ags in BM with high avidity die by apoptosis (clonal deletion/anergy) or undergo receptor editing and change their BCRs. What is receptor editing
further rearrangement of the L chain genes that ocurs until nonself recognizing receptors are produced or the cell dies
Low avidity of B cells to recognize self Ags in BM may lead to anergy, which means?
Functional inactivation of the B cells, which fail to enter follicle in periphery and have a reduced life span
BCR editing uses RAG1/2 to rearrange IgLchain when B cells are self reactive. This recombination can either result in apoptosis due to another self reacting receptor or can lead to?
Innocuous receptor, lacking self reactivity
Mature B cells who recognize self ags in the periphery in the absence of Th cells are rendered unresponsive or die by apoptosis. It can also be fixed by CD22 inhibitory receptor, which occurs by?
CD22 is phosphorylated by Lyn and recruits SHP1, which inactivates the B cell signaling. SO IF THERE IS A DEFECT IN LYN SHIP OR CD22 it can lead to autoimmunity.
It is said there are genes that interefere with pathways of self tolerance and lead to the persistence of self-reactive T and B lymphocytes. Infections and other inflammation promote influx of lymphocytes into tissues and activate APCs. What can APCs then do?
Activate self reactive lymphocytes resulting in generation of effector T cells and Autoantibodies that are responsible for autoimmune disease.
AIRE: autoimmune regulator gene, deficiency causes destruction of endocrine organs by antibodies, leading to the failure of central tolerance. What human disease is caused by this?
Autoimmune polyendocrine syndrome (APS)
Impaired production of T regulatory cells cause by FOXP3 deficiency can cause multi-organ lymphocytic infiltrates and wasting, causing what human disease?
IPEX:immune dysregulation polyendocrinopathy
When there is a mutation in C4 and Clq complement proteins, it leads to defective clearance of immune complexes and impaired toerance induction by apoptotic cells, causing what human disease?
SLE = LUPUS
When there is deficiency in CTLA4, causes uncontrolled proliferation of T cells, causing failure of anergy in cd4Tcells. What human disease is this?
CTLA4 polymorphisms associated with several autoimmune diseases
Negative selection of T cells in thymus is key for maintanence of self tolerance. medullary thymic epithelial cell are a key function in APCs which express a large number of self ags that are presented to developing T cells. Mutations in AIRE protein, autoimmune regulator protein, causes?
breakdown of the central tolerance
* CENTRAL TOLERANCE* AIRE is considered to be a transcription factor for the production of self Ags (tissue restricted antigens (TRAs), meaning that when there is a mutation in AIRE, it leads to?
decreased expression of self-ags in the thymus
AIRE is a transcription factor in medullary thymic epithelial cells in the thymus, which produce tissue restricted antigens. Giving immature T cells the option to recognize its self and be negatively selected. What occurs whenAIRE is absent?
TRAs are not produced, self reactive T cells are not eliminated and can enter tissues where the antigen is produced and start killing the cells!
When T cells recognize self Ags, they may engage inhibitory receptors of the CD28 family, whose function are to? Best inhibitory receptors are CTLA4
CD28 family function to terminate T cell responses
CTLA (cytotoxic T-lymphocyte antigen 4) is a homolog of CD28. It causes contraction(inhibition) of T cells (death) while CD28 causes expansion upon Ag recognition. In the absence of CTLA4, what is seen?
Uncontrolled lymphocyte activation with enlarged LNs and spleen, with fatal multi-organ lymphocytic infiltrates
Polymorphisms of CTLA4 are seen in type 1 diabetes and graves disease. What are two important properties of CTLA-4?
- expression is low on resting T cells until they are activated by Ag
- Once expressed, CTLA4 terminates continuing activation of responding T cells (helps balance activation)
one of the modes of CTLA4 (B7) is called cell intrinsic function. Which is engagement on a T cell may deliver inhibitory signals that?
terminate further activation of that cell
Cell extrinsic action of CTLA4: On Treg cells or responding T cells bind to the B7 molecules on APCS, which does what?
CTLA4 on Treg will bind to B7, not allowing CD28 (activation signal) to bind, therefore not being able to activate the T cell. (REDUCED B7 costimulation)
Soluble or sCTLA4 activates CTLA4 fucntion, blocking autoimmunity when there is a lack of CTLA4 , leading to T cell proliferation/differntiation. Anti-CTLA4 Abs bind to B7(CD80/86) and CTLA4, stimulating?
anti-tumor immunity
5% (12-15million) people have autoimmune diseases. Which have no cures and are treated symptomatically. There is no fundamental difference between auto-ags and non-self ags because all proteins are composed by the same AAs. What pathologic immune reponse against self antigens usually clinically present as?
immune-mediated inflammatory diseases caused by activation of immune sys in absence of non-selfantigens. Hypersensitive immune system
What are 4 ways autoimmunity is prevented?
- immunologic ignorance, meaning there is an anatomical barrier between self Ag and T cell
- FasL + Fas (deletion)
- CD152(CTLA4) leading to no activation (inhibition)
- Treg releasing IL10/TGFB so T cell doesnt activate (supression)
Most autoimmune diseases are complex polygenic traits. Affected people inherit multiple genetic polymorphisms that contribute to disease susceptibility. What genes have the strongest associations with autoimmunity?
MHC genes, sometimes polymorphic non-HLA genes
Microbial antigens can intiate autoimmune disorder through what 3 ways?
Molecular Mimicry
Polyclonal (bystander) activation
Release of previously sequestered Ags
Molecular Mimicry: occurs when an APC presents a microbial antigen to a self-reactive T cell that can also recognize microbial peptides, leading to?
activation of T cells that recognize self antigens and autimmune disorders
autoimmune disorder- rheumatic fever, is triggered by streptococcal infection and mediated by cross-reactivity between?
Ags and cardiac myosin
autoimmune disorder Multiple sclerosis: T cells react with myelin basic proteins and peptides from EBV, influencez virus type A and?
HPV
MIcrobial infection can cause polyclonal activation of autoreactive lymphocytes, known as?
cytokine field
Microbes that kill cells can cause inflammation, the release of sequestered Ags and?
autoimmunity
Autoimmune diseases are more common in women than men becuase why?
estrogens exacerbate systemic lupus erythematosus (SLE) by altering the B cell repertoire in the absence of inflammation
Penicillins and cephalosporins can alter the immune repertoire by?
Binding to RBC membranes and generate a neoantigen that elecits an auto-ag that causes hemolytic anemia
The blockade of TNF-A (ENBREL) can induce antinuclea Abs and even lupus and MS due to its?
inhibitory effects on activated T cells
Retinoic acid (RA) acts via retinoic acid receptor alpha (RARA) inhibits the formation of Th17 but promotes?
FOXP3 expresssion
**RA is produced by DCs generates FOXP3+ from naive CD4+CD25- T cells
Clearance of immune complexes:
Small Ag-Ab complexes form in circulation, C3b are added to the complex, then what happens?
Complement receptor CR1 on erythrocytes bind the complex via C3b
in the spleen and liver, phagocytic cells remove complexes from erythrocyte surface via CR1 and FcR
What are the sites where immune priviledge (skin grafts that survive for a long time) occurs?
Eye:cornea, ant chamber, vitreous cavity and subretinal space
brain, pregnant uterus, ovary, testis, adrenal cortex and hari follicles
MHC genes have the strongest associations with autoimmune disorders, what is the disease for each MHC allele and relative risk? HLA B27 Class I RR:90 HLA DRB1 Class II RR: 4-12 HLA DRB1 Class II RR: 35 HLA DR4 Class II RR: 14
- Ankylosing spondylitis
- Rheumatoid arthritis
- Type 1 diabetes
- Pemphigus vulgaris
