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100 Cards in this Set
- Front
- Back
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What if there is an exaggerated reponse by our immune system to a n environmental innocuous antigen?
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Hypersensitivity reactions
-> allergies |
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What happens when the immune system is misdirected and attacks self tissue
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Autoimmune disease
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What is the aim of the immune response
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To recognize an antigen on a foreign pathogen and to eliminate it
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What happens when an immune response occurs against a self antigen?
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Immune mechanisms cannot eliminate the Ag completely
Sustained (chronic) response occurs Chronic inflammation, followed by tissue damage and even death may occur |
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What percentage of the population are affected with an autoimmune disorder?
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3%
.: there must be control mechanisms in our body that prevent he immune system from attacking itself |
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Wat did Paul Erlich mean by the term "horror autotoxicus"?
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The presence of mechanisms of self tolerance that prevented the immune system from attacking self tissues
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What is autoimmunity?
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Alteration in the normal homeostatic mechanisms of tolerance (which regulkate self/non-self discrimination)
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What are some effector mechanisms for autoimmune damage?
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Specific components (part of the adaptive):
-Ab, T-cells Non-specific components (innate immunity): -Complement, phagocytes (PMNs, macrophages), TLRs, NK cells etc |
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How cana very broad repertoire of cell that recognize different pathogens be created?
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Molecular mechanisms to make fctnal Ag receptors (TCR/BCR) is a random process
->make this kind of diversity, bound to make some self-reactive lymphocytes |
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Are all the self-reactive lymphocytes eliminated?
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No
->don't want to delete them all ->some self-reactive lymphocytes provide immunity vs non-self Ag |
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What are hte mechanisms of tolerance?
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Central tolerance
Peripheral tolerance |
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What is central tolerance?
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Maturig lymphocytes are deleted in the thymus (T cells) and bone marrow (B cells), if they are strongly auto-reactive (recognize self Ag with high affinity)
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What is peripheral tolerance?
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Remaining auto-reactive lymphocytes with lower affinity got self Ag escape the thymus/BM
They are inactivated in the periphery (outside the thymus/BM) |
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What are many autoimmune diseases the result of?
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Failure to maintain T-cell tolerance
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What is the thymus?
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Gland in our chest
Primary site of T-cell production |
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What happens to pre-T cells in the thymus?
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Undergo stringent selection process
95% of them are killed |
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What is negative selection of thymocytes?
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Thymocytes with excessive reactivity to self-Ag die through apoptosis
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What happens to Thymocytes that survive negative selection (don't show too high an affinity for self)?
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Undergo positive selection
->Non-fctnal thymocytes undergo apoptosis (if they don't have a proper TCR) -> Fctnal thymocytes exit the thymus as mature T-cells (only 5% of original thymocytes). |
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What do fctnal T-cells express?
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CD4+ or CD8+
->don't have strong autoreactivity ->only a fraction of the cells that leave the thymus have low self-reactivity |
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Asmanex
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Mometasone
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What do some other mechanisms use?
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Tolerogenic dendritic cells
Regulaory T-cells |
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What happens in transgenic mice for a TCR that recognizes a single known peptide for MHC?
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All T-cells have the same specificity
The peptide is recognized as a foreign particle |
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What happens in the absenceof this peptide?
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Thyocytes mature and migrate to the periphery
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What happens in the presenceof this peptide?
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Massive death of these thymocytes in the thymus
-> During T cell maturation in the thymus, if some T cells react with self A with high affinity, then they are removed from the repertoire |
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What is AIRE (autoimmune regulator)?
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TF expressed in thymic medullary cells
AIRE allows thymic medullary cells to produce self tissue Ag (from other areas of the body: i.e retina/ovaries) .: all the T cells that have autoreactive potental will be eliminated by undergoing apoptosis through negative selection |
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What happens in the absence of AIRE?
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Tissue-specific Ag are no longer expressed in the thymus
Autoreactive T-cell clones can .: mature and leave the thymus without undergoing negative selection |
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What is APECED?
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Rare mendelian autosmal recessive disorder
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What causes APECED?
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Mutations in AIRE
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What does APECED include?
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Autoimmune PolyEndocrinopathy
Candidiasis Ectodermal Dysplasia (APECED) |
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What happens in autoimmune polyendocrinopathy?
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A lot of autoimmunity is generated against the endocrine glands
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What is Candidiasis?
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Fungal infection
->AIRE plays a role in our defence vs fungus |
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What is ectodermal dysplasia?
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These ppl end up with funny looking faces
.: the AIRE TF is important for maintaining our complexion ->APECED is a problem with the central tolerance of T-cells |
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What happens in central tolerance of B cells?
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B-lymphocytes in the bone marrow express surface IgM molecule whih see multivalent self molecules
When these IgM get cross-linked, a signal is sent inside the B-cell The B-cell will then undergo clonal deletion (if it recognizes self) or receptor editing |
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When does receptor editing take place?
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In the bone marrow, if the B cell sees a multivalent self Ag
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Whathappens during receptor editing?
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The autoreactive B cell undergoes maturational arrest
Get a V-J rearrangement on the OTHER Chr A new light chain is expressed and assembles itself with the heavy chain of the Ab molec (get a whole new specificity, a whole new clonal B cell) -.: a new receptor with a new specificity has been generated |
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What happens if this receptor still recognizes self?
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Apoptosis
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What happens if this receptor does not recognize the multivalent self Ag?
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The B cell undergoes full maturation, exits the bone marrow and becomes a fully fctnal Ab producing B cell
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What happens if a maturing B cell in the BM recognizes a soluble self molec with high affinity?
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Becomes mature and migrates to the periphery, but willbecome ANERGIC (won't be fctnal and won't produce any Ab)
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What happens if the mature B cell recognizes self with low affinity?
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Also goes to the periphery and can mature
->however, this type of B cell will be clonally IGNORANT -The cell is thre and fcnal, but cannot produce Ab because it will remin ignorant of self Ag |
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What happens once B-cells leave the bone marrow for the periphery?
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Somatic hypermutation
-When the B cell is in the periphery and sees an foreign Ag, it tries to increase its affinity for it - .: it undergoes small modifications in its Ag-recognizing portion, making several B-cell clones -Some of these clnes will have higher affinity for the Ag and will survive -Some of the clones will end up seeing self Ag with high affiniy. These cells will undergo apoptosis |
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What are the mechanisms that affect T-cells in the periphery and induce tolerance?
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Ignorance
Anergy Phenotypic skewing Apoptosis |
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What is ignorance?
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T cells with low affinity for self Ag that exit the thymus can:
-Never see the self Ag (cuz its protected/hidden somewhere) and remain ignorant: these clones on't be able to recognize self Ag, but can recognize foreign Ag -Avoid getting activated by self Ag under normal conditions: remain ignorant of self, but fctnal with non-self, as long a they're not activated by their self Ag |
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How can ignorance be overcome?
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Wrong stimulus (i.e. from infection)
-> Infection can cause massive tissue injury, resulting in the release of elf Ag By dendritic cells expressing high levels of co-stimulatory molecules ->If there are foreign Ag that are helping the dendritic cells that are presenting the self Ag to the TCR, ignorance can be vercome Exact mechanism for overcoming ignorance is not understood |
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What is sequestration?
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Ag are kept hidden inside immunopriviliged sites
->these Ag are not released, .: this keeps all the lymphocytes with the potential for autoreactivity ignorant |
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Do sequestered Ag induce a response by themselves?
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No, but if a response is induced somewhere els, they can serve as targets for attack
-> Hockey player with trauma in one eye ended up blind in both eyes |
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What is anergy?
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Naive T cells recognizing self peptides on tissue cells are not activated
->enter a state of unresponsiveness (anergy) ->when the T cell clone sees the self Ag anew, there will be no response |
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What kind of interactions take place if a T cell undergoes anergy?
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The APC presents the self-Ag without the co-stimulatory molecule or there are co-inhibitory molecules present at the surface of the APC
-Because there is no co-stimulatory molec present or because there are co-inhibitory molec, the interaction between the APC and the T-cell lead to T cell anergy and functional unresponsiveness .: in the presenc of co-inhibitory molec or the absence of co-stimulatory molec, Ag recognition by T cells leads to T cell tolerance |
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What is phenotypic skewing?
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Cytokine deviation
-Some T cells have more autoreactive potential than others -But since they interact with one type of dendritic cell (tolerogenic DCs) or because they're interacing with a subset of T cells: T regulatory cells, then they produce non-pathogenicv cytokines (instead of producing pro-inflammatory cytokines) -> .: no disease |
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What is activation induced cell death?
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Some lymphocytes that are activated by pathogens have autoreactivepotential
-if these lymphocytes aren't removed, they can cause autoimmunity |
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What happens following the proliferation of lymphocytes after the proliferation of a pathogen?
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Most of the lymphocytes undergo apoptosis
->this decreases the amount of lymphocytes that have proliferated |
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Whaqt do some of the lyphocytes become?
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Memory cells (allow for faster response next time the same pathogen is encountered)
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What is ALPS?
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Autoimmune Lymphoproliferative syndrom
->ppl that have a defect in their apoptotic pathway (mutations in molecules that are extemely important fo apoptosis) |
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What are the 2 major problems associated with ALPS?
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1) Lymphoproliferation: no apoptosis, so lymphocytes will multiply eternally
2) Autoimmunity: no apoptosis, .: can't get rid of autoreactive T cells |
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What kind of diseases do ppl with ALPS get?
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Hemolytic anemia
Idiopathic thrombocytopenic purpura (ITP) (platelets are attacked) Neutropenia (neutrophils are attacked and eliminated) Kidney disease etc |
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What physiological effects does ALPS also cause?
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Enlarged spleen,liver and lymph nodes (since lymphocytes divide indefinitely and don't die)
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What areT regulatory cells?
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Can directly contact autoreactive T cells or produce different cytokines (indirectly affect autoreactive T cells) to keep harmful autoreactive T cells under control
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What are the different kinds of Treg cells?
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Treg's that are CD4+CD25+ (also FoxP3+): express high levels of the alpha chain of the IL2 receptor
Tregs that are called TH3 cells Tregs that are caled TR1 cells T regs that are CD8+ regulatory cells |
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What do all these Treg cells have in common?
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They produce IL-10 ad TGF-beta
-once these cytokines interaact with APCs, they decrease their level of expression of MHC and the level of co-stimulatory molec on the surace of the APC -these cytokines also decrease the APC fct and th action of the pro-inflammatory cytokines that the dendritic cells produce |
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What is the result of T reg cells?
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Cause autoreactive T cell clones to have decrease potential for T cell proliferation
->they will secrete less proinflammatory cytokines |
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What happens when Treg cells interact with dendritic cells?
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Can make them tolerogenic DC
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Describe FocP3+ T regs.
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T cells that have high affinty for self during maturatioin
Exprss CD4 on their surface Upregulate expression of FoxP3 ->They will migrate out to the perphery, contact APC or the autoreactive T cell clone directly and will decrease their harmful potential by controlling them |
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What happens to ppl who have a mutation in the FoxP3 TF?
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Have a non-fcnal FoxP3
Don;thave T-reg cells End up with IPEX syndrome |
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What is IPEX?
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Immunodysregulation Polyendocrinopathy Enteropathy X-linked syndrome
-X-linked .: FoxP3 is present on the X-chr -Rare disease -Leads to the dysfct of T reg cells and subsequent autoimmunity |
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What are tolerogenic DCs?
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Immature DCs that are always sampling self-Ag/peptides and presenting them through their MHC
-These DCs don't upregulate their co-stimulatory molec or may express co-inhibitory molec |
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What happens when tolerogenic DCs see T cells with an auteactive receptor?
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Don't activate that T-cell
->leads to T cell tolerance |
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What processes can lead to autoimmunity?
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Failure in thymic education (mutation in AIRE)
Release of normally sequestered Ag Defect in apoptotic path Decrease in the number of T reg cells (IPEX) Altered cytokine secretion pattern Molecular mimicry Release of pro-inflammatory mediators Modification of self Ag |
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What do Th1 cells produce?
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IFN-y (gamma)
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What do Th2 cells produce?
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IL-4,5,13,10
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What do Tregs produce?
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IL-10, TGF-B
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What do Th17's do?
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Produce cytokines specific for their class
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Which Th cells are important in inducing autoimmune diseases?
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Th1
Th17 |
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What are Th17 cell important in defending against?
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Microbes in epithelial and mucosal areas
(Have a high pro0inflammatory capacity) |
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What do Th17 cells produce?
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IL17
IL 22 |
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What is IL 22 important for?
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Defense vs Candida fungus and Staph bacteria
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What happens to ppl lacking Th17?
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Very susceptible to bacterial and fungal infections
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What happens to ppl who have excess Th17?
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Autoimmune disease susceptible
-> MS, psoriasis, rheumatoid arthritis These cells are proinflammatory .: can cause infammation at the sites where they're present |
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How can autoimmune diseases be classified?
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On the organs they're involved in
The arm of the immune system that is most involved in disease |
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What are some diseases that involve only 1 organ?
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MS: CNS
Diabetes mellitus: Pancreas IBD (inflammatory bowel disease): gut -> there are a few different types of self Ag involved that are uniquely expressed inside these organs/tissues |
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What is an example of a multisystemic disease?
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Systemic lupus erthomatus (SLE)
->in multi-systemic diseases, there are Ag that are ubiquitous ->SLE: ribonucleoptns serve as self Ag |
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How can you figure out which arm of the immune system causes the most harm in a disease?
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Use Transfer Experiment
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How do you know if autoantibodies are responsible?
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If you take blood from someone with Grave's diseases (disease where there are auto-Abs vs the thyroid stimulating hormone receptor) and inject the autoAbs into a healthy mouse
After a few days: mouse has increased thyroid H release (has a hyperactive thyroid gland) Indicates that it is in fact the autoAbs that are responsibly for the disease |
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What is responible for causing Myasthenia gravis?
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AutoAb
->if you inject T-cells from someone who has this disease into a healthy mouse, nothing happens -if autoAb are injected from the diseased mouse to a healthy one, the mouse develops the disease |
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Describe the MS experiment.
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Inject mouse with myelin basic disease then the EAE experimental disease (resembles MS) is induced
-This disease is mediated by myelin basic ptn-speciic Th1 cells -If we take these Th1 cells and inject them in healthy mice, the mice will be paralyzed -> See that autoreactive T cell clones play a major role in a particular autoimmune disease |
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What can pregnancy do?
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Allows transfer of maternal antibodies (but not T-cells)
Child can get a disease that resembles Grave's disease if the motehr has it, but after a few weeks, the newborn will return to its healthy state |
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Are there diseases where both autoAb and autoreactive T cells play a major role?
How is this visualized? |
Yes
-> B cells are able to generate autoAb that can cause harm -> These autoreactive B lymphocytes can also play an Ag-presenting role. Through its AP capacity, the autoreactive B lymphocyte can present self peptides to autoreactive T cells -> These cells can present harm to the host |
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What is an example of a disease in which both autoAb and autoreactive T cell clones play a major role?
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SLE
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What are factors that predispose a person to develop autoimmunity?
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Genetic factors
Environental factors |
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Why are autoimmune diseases a lot more complex then Mendelian diseases?
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Mendelian: mutation in a gene produces a genotype that leads to a phenotype (ie mutation in AIRE)
Autoimmune: can sometimes need genetic variation and polymorphisms in multiple genes, in addition to an encounter with the right environmental factor (i.e. a virus) and other events (i.e. smoking) to get the particular disease -> If one of these conditions are missing, then the individual will remain healthy |
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Do genetics play a role in autoimmune diseases?
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Possible
-> Studis involving monozygotic twins show that there is a higher concordance (presence of the same trait in both members of a pair of twins) rate in terms of the presence of autoimmune disease |
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If both monozygotic twins are the same genetic background, does it mean that they have to have the same autoimmune disease?
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No
->concordance rate between identical twins can actually be relatively low, depending on the disease ->There are mechanisms in one's immune system that makes one person different from another (VJ?VDJ rearrangements, receptor assembly, somatic hypermutation) |
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Is ther a clear ass't btw the presence of certain HLA haplotypes and disease?
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Yes
-> Ppl with HLA B27 have a higher risk of having an autoimmune disease that affects the back and that causes back pains ->Most disease susceptibility is strongly ass't with MHC II |
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What explains MHC genotype ass't with autoimmunity
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Susceptibility is determined by differences in ability of different allelic variants to present autoreactive Ag peptides to autoreactive T cells
-Also this ass't because MHC molec are shaping the TCR repertoire |
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How do aa changes of MHC correlate with susceptibility to disease?
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If a given aa is present in the peptide binding groove, then an ass't will be made with one of the aa in the alpha chain, leading to resistance to diabeted
-If another aa is present that does not interact with the aa on the alpha chain in the peptide binding groovem then there will be susceptibility to diabetes |
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Is a specific MHC haplotype sufficient to develop autoimmune diseases?
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No
-Autoimmunity'ass't haplotypes are also found in individuals with no clinical signs of disease (and vice versa) -The number of non-MHC genes may also contribute to autoimmunity |
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Does having the gene that predisposes an individual to have the disease mean you'll get the disease?
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No, at most 20% of the ppl will have the disease ass't with the gene
-> Emphasizes the importance of environmental factors |
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What happens in Goodpasture's syndome?
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Caused by autoAb (vs self-Ag)
Glomerulonephrititis (kidney disease) in all patients Only see development of pulmonary haemorrhage in 40% of individuals Most of these individuals are smokers Lack of tissue integrity gives autoAb access to basement mb lungs |
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Can medications and drugs cause autoimmune diseases?
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Yes
-> Procainamid inducing lupus-like Ab |
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How can toxins cause autoimmune diseases?
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By haptenizing (changing the shape/appearance of a molecule by binding to it) self ptns recognized as non-self
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How can infections cause autoimmunity in different ways?
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Causing the release of pro-inflammatory cytokines
Increasing thelevel of expression of co-stimulatory molecules at the surfce of DC/decreasing the level of expression of co-inhibitory molecules (can activate reactive bystander lymphocytes) Dysregulatin of the immune system: prevent apoptosis, secreting own cytokine-like molecules Moleclar mimicry: cross-reactivity btw infecious Ag and self Ag |
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What can superAg ptns do?
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Can activate a minute fraction of the T cell clones
The number of lymphocyte clones then increases rapidly with further superAg activation T lymphocytes that have been activated by the superAg can alsohave autoreactive potential, leading to autoimmunity |
