9. Autoimmunity I Flashcards
Autoimmune Disease “horror autotoxicus”
• Immune reactions (T-cells or antibody) directed against ____- (auto) antigens which lead to tissue injury and clinical manifestations of disease
* Hypersen > result from immune response to a \_\_\_\_ antigen (hapten) * AID > result from immune reaction, directed against \_\_\_\_ antigens, use same mechanisms with similar outocme, but the antigens are different * Clinical manifestations depend on where reaciton is \_\_\_\_, but immune mechanism will contribute * Multifactorial disorders > involve derangement of \_\_\_\_ reg, contributing \_\_\_\_ component (UV radiation), or exposure to substances/toxins in the environement that alter tissue/immune response, and a \_\_\_\_ component * Autoimmune disease can be caused directly by reacting to \_\_\_\_. * AID can be \_\_\_\_ to another disorder * Autoimmunity may develop, but doesn't lead to any \_\_\_\_
self foreign own occurring immune environmental genetic self secondary pathogenesis
Autoimmune Disease
• May be organ ____ (localized antigen) or involve multiple ____ (widespread deposition of antigen or immune complexes)
– Note: clinical manifestations depend on ____ injured by immune system
• ____ disease, diabetes and ____ are among most common autoimmune diseases
• Collectively, afflict 2-8% of U.S. population:
– 75% of those afflicted are ____
– 4th largest cause of disability among ____ in U.S.
• Antigen - limited to organ - autoimmunity to antigen, and limited to organ • Antigen widespread > will become a multi-organ disease • \_\_\_\_ contribute to the disease (75% are female) ○ \_\_\_\_ - upregs immune system ○ \_\_\_\_ - dampens immune response
specfic organs organ/tissue thryoid SLE women women hormones estrogen androgens
Mechanisms of Autoimmunity
• Many autoimmune diseases are of ____ etiology
• Most autoimmune diseases have complex etiologic (or susceptibility) patterns
– ____
– Hormones
– ____
– Infection
• HLA genes (____ associated; ____ predispostion)
• Regulate immune response
• Affect negative selection of T-cells (____)
• Mutations in other ____ genes (e.g. Fas, AIRE, CTLA-4)
• Know the pathogenesis, clinical manifestations, and antigen - don't know the \_\_\_\_ • Autoimmunity vs hypersen > unable to respond to our own antigens - active process [tolerance]; in order for AI to occur > must lose \_\_\_\_ > loss of tolerance unleashes immune response to react to self • Risk factor > HLA protein; 4 loci with MHC (a-d; d is II, a-c is I); DR3, inherited for type 1 diabetes, your risk factor goes up \_\_\_\_x; inherit B8 (\_\_\_\_ fold increase for addison's), etc. ○ Risk increases, not \_\_\_\_ you develop ○ Infectious agents are contributing factors • You can also get these genes without these genetic mutations. Basically, we can see that the \_\_\_\_ may be involved in the development of autoimmune diseases. Might do this through presentation of self antigen or by acting as a receptor for an infectious agent.
unknown genetics environnment disease genetic central tolerance immunoregualtory
etiology tolerance 5 4 guaranteed MHC
Immunologic Self-Tolerance:
• Specific repression of the immune response to autoantigens
• Requires exposure to ____ (auto)
Properties:
• “____” phenomenon
• ____ lymphocytes are more susceptible to induction
• Immunologic tolerance to self exhibits the same properties as those of ____ immunity (inducible, ____ and memory)
• Both ____ and peripheral mechanisms exist to induce and maintain tolerance to self
antigen acquired or learned immature adaptive specificity central
Immunologic Tolerance
• ____ Tolerance
• ____ Tolerance
• Sequestered ____
Serves to eliminate or inactivate auto- reactive lymphocytes
* No tolerance, but due to fact that self-antigens are sequesterd and immune system doesn't have \_\_\_\_ * Each contributes to inability to react to self
central
peripheral
self-antigen
access
Central tolerance
• Clonal deletion of self-reactive ____- and B- cells
• AIRE (autoimmune regulator) protein:
– Stimulate expression of auto-antigens in ____
– Critical to elimination of immature auto-reactive T-cells
– Defects/mutations may contribute to susceptibility to ____ disease
• Central tolerance induction is not ____ effective; autoreactive lymphocytes gain access to the peripheral circulation.
• Primary lymphoid tissue (thymus/bone marrow) • Immature lymphocyte exposed to antigen > the cell undergoes deletion (apoptosis); another outcome (happens to both B and T cells) is that the receptor (IgM, and Tcl, both antigen specific) undergoes \_\_\_\_ so specificity changes and the autoreactive cell no longer recognizes antigen (when it's immature) ○ Exposure newborn to foreign antigen before it can mount a response, you can make it \_\_\_\_ (exposure during development) ○ During development, should be only autoantigens
T
thymus
autoimmune
100%
editing
tolerant
Peripheral tolerance
• Peripheral tolerance necessary to prevent activation of autoreactive lymphocytes that escape central tolerance or arise later
• Suppression by ____ T cells
– IL-10, TGF-B
• Anergy (prolonged or ____ functional inactivation)
• Activation-induced ____
• Generation of specific Treg (antigen-specific), they see autoantigen, but they make inhibitory cytokines (IL10, and TGFb) • T cell becomes anergic (can't respond, \_\_\_\_ and cannot be activated), or activation of cell (but goes halfway and undergoes \_\_\_\_) > activation induced cell death ○ Same applies to B cells • Peripheral mechanisms that actively remove, and require a continual exposure of antigen
regulatory
irreversible
death
survives
apoptosis
Sequestered self antigen
unable to activate immune response, but tolerance does not exist
- ____ barrier
- ____ privileged site
- Auto-antigens unavailable to____ system to induce tolerance• ____ antigens > similar, no tolerance
physical
immunologically
immune
intracellular
Mechanisms of Autoimmunity (“breaking of tolerance”)
• ____ of T/B cell receptors—-autoreactive cells
• Deletion or altered activity of ____ T-cell function
• ____ modulation of immunity
• Nonspecific activation (PCA)
• Altered self:
– Mutation
– ____ binding (drug)
– Tissue injury (inflammation, degradation) – ____
• Antigenic mimicry
• ____ antigens
Typically receptors mutate to make higher affinity receptors for pathogenic antigens. However, in times
when your immune system is trying to do this (when you’re infected), it might lead to the creation of an
____ T/B cell receptor.
Hormones may drive an immune response to the point where it doesn’t respond to ____ mechanisms. Some of the effects may be on the peripheral tolerance system.
PCA = Polyclonal Cell activator (mentioned in 1st lecture); these will activate a B/T-Cell. It will be very
similar to antigen-driven activation. But b/c they are polyclonal, they ____ activate B/T cells and
if one of those cells is auto-immune reactive, it could cause disease.
During life if any self antigens are altered (e.g. mutation; hapten binding -> won’t just respond to the
hapten or complex, it will also react with the self-protein as well; tissue injury -> degraded products might
be reacted to; ____ = we have some antigens that are similar to bacterial antigens. So, when
we get infected by a bacteria with a similar antigen, we’ll make antibodies against it. This could cause some cross-reactivity, so those activated cell and antibodies attack our own cells that have a similar
antigen to the bacteria)
Maturation antigens = self-antigens that develop on later on in life. These antigens are like ____ antigens, in that we don’t have tolerance for them. This means we don’t need to go through the process of “breaking ____” when we’re exposed. It’s just like a normal immune reaction.
mutation regulatory hormonal hapten infection maturation
auto-reactive
feedback
non-specifically
antigenic mimicry
sequestered
tolerance
Mechanisms of Autoimmunity (immune mediated mechanisms of tissue destruction)
• Cell mediated injury-DTH – e.g., ____
• Antibody mediated:
– Immune cytotoxic reactions- ____ Hyp
• e.g. ____ vulgaris
– Immune complex reactions-Type ____ Hyp
• e.g., ____
– Receptor ____ (e.g., Graves disease)
– Receptor ____ (e.g., Myasthenia gravis)
Once ____ is broken, the immune system is unleashed. When antibodies are involved, the antigen may be ____ (resulting in immune complexes) or ____ to cells or tissue such as basement membrane, making it a type II reaction that may involve: complement activation, attraction of NK cells, macrophages etc.
Type I diabetes Type II pemphigus III SLE stimulation blockade
tolerance
soluble
attached
Mechanisms of Autoimmunity
Hypersensitivity diseases: foreign antigen, NO NEED TO BREAK ____. There’s no tolerance to foreign antigens.
Autoimmune diseases: requires that the etiologic events break tolerance. This starts a pathogenic mechanism that might involve ____ immunity. If cell mediated immunity causes tissue damage we call it ____ hypersensitivity. Type 2/3 reactions: reactions that involve fixed/soluble antigen that interacts with ____ class antibody.
All the AI (autoimmunity/immune) diseases we’re gonna look at either due to process of: ____ hypersensitivity (t-cells, cytokines etc…ex. Type 1 diabetes) OR ____ mediated where the antigen is fixed, and these involve cytotoxic reactions associated with type ____ sensitivity, except now we’re dealing with an autoantigen (ex. Pemphigus vulgaris).
There are diseases that involve soluble antigen and the formation of ____. If they form in the blood (where they tend to accumulate), they activate complement and
platelets and as a result this complement mediated attracted of neutrophils leads to neutrophilic destruction of tissue and formation of microthombi and ischemia. Ex. Systemic Lupus Erythematosis.
tolerance
cell mediated
delayed type
GRM
delayed type
antibody
2
immune complexes
• Involves ab (IgG) > instead of ab binding antigen > ab binds something functional
○ Ab binds to receptor and mimics the ligand > change in organ bc antibody is blocking ligand, or will mimic and stimulate
§ Thyroid reg by pit by PSH, which is reg by hypo (TSH on thyroid is stimulatory) producing ____
§ Graves > autoimmune against the receptor > ab mimics the ligand (____) > loses the normal feedback mechanism > constantly ____
○ Ab blocks function > neuromuscular junction; presynaptic side of the junction has nerve endings where the impulse travels down to the nerve and ACH is released > binds to receptors on the ____ side, which transmits the impulse across the synapse
○ In myasenthia gravis, AB are produced to those receptors that block the receptor from binding to ACH and signal transduction is disturbed; these are mechanisms you don’t see in typical hypersensitivity disease that are involved in some AI diseases.
thyroglobulin
TSH
stimulated
muscle
Pernicious anemia
• Antigen:
– ____ factor
• Pathogenesis: – Autoantibody • Blocks binding to vitamin \_\_\_\_ • Blocks binding of complex to \_\_\_\_ – May be associated with other types of autoimmune disorders (\_\_\_\_ and adrenalitis)
• Clinical symptoms; associated with malabsorption of vitamin B12 (req. for ____ synthesis)
– Megaloblastic ____
– Reduced ____ (anemia)
– Classic triad of weakness, ____ tongue (erythema and atropy), and paresthesias
• Autoantigen > intrinsic factor > involved in B12 absorption ○ Produced by \_\_\_\_ epithelium, binds ingested B12 > complex binds \_\_\_\_ on epi cells (Cubam) > internalized • Not clear what breaks \_\_\_\_ • Patient develops ab's that binds intrinsic factor and prevents B12 from binding > patient becomes B12 deficient ○ Not clinical manifestations directly of ab function, but indirectly bc of \_\_\_\_ deficiency • Suffers anemia > lack sufficient RBC (maturation process) ○ Abnormal \_\_\_\_ in BM ○ Reduced ability of getting \_\_\_\_ to the tissue; has a toll of neurons (\_\_\_\_) • Epithelial cells of \_\_\_\_ tract are affected ○ The tongue is an example
B12
Cubam
thyroiditis
DNA
anemia
hematocrit
sore
gastric receptor tolerance B12 megablasts oxygen parasthesia
GI
• Megaloblastic anemia:
– Bone marrow is ____ with large megakaryocytes
– PMNs are ____
– RBC oval, ____-shaped
* Abnormal megakaryocytes > larger, and more of them > cannot \_\_\_\_ properly without B12 * Blood smear > neutrophils > hyper-segmented > \_\_\_\_ lobes (as opposed to 4); also the RBC are ovoid (and reduced in number) * Morphologic changes that have functional change
hypercellular hypersegmented egg mature 5/6
Autoimmune hemolytic anemia
• Antigen:
– ____ on RBC (e.g. drugs)
• Pathogenesis:
– autoAb (____ or IgM) leads to removal and destruction of RBC by lysis and/or phagocytosis
• Clinical symptoms:
– ____, splenomegaly, ____ and weakness, pale skin, Increased ____, dyspnea
• Warm agglutinins (IgG): ____ affinity antibody cause hemolysis and opsonization; reactive at ____C
• Cold agglutinins (IgM)> ____ affinity, react with RBC below ____°C (i.e., ears, hands, toes) and may cause ____ phenomenon
• Tx: RBC ____, steroids, ____
• Substance adsorbs to RBC > immune response • If immune response to just hapten > hypersensitivity ○ If the response is to the \_\_\_\_, and to the RBC w/o hapten > autoimmune • Similar manifestations to \_\_\_\_ ○ Jaundice > reflects pathologic mechanisms > extensive hemolysis > release of hemoglobin/billirubin > jaundice ○ They also present with \_\_\_\_ because a lot of these AB coated RBC being removed by phagocytes is taking place in the spleen. • Raynaud's phenomena > due to \_\_\_\_ agglutinins ○ Class of IgM antibodies (not all); binds same antigen on RBC, instead of hemolysis, these cells aggregate and block blood flow where it's cool out in \_\_\_\_
neoantigens
IgG
jaundice
fatigue
HR
high 37 low 30 raynaud's
transfusion
immunosupp’s
complex pernisicia anema splenomegaly cold periphery
