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94 Cards in this Set
- Front
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innate immunity |
-receptors are germ line encoded -response is fast and non-specific -no memory -consists of PMNs, macrophages, DCs, NK cells, complement |
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adaptive immunity |
-receptors generated during lymphocyte development -response is slow on first exposure -memory response is fast and more robust -consists of T cells, B cells and circulating antibody |
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macrophages |
phagocytosis and activation of bactericidal mechanisms
antigen presentation |
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dendritic cells |
antigen uptake in peripheral sites
antigen presentation |
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neutrophil |
phagocytosis and activation of bactericidal mechanisms |
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eosinophil |
killing of antibody-coated parasites |
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basophil |
promotion of allergic responses and augmentation of anti-parasitic immunity |
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mast cell |
release of granules containing histamine and active agents |
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MAMPS/PAMPS |
microbe/pathogen associated molecular patterns - used in detection by innate immune system |
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DAMPS |
danger associated molecular patterns - molecules released by cells undergoing necrosis to signal for a stronger immune response |
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macrophage activation |
Th1 cell recognizes complex of bacterial peptide with MHC
Th1 cell has CD28, macrophage B7 (CD80 and CD86) |
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B cell activation |
Helper T cell recognizes complex of antigenic peptide with MHC class II
T cell has CD40L, B cell has CD40 |
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ways antibodies prevent infection |
neutralization, opsonization, complement activation |
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Autoimmune Polyglandular Syndrome (APS) type 1 |
-autosomal recessive -autoantibodies to endocrine glands, skin and liver antigens, platelets -ectodermal abnormalities - nails, teeth, skin -susceptible to candidiasis -gene: AIRE, a transcriptional regulator that affects expression of autoantigens in thymus during development |
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autoimmunity |
-an adaptive immune response against self antigens due to loss of tolerance -the response is designed to clear the antigens and avoid a sustained immune response -unknown trigger - both genetic and environmental influences |
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concentration and self vs. nonself |
high and constant concentrations of an antigen correlates with self vs. sudden increase with non-self |
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central tolerance |
deletion and editing - occurs in bone marrow and thymus
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antigen segregation / immune privilege |
physical barrier to self antigen access - occurs in peripheral organs |
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anergy |
cellular inactivation by weak signal, absence of co-stimulation - occurs in secondary lymph tissue |
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AIRE |
autoimmune regulator gene - promotes expression of some tissue specific antigens in medullary thymic epithelial cells (mTEC) causing deletion of self reactive T cells (negative selection)
in the absence of AIRE, T cells reactive to tissue specific antigens mature and leave the thymus |
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peripheral tolerance |
a fraction of self-reactive T cells escape deletion and exit the thymus
ignorance, anergy, phenotypic skewing, apoptosis, tolerogenic dendritic cells, regulatory T cells |
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phenotypic skewing |
auto-reactive T cell secretes cytokines that will not promote an immune response against the self antigen |
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conditions that may activate lymphocytes that weakly recognize self |
-bystander activation during an infection -change in antigen composition due to infection or unmethylation of DNA (looks like microbial DNA) -change in availability of antigen - ex. after MI -autoantigen form changes - ex. immune complexes after infection or vaccination -B cells in germinal centers - somatic hypermutation leads to autoreactive B cells
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immune privilege |
-traditionally thought to be excluded from immune surveillance - brain, eyes, testis, uterus -limited communication or lymph drainage -tissue barriers, suppressive cytokines, apoptosis promoting proteins like Fas L expressed -sites can still be affected by autoimmunity |
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sympathetic ophthalmia |
-trauma to one eye results in release of sequestered intraocular protein antigens -released intraocular antigen is carried to lymph nodes and activates T cells -effector T cells return via bloodstream and encounter antigen in both eyes |
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Immune Dysregulation, Polyendocrinopathy, Enteropathy X linked (IPEX) disease |
defective FOXP3 gene (normally expressed in regulatory T cells)
Treg cells unable to inhibit naive T cell development into T helper cells, leading to proliferation of effector cells causing autoimmune disease, allergy, graft rejection, IBD, cancer, infectious disease |
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alternative regulatory cells |
-mucosal immune system (Th3, Tr1) -NK cells -NKT cells -CD8 -regulatory B cells -tolerogenic dendritic cells |
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limiting the immune response |
-activation induced cell death -intrinsic, inherent death pathways -extrinsic - Fas L, Treg cells
mutations in death pathways can result in autoimmunity |
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organ specific autoimmune diseases |
-DM, MS, Hashimoto's, Graves |
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systemic autoimmune diseases |
SLE, RA, scleroderma |
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immune responses in autoimmunity |
-can be T or B cell dominated -tissue and environmental effects involved -dysregulation of immune response - inability to turn off immune response, defects in central tolerance -inability to clear antigen leads to amplification of immune response --> epitope spreading |
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Myasthenia Gravis |
antibodies to AchR at NMJ
progressive weakness |
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DM1 |
autoantibody production and destruction of islet cells - combination of increased T cell pathogenicity, decreased Treg function, myeloid cell recruitment
Type IV HSR
can intervene if found early enough |
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IBD |
-Crohn's and ulcerative colitis -T cells recognize antigens derived from commensal microbiota
Type IV HSR |
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Graves disease |
-antibodies against TSH receptor (agonist)--> hyperthyroidism -levels of TSH are low because thyroid hormone shuts down TSH production by the pituitary but antibodies keep stimulating TH production -antibodies may cross the placenta and affect the fetus -the newborn will also suffer from Graves, but plasmapheresis removes the maternal antibodies and cures the disease
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chronic inflammation may perpetuate autoimmune disease |
circulating B cell may bind self antigens released from injured cells, get activated by T cell specific for that antigen, differentiate and cause more inflammation at site of injury, amplifying cycle of tissue damage |
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epitope spreading |
B cells specific for components of a complex antigen are stimulated by an autoreactive helper T cell of a single antigen specificity
ex. SLE anti DNA and anti histone antibodies |
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autoimmune hemolytic anemia |
antibody against Rh blood group antigens, I antigens --> destruction of RBCs by complement and FcR+ phagocytes --> anemia
splenectomy if this cannot be stopped
nonautoimmune causes of hemolytic anemia: mycoplasma, blood transfusion reaction, maternal response to Rh factor from fetus |
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autoimmune thrombocytopenic purpura |
antibody against platelet integrin GpIIb:IIIa --> abnormal bleeding
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Goodpasture's syndrome |
antibody against noncollagenous domain of basement membrane, collagen type IV --> glomerulonephritis, pulmonary hemorrhage
hematuria and hemoptysis |
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Pemphigus vulgaris |
antibody against epidermal cadherin --> blistering of skin |
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acute rheumatic fever |
antibody for streptococcal cell wall antigens cross react with cardiac muscle --> arthritis, myocarditis, late scarring of heart valves |
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DM2 |
antibody against insulin receptor (antagonist) --> hyperglycemia, ketoacidosis |
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hypoglycemia |
antibody against insulin receptor (agonist) |
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chronic urticaria |
antibody against receptor bound IgE or IgE receptor (agonist) --> persistent itchy rash |
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mixed essential cryoglobulinemia |
rheumatoid factor IgG complexes with or without hep C antigens --> systemic vasculitis |
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rheumatoid arthritis |
rheumatoid factor IgG complexes --> arthritis
also unknown synovial joint antigen triggers Type IV HSR leading to joint inflammation and destruction - cytokine release induces production of MMP and RANKL by fibroblasts which activate osteoclasts |
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Multiple Sclerosis |
autoantigens = myelin basic protein, proteolipid protein, myelin oligodendrocyte, glycoprotein --> brain invasion by CD4 T cells, muscle weakness, other neurological symptoms |
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psoriasis |
unknown skin antigens trigger inflammation of skin with formation of plaques |
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incidence of autoimmunity and gender |
affects 2-5% of US population, 78% women
SLE more common in reproductive aged females F:M is 8-15:1
MS - F:M is 2-3:1
Graves, Sjogren's Primary biliary cirrhosis more common in females
ankylosing spondylitis M:F is 2:1 |
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genetic basis of autoimmunity |
DM1: concordance of 35-50% in monozygotic twins, 5-6% in dizygotic twins
susceptibility most consistently associated with HLA genotype
mutations in: antigen clearance/presentation, receptor signaling, co-stimulatory molecules, apoptosis, cytokines |
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HLA genotype and DM1 |
a portion of healthy individuals have HLA DR2/x which diabetic patients lack - is it protective??
affected siblings tend to have 2 shared haplotypes - much higher number than expected if there's no HLA association in DM1 |
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hypothesis regarding MHC/HLA and T cells in autoimmunity |
different allelic variants of MHC may vary in ability to present self peptides - breakdown in selection of T cells during development because of poor MHC binding of self peptides |
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AIRE knockout |
decreased expression of self antigens in the thymus, resulting in defective negative selection of self reactive T cells
seen in APECED |
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CTLA4 knockout |
failure of T cell anergy and reduced activation threshold of self reactive T cells
seen in Graves, DM1 |
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FOXP3 knockout / mutation |
decreased in function of CD4CD25 regulatory T cells
seen in IPEX |
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FAS mutants |
failure of apoptotic death of self reactive B and T cells
seen in ALPS |
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C1q knockout |
defective clearance of immune complexes and apoptotic cells
seen in SLE |
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infection and autoimmunity |
Lyme arthritis, rheumatic fever, Reiter's syndrome - caused by molecular mimicry where T cell crossreacts with a self protein
Lupus, DM1 - bystander activation - also, sometimes drugs induce lupus (ex. procainamide, used to treat arrhythmias) |
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immune dysregulation in celiac disease |
it's unclear how it works...
at steady state, Anti-gluten Treg FOXP3+ cells suppress any reaction
in inflammatory state, something mysterious happens and gets antigluten antibodies - these are what you test for when diagnosing |
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corticosteroids |
inhibit inflammation - many targets including cytokine production by macrophages
decrease NO, prostaglandins, leukotrienes, adhesion molecules
increase endonucleases |
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azathioprine, cyclophosphamide, mycophenolate |
inhibit proliferation of lymphocytes by interfering with DNA synthesis |
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cyclosporin A, tacrolimus (FK506) |
inhibit calcineurin-dependent activation of NFAT; block IL-2 production and proliferation by T and B cells |
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rapamycin (sirolimus) |
inhibits proliferation of effector T cells by blocking Rictor-dependent mTOR activation |
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fingolimod (FTY270) |
blocks lymphocyte trafficking out of lymphoid tissues by interfering with signaling by the sphingosine-1-phosphate receptor |
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anti-TNFa therapy |
antibody to TNFa - used to treat RA, Crohn's disease, psoriatic arthritis and ankylosing spondylitis
increased risk of TB and lymphoma |
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most commonly transplanted organs |
kidney, liver, heart, lung........pancreas, intestine, face, limb
cornea most common non-vascularized |
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autograft |
tissue grafted back to original donor - burn patient gets skin from thigh |
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isograft |
graft between members of the same inbred strain or identical twins |
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allograft |
between members of the same species but of different genotypes - solid organ and bone marrow transplants |
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xenograft |
between two different species - pig liver into humans (in this case we react to glycoproteins on organ) |
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most commonly rejected HLA complex |
MHCII - DR |
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mixed lymphocyte reaction |
mix MHC T cells from two different people - irradiate one of the samples
measure proliferation of unradiated T cells to measure differences in MHCII molecules
measure killing of labeled target cells to detect activated cytotoxic T cells which depends on differences in MHCI |
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minor H antigens |
peptides derived from proteosome digestion
despite being the same protein in two people, this peptide may differ in aa sequence and thus be recognized as nonself in a recipient |
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2 ways for host to recognize alloantigen |
direct: donor APC activates recipient T cells specific for graft
indirect: recipient's APC presents graft peptides to recipient T cells |
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hyperacute rejection |
pre-existing recipient antibodies (blood transfusion) react to donor antigen (type II HSR) and activate complement - endothelial damage, inflammation, thrombosis
occurs within minutes - must remove graft |
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acute rejection |
inflammation due to cytokines released by recipient CD4 cells, killing of parenchyma and endothelial cells, and antibodies that are made after transplant
occurs weeks to months after
treat with immunosuppressants |
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chronic rejection |
recipient T cells perceive donor MHC as recipient MHC and react against donor antigens presented
stromal cell proliferation in small vessels, bile ducts, renal tubules, bronchioles
months to years later
can't be reversed |
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hematopoietic stem cell transplant |
treatment for leukemias and lymphomas, primary immunodeficiencies, inherited blood disorders
HLA matching similar to solid organ |
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Graft vs. Host Disease |
-donor T cells attack recipient tissues - severe inflammatory disease -most common in skin, liver, gut, lung - rash, jaundice, diarrhea -worse if MHC mismatch is also present -beneficial in leukemia -occurs most often in bone marrow and liver transplants because they have a lot of lymphocytes |
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why doesn't a fetus get rejected? |
many reasons, obviously there can't just be one explanation
syncytiotrophoblasts lack MHC molecules, uterus as physical barrier, complement control proteins, etc |
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what should immunosuppression focus on? |
blocking or killing T cells |
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some "mechanisms" of mutations that lead to cancer |
activating mutation of oncogene (1 hit)
inactivating mutation of tumor suppressor gene (2 hits)
germline mutation in a DNA mismatch repair gene (2 hits) |
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CD8 cells as a prognostic factor in colorectal cancer |
100% of patients will live 3 years if there are CD8 cells in the tumor
50% will die within 3 years if there are no CD8 cells in the tumor |
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perforin knockout |
increased lymphomas due to inhibited killing mechanism of NK cells and CD8 |
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RAG and STAT1 knockout |
gut epithelial and breast tumors due to deficiency in both adaptive and innate immune mechanisms |
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gamma:delta T cell knockout |
increased susceptibility to skin tumors by topical carcinogens |
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T cells activation |
signal 1: T cell receptor binds to HLA presented peptide on APC
signal 2: co-stimulatory interaction between T cell CD28 and APC B7 |
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tumor antibody immunotherapy |
1: Ab binds to tumor cell. NK binds to Fc on Ab and kills the cells.
2: Ab conjugated to toxin. Complex binds to tumor, gets internalized and killed.
3: Ab conjugated to radionuclide and binds to cell. Radiation kills cell and neighboring cells. |
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active immunotherapy (vaccine-based) |
identify tumor antigen that T cells recognize. Clone the antigen and administer as a vaccine by loading it on APCs
Provenge |
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adoptive immunotherapy (designer T cells) |
transfer mice T cells that recognize antigens
can be dangerous because antigens may in other places than tumor cells and you get a massive inflammatory response |
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3 E's of cancer immunoediting |
elimination, equilibrium, escape |
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mechanisms of evading anti tumor response |
-down regulate MHC (can still be killed by NK) -lose expression of immunogenic antigens -secrete anti-T cell cytokines like IL10 and TGFB -present antigens in tolerogenic form -antigen masking with mucopolysaccharides -don't express costimulatory molecules or express PD-1L which binds to PD-1 on T cells (but then you can give antibodies that bind PD-1L) |
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CTLA-4 blockade |
normally CTLA-4 on T cell binds to B7 on APC which inhibits cell cycle of T cell. use an antibody against CTLA-4 to allow T cell to proliferate |
