Term
|
Definition
| immune response directed at "self" antigens/tissues |
|
|
Term
| What is an autoimmune response? |
|
Definition
| any immune response that is directed against host tissues |
|
|
Term
| what are the effectors of autoimmune responses? |
|
Definition
| autoantibodies and autoimmune T cells |
|
|
Term
| What is an autoimmune diseases? |
|
Definition
| chronic disease state that results from autoimmune responses |
|
|
Term
|
Definition
| Antibody that inds to a cell surface receptor, thereby preventing its function |
|
|
Term
|
Definition
| Antibody that binds to a cell surface receptor in a way that mimics binding of the actual ligand to the receptor |
|
|
Term
| How are autoimmune diseases classified? |
|
Definition
| similarly to hypersensitivity reacitons; defined by immunological effector that causes diseases |
|
|
Term
| How do autoimmune diseases arise? |
|
Definition
| breakdown of negative selection processes that remove self-reactive B cells and T cells from lymphocyte repertoire |
|
|
Term
| How many people experience autoimmune diseases and in what populations, typically? |
|
Definition
| 2-3% of people in developed countries with higher incidence in females |
|
|
Term
| Which antibodies NEVER mediate autoimmune diseases? |
|
Definition
|
|
Term
| What causes Type II autoimmune diseases? |
|
Definition
| antibodies specific for components of cell surfaces or extracellular matrix |
|
|
Term
| What causes autoimmune hemolytical anemia? |
|
Definition
| IgG and IgM binding to surface of erythrocytes |
|
|
Term
| Through which complement cascade does autoimmune hemolytic anemia activate the membrane attack complex? |
|
Definition
|
|
Term
| What does activation of the classical pathway do in autoimmune hemolytic anemia? |
|
Definition
| destroys RBCs; bound Ab and C3b mediate clearance of RBCs from phagocytes in spleen |
|
|
Term
| What does RBC depletion cause? |
|
Definition
|
|
Term
| How do you test for autoimmune hemolytic anemia? |
|
Definition
| Direct Coomb's hemagglutination assay |
|
|
Term
| What autoimmune disease is caused when white blood cells are targeted for destruction by autoimmune response? |
|
Definition
|
|
Term
| How are WBCs cleared in neutropenia? |
|
Definition
| through phagocytes b/c nucleated cells are not efficiently killed by complement activation |
|
|
Term
| What is reduced in patients with neutropenia and why? |
|
Definition
| Reduced number of circulating neutrophils because autoimmune response is directed at surface antigens of enutrophils |
|
|
Term
| What are neutropenic patients more susceptible to? |
|
Definition
|
|
Term
| How do you treat patients with chronic autoimmunity to blood cells (in the neutropenia section)? |
|
Definition
| splenectomy (removing spleen reduces rate of blood cell destruction) |
|
|
Term
| Which autoimmune disease is caused by antibodies specific for extracellular matrix autoantigens? |
|
Definition
|
|
Term
| What are antibodies specific for in Goodpasture's syndrome? |
|
Definition
| alpha-chain of type IV collage (found in basement membranes throughout the body) |
|
|
Term
| Where do antibodies become deposited in Goodpasture's syndrome and what results? |
|
Definition
| deposited along basement membranes of renal glomeruli and renal tubules, eliciting inflammatory responses and eventually impaired kidney function/failure |
|
|
Term
| How do you treat Goodpasture's syndrome? |
|
Definition
| plasma exchange to remove self-reactive Abs and immunosuppressive drug treatment to prevent production of new autoantibodies |
|
|
Term
| What percentage of kidney failure is due to damage caused by immune system? |
|
Definition
|
|
Term
| What causes acute rheumatic fever? |
|
Definition
| antibodies which are produced in response to bacterial infection; antibodies cross react with self antigens of the human heart, and therefore are autoantibodies |
|
|
Term
| What special autoimmune mechanism is used in acute rheumatic fever? |
|
Definition
|
|
Term
| Describe the molecular mimicry mechanism in acute rheumatic fever. |
|
Definition
| Streptococcal cell-wall components are very similar to some constituents of the human heart tissue; antibodies raised as a component of protective response against Streptoccous are detriment to host because of similaritiies between Streptococcal antigens and self-antigens |
|
|
Term
| What do Streptococcal antigen-specific antibodies do? |
|
Definition
| They can bind to constituents of the heart tissue, initating an inflmmatory response tha causes heart damage (heart valve scarring, myocarditis) |
|
|
Term
| Why are B cells not fully activated in acute rheumatic fever? |
|
Definition
| T cells do not recognize Streptococcal surface antigens |
|
|
Term
| What benefit is drawn by the B cells NOT being fully activated (rheumatic fever)? |
|
Definition
| no immunological memory results and autoimmune disease is transient |
|
|
Term
| What symptoms are typically seen in acute rheumatic fever? |
|
Definition
| chest pain, fever, weakness, fatigue, joint pain |
|
|
Term
| What is caused by antibodies that bind to the thyroid stimulatory hormone receptor? |
|
Definition
|
|
Term
| What results from antibodies binding to the TSH receptor? |
|
Definition
| chronic overproduction of thyroid hormone that is independent of regulation by TSH |
|
|
Term
| What symptoms results from hyperthyroidism in Grave's disease? |
|
Definition
| heat intolerance, nervousness, irritability, warm/moist skin, weight loss, enlargement of thyroid, bulging eyes, characteristic stare (from autoantibodies binding to eye muscles) |
|
|
Term
| What is the autoimmune response biased towards in Grave's disease and what does this result in? |
|
Definition
| TH2 and little-to-no tissue destruction |
|
|
Term
| How do you treat Grave's disease? |
|
Definition
| drug therapy to reduce thyroid function/removal or destruction of thyroid |
|
|
Term
| What is unique about TSH receptor specific Abs? |
|
Definition
| can be transported across placenta to developing fetus causing enwborn to present with symptoms of disease; can be treated with TSH-receptor specific Abs via total plasma exchange; once maternal Abs are cleared, however, baby will "lose" disease |
|
|
Term
| How do you diagnose Grave's disease and other antibody-mediated autoimmune diseases? |
|
Definition
| inject patient serum into rat and monitor production of hormones; whole animal approach is now replaced by use of cultured cell lines |
|
|
Term
| What is myasthenia gravis? |
|
Definition
| an autoimmune disease in which signaling from nerve to muscle across the neuromuscular junction is impaired |
|
|
Term
| What are the autoantibodies specific for in myasthenia gravis? |
|
Definition
| acetylcholine receptors on muscle cells |
|
|
Term
| How does the autoimmune mechanism work in myasthenia gravis? |
|
Definition
| autoantibodies bind Ach receptors on muscle cells, inducing endocytosis and degradation in lysosomes |
|
|
Term
| What results from loss of Ach receptors? |
|
Definition
| muscle cell is less sensitive to neuronal stimulation |
|
|
Term
| How do you treat myasthenia gravis? |
|
Definition
| immunosuppressive drugs to prevent formation of autoantibodies; pyridostigmine (drug) to inhibit cholinesterase (Ach degrading enzyme) and allow longer-lived Ach more time to compete with autoantibodies for the receptors |
|
|
Term
| Describe mechanism of Guillain Barre Syndrome |
|
Definition
| molecular mimicry; mediated by IgG specific for gangliosides (common components of human nerve tissue); results in an acute inflammatory demyelinating polyneuropathy (AIDP) |
|
|
Term
| What does onset of Guillain Barre typically follow? |
|
Definition
| typically follows infection because immune response made against the pathogen cross-reacts with gangliosides; often a diarrhea-causing Campylobacter jejuni infection |
|
|
Term
| What are symptoms of Guillain Barre? |
|
Definition
| symmetrical weakness of lower limbs that rapidly ascends to upper limbs and face; difficulty swallowing and breathing and drooling are also common once muscle weakness has ascended to the face; ascending muscle weakness/paralysis can occur in hours/days and is highly characteristics/diagnosic |
|
|
Term
| What type of paralysis typically occurs in Guillain Barre? |
|
Definition
| partial paralysis; patients usually regain most motor function with appropriate and effective treatment |
|
|
Term
| What type of treatment is there for Guillain Barre? |
|
Definition
| plasma exchange with immunosuppressive drug treatment |
|
|
Term
| what is a rare variant of GBS? |
|
Definition
|
|
Term
| How does Miller-Fisher syndrome differ from GBS? |
|
Definition
| paralysis develops in a descending fasion; initally affect ocular muscles and then descend to arms and then legs |
|
|
Term
| What is Wegnener's Granulamatosis? |
|
Definition
| typified by molecular mimicry; a type II autoimmune disease mediated by anti-neutrophil cytoplasmic antibodies (ANCAs, IgG); most common determinant is proteinase-3 |
|
|
Term
| What do ANCAs do in Wegener's Granulomatosis? |
|
Definition
| ANCAs bind to neutrophils, activating them; these cells upregulate adhesin molecule expression, allowing them to bind to vascular endothelial cells; they then degranulate causing damage to vasculature (vasculitis) |
|
|
Term
| When does Wegener's Granulomatosis typically onset? |
|
Definition
| After bacterial or viral infection; response to pathogen elicits production of IgG that cross reacts with neutrophil determinants |
|
|
Term
| What are the symptoms of Wegener's Granulomatosis? |
|
Definition
| 1st, rhinitis; Upper airway, airways, kidney, arthritis, skin, nervous system, heart/GI tract/brain/other organs rarely affected |
|
|
Term
| Describe the nasal symptoms of Wegener's |
|
Definition
| pain, stuffiness, nosebleeds, rhinitis, saddle-nose deformity due to perforated septum |
|
|
Term
| Describe the ear symptoms of Wegener's |
|
Definition
| conductive hearing loss due to Eustachian tube dysfunction, sensorineural hearing loss (unclear mechanism) |
|
|
Term
| Describe the eye symptoms of Wegener's |
|
Definition
| pseudotumors, scleritis, conjunctivitis, uveitis, episcleritis |
|
|
Term
| Describe the airway symptoms of Wegener's |
|
Definition
| Trachea: subglottal stenosis; Lungs: pulmonary nodules ("coin lesions"), infiltrates (often interpreted as pneumonia), cavitary lesions, pulmonary hemorrhage causing hemoptysis, rarely bronchial stenosis (abnormal narrowing) |
|
|
Term
| Describe the kidney symptoms of Wegener's |
|
Definition
| rapidly progressive segmental necrotising glomerulonephritis (75%), leading to chronic renal failure |
|
|
Term
| Describe the arthritis associated with Wegener's |
|
Definition
| pain or swelling (60%), often initally diagnosed as rheumatoid arthritis |
|
|
Term
| Describe the skin symptoms of Wegener's |
|
Definition
| nodules on elbow, purpura, various others (cutaneous vasculitis) |
|
|
Term
| Describe nervrous system symptoms of Wegener's |
|
Definition
| occasionally sensory neuropathy (10%) |
|
|
Term
| What is the treatment for Wegener's? |
|
Definition
| plasma exchange with anti-inflammatory drug treatment |
|
|
Term
| What is a type III autoimmune disease? |
|
Definition
| caused by immune complexes that are deposited in the tissues |
|
|
Term
| What is systemic lupus erythematosus (SLE)? |
|
Definition
| autoimmune disease caused by autoantibodies specific for many intracellular macromolecules present in all cells in the body (DNA< histones, ribosomes) |
|
|
Term
| What is the butterfly rash? |
|
Definition
| Characteristic facial rash found in SLE |
|
|
Term
| Describe the incidence of SLE |
|
Definition
| more common in women than in men, especially Asian or African descent (1/500 Asian/African women contract it) |
|
|
Term
| How many SLE patients suffer from arthritis and typically when? |
|
Definition
| over 90% have arthritis and usually it is the first symptom noticed |
|
|
Term
| What happens in SLE (i.e. what do the autoantibodies do etc)? |
|
Definition
| autoantibodies bind to cell surface components initiating inflammatory reactions that lead to tissue destruction; SLE is a chronic inflammatory disease affecting tissues throughout the body; autoantibodies bind to macromolecules released from damaged cells, forming solule immune complexes |
|
|
Term
| What do the immune complexes do in SLE? |
|
Definition
| deposit in blood vessels, kidneys, joints, and other tissues leading to further initation of inflammatory responses (Type III hypersensitivity disease) |
|
|
Term
| What happens to SLE over time? |
|
Definition
| progressive disease; as tissue is damaged and inflammatory responses are initated, additional priming of autoimmune reactions occurs; autoimmune response that cause SLE mature over time and disease gets worse |
|
|
Term
| What course does SLE typically follow? |
|
Definition
| outbreaks of intense inflammation alternate with periods of relative calm; cycling |
|
|
Term
| How SLE patients commonly die? |
|
Definition
| progression is variable but many patients die of organ failure (kidney, brain) as a result of damage caused by immune complex mediated inflammation |
|
|
Term
| What do experiments in mice indicate about SLE? |
|
Definition
| suggest that breakdown of T cell tolerance may be key to development of disease; emergence of single autoreactive effector CD4 T cell specificity can lead to activation of B cells that are specific for many self-antigens |
|
|
Term
| What is insulin-dependent diabetes mellitus (IDDM)? |
|
Definition
| autoimmune disease that results in the selective destruction of insulin-producing cells in the pancreas |
|
|
Term
| How does insulin work in a normal person? |
|
Definition
| secreted by pancreas in response to increased blood glucose levels; binds to cell surface receptors stimulating uptake of glucose by body's cells; critical regulator of cellular metabolism and critical for proper development during childhood |
|
|
Term
| What do patients with IDDM produce? |
|
Definition
| T cell mediated autoimmune response that destroys insulin-producing cells in the pancreas; produce CTLs specific for an undefined protein component of B islet cells; also produce autoantibodies and T cells that aer specific for a number of products of B islet cells; CTLs progressively destroy B islet cells over time |
|
|
Term
| Who does IDDM primarily affect? |
|
Definition
|
|
Term
| When do IDDM patients typically present with symptoms? |
|
Definition
| manifest in childhood or adolescence; can progress to coma and death if untreated |
|
|
Term
|
Definition
| daily injections of insulin purified from pancreas tissue of cattle or pigs |
|
|
Term
| What can go wrong with insulin injections in IDDM patients? |
|
Definition
| patients may produce immune responses against pig/bovine insulin (non-self) resulting in reduced activity of insulin and leading to immune complex disease (Type III) |
|
|
Term
| What can you do to help patients who developed antibodies to animal insulin? |
|
Definition
| receive recombinant human insulin (more expensive) |
|
|
Term
| What is rheumatoid arthritis? |
|
Definition
| autoimmune disease resulting in chronic or episodic inflammation of the joints |
|
|
Term
| who does rheumatoid arthritis affect? |
|
Definition
| 1-3% of the population; women outnumber affected men 3:1; noticeable in ages 20-40 |
|
|
Term
| To what do patients develop autoantibodies in rheumatoid arthritis? |
|
Definition
| 80% of patients produce autoantibodies (IgM, IgG, IgA) specific for Fc regions of human IgG molecules; these autoantibodies are referred to as rheumatoid factor |
|
|
Term
| Is rheumatoid factor required for rheumatoid arthritis? |
|
Definition
| no, it is not required for tissue damage; in fact, 20% of patients do not produce rheumatoid factor |
|
|
Term
| What do you find in the affected joints of all patients? |
|
Definition
| characteristic leukocyte infiltrate that includes CD4 and CD8 T cells, B cells, plasma cells, neutrophils, and macrophages; inflammatory responses result in tissue damage |
|
|
Term
| What do neutrophils release in rheumatoid arthritis? |
|
Definition
| lysosomal enzymes causing tissue damage |
|
|
Term
| What do CD4 effector cells do? |
|
Definition
| activate macrophages that accumulate in the synovium, adding to the tissue damage |
|
|
Term
| How do you treat rheumatoid arthritis? |
|
Definition
| physiotherapy and various anti-inflammatory and immunosuppressive drugs; TNF-alpha blockers |
|
|
Term
| What is a mediateor of rheeumatoid arthritis? |
|
Definition
| TNF-alphai a primary mediator of inflammation |
|
|
Term
| Can rheumatoid arthritis be mediated by anything other than T cells? |
|
Definition
| possibly; a new treatment that is relatively effective is infusion of monoclonal antibodies (rituximab); rituximab has specificity for B cell surface marker CD20; Ab bind to B cells and serve as trigger for ADCC by NK cells and kills B cells (benefits 80% of patients; majorly benefits 50%) |
|
|
Term
| What is multiple sclerosis (MS)? |
|
Definition
| autoimmune disease caused by immune reponse directed at myelin sheath of nerve cells |
|
|
Term
|
Definition
| 1 in 1000 in some populations |
|
|
Term
|
Definition
| sclerotic plaques of demyelinated tissue in the white matter of CNS |
|
|
Term
| What symptoms are seen in MS? |
|
Definition
| motor weakness, impaired vision, lak of coordination, spasticity (spasms, overtoning of muscles) |
|
|
Term
| Describe the course of MS. |
|
Definition
| progression is highly variable; may be a slow progressive course or can involve acute attacks of exacerbating disease followed by periods of gradual recovery; extreme cases can lead to severe disability or death within a couple of years; mild cases can result in little to no neurological impediment |
|
|
Term
| What is responsible for the demyelination experiences in MS? |
|
Definition
| activated TH1 CD4 effector cells enriched in blood and CSF; cells produce IFN-gamma that activates sclerotic plaques; activated macrophages release proteases and cytokines which are directly responsbile for the demyeination that occurs |
|
|
Term
| What are the autoantigens of MS? |
|
Definition
| structural proteins of myeline (myelin basic protein, proteolipid protein, myeloid oligodendricyte glycoprotein) |
|
|
Term
| What are the treatments for MS? |
|
Definition
| high doses of immunosuppressive drugs (reduce severity of disease) and subcutaneous injections of IFN-beta 1 (reduces incidence of disease attacks) |
|
|
Term
| Describe the animal model for MS (Experimental allergic encephalomyelitis) |
|
Definition
| inbred strain of mice immunized with myelin basic protein emulsified in Freund's complete adjuvant produce myelin specific immune responses that attack CNS of the animal resulting in complete paralysis |
|
|
Term
| What is Sjogren's syndrome? |
|
Definition
| a systemic T cell mediated autoimmune disease that attacks exocrine glands that produce tears and saliva |
|
|
Term
| Who does Sjogren's syndrome affect? |
|
Definition
| 9/10 patients are women and average age of onset is late 40s; second most common autoimmune rheumatic disease |
|
|
Term
| What is primary Sjogren's syndrome? |
|
Definition
| syndrome existing as a disorder on its own |
|
|
Term
| What is secondary Sjogren's syndrome? |
|
Definition
| develops years after onset of an associated rheumatic disorder such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, primary biliary cirrhosis, etc |
|
|
Term
| what are the hallmark symptoms of Sjogren's syndrome? |
|
Definition
| mouth and eye dryness; skin, nose, and vaginal dryness; may also affect kidneys, blood vessels, lungs, liver, pancreas, peripheral nervous system and brain |
|
|
Term
| How do you diagnose Sjogren's syndrome? |
|
Definition
| Diagnosing it is very complicated and requires multiple tests including: blood tests for anti-nuclear antibody and rheumatoid factor; Schirmer test to measure tear production (strip of filter paper absorbs tears in lower eyelid); a slit lamp exam to measure dryness on eye's surface; savliary gland function test; lip biopsy reveals lymphocytes clustered around salivary glands; ultrasound of salivary glands is simplest |
|
|
Term
| What are the treatments of Sjogren's syndrome? |
|
Definition
| moisture replacement with artificial tears; wearing goggles to increase local humidity ; insertion of punctal plus gretain tears on the ocular surface; drug therapies to reduce inflammation or stimulate salivation |
|
|
Term
|
Definition
| genetic absence of transcription factor AIRE |
|
|
Term
|
Definition
| transcription factor that normally induces expression of immuune specific proteins in the thymus |
|
|
Term
| What happens when immune specific proteins in the thymus are not expressed? |
|
Definition
| negative selection of T cells is impaired |
|
|
Term
| What happens as a result of no negative selection? |
|
Definition
| autoimmune B cells and T cell responses develop against peripheral tissues, including most endocrine glands |
|
|
Term
|
Definition
| progression is different from patient to patient but most suffer from disorders of multiple organs/tissues |
|
|
Term
| Does autoimmune disease susceptibility run in families? |
|
Definition
| yes. Population studies revealed that HLA type correlates with susceptibility to IDDM |
|
|
Term
| What are the most important genetic factors in autoimmune disease susceptibility? |
|
Definition
| HLA antigen expression (either MHC class I or class II) |
|
|
Term
| Are particular HLA allotypes associated with certain autoimmune diseases? |
|
Definition
| yes. For example, those exprssing HLA-DR2 are almost 16X more likely to suffer from Goodpasture's syndrome than those who don't |
|
|
Term
| What factors other than HLA haplotype predispose to susceptibility to autoimmune disease? |
|
Definition
| many genetic factors in combination; differential susceptiblity of males and female indicate genetic factors other than HLA type |
|
|
Term
| How do environmental factors, such as the hazards of cigarettes, influence Goodpasture's syndrome? |
|
Definition
| 40% of Goodpasture's patients develop pulmonary hemorrhage and typically these are habitual smokers |
|
|
Term
| Why do habitual smokers often develop lung hemorrhage in Goodpasture's syndrome? |
|
Definition
| basement membranes of alveoli in nonsmokers are inaccessible to autoantibodies while smoking damages the alveoli, reudcing tissue integrity and allowing access of autoAb to basement membranes of alveoli; Ab initate inflammation that ultimately reuslts in hemorrhage |
|
|
Term
| What happens to an immunologically privileged site when it receives physical trauma? |
|
Definition
|
|
Term
| What is special about the anterior chamber of the eye? |
|
Definition
| contains specialized proteins involved in vision; immunologically privileged |
|
|
Term
| What happens if the eye is ruptered in some trauma? |
|
Definition
| eye proteins can drain to local lymph nodes where they can be processed and presented to naïve T cells; if an autoimmune response develops killer T cells will attack and destroy tissue in either eye |
|
|
Term
| What is the name of the malady describing an autoimmune reponse developing/kill T cells attacking and destroying ttise in either eye? |
|
Definition
|
|
Term
| Why do corneal transplants not require MHC haplotype matching? |
|
Definition
| corneal antigens will remain sequestered in eye after grafting; no corneal antigens will be available for presentation in secondary lymphoid tissues |
|
|
Term
| What are the immunlogically privileged sites? |
|
Definition
|
|
Term
| What is molecular mimicry? |
|
Definition
| A result of pathogens producing proteins that are similar to self-proteins or when antigens closely mimic self components |
|
|
Term
| What happens when molecular mimicry occurs? |
|
Definition
| can lead to autoimmun responses; immune effectors are produced by the immune system in response to antigen but they recognize both pathogen-derived antigen and self components that the antigen mimics, resulting in tissue damage |
|
|
Term
|
Definition
| an autoimmune diseases resulting from normal immune responsivenss to Streptococcal pathogen; the antibodies for the pathogen cross react with unique components in heart tissue, leading to inflammation and damage to the hear |
|
|
Term
| What can priming of T cells against peptided from pathogen components do? |
|
Definition
| lead to autoimmune diseases if the pathogen-derived peptides mimic peptides from a self-component |
|
|
Term
| When are T cell cross reactivities observed? |
|
Definition
| when two very similar peptides bind to MHC molecules of the same/similar allotype |
|
|
Term
| When else might you find T cell cross reactivities? |
|
Definition
| As a result from binding of 2 unrelated peptides to unrelated MHC allotypes |
|
|
Term
| Where are naïve T cells restricted to in contrast to effector T cells? |
|
Definition
| effector T cells have access to almost any tissue; naïve T cells are restricted to blood and secondary lymphoid tissue ( differential expression of adhesion molecules in effector T cells allows accessibility to tissues) |
|
|
Term
| What happens to T cells within tissues? |
|
Definition
| activated in response to pathogens but may encounter self material that did not participate in negative selectino or peripheral tolerance; if this self-material bears cross reactive determinants, pathogen specific T cells will attack that tissue |
|
|
Term
|
Definition
| antigens which vary between members of the same species |
|
|
Term
|
Definition
| immune responses directed against alloantigens |
|
|
Term
|
Definition
| subfield of immunology devoted to the genetics of alloantigens |
|
|
Term
|
Definition
| graft of tissue from one site to another site on the same individual (no rejection results) |
|
|
Term
| What is a syngeneic graft (isograft)? |
|
Definition
| graft of tissue from one individual to another individual that is genetically identical (no rejection results) |
|
|
Term
| What is an allograft (allogenic transplant)? |
|
Definition
| graft of tissue from one person to another person who is genetically different (rejection can result) |
|
|
Term
| What is transplant rejection? |
|
Definition
| alloreactions developed by patients immune system that are specific for grafted tissue and tissue is killed |
|
|
Term
| What is graft vs host disease (GVHD)? |
|
Definition
| reaction mounted by mature T cells contained in grafted tissue against tissues of the recipient |
|
|
Term
| What 3 basic problems must be addressed when transplanting tissues? |
|
Definition
| 1. You must introduce the transplanted in away that will allow it to perform its basic function; 2. donor and recipient must be in good health that is maintained during transplant surgery; 3. immune system of recipient must be prevented from mounting adaptive immune responses that destroy grafted tissue |
|
|
Term
| Are their techniques for ensuring the recipient's immune response will not mount a response to donor tissue? |
|
Definition
| No. There are no known procedures for selectively suppressing responsiveness to grafted tissues; systemic suppression of immune responses must be elicited for a recipient to tolerate an allogeneic graft |
|
|
Term
| What causes the immune responses against transplanted tissues? |
|
Definition
| genetic differences between donor and recipient (polymorphic gene expression, eg MHC molecules) |
|
|
Term
| What are the most important genetic differences in transplanation? |
|
Definition
| differntial expression of HLA molecules; HLA genes are highly polymorphic; differences in HLA molecules are the basis of most of alloreactivity produced by a recipient's immune system |
|
|
Term
| What is a blood transfusion? |
|
Definition
| transfer of blood from one individual to another; the easiest and most commonly used transplantation procedure |
|
|
Term
| What makes a blood transfusion an easier transplant than other tissues? |
|
Definition
| transfused blood components are only needed for a short time; RBCs do not express MHC class I or II molecules so alloantigens causing transplant rejections are not a problem |
|
|
Term
| Life-threatening alloreactions may occur from blood transfusions. What causes them? |
|
Definition
| based on the structural polymorphisms in the carbohydrates on glycolipids of the erythrocyte surface; known as A, B, and O blood group antigens |
|
|
Term
| How is that people produe antibodies to blood group antigens that are not their own? |
|
Definition
| many bacteria have surface carbohydrate molecules that a re structurally very similar to blood group antigens; antibodies produced to these bacteria react with blood group antigens in the same way |
|
|
Term
| What happens if a person is not matched properly for a blood transfusion? |
|
Definition
| person's anti-blood group antibodies will bind to transfused RBCs, resulting in complement activation and rapid clearance of transfused RBCs, thwarting purpose of transfusion |
|
|
Term
| What symptoms present when someone has had a mismatched blood transfusion? |
|
Definition
| fever, chills, shock, renal failure, sometimes death (similar to experiences in Type II hypersensitivity reaction) |
|
|
Term
|
Definition
| 50 defined Rh blood group antigens that are polymorphic with respect to expression within the population (most important is RhD- it is typically referred to as "Rh factor") |
|
|
Term
| How is Rh factor different from ABO antigens? |
|
Definition
| there are no structures on normal flora bacteria that are similar to RhD so people who do not express RhD will not have antibodies specific for RhD in their circulation |
|
|
Term
| What happens if someone who is RhD-neg is transfused with RhD-pos blood? |
|
Definition
| They will develop RhD specific antibodies; if they are subsequently transfused with RhD-pos blood, they will experience a life-threatening blood reaction |
|
|
Term
| Why is pregnancy interesting? |
|
Definition
| fetus is an allograft that can be tolerated repeatedly; its lack of rejection has fascinated scientistis |
|
|
Term
| What are some reasons that the fetus may not be rejected by the mother? |
|
Definition
| placenta is a partial barrier to mother's T cells and because it is fetal tissue, it lacks expression of MHC class I molcules |
|
|
Term
| What is another reason the fetus may not be rejected by the mother? |
|
Definition
| secondly, the placenta and uterine epithelium expresses an array of TH2 cytokines that promote antibody responses while suppressing T cell mediated responsiveness |
|
|
Term
| What does it mean for there to be RhD incompatiblity in pregnancy? |
|
Definition
| Rh factor negative mother (RhD-) carries RhD+ child |
|
|
Term
| Is there an immune response directed at the fetus in the case of RhD incompatibility (first pregnancy)? |
|
Definition
|
|
Term
| Why won't the mother mount an immune response to RhD incompatible fetus during the first pregnancy? |
|
Definition
| the normal flora in the body do not produce RhD-like antigens as they do for the other blood groups, so the mother has never been exposed to RhD (or RhD-like things) and will never have mounted an immune response |
|
|
Term
| Why might a mother reject a fetus due to RhD incompatibility during a subsequent pregnancy? |
|
Definition
| mother is exposed to large levels of fetal blood during birth/trauma/etc and mounts an RhD immune response; in the second pregnancy to an RhD+ fetus, preformed RhD-specific Ab will attack the new fetus |
|
|
Term
| How do you treat RhD issues? |
|
Definition
| passive immunization with Rhogam |
|
|
Term
|
Definition
| preparation of Ab that are specific for RhD+ erythrocytes |
|
|
Term
|
Definition
| Rhogam works by destroying all fetal RBCs that enter mother's circulation (by targeting RhD+ RBCs); prevents mother from producing an Rh-specific immune response by eliminating antigen before immune response can be initated |
|
|
Term
| Can Rhogam be given during pregancy and why would it be? |
|
Definition
| mother could have a minor accident during pregnancy that causes fetal blood to enter circulation; also, there is continuous exposure between maternal and fetal blood, so even without trauma, fetal RBCs may infiltrate maternal circulation |
|
|
Term
| Why must you consider A, B, O antigens in tisue and organ transplantation? |
|
Definition
| these antigens are expressed on endothelial cells of blood vessels, making them an important determinant in transplantation |
|
|
Term
| What happens in a person of type O blood who receives an organ transplant from a donor with blood type A? |
|
Definition
| anti-A antibodies of recipient would bind to A antigens along vascular endothelium of grafted tissue |
|
|
Term
| After anti-A antibodies bind A antigens, what happens? |
|
Definition
| complement activation throughout vasculature of the graft with very rapid rejection (12-48 hours) |
|
|
Term
| What else can mediate hyperacute graft rejection? |
|
Definition
| preformed antibodies specific for allogeneic HLA antigens |
|
|
Term
| How might anti-HLA antibodies be generated in a recipient (prior to transplant)? |
|
Definition
| immune responses to a previous pregnancy, blood transfusion, or previous tissue graft |
|
|
Term
| How do you test the levels at which a patient has been sensitized to potential donors? |
|
Definition
| test patient's sera against a panel of individuals from the population and results are expressed as percentage of positive reactions against panel (Paneal reactive antibody- PRA) |
|
|
Term
| How is an acute graft rejection mediated? |
|
Definition
| effector T cells that respond to HLA differences between donor and recipient |
|
|
Term
| What is an acute graft rejection a result of? |
|
Definition
| newly formed acquired immune response that is initated against alloantigens, following graft procedure (no preformed repsonses to alloantigens b/c no previous exposure) |
|
|
Term
| What happens when a skin graft is transplanted from a mouse to another mouse of the same inbred strain (identical MHC expression) |
|
Definition
| graft tissue is tolerated |
|
|
Term
| What happens when a skin graft is transplanted from a mouse toa another mouse of a different inbred strain? |
|
Definition
|
|
Term
| When does acute rejection occur? |
|
Definition
| typically between days 11-15 post-transplanation (time necessary for an acquired immune response to form against grafted tissue and for some tissue to be killed |
|
|
Term
| What happens in a mouse that previously received an allogeneic transplant (and rejected tissue) receieves a second transplant from same donor? |
|
Definition
| new graft is rejected much faster than normal acute rejection response (6-8 days post transplanat) |
|
|
Term
| Why is there more rapid rejection in a trnasplant patient who has been previously exposed and rejected tissue from a particular donor? |
|
Definition
| preformed acquired immune response produced AGAIN against first graft |
|
|
Term
| Describe the direct pathway by which HLA molecules can stimulate acquired immune responses |
|
Definition
| naïve T cells of RECIPIENT recognize self-peptides of DONOR loaded onto donor HLA molecules on donor APCs |
|
|
Term
| Describe the indirect pathway by which HLA molecules can stimulate acquired immune responses? |
|
Definition
| peptides derived from DONOR HLA molecules are processed and presented by RECIPIENT APCs to naïve T cells of the recipient |
|
|
Term
| What is the source of donor HLA molecules in the indirect pathway? |
|
Definition
| primarilyl donor APCs which migrate to secondary lymphoid tissue of the RECIPIENT and undergo apoptotic death |
|
|
Term
| What happens to the components of dead cells that have been processed in the indirect pathway? |
|
Definition
| phagocytosed/endocytosed by resident APCs; antigens are processed primariyl via MHC class II processing and presentation pathway |
|
|
Term
| What effectors are generated via the indirect pathway? |
|
Definition
| CD4 effector T cells that participate in acute graft rejection and are also a critical component of chronic rejection due to their role in the alloantigen-specific antibody resopnse that mediates chronic rejection |
|
|
Term
| What happens in minor histocompatibility antigen-mediated rejection? |
|
Definition
| results from immune responses to minor histocompatability antigens (when donor and recipient are identically matched with regard to MHC expression) |
|
|
Term
| Why do minor histocompatbility complexes play a role? |
|
Definition
| they are also polymorphic genes that can affect transplant outcome |
|
|
Term
| How long does rejection involving minor histocompatibility complexes take? |
|
Definition
|
|
Term
| What is chronic rejection? |
|
Definition
| can occur over months or years after transplantation |
|
|
Term
| What is chronic rejection correlated with? |
|
Definition
| presence of antibodies specific for MHC class I molecules of the grafted tissue |
|
|
Term
| What is chronic rejection characterized by? |
|
Definition
| reactions in the vasculature of the graft that results in thickening of the vessel walls and narrowing of their lumina; blood supply is gradually reduced to point that function of grafted tissue is lost |
|
|
Term
| What is the typical failure rate within 10 years of transplant with chronic rejection? |
|
Definition
| 50% for heart and kidney transplants |
|
|
Term
| Wh yis HLA matching important? |
|
Definition
| the more closely related, with respect to HLA expression, the donor and receipient tissues are, the better the outcome for the transplant |
|
|
Term
| Why are grafts between identical twins or family members often accepted? |
|
Definition
| identical twins: identical MHC expression (routinely accepted); same family: more likely to find good HLA match in a family than in general population |
|
|
Term
| why is it difficult to match donor tissue to a recipient with exact same complemetn of HLA antigens? |
|
Definition
| polygeny and extreme polymorphism of MHC expression in general population |
|
|
Term
| Why use immunosuppressive drugs for transplant patients? |
|
Definition
| suppress recipient's immune reactivity to allogeneic tissue grafts |
|
|
Term
| What do corticosteroids do? |
|
Definition
|
|
Term
| What do cytotoxic drugs do? |
|
Definition
| Kill proliferating cells, cyclosporin A, tacrolimas, and rapamycin selectively inhibit T cell activation |
|
|
Term
| What is the disadvantage to immunosuppression? |
|
Definition
| prevents immune system from reacting normally to pathogens that the host encounters (although the graft ed tissue is better tolerated) |
|
|
Term
| When is HLA matching not necessary? |
|
Definition
| liver and corneal transplanation |
|
|
Term
| Why do you not need HLA matching in corneal transplants? |
|
Definition
| cornea is not vascularized (immunologically privileged tissue) and unavailable to immune effectors |
|
|
Term
| Why does liver transplanation not need HLA matching? |
|
Definition
| has specialized architecture and vasculature; hepatocytes express very low levels of HLA class I or HLA class II |
|
|
Term
| What needs to be taken into account with liver transplantation? |
|
Definition
| it just does not require HLA cross-matching; only ABO type needs to be considered; some even claim that liver transplantation outcome is inversely correlated with degree of HLA match |
|
|
Term
| What improves liver transplantation? |
|
Definition
| cyclosporin A and tacrolimus |
|
|
Term
| What is the major cause of morbidity/mortality following bone marrow transplantation? |
|
Definition
| acute graft vs host disease (GVHD) |
|
|
Term
| How does bone marrow transplantation differ from solid organ transplantation? |
|
Definition
| solid organ:: alloreactions are limted to transplanted organ; bone marrow: systemic alloreactions |
|
|
Term
| what are the primary targets for GVHD? |
|
Definition
| skin, intestines, and liver |
|
|
Term
| what is GVHD mediated by? |
|
Definition
| mature T cells in the donor tissue that react to antigens of the recipient's tissues |
|
|
Term
|
Definition
| mature T cells can be depleted from bone marrow prior to grafting |
|
|
Term
| How can you control the incidence and severity of GVHD, in addition to depleting mature T cells from transplanted tissue? |
|
Definition
| methotrexate in combination with cyclosporin therapy |
|
|
Term
|
Definition
| diseases caused by malignant tumors |
|
|
Term
|
Definition
| mass of cells resulting from abnormal multiplication of host cells |
|
|
Term
|
Definition
| changes introduced into DNA (substitutions, insertions, deletions, recombinations, or chromosomal rearrangements) |
|
|
Term
|
Definition
| spreading of cancer cells through the lymph or bloodstream to distant parts of the body other than the original site |
|
|
Term
| What is a malignant transformation? |
|
Definition
| when a cell has become able to form a cancer |
|
|
Term
| What are proto-oncogenes? |
|
Definition
| genes that normally contribute positively to initiation and execution of cell division |
|
|
Term
|
Definition
| mutant forms of proto-oncogenes that contribute to malignant transformation |
|
|
Term
|
Definition
| a chemical or physical agent that increases mutation rate |
|
|
Term
|
Definition
| mutagen that increases risk of cancer cell formation |
|
|
Term
|
Definition
| from a single cell that has accumulated multiple mutations in genes that are involved in cell multiplication and cell survival |
|
|
Term
| Which two type of genes, that if mtuate or mis-expressed, can contrbiute to malignant transformation? |
|
Definition
| proto-oncogenes (usually initate or execute cell division) and tumor suppressor genes (normally function to prevent unwanted proliferation of cells |
|
|
Term
| How many mutations must cells accumulate to become a cancer cell? |
|
Definition
|
|
Term
| Why does cancer not usually occur at a high rate? |
|
Definition
| low mutation frequency and this requirement for multiple mutations |
|
|
Term
| When does incidence of cancer increase? |
|
Definition
|
|
Term
| what are some environmental insults that increase mutation rate? |
|
Definition
| chemical and physical agnets known as mutagens (carcinogens are mutagens specific to cancer) |
|
|
Term
| What do chemical carcinogens typically give rise to? |
|
Definition
| single base change mutations |
|
|
Term
| What people are higher risk for developing cancer? |
|
Definition
| elderly; those with prolonged, heavyexposure to carcinogenic agents |
|
|
Term
| what does radiation do (in regards to DNA)? |
|
Definition
| more pronounced mutations than chemical carcinogens, such as DNA breaks, cross-linked nucleotides, abnormal recombination |
|
|
Term
| What do human oncoviruses do? |
|
Definition
| contribute to development of cancer cells; infect cells and express virally encoded proteins that can override the cell's normal mechanisms for regulating cell division |
|
|
Term
| What do some viral pathogens do to cause development of cancer cells? |
|
Definition
| prevent normal tumor suppression mechanisms of infected cells from operating; gives rise to abnormally proliferating cells |
|
|
Term
| Can tumor cells be recognized and killed by CD8 T cells? |
|
Definition
| Yes, by allogeneic CD8 T cells; if a tumor cell from one strain of mice is injected into a mouse of a different strain, the tumor cels can be killed (Much like transplant rejection); this showed that tumor cells can be recognized by immune effector cells |
|
|
Term
| Are cancers eliminated by the immune system? Why or why not? |
|
Definition
| most cancers are not; probaly due to inability of immune system to recognize tumors cells as non-self |
|
|
Term
| Why might tumor cells still be recognized as self? |
|
Definition
| the mutations leading tumor cells result in only small changes that are unrecognized; cancer cell can proliferate with more mutations accumulating; eventually new antigens are produced by tumor cell (tumor antigens) |
|
|
Term
|
Definition
| new antigens produced by a tumor cell (after many accumulated mutations |
|
|
Term
| What are tumor-specific antigens? |
|
Definition
| antigens present on tumor cells but not normal cells |
|
|
Term
| What are tumor-associated antigens? |
|
Definition
| antigens found on tumor cells but also found on normal cells (though often in smaller amounts) |
|
|
Term
| what are the most common tumor antigens? |
|
Definition
| peptides bound to MHC class I molecules (recognized by CD8 T cells) |
|
|
Term
| Can protective immunity to tumors be elicited? |
|
Definition
| yes: mice were effectively immunized by injecting irradiated tumor cells; the anti-tumor immune response prouced can prevent subsequent transfer of live tumor cells of the same type; confirms that the immune system can kill tumor cells if a tumor-specific immune response can be generated |
|
|
Term
| What happens as tumor cells grow in a host? |
|
Definition
| newly formed cells within the tumor acquire different mutations |
|
|
Term
| What happens to tumor cells thatreceive a selectively ability to proliferate in the host? |
|
Definition
| they will continue to replicate |
|
|
Term
| What happens if the immune system is producing tumor-specific effector cells? |
|
Definition
| selective pressure for cells that do not present tumor antigens on their surface and cannot be recogized by CTLs |
|
|
Term
| Do tumor cells have defects in expression of HLA molecules (MHC class I molecules)? |
|
Definition
| usually between 1/3 and 1/2 of have defects |
|
|
Term
| What the alternative response to tumor cells that do not express MHC class I (to be killed by effector CTLs)? |
|
Definition
| can be killed by natural killer cells- cells must be devoid of production of EACH of the MHC clas I alleles |
|
|
Term
| what sort of zone do tumors create and how? |
|
Definition
| zone of immunosuppression by producing cytokines that suppress or misidrect immune responses |
|
|
Term
| Can monoclonal Ab be used to target tumor cells for destruction? |
|
Definition
| yes; monoAb specific for a tumor antigen can be produced if a tumor is characterized to the point that it has a unique tumor antigen identified |
|
|
Term
| What can tumor-specific Ab do? |
|
Definition
| detect tumors; target tumor cells for destruction |
|
|
Term
| How do tumor specific Abs target tumor cells for destruction? |
|
Definition
| mAbs conjugate to toxin molecule injected into a patient; the conjugate binds to tumor cell and toxin molecule is taken up by cell; cell is poisoned from the inside; mAb can also be conjugated to a radionuclide and inject into patient; when conjugate binds cell, the cell is irradiated and rendered unable to replicate |
|
|
Term
| What is the drawback to monoAb treatments? |
|
Definition
| immune system will produce acquired immune responses specific for the foreign antibodies and no further treatments by the Ab can be performed successfully |
|
|
Term
| How can you boost T cell responses? |
|
Definition
| isolate T cells specific for tumor antigen and grow/expan them in vitro (tissue culture); inject the expanded effector T cell population into patient |
|
|
Term
| Does boosting T cell responses successfully treat cancer? |
|
Definition
| yes, it has been shown to do so |
|
|
Term
| Describe the recombinant DNA approach of boosting T cell responses. |
|
Definition
| transfect tumor cells with cytokines or chemokines that either stimulate or chemattract dendritic cells to tumor, facilitating uptake and evetual presentation of tumor-specific antigens to naïve T cells |
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