immunopathology II - lecture notes - julia Flashcards
what is the cause of type III immune reactions?
- disease is due to deposition of antigen-antibody complexes
- can be localized or systemic
describe the process of type III immune reactions
- sensitization of the immune system results in production of antibodies
- continuous or repeated antigen exposure results in ag/ab complexes being formed and deposited in tissue
- complement cascade activated (C3a, C3b, C5 frags, MAC)
- neutrophils and macrophages are attracted and activated
- focal acute inflammation causes tissue destruction
note: no direct attack on any tissue or organ or structure
what cell type is mostly involved in type III immune reactions?
mostly the neutrophils that cause tissue damage
but there’s also macrophages involved
what determines the type and location of tissue damage in type III reactions?
where and how the complexes are deposited
can be systemic or localized
what are some examples of systemic type III hypersensitivity reaction? (3)
- serum sickness
- SLE
- drug reactions
what are some examples of localized type III hypersensitivity reactions? (5)
- arthus reaction
- vasculitis
- glomerulonephritis
- arthritis
- pneumonitis
describe the pathogenesis of type III hypersensitivity reactions
- Fc receptor engagement and chemotactic factors released due to complement activation recruit neutrophils and monocytes => activation of phagocytes => release of lysosomal enzymes => necrosis
- complement activation also generates anaphylatoxin => release of vasoactive amines => vasodilation and edema
- platelet aggregation and activation of hageman factor => microthrombi formation => ischemia => necrosis
- activation of hageman factor => release of kinins => vasodilation and edema
what determines where antigen/antibody complexes localize?
- size:
- if little, can be removed by phagocytes in spleen
- if very large, may not get out of tissue at all
- hemodynamic and structural factors
- if flow not enough or chragd, may not be removed
- vascular permeability
- IgE mediated vascular permeability => blood vessel starts leaking and complexes inside lumen of vessel will be flushed into the tissue
what are the consequences/actions of the various complement components involved in type III hypersensitivity reactions?
- C3b => phagocytosis
- C3a + C5a => increased vascular permeability
- C3, C5 fragments, C5,6,7 complex => chemotaxis
- C5-9 => lysis
overall cause:
- vasculitis
- glomerulonephritis
- arthritis
- endocarditis
review the things released into tissue in a type III reaction (don’t memorize the table!)
note: you can zoom in on the computer
what type of immune reaction is post-streptococcal glomerulonephritis?
- localized type III hypersensitivity
what is the process by which post-streptococcal glomerulonephritis causes an immune reaction?
- individual gets an infection with a particular type of streptococcus (not the kind associated wtih rheumatic fever)
- this infection is usually infected with a particular phage
- results in antigen/antibody complex formation - circulate
- these complex are tiny and have a specific charge associated with them - allows them to cross the vascular membrane and enter the blood vessel lumen
- form large nodules of aggregated antigen antibody compelx
- deposited in glomerulus
what will post-streptococcal glomerulonephritis look like histologically (H&E stain)?
- neutrophils in glomerular tufts
- basement membranes thicker
what will post-streptococcal glomerulonephritis look like histologically with a immunoflorescent stain?
- granular “lumpy-bumpy” basement membrane staining due to IgG antigen deposits
- nonlinear localization of antibody
- aggregated antibody
what causes vasculitis (describe pathological process)? what type of reacton is it?
- type of type III hypersensitivity reaction
- occurs when antibody/antigen complexes are deposited in wall of blood vessels and then compliment is activated
- attracts neutrophils
- the combination of neutrophils and compliment results in destruction/disolution/digestion of the vessel wall
- results in hemorrhages, large infarctions, processes in adjacent tissue that cause that tissue to die
what types of arteries are affected in vasculitis? what determines where the tissue damage is located?
- affects medium to small sized arteries - the ones visible to the naked eye
- damage depends on where the complexes are deposited
what will vasculitis look like histologically?
- in this image, this is a muscular blood vessel
- the internal elastic lamina is the squiggly dark pink line
- there’s no smooth muscle left on the left side of the blood vessel
- thrombus formation in lumen
what will the necrotic phase of vasculitis look like histologically?
- hard to even tell it was a blood vessel
- few smooth muscle cells on bottom right corner of vessel, but otherwise muscle layer destroyed
- thrombosis in vessel lumen
what will vasculitis in the very small vessels look like histologically (as opposed the the medium/small vessels that are visible to the naked eye)?
- same pathological picture, but nto as dramatic
- this image is of lung
- note that this is often drug induced
what is the difference between vasculitis in really small vessels and in larger vessels? what is each condition called? how do the processes differ?
- the difference is in the phases of the disease and what likely causes it
- if it’s in small vessels, it’s likely caused by a drug induced/associated type III hypersensitivity response
- if its in the large vessels its still a type III hypersenstivity response, but not associated with drugs (they didn’t say what it is associated with…)
- the processes are the same for both
- for small vessels, called “microangitis” or “microvasculitis”
- for large vessels, called “polyarteritis nerdosa” (PAN)
what type of immune response is serum sickness?
- systemic type III hypersensitivity
describe the progression/pathology of serum sickness. (ie what occurs to create disease?)
- in this graph, the dark line is antigen, horse IgG in this case
- it’s being normally eliminated from the circulation by the same mechanisms by which all antibodies are removed (so the line is droping)
- however, at 6-7 days, the body begins to make antibodies against the horse antibodies (human, anti-horse)
- these human anti-horse antibodies will make antibody/antigen (or really antibody/antibody) compexes with the horse antibodies
- complexes will fix compliment (the line made of round dots at the top of the graph is the complement level - this drops because the complement is being used up)
- the hazy area on the graph depicts the deposition of these complexes in tissues
- will get a type III hypersensitivity response whereever these complexes deposit (in this case, the reaction caused heart, joint, and kidney lesions)
what clinical problems will serum sickness cause? (ie what tissues will it damage, and how?)
- vasculitis
- glomerulonephritis because of deposition of complexes in basement membranes
- activation of compliment => vascular constriction and constriction of bronchioles so trouble breathing
- arthritis
- tissue will likely scar
how long will serum sickness last? will episodes reoccur?
- monophasic so it won’t come back unless you give another dose
- however, there will be scarring of the tissues
what causes type IV hypersensitivity reactions?
- due to cell or tissue injury caused by attack of antigen-specific, sensitized T-cells accompanied by macrophages
- macrophages cause most of the disease
what are the three types of cell-mediated hypersensitivity (type IV reactions)? (list)
- delayed-type hypersensitivity (DTH)
- T-cell mediated cytotoxicity
- rejection of a transplanted organ
what cell types mediate delayed-type hypersensitivity reactions?
- CD4+ cell and macrophage mediated
what cell type mediates T-cell mediated cytotoxicity? (type of T cell…) what are some examples of things that can cause this?
- mediated largely by CD8+ cells
- can be in response to tumors, viruses, and allogenic cells
what cell types mediate the rejection of transplanted organs?
- both CD4+ and CD8+ cells participate
- B-cells/antibodies may also be involved
what are some detrimental macrophage/monocyte/microglial cell products that are released in type IV reactions? (6)
- TNFalpha/beta
- IL-1
- superoxides
- nitiric oxide
- hydroxyl radicals
- neuron toxins
what are some beneficial macrophage/monocyte/microglial cell products released in type III reactions? (3) how can these also be detrimental?
- TGF beta
- growth and trophic factors
- GM-CSF
all of these lead to fibroblast activation and therefore to scarring
describe the pathogenesis of type IV hypersensitivity (ie how does it occur, what do the cells involved do, etc.)
- some invasive material is intracellularly processed (ie a virus)
- antigen from this material is presensted in the context of MHC class II to its CD4 T cell
- results in the release of cytokines
- cytokines induce localized inflammation (macrophages are predominant in this)
- if CD8 T cells are stimulated in teh context of MHC class I, it can recognize the antigen on tissue cells that have that antigen
- if the antigen is a viral protein or is of an abnormal type of protein that those cells happen to make, those cells will be killed off
- often results in granuloma formation
what determines whether granulomas form in immune reactions (using TB and poison ivy as an example)?
- with PPDs, you only get swelling if you’ve seen TB before - this is a type IV reaction
- since a soluble protein is used for the test, though, you won’t get a granuloma because the protein will just be degraded or diffuse away - eventually the swelling will dissipate
- if there’s real bacterial TB in a macrophage, the antigen won’t go away, so it’ll create a persistent response
- immune system can’t kill it, so it’ll keep sending macrophages at it => granuloma
- poison ivy is also a type IV response
- vessicles are due to destruction of the epithelium, but don’t get granulomas cause there’s no damage to the basement membranes
what will type IV hyperactivity responses look like histologically?
- granulomas in llung in this picture, but would see granulomas elsewhere too (this is TB)
- classic giant cells
- sarcoidosis
- granulomas ringed by lymphocytes
- sometimes focalized encrosis
what would you expect to see in a patient with chronic TB? (gross)
miliary TB (tiny black dots = lots of little granulomas around diffuse sites of infection)
what are the three types of transplantation rejection reactions? in what time frame would you expect to see each reaction type?
- hyperacute - moments to 48 hours
- acute - weeks to months
- chronic - months to years
what causes hyperacute rejection? where does this reaction occur? what is the consequence of the rejection?
- caused by antibodies already in the serum - therefore will only occur if the patient has “seen” tissue from this donor before
- get an Ag/Ab reaction at the endothelium
- results in rapid thrombosis of vessels
- tissue just infarcts - never really gets perfused
what are the two types of acute rejection? what types of cells are involved in each type? what pathologies can they cause?
- acute cellular
- involves sensitized CD4 and CD8 cells
- lymphocyte/macrophage infiltrates
- acute humoral
- involves anti-graft antibodies
- causes vasculitis, thrombosis, endothelial proliferation
- can also have a mix of cellular and humoral
note that acute here doens’t mean that neutrophils are involved (ie its not acute inflammation)
what does chronic rejection cause pathologically?
- chronic vasculitis
- intimal fibrosis (fibrosis of blood vessels)
- obliteration of lumen (endothelial cells proliferate into the lumen)
- organ ischemia
- interstitial mononuclear cell infiltrates
- organ atrophy due to ischemia
what are the two mechanisms by which graft rejection can occur (ie what are the two ways the immune response can be triggered?)
- indirect pathway
- a donor cell dies and is processed by the recipient’s APCs
- these present the processed donor antigen to CD4 and CD8 cells
- these cells are no looking for donor antigens
- will result in some CD4+ helper t cell activation => macrophage activation and B lymphocyte activation and therefore antibody production
- direct pathway
- actual antigen is donor’s MHC molecule on the surface of the donor’s APC molecule
- CD8 and CD4 cells react directly to tehse MHC molecules
- these activated cells then are looking for donor MHC molecules
- results in CD8 CTL activation => tissue damage
- results in CD4+ helper T cell activation also
what would you expect to see in donor tissue that has been rejected? (histologically)
- blood vessel walls damaged, vessel killed off
- endothelial cells basically all dead
- may be recipient T cell and macrophages in lumen
what would you expect a kidney that has undergone acute graft rejection to look like? (gross level)
- congested, swollen
- may be focal areas of infarction due to blood vessel/endothelial damage
how would a kidney that has undergone chronic graft rejection appear? (gross level)
- shrunken, scarred, damaged
- couldn’t identify as kidney
- parenchyma destroyed
- blood vessels occluded => ischemia
- very pale
what is graft athersclerosis? what would it look like histologically?
- chronic graft rejection secondary to extensive damage to endothelium and artery wall
what would you expect kidney that has undergone chronic rejection to look like? (histologically)
- scarred parenchyma and occluded vessel
- wouldn’t know it’s kidney
- focal damage to vessel wall
- lumen so compromised by repeated and longstanding damage there’s no lumen left
how do acute and chronic graft rejection differ pathogenically?
- they really don’t - in this context (as opposed to inflammation) the words acute and chronic really only refer to the length of time before the response occurs
- the time difference does affect which organs are affected:
- in acute, it’s typically limited to skin, GI tract, and liver (note: even though these are the things showing damage early on, damage is occuring elsewhere as well)
- in chornic, since it’s been around for a long time, many more organs are damaged as well
how does the primary pathology of acute and chronic rejection differ?
- in acute: destruction of epithelium because there’s lots of MHC molecules there so it’s the first target
- in chronic: mixed epithelial and mysenchmal lesions
