5.7 Immunopath 2 Flashcards
Graft Rejection
Hyperacute, Acute, Chronic
Hyperacute is malpractice bc
hyperacute rejection is based on ABO matching bc those are the Abs we have just floating around to produce and immediate response (everything would take time to develop a response), so if you have hyperacute rejection, you know there was a mess up in protocol where they skipped the blood type matching
What is the proximal cause of hyperacute rejection
the endothelial cells are targetting and damaged so you have exposure of collagen, thrombosis, and you infarct the organ –> ischemia of the organ
Acute graft rejection
happens if you do not have a perfect match
Chronic graft rejection
tends to happen anyway, it can be really bad or take years to develop, it is mostly vascular where you get thickening of the vessel and slow ischemia
What does hyperacute rejection look like on a slide
dead tissues – coagulative necrosis due ti infarct
What does acute rejection look like
you see lots of lymphocyte infiltration (not neutorphils) bc rejection is autoimmunity mediated by your lymphocytes
What does chronic rejection look like
you see less infiltrating lymphocytes and more scar tissue and vessel thickening
Mechanisms of graft rejection
Dircet, Indirect, Antibody, CD8 kill/ Ab-complement
Direct rejection
APCs in the graft think your body is foreign
Indirect rejection
your body’s apc’s present the graft as foreign
Indirect vs Direct rejection
indirect takes time and reaction to other peptides occurs, direct more associated with initiation and acute rejection, indirect more associated with late acute and chronic, Ab associated with both, Data not conclusive with great amount of overlap
BM transplans are good for
cancer chemotherapy, metabolic deficiencies , and immune deficiencies
Graft vs host
BM transplant is putting immunocompetent cells into an immunosuppressed pt creating the possibility of graft vs. Host
Acute GVH
takes days and occurs in the skin, liver, intestins and reamining immune system, manifests as rash, destruction of small bile ducts, GI ulcers, and bloody diarrhea, enhanced infections esp CMV, but mostly don’t see acute bc it is well managed
Chronic GVH
insideous, skin effects similar to systemic sclerosis, jaundice from chlestasis, severe GI strictures, devastation of the immune system, can be managed by immunosuppressive therapy
in a biopsy of liver with acute GVH what would you see
big dialated small bile ducts full of bile bc the distal bile ducts have been closed and scarred
Therapeutic intervention to prolong graft survival
tissue matching, azathioprine and other modified nucleosides, steroids, cyclosporin
what organ do you not worry about tissue mathing
heart transplant, you just try to manage it
Effect of Steroids
shut down all interactions of macs, DC,s T cells
what is an ideal immuno suppressant
something that stops you from reactin to the graft leaving everything else in tact__..or at least something that stops you from interactin with new ag bc you ben exposed to most thing in childhood anyway
Effect of Cyclosporin
inhibits Il2 signaling so you don_t get presentation of new ag, and don_t get new B cell T cell interaction, but B cells can still secrete low affinity ab’s without Tcells —but steroids would knock this functionout
CD4 cells
help CD8s via th1 and B-cells via Th2
What is the down side of Cyclosporins
they are renal toxic
Autoimmune Diseases
Autoimmune reaction, Evidence that reaction is not secondary–meaning disease is directly related to immune system atacking self, no other cause of disease
Tolerance
prevention of immune responses to self antigens, also Suppressor T cells help
Central tolerance
clonal deletion and re-editing of self-reactive lymphocytes in thymus and bone marrow
Peripheral tolerance
elimination of later developing self reactive clones
central tolerance develops
in thymic epithelium for T cells that are positively selected if they don_t respond to self (if they do respond to self we kill them), and B cells are selected in BM, they have a chance to rearrange their Ab genes so they are not self reactive
Peripheral tolerance
Clonal deletion — FasL expression on T cells is increases when you have a clone that recognizes self and it undergoes apoptosis due to burn out, Clonal anergy — APCs only upregulate costimulatory molecules when they are presenting ag on MCHII, but costimulatory molecules are not expressed when presenting self peptides, and without the costimulation the clone is turned off–possibly forever
Suppressor T cells
CD4 Tcells constitutively expressing CD25 (the alpha chain fo IL2) are suppressive of immune reactions, possibly suppression via secretion of IL10 and TGF beta, gene called Foxp3 required for development of CD4+ and CD25+ cells, mutation in Foxp3 causes severe autoimmunity, polymorphisms in CD25 correlate with Multiple Sclerosis and autoimmune diseases
Tolerance Failure
peripheral tolerance broken, not central tolerance; complex interplay of environmental, genetic, and microbial and immunologic mechanisms
Clonal Deletion Breakdown
Fas or FasL knockout mice all develop severe autoimmune disease similar to Lupus
T cell anergy
B7-1 expression in sites of infection and presence of auto-reactive T-cells, Murine model of Type I diabetes –transgenic mice express both a viral ag and B7-1 under insulin promoter
Loss of suppressor cells
attractive hypotesis but least understood, selective IL10 secreting Th2 cells isolated from man and mouse
Molecular Mimicry
post-streptococcal rheumatic heart disease, Myelin basic protein/viral cross reacting T-cells in MS – This is autoreactivity, your heart has ag that cross reactive with the strip ag
Polyclonal lymphocyte Activation
LPS induce polyclonal activation, bacterial superantigens, A polyclonal activator will hit averything and activate it so if you hit a self reactive clone you’ll get autoimmune disease
Exposure to Sequestered Ag
anatomic and molecular sequestration
Genetic Factors
familial nature of many autoimmune diseases, induction of autoimmune disease by HLA–B27 placed in rats transgenically, Association of rheumatoid arthritis with MHC II HLA-DR4 and 1, many with these genes do not develop autoimmune diseases
