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180 Cards in this Set
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7th packet |
Antigens and Immunogens |
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What is adjucant? |
given with immunogen to enhance response of immungoen |
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What is immunogenicity? |
ability of antigen to induce an immune response |
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What is hapten? |
molecules bound by antibodies but can't induce an immune response by themselves...cant stimulate antibody production and can bound once AB is made
**can become immunogenic once they have been conjugated to carrier protein (ex: penicillin to RBC) |
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What are the factors affecting immunogenicitY? |
1. host factrs 2. factors intrinsic to immunogen 3. antigenic factors associated with exposure |
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What are the host factors? |
GENETICS...we make different HLAs (alleles for MHCs)....
1. proteasome allele: proteins will be degraded 2. TAP1/2 alleles: peptides transported to ER 3. MHC haplotype: peptides will be loaded onto MHC molecule 4. antigenic repertoire: antibodies/TCR currently circulating
**also miscellaneous factors like environment, APC population etc |
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What are the factors intrinsic to immunogen: |
1. chemical complexicity (more complex, more foreign like....homopolymers psych but complex are great 2. chemical characteristics- charged and hydrophilic 3. degradability- prostethics won't give response 4. epitope density- greater the more immunogenic...the bigger it is the more it can bypass need for T cell activation 5. foreignness 6. size- larger the better....100,000 or more are great= polysaccharides (<10,000 not so good like penicillin and aspirin) |
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What are the antigenic factors associated with exposure? |
1. dosage: too little immune won't be mounted...too much= cels are anorexic zombies
2. route of admistration (if antigen likely through mucosal surface u want a mucosal response)
**....give subQ/IM strongest response (IgG) flu vaccine or intranasal (IgA)....IV/intragastric is poorest response |
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What are the epitopes? |
antigen= pizza, epitopes= toppings...different toppings and plenty of each epitope....epiope is what binds to antibody |
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What are B cell/antibody epitopes? |
must be accessible!
1. sequential: number of AAs in a row 2. conformational/discontinuouse: shape made by folding 3. whole: not broken down or processed 4. different types of biomolecules: proteins, polysacch, nucleic acids, lipids 5. soluble/on antifen surface: soluble antigens=secreted toxins or epitopes on antigen
**binary (antigen:antibody).....binds soluble antigen.....no recognition molecule required...protein, lipids, polusaccharide, AA........ccessible, hydrophils, external....usually not sequential! |
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What are T cell epitopes? |
1. sequential: only recognize epitopes that have been processed! 2. protein peptides 3. lipids: CD1 4. internal or external: doesn't need to be on folded protein 5. presentation bound to MHC or CD1 on surface of APC
**tertiary antigen interaction (MHC:antigen:TCR)...cant bind soluble antigen....recognition molecule requird.....proteins and lipids usually |
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What is immunodominance? |
certain epitopes will elicit a stronger immune response than other....we make antibodies to certain epitopes but not other....if the antigen has different topics we can develop a better immune response
**u and I get salmonella but our ABs recognize different things |
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What are happiness? |
small organic molecules that don't elicit production of antibodies themselves....but antibodies can be raised against these small simple molecules if they're attached to carrier proteins!!
1. happen specific antibodies 2. carrier specific antibodies 3. antibodies react with hapten-carrie conjuggate
**antihapten antibodies will cause drug allergies (penicillin binds to RBC.....we make anti penicillin and anti RBC antibodies) |
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What are the classes of antigens? |
1. proteins 2. polysaccharides 3. nucleic acids 4. lipids 5. superantigens 6. mitogens
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What are the protein antigens? |
most immunogenic....size, 3d shape, complexity accessibility, multiple epitopdes on protein
1. primary: amino acid sequence= sequential 2. secondary: alpha and beta sheet = 3d structure 3. tertiary: protein folds into conformational isotope 4. juxtaposition of different polypeptides |
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What are the polysaccharide antigens? |
repeating subunits....makes EPITOPE DENSITY high
**not proceed and presented to T cells.....hey will not activate T cells (T-independent antigens) |
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What are nucleic acid antigens? |
poor immunogenic by themselves...but more immunogenic when bound by protein...
**immune reactions to nucleic acid= Lupus |
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What are lipid antigens? |
rarelt immunogenic unless attached to proteins or polysaccharides making them huge and complex
**very potent: LPS, MALP on mycoplasma) |
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What are super antigens? |
1. proteins able to stimulate T lymphocytes non-specifically than regular antigens ...bind to outer surface of MHC on an APC (loaded with peptide) and binding the outer surface of TCR making a bridge......tricks it
**this T cell activation is based on the genetics of the Beta chain of TCR (not specificity) |
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What are mitogens? |
non specific polyclonal activation of lymphocytes....more potent than superantigen
**induce mitosis of lymphocutes of many different specificity....activate T and B cells....
**many are lectins (proteins that bind carbs)
****act by aggregating the stimulatory receptors of lymphocyte....directly activting the signaling pathway with bypassing the need for antigen receptors |
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What are adjuvants? |
enhance, prolong, accelerate immune response to immunogens but doesn't confer immunogenicity....no stable linkage to antigen
**aluminim potassium sulfate (alum) in the US.....salt will precept the antigen allowing slower release of the antigen...increase exposure time to the immune system as well as increase size...more PHAGOCYTOSIS |
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What are the mechanisms of adjuvants? |
1. increase half life of antigen 2. increase production of local inflammatory cytokines 3. improve antigen delivery and antigen processing/presentation |
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How does adjuvant increase half-life of antigen? |
FCA consists of killed Mycobacterium tuberculosis in oil....this mix allows antigen to be released slow and continuous |
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How is increasing the production of local inflammatory cytokines in adjuvants? |
exploit the immune cell activation properties.....many adjucants bind to PRRs expressed by any innate cells and respond by release of cytokines to stimulate B and T cells |
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How do adjuvant improve antigen delivery, processing and presentation by APCs? |
cause the antigen to precipitate and increase size....increase the probability of phagocytosis |
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8th packet |
Antigen - Antibody Interactions |
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Describe the specificity of the antigen-antibody interaction |
most aa of the AB make contact with antigen within the CDRs of the H and L chains.....some on framework.
**most AAs of antigen that come in contact are non-sequential (conformational or discontinuous) |
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What is cross-reactivity? |
when antibody made for one specific epitope on one antigen will bind an epitope on another antigen.....
1. same antigen may be present on different cells/organs (CD4s are on T cells and neurons)...ex: LPS on E. coli and P. auerginosa
2. antigens are similar that they share the same epitopes (albumin....anti-serium from horse to clear)
3. completely different antigens share a common epitope (same 2 AAs)
**epitopes are chemically different but take on the same 3D conformational shape |
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How are toxoid vaccines developed? |
from the idea that epitopes can be SIMILAR but not identical, differing by 1-2 AAs. toxin altered to destroy biological activity but toxoid retains enough of origin toxin to generate an immune response
**sheep RBC with epitope to anti-EBV |
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Cross-reactive ABs leading to autoimmune disorders: |
1. rhematic fever: antibodies of M proteins on S. pygenes bind to epitope on heart muscles
2. Chagas= antibodies to Trypanaosma cruzi bind to epiopes on nerve cells |
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Polureactive antibodies have: |
low specificity and can bind to multiple antigenic epitopes
...come from B cells making ABs for first time but don't undergo affinity maturation (IgM usually)..."sloppy fit" for early defense since they can bind with less stringent requirements |
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What is the physical nature of the antigen-antibody interactions? |
Affinity vs Avidity |
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What is affinity? |
the strength of all the non-covalent interactions between antigen and antibody at one Fab
1. measured by rate of association and the rate of disassociation...high affinity= low dissociation, low affinity= low association/high dissociation
**related to specificity: more specific, the less dissociation and higher affinity
**SCATCHARD plot |
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What is avidity? |
overall strength of antigen-antibody interaction at ALL THE BINDING SITES (all the Fabs)
**can compensate for low affinity 1. IgM have low affinity but bind well because of its multiple Fabs 2. antibodies to polysaccharide antigens tend to be of low specificity but bind well to high epitope density causing higher avidity
*not related to specificity ...think of flag football....bringing many people around the guy with the ball is avidity? |
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What are the forces between antigen and antibody? |
interactions are non covalent, weak, reversible and depend on distance
1. H bonds 2. ioni 3. hydrophobic interactions 4. van der Waals |
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What are the experimental systems (serology) and what do they do |
utilize RECOGNITION and SPECIFICITY of the interactions....can test for antigen or antibody.....specific and sensitive tests
"PACE"
1. Precipitation 2. Agglutination 3. Cellular 4. Enzyme linked |
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What is zone of equivalence? |
required for P and A....the antigen-antibody must be present in appropriate ratio....ZONE OF EQUIVALENCE! = point where the antigen-antibody ratio is such that cross linking can occur making large, insoluble complexes
**presence of too much of either= prozone effect * IgM are best for P and A |
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What are precipitation reactions? |
antibody and soluble antigen in aqueous soluton
1. Single/Radial immunodiffusion 2. Double Immunodiffusion 3. immunoelectrophoresis |
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What is single/radial immunodiffusion? |
1. antibody added to gel and gel solidifies 2. antigen added and diffuse in gel---radiates out in 360 degree circle 3. visible ring forms at zone of equivalence |
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What is double immunodiffusion? |
1. antigen and antibody placed in separate wells 2. antigen and antibody diffuse into gel 3. visible line forms at zone of equivalence
**allows you to test for multiple patients |
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What is immunoelectrophoresis? |
1. antigen added to wellcut into prepared gel 2. electric current applied and proteins in antigen move through gel, separated by ize 3. trough cut along length of gel 4. antibody sample added to trough and allowed to diffuse into the gel....visible line of precipitation forms at zone of equivalence |
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What are agglutination reactions |
interaction between antibody and particulate antigen when clumping
1. direct hemaaglutination 2. passive/indirect agglutination 3. bacterial agglutination |
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What is direct hemagglutination? |
1. Forward Typing 2. Reverse typing |
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What is forward typing? |
1. persons RBCs are mixed with antibodies (anti-A or anti-B)
2. if antigen is present on their RBC, then agglutination occurs
**type A blood clots when mixed with anti-A |
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What is reverse typing? |
1. my serum mixed with RBCs (type A or typee B) 2. my serum is anti-A or anti-B, blood will clot (anti-A ABs= type B.....will have anti-A antibodies in my blood)
**no antibodies in my blood= type AB blood **both antibodies= typeO |
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What is passive/indirect agglutination? |
antigen attached to beads or particles mixed with serum....if serum contains ABs to the antigens.....AGGLUTINATION |
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What is bacterial agglutination? |
bacteria mixed with serum....if antibodies are present....agglutination! it determined if person has been exposed to the bacter but not if they are currently infected |
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What are enzyme-linked assay? |
enzyme attached to antibody to detect a reaction via colimetry
1. primary antibody binds to antigen 2. secondary antibody binds to the Fc or primary or to the antigen (enzyme linked here)...substrate cleaved by this enzyme causing the color change |
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How does enzyme-linked assay work? |
1. primary antibody mixed with sample containing antigen 2. unbound antibodies washed away 3. add secondary antibodies with enzyme..... 4. unbound antibodies wash away 5. add substrate...enzyme on secondary cleaves and causes color change |
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what are the two types of enzyme linked assays? |
1. Western Blot 2. ELISA |
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What is Western Blot? |
1. proteins separated by electrophoresis and transferred onto a membrane 2. add antigens to detect location of the protein antigen 3. primary antibody binds to protein on membrane, secondary binds to Fc or primary and color change with substrate added
**radioactivity can be used |
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What is ELISA? |
presence of antigen (direct) or antibody (indirect) can be determined
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What is indirect ELISA? |
1. antigen bound to the well.....serum containing primary antibody(suspected) is added and binds....secondary antibody added ad binds to Fc or primary.....sibstrate added and color change
**detects presence of antibodies in serum and is used for HIV testing! |
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What is direct ELISA? |
" SANDWICH" ELISA
primary antibody added to well....sample of serum with antigen (suspected) added and bound by primary antibody...secondary comes and binds antigen bound to the primary...substrate added..
**detects if antigen is present and used for Pregnancy detection of HCG! |
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What are cellular assays? |
different cells mixed together to measure cellular immunity! 1. flow cytometry 2. FACS 3. Lymphocyte proliferation assay 4. cytotoxic assa7 |
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What is flow cytometry? |
fluorescent antibodues bound to cell-surface antigens....cells passed one at a time by a light that activates the FLOUR and can be detected
**we can look for CD4 (only a % should be there.....CD4 leukemia would have an increase in CD4"
this is cell counting |
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What is FACS? |
same of flow cytometry but once cells are identified, they are sorted into different collection tubes according to their fluorescent marker |
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What is Lymphocyte proliferation assay? |
1. measures the response of a T cell to an antigen....APCs, antigen and CD4 T cells from immunized animal are mixed in solution with radioactive H tritium...
2. after 3-5 days, proliferation of T cells measured by detecting the amount of tritium thymidine incoportated into the DNA of replication cells and determines the amount of IL2 produced by the CD4 T cells by direct ELISA (we want less color change)
**helps determine compatibility (degree of foreigness in donor/recipient transplants |
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What is cytotoxic assay? |
measure response of T cell to antigen....CD8 T cels mixed with target cells (labeled with marker released once cell is killed....chromium sulfate or lactate dehydrogenase)
**amt of label measured via radioactivity for chromium or direct ELISA for LDH |
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9th Packet |
Vaccines and Immunotherapy |
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What is immunoprophylaxis? |
manipulating the immune response to fight infection |
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What is passive immunity? |
introduction of antibodies...rapid and temporary....
**artificial : ISG = pooled antibodies from 1000 donors, hyperimmune sera= antibodies pooled from donors with high titers, antitoxins= antibodies against specific toxins
**natural= mom's antibodies to a child thru placenta (IgG) or colostrum (IgA) |
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What is active immunity? |
introduction of antigen ...slow and long lasting...memory as a result
1. artificial via vaccination or natural via infection |
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What are vaccines principal |
development of herd immunity .....if large # of people are immune to pathogen the transmission of communicable disease is interrupted (check the R not....measles= 18, ebola = 2) |
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What are the principles of vaccination? |
1. more similar vaccine antigen to disease causing form, better response and more protective 2. production of active immune response though stimulation of antibody production and memory lymphocytes 3. immunity and immunologic memory should be similar to natural infection w/o risk of disease |
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Route of vaccination! |
oral for GI, inhaled for respiratory...want to put it where it will max out the efficiency
**benefit of IM vaccines: muscles are filled with DCs and take up/process antigen....muscle tissue acts like an adjuvant by precipitation antigen so it is absobed slowly and increase exposure time. |
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What are the problems in developing effective vaccine? |
1. structural serological varbility in polysaccharide antigens 2. cross reaction with host epitope due to chemical similarity 3. antigenic variation: same protein made with different AA combos (HIV undergoes varition) 4. phase variation: expression of protein turned on or off) 5. complicated life cycle |
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What are live attenuated vaccines? |
1. produced by modifying organism to non pathogenic....if alive, organism can multipley and emulate an actual infection = stronger immune response....DONT DO TO IMMUNOCOMPROMISED
2. induce humoral and cell mediated...can cause inflammatory response due to natural infection and revert back to bad version
3. immune response is identical to that produced by natural infection and effective with one dose.....
4. circulating antibodies eliminate the organism,
5. fragile! killed by light/heat
**best for viral/intracellular ...mimmic natural and make memory CTLs |
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What are inactivated vaccines? |
1. composed of whole organisms of fractions 2. produce HUMORAL response 3. organism is dead, more antigen is required for immunity....need multiple doses and require boosters..give to immunocompromised
**four types: killed whole cell, fractional protein, fractional polysaccharide, recombinant
**not good for viruses and need adjuvant |
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What is killed whole cell, inactivated vaccine? |
dead bacteria or viruses...
1. bacterial : cholera, plague, pertussis 2. viral: polio, rabies, hepA
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What is fractional protein inactivated vaccine? |
subunitwith multiple antigenic proteins...acellular pertussis, anthrax, lyme dz
-toxoud: tetanus, diptheria |
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What is fractional polysaccharide based? |
1. conjugate: links non immunogenic polysacc with antigenic component
**HIB, pneumococci, meningococci
*pure= purified polysaccharide |
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What is recombinant sector? |
produced by genetic engineering, inserting vaccine antigen in organism not pathogenic to human (yeast)....hetpatitis B, HPV, cholera, WNV |
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General rules about vaccination: |
1. inactivated Vacs not affected by circulating antibodies....can give to kids less than 6 months old 2. live attenuatied are affected......dont give to kids less than 12 mos old
3. simultaneous vaccination doesn't screw up anything....increasing interval b/w doses of multiple dose vaccines doesn't diminish effectiveness but decreasing the interval can affect AB response...
**only contradiction = allergy to vaccines. |
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What is allergy desensitization? |
used to treat IgE mediated disease by injections of allergen extracts...not effective in T cell mediated allergies (poison ivy) or immune complex dz (serum sickness)
**used as adjunct to symptomatic drug therapy....effective when allergen avoidance is not possible |
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What are he methods to allergy desensitized? |
gradually increasing quantities of allergen protein once or twice a week.....max tolerance is 100x the initial dose...clinical benefit for 3-4 years
**alternative methods aim to prevent IgE from binding to mast cells on the Fc receptor...antiIgE antibodies can blow it from interacting....or they can bind to the Fce receptors on mast cells |
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What is the goal of allergic immunotherapy? |
(type I hypersensitvity )... 1. to develop tolerance to antigens 2. shift T cell response away from TH2 to TH1
**IgE mediated allergies are result of TH2 response... |
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How does allergy immunotherapy work? |
1. IgG low doses....next counter, IgG will bind to it before degranulation 2. T cells become anergic 3. mast cells, basophils are decreasingly sensitized |
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What are the treatments for immune related diseases? |
1. replacement therapy 2. immunosuppresive therapy 3. cytokine/cytokine inhibitor therapy |
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What is replacement therapy? |
provide relief of symptoms and leads to better quality of life....doesnt stop progression of disease
**insulin for DM, synthroid for Hashimoto |
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What is immunosuppressive therapy? |
screw up the immune response....not selective so the good responses are blocked..
**cyclosprine blocks T cell activation **cytokines/cytokine inhibitors block immune cell function |
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What are cytokine/cytokine inhibitor therapy? |
1. anti-inflammatory cytokines to counteract the inflammatory ones.....the use of anti-cytokine antibodies block binding of cytokines to their receptors (anti-TNFalpha antibodies aid in therapy for Rheumatoid Arthritis)
2. cytokine analogs bind to cytokine receptor without triggering the cell
3. soluble cytokine receptors bind to cutokines preventing binding
4. anti-CD18 antibodies prevent leukocytes from adhering to vascular endothelial cells, so they can't extravasate |
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10th Packet |
Immunodeficiency disorders and Neoplasias |
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Immunodeficiency causes: |
1. infection = hallmark 2. anemia 3. arthritis 4. autoimmune disease 5. growth retardation
1. congenital/primary immunodeficiency 2. acquired/secondary immunodeficiency= malnutrition, alcohol, drug abuse, immunosuppresive drugs, cancer |
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What is lymphoid neoplasia? |
loss of regulation between the components of the immune system....results in one component getting unchecked...
**cancers caused by oncogenic virus (EBV)...T cell immunodeficiency |
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What are primary immunodeficiency disorders? |
1. result in conditions that affect process which occur PRIOR to the introduction of antigen....cellular, humoral, combined, phagocytic, or complement
2. if both B and T cells screwed= SCIDS but defect could be in one type of lymphocyte....always T sometimes B and NK cells (lymphoid)
3. myeloid cell disorders screw phagocyte function....
4. the earlier in development that this defect occurs, the more global and severe it will be.
*****most occur at 6 months when mater Ig goes down and no replaced by own. will notice at 2 y/o with 8+ chronic ear infections/year |
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What are the cellular primary immunodeficiencies? |
think T cells...T- cell associated deficiencies= susceptible to viral, fungal, protozoan infections.....overgrowth of Candida albicans making white spots in mouth
ex: Autoimmune Lymphoproliferative Syndrome (ALPS) |
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What is ALPS? |
mutation in gene encoding Fas
- cells that should've died stay alive and proliferate/secrete cytokines....massive proliferation of lymphoid tissue (spleen) with early lymphoma development * chronic viral infections * increased # of CD4-CD8- T cells.....no +/- selection in the thymus....severe autoimmune cytopenias |
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What are the humoral primary immunodeficiencies? |
defective B cell development with complete absence of all Ig classes to a specific class...hard to fight infection against pyogenic encapsulated bacteria (opsonization gone)....normal immunity t viral and fungal
1. common variable immunodeficiency/hypogammaglobulinemia
2. Selective IgA deficiency (dysgammaglobulinemia)
3. X-linked infantile agammaglobulinemia (XLA, Brutons) |
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What is CVI/Hypogammaglobulinemia? |
**mature B cells don't proliferate into plasma cells, but the # of peripheral B cells is normal **
1. low levels of all isotopes...increased risk for bacterial infections....
2. 15 y/o or older...recurrent sinopulmonary infections..high prevalence of auto immune disease |
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What is Selective IgA def (dysgammaglobulinemia)? |
most Common......1:500. complete absence or low level of IgA.
1. increased IgM or IgG and secreted IgM on mucosal surfaces.....respiratory, diarrheal infections
2. defect in B cell differentiation to IgA (IgA genes are normal)..... |
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What is XLA, Burtons? |
defect in B cell maturation due to mutation in B cell tyrosine kinase gene (btk).....necessary for growth of pre-B cells....absence of mature B cells (no plasma cells/antibodies)
-notice at 6 months without maternal IgG...recurrent otitis media, bronchitis, pneumonia. **secondary lymph nodes are small or absent. treat with IVIg every 2 weeks |
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What are the different SCIDS? |
B AND T cells screwed up ....T cells needed to produce antibodies to TD antigens
1. DiGeorge 2. XLinked HyperIgM 3. Wiskott-Aldrich 4. Bare Lymphocyte Syndrome |
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What is DiGeorge syndrome (congenital thymic aplasia)? |
1. lack of thymus or underdeveloped thymus....causes absence or reduced alphabeta T cells (normal gamma delta)...normal # of B cells
2. no isotype switching because of the CD40-40L interaction.....newbors with hypocalcemia as well as congenital heart disease.....
3. Bcell/IgM normal still to TI antigens
**physical characteristics: low pinned ears, fish mouth notched ear pinnae....deletion of chromosome 22! |
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What is X linked hyperIgM? |
lsck of Ig except IgM.....recurrent infections from pyogenic bacteria....result of mutation in CD40 L in T cell.... |
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What is Wiskott Aldrich syndrome? |
1. serum IgM low but IgA and IgE higher than normal....starts with normal T cells but T cell pool declines because of defect in WASP (failure to activate T cells...no proliferation/memory cells)
2. bacterial to viral...eczema due to over production of TH2 cytokines...increased frequency of autoimmune disease...thrombocytopenia with gradual loss of both humoral and cell mediated....
happens in boys! |
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What is Bare Lymphocyte syndrome? |
inability to express MHC I or MHC II (more common) on surface....inability to + select CD8 or CD4 during development causing lack of alphabeta CD8 and CD4 T cells
**genetic defect in transcription factor required for transcription of MHC Class II (MHC genes are normal)
**MHC class I: no loading/carried to surface (bunch of CD4s) no CD8s....mutation in TAP 1 or 2 **MHC class II: mutation in transcription factor...no CD4s (bunch of alphabetaCD8s)...gammadelta normal |
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What are the phagocytic PIs? |
1. Chronic Granulomatous Disease 2. Chediak-Higashi 3. Leukocyte Adhesion Deficiency |
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What is Chronic Granulomatous Disease? |
dysfunction in enzyme of oxidative burst of activated macrophages and neutrophils....reduced killing of intracellular or phagocytosed pathogen......decreased antigen presenttion
1. formation of granulomas (central area of phagocytic cells fused into multinucleate cells)....lymphadenopathy, splenomegaly
2. common in gingivitis |
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What is chediak-higashi syndrome? |
Lysosomes fuse to each other!
1. no phag-lyso link....no oxidative birst...recurrent bacterial infections and dalbinism!
**defect in LYST gene responsible for intracellular protein trafficking |
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What is Leukocyte Adhesion deficiency? |
defects in leukocyte extravasation.....mutation in B2 subunit of CD18 integrin protein required for binding adhesion molecules on vascular endothelial surface
* CD18 = surface proteins ...screws the interaction..
1. LADI= soft tissue, bacterial and fungal infections and increased WBC but less pus formation (gram- infections)
2. LAD2: CD18 is normal but impaired focus metabolism with metal retardation (absence of silalyl Lewis X in neutrophils impairing neutrophils migration into tissues. causing bacterial infections |
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What are the complement PIs? |
genetic def. for each one except Factor B 1. C1: increased Type III hypersensitivity (encapsulated bacteria wins) 2. C2: most common...resembles Lupus due to failure to clear circulating immune complexes **C2/C4 deficiencies not associated with increase susceptibility to infection (can get Rhematoid arthritis) 3. C3: most secere....increased infection by encapsulated
4. MAC: increased propensity for recurrent disseminated infections by N. meningitidis and N gonorrhea 5. Factor D and properdin: increased infection with encaptulated and Neisseria 6. Factor H and I: accelerated turnover of C3....depletion of C3 in serum
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What are the deficiencies in Complement regulatory proteins? |
deficiency in C1Inh: hereditary angiodema.....C1,C4,C2 are uncontrolled causing increased permeability and local edem |
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What is the feficiency in complement receprots? |
CR3 and CR4 defiencies = mutations in CD18.....increased infections by encapsualted |
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What are secondary immunodeficiencies? |
consequence of health-related problems...MALNURITIOn and iatrogenic....drug therapies that kill or inactivate lymphocytes
**example: AIDS resulting from HIV |
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What are lymphoid neoplasms? |
1. lymphocytic leukemia 2. plasma cell myelomas 3. lymphoma |
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What is leukemia? |
malignant cells in circulation.....arise from proliferation of single cell...develop from B, T cell or myeloid cells (macrophage, neutrophil)
**acute= immature cells and at any age **chronic= develop in mature cells and more in adults |
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What is lymphoma? |
solid mass in the lympoid tissues |
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What is myeloma? |
cancer involving th bone marrow |
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What is a tumor? |
frozen in development with all the same markers but no maturation and stay there....continue to divide from an original clone (if theres a mutation at the pro B cell stage....none of them would have a light chain) |
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What is acute lymphocytic leukemia (ALL)? |
proliferation of immature lymphocytes....usually B cells..children and young adults....most common form of cancer in young children..
**Bones, LN,, hepatosplenomegaly |
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What is chronic lymphocytic leukemia? |
malignant proliferation of B cells....gene that inhibits apoptosis,.....less normal B cells...slow onset and mostly in adults |
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What are the diseases of plasma cell proliferations? |
1. multiple myeloma 2. waldenstrom macroglobulinemia |
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What is multiple myeloma? |
malignant plama cells as nodular masses in bone....destroy and punch hols in the soul and spine......replace normal lymphocytes so less antibodies by normal placma cell
**most often in elderly adults..none pain, jypercalemia and anemia
**renal failure due to Bence-Jones Protein.....antibody L chains produced by bad plasma cells that only make L chains (can pass through the glomerulus and go into urine)
**chemo not effective |
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What is Waldenstrom macroglobulinemia? |
malignant cells make IgM making blood viscous....headaches diziness and clotting.....patient over 60.
**anemia, weight loss, fatigue, weakness |
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What are the diseases of lymphoma? |
1. Hodgkins 2. Non-Hodgkins |
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What is Hodgkins Lymphoma? |
spread of disease from LN to LN.....predictable and orderly....begins in LNs in upper neck area....presence of Reed-Steinberg cells (large abnormal binucleate B cells) ....could be due to previous EBV infection
**most common in Americans 10-30 y/o and big time in white dudes... |
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What is Non-Hodgkins lymphoma? |
malignant tumors of B lymphocytes....more aggressive and occurs in more advanced stage... spread is not orderly and goes everywhere.......lack of predictability makes a bad prognosis
1. follicular lymphoma: antigen experienced cells proliferating in the follicles .....due to bcl2 gene which inhibits apoptosis being translocated next to the H chain gene 2. diffuse lymphoma: uniform growth pattern but not in follicles....most common in patiens 60 and above...bad prog. |
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What are myeloid neoplasms |
myeloid progenitor cells become neutrophils, basophils, eosinophils.....
1. acute mkelocitic leukemia 2. chronic myeloproliferative disorders |
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What is acute myelocytic leukemia? |
cancer involving immature granulocyte precursor cells that do not mature enough to develop granules....genetic mutations that precent full maturation process
**as cancer cells grow and divide, they replace normal cells inside bone marrow and lower healthy cell number.....RBCs and megakaryoctes! cause neutropenia
**migrate to other organs |
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What is chronic myeloproliferative disorders? |
1. chronic myelocytic leukemia 2. polycythemia vera 3. malignant thrombocythemia 4. myeloid metaplasia= replacement of bone marrow with fibrous tissue |
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11th Packet |
Hypersensitivity |
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What is hypersensitivity? |
immune response to non-infectious or environmental agents...chief factors: type of immune response that causes tissue injury and nature/location of the antigen that is causing the response |
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Which types of hypersensitivities deal with humoral? Which one is strictly cell mediated? |
1-3 is humoral.
4 is cell mediated |
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What are the three phases of hypersensitivity? |
1. sensitization: antibody produced in response to antigen exposure and binds to Fc receptors on mast cells and basophils 2. activation: re exposure to antigen triggers response 3. effector: response as a result of activated cells which were previously sensitized |
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What is Type I Hypersensitivity? |
"immediate hypersensitivity, allergy, hayfever"
1. IgE mediated reactions stimulated by release of inflammatory mediators by the mast cells ...and basophils when the IgE molecules bind to their surface and cross linked by allergen binding
2. release of inflammatory mediators leads to a anaphylaxis
3. reactions within minutes of re-exposure and resolve within about 2 hours or removal
4. most allergens highly soluble, small proteins carried on desicatted particles (pollen).....low doses favor TH2 differentiation of CD4 T cells (induce IgE via IL-4 and IL-5) |
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What are the mechanisms of allergic response in Type I? |
1. allergen binds and cross links IgE on surface of mast cells and causes release of effector molecules (release of IP3 causes rush of calcium into mast cell cytoplasm and required
2. release histamine outside the cell (binds to H1 receptors on SM --constriction in asthma + binds to H1 receptors on endothelial cells to increase vascular permeability)
3. release of prostaglandins and leukotrienes : made de novo during granulation...more SM constriction and recruit neutrophils to the site (bystander effect!)
4. release of cytokines: TNF release immediately to attract leukocytes from blood (IL8 recruits inflammatory cells, IL 13 = mucus production) |
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What is type II hypersensitivity? |
"cytotoxic hypersensitivity"....IgM or IgG directed against antigens that are on cell surface of cell
-resolves w/i 24 hours
**can result in immune system attack on own body's tissues (antigens on host cells....cells can be free (RBCs) or fixed (organ/tissue)
**can be a self-antigen (autoimmune) or antigens attached to host cell (penicillin)
**Host cells killed via complement or ADCC |
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What are examples of Type II Hypersensitivity? |
1. Blood transfusion 2. Rhesus-incompatability 3. Antibiotic/Pharmacology sensitivity |
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What is blood transfusion with Type II? |
we have antibodies against non self blood antigens.....receive transfusion of blood with incompatible blood groups, antibodies of recipent will ACTIVATE THE CLASSICAL COMPLEMENT pathway......lysis of transfused cells
**Type AB: no antibodies ...Type I= universal donor |
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What is Rhesus-incompatibility reactions? |
Rh- moms become sensitized to Rh+ antigens in first pregnancy....babys RBCs enter moms circulation ...
1. if anti-Rh antibodies are of IgG, they can cross the placenta during next pregnancy causing risk to Rh+ baby.....give Rhogam to prevent erythroblastosis fetalis (will become bilirubin when HgB released)....
**rhogam is anti-Rh antibody at 28 weeks and binds to fetal RBCs to remove them before B cells are activated to make anti-Rh antibodies |
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What is antibiotic/pharm sensitivity? |
abx (penicillin) binds to surface of RBC (hapenation).....first exposure causes antibodies to be made but no symptoms.......next time: antibodies attach to drug on host cells causing destruction of RBC (no bystander effect)
**Schwartzman reaction: hemorrhagic response in person sensitized to a drug |
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What is Type III hypersensitivity? |
"Immune complex mediated hypersensitivity"
1. soluble complexes of antigen + IgM or IgG accumulate in circulation or tissues and activate complement cascade
2. settle in capillary beds and cause inflammatory rxn in blood vessels
**should be removed via phagocytosis or transported to liver by Fc or C3b receptrs on RBCs
*can have self antigens or non-self antigens |
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What is the difference between Type II and III? |
type II:tissue is damaged when antibody binds it directly and causes ADCC/complement lysis
type III: amages to tissues= bystander effect which occurs when soluble-antigen-antibody complexes become deposited |
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Why does injury occur in Type III? |
activation of complement cascade.....immune complex is deposited in the tissue....release C3a, 4a, 5a which recruit neutropjhils.....activated through Fc receptors and release effector molecule and lytic enzymes: bystander damage
* if damaged tissue = capillary then loss of circulation to the area
**if it attacks glomerulus, ca cause loss of function |
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What are examples of Type III hypersensitivity? |
SLE, Arthis reaction, serum sickness
**serum sickness= we get antitoxin/antivenom from horse and recognize proteins in the serum as foreign and make antibodies against them....make soluble/circulating complexes
**can happen @ first exposure!! due to long half-life of IgG |
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What is Type IV hypersensitivity? |
Delayed Type Hypersensitivity.....use CMI
1. help fight intracellular infections 2. mediated by TH1 to release cytokines causing activation of macrophages!! 3. erythema/hardening of tissues at site of exposure....more monocytes/macrophages than neutrophils 4. peak reaction takes 24-72 hours....delayed because antigen specific T cells secrete cytokines to bring and activate macrophages 5. usually an antigen that person should not respond to.....antigens eliciting these responses = foreign tissuesm intracellular pathogens, soluble proteins or chemicals coupled to host proteins (soap, metal, plant, rubber) |
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Most of type IV involve what? |
skin...contact hypersensitivity (langerhans DCs)
1. poison ivy (pentadecacathechol): happen that pentrates skin and haptenates extracellular pathogens 2. nickel 3. formaldehyde, cosmetics
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Clinical manifestation: |
indurated nodule (hard bump) caused by infiltration of cells and fibrin....when DTH is unable to respond, granula formation will happen
**macrophages undergo differentiation to form giant cell....release of enzymes/reactive oxygen species cause damage to local tissues |
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12th Packet... |
Tolerance and autoimmune disease
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What is tolerance? |
becoming non responsive induced by prior exposure to antigen |
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What is autoimmune disease: |
pathologic conditions resulting from failure of tolerance mechanisms to keep autoimmune T and B cells in check
**mediated by both antibodies and T cells
1. organ specific 2. systemic |
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What is tolerancee in depth? |
active state of specific non-responsiveness to antigen....result of inactivation or death of antigen specific lymphocyes
1. tolerance= immunologic state....not absent but chose not to..... 2. exhibits immunologic specificity (recognition of tolerogen) by specific lymphocytes
3. can be tolerant to self-antigens or foreign....
**opposite theory behind vaccination (induce strong protective immune response)
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What are the two types of tolerance? |
1. central tolerance (during lymphocyte development we negative select and remove thymocytes o B cells that recognize self-antigen)**DOMINANT**
2. peripheral (mature lymphocytes encounter antigens without required 2nd signal).....can be induced as a result of repeated stimulation by antigen in peripheral tissues |
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What are the 4 mechanisms for developing tolerance? |
1. Deletion 2. anergy 3. Suppression 4. antigen sequester |
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What is deletion? |
removal of auto reactive lymphocytes..can occur in primary lymphoid organ during development .....apoptosis of lymphocytes can be due to repeated stimulation of small does of antigen
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What is anergy? |
during perihery.....occurs to B or T cells when costim signal is absent (CD40-40L for B cell)......no apoptosis but never respond again to antigen..ZOMBIE!
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What is suppression? |
regulatory CD4 and suppressor CD8s secrete immunosuppresive TGF beta...antigen non specific and inhibits proliferation of CD4 and CD8 T cells....prevent IL2 transcription
**controlled by signals from innate response |
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What is antigen aggregation? |
immune priveliged sites where foreign antigens and lymphocytes rarely enter....eyes, testes, ovary, placenta brain |
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What are autoimmune diseases? |
1. loss of tolerance to self-antigens....when u develop an immune response to self-antigens, not possible to eliminate it...RESPONSE. causing chronic inflammation, injury to tissues....
2. internal dysregulation of immune system |
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What are the factors that contribute to the development and etiology of autoimmune disease? |
1. genetic susceptibility 2. infectious agents 3. anatomic alterations of tissues |
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What is genetic susceptibility? |
strongest associations with autoimmunity: HLA (especially class II)
B8= graves dz, B27: IBS, DR2= hay fever, DR4= RA, type I diabetes |
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What are infectious agents? |
not a direct result of infectious agent but a result of the immune response to the pathogen
1. bystander activation 2. molecular mimicry 3. superantigens |
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What are examples of central autoimmune diseases? |
1. rheumatoid arthritis 2. lupus 3. Multiple sclerosis |
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What happens in RA? |
chronically inflamed synovium bc of lymphocytes resulting in destruction of cartilage and bone....
**deposition of immune complexes (type III) , inflammatory CD4, CTLs, macrophages and digressive enzymes |
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What happens in lupus? |
patients make autoantibodies against DNA histones of cell nucleus (antinuclear antibodies).....attacks many organs of the body
**deposition of immune complexes filtered by kidneys TYPEIII |
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What is multiple sclerosis? |
demyelination of CNS due to auto reactive T cells |
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What are the organ specific autoimmune diseases? |
1. myasthenia gravis 2. hashimotos 3. graves dz |
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What is myasthenia graves? |
autoantibodies against Ach receptor at NMJ....antagonistic antibodies block bind of Ach to receptor causing less nerve impulses transmitted thru the junction
**weakness, difficulty checking, swallowing, breahting |
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What is Hashimoto's thyroiditis? |
antigens appear to be inimpicated causing goiter then hypothyroidism,
**destruction of thyroid follicles...compensation = large goiter but at some point, thyroid hormone output declines |
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What is Graves' diseasE? |
AGONISTIC autoantibodies directed against TSHR resulting in overstimulation of gland causing overproduction (hyperthyroidism) |
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What is Type I Diabetes mellitus? |
chronic inflamm destruction of insulin producing cells of pancreas...mediated by CTLS...into islets of Langerhans,,,,caused by release of cytokines and lytic enzymes |
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13th packet...the last %@&*#@( one |
Transplantation Immunology |
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What is the main reason a person rejects a transplant? |
incompatability between the donor and recipient MHC antigens present on the tissues..there is a lot of polymorphism in the MHC alleles which make matching super hard |
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What are the types of grafts? |
1. autograft: from one are to another on same person
2. isograft: transplant from genetically identical twin
3. allograft: transplant from genetically non-identical person
4. xenograft: transplant between pig and human |
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What are the major antigenic targets for T cells? |
MHC molecules....they are the reason for graft rejection bc products of the MHC genes are cell surface proteins and all nuclide cells express MHC I |
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What are other causes for rejection?? |
if d/r have identical match by HLA typing, still some differences in MINOR histocompatibility antigens (except for self or identical twin)....result in rejection but slower |
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What are first-set and second set rejection? |
1. fist set: lag time is 2 weeks while lymphocytes undergo processes of recognition, expansion, effector
2. second set rejection: recipeint receives 2nd graft from same donor, graft rejected within 6-8 days...more rapid bc of memory lymphocytes |
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What is the difference between direct and indirect recognition? |
direct= APC from donor to presents to recipient T cells
indirect= APC from recipient to recipient T cells |
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What are the three major clinical categories ? |
1. hyperacute 2. acute 3. chronic |
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What is hyper acute rejection? |
within hours of transplant due to PREFORMED antibodies present in the recipient...
remove the tissue immediately |
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What is acute rejection: |
10-14 days....decrease in tissue function, tenderness, swelling
**infiltration of donor tissue with lymphocytes and macrophages ...control with immunosuppresants |
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What is chronic rejection? |
months after transplant...slow deterioratin |
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Mismatching of which MHC is better to have |
MHCI |
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Which grafts are almost always rejected? |
skin, bone, kidney |
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Graft rejection is mediated by: |
T cells...educated to recognize their own host's MHC molecules, respond negatively when presented with non-self MHC molecules
**usually CD8s since epithelial and endothelial cells of grafted tissues expressMHC1
**TH1 and CTLs are more severe reactions while TH2 and B cells lead to tolerance of transplant or result in more mild form of rejection |
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What is graft-versus-host disease? |
donor's tissue attacks the recipient's tissues.....grafted tissue includes transfer of mature cells.....mature cells of donor recognize the recipient's as foreign and cause massive immune rresponse.
**BONE MARROW TRANSPLANTS.....recipients immune cells killed by radiation and donors bone marry treated to kill mature cells as well, leaving the immature stem cells to reconstitute the recipient's immune system with healthy cells....requires HLA and ABO typing |
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What is cyclosporine: |
Specific T cell supressors by blocking transcription of IL2 |
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What ae ways to reduce rejection? |
1. mitotic inhibitos 2. corticosteroids 3. cyclosprine 4. antibodies (anti-CTLA4 to prevent APC from providing 2nd signal... cell becomes anergic ZOMBIE |
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THE..... |
END |
