Flashcards in Immunogenics, Immunizations Deck (22)
Define the Major Histocompatibility Complex. Distinguish between HLA-A and HLA-B antigens on the one hand, and the HLA-D group on the other, in terms of: which associate with foreign antigens for recognition by helper T cells; which, in association with foreign antigens, are the targets for killer T cells.
All the strongest histocompatibility antigens coded for by a family of genes on a single chromosome; ►the group was therefore called the Major Histocompatibility Complex, or MHCHelper T cells are programmed to recognize MHC antigens of the HLA-D loci (Class II); killer T cells (CTL) recognize MHC antigens of the HLA-A and HLA-B (Class I) loci.
Define alloantigen and haplotype.
alloantigen: An alloantigen is an antigen that is a part of an animal's self-recognition system. e.g., Major histocompatibility complex molecules. When injected into another animal, they trigger an immune response aimed at eliminating them. Therefore, it can be thought of as an antigen that is present in some members of the same species, but is not common to all members of that species. If an alloantigen is presented to a member of the same species that does not have the alloantigen, it will be recognized as foreign. They are the products of polymorphic geneshaplotype: The MHC gene set that you inherited from one parent is called a haplotype.
Distinguish Class I and Class II histocompatibility antigens.
Remember that Class I antigens are found on all nucleated cells including platelets, which are honorary nucleated cells. Expression of Class II, on the other hand, is restricted to B cells, macrophages, dendritic cells, and a few related cells like Langerhans cells in the skin.
Identify the chromosome on which the MHC is found in humans.
Discuss HLA-A and B typing in terms of how many antigens a person expresses at each locus; given two unrelated parents' haplotypes, predict their children's phenotypes.
Typing at the HLA-A and HLA-B loci can be done by treating the patient’s leukocytes with allele-specific anti-HLA antisera and complement. The most sophisticated labs actually sequence the HLA genes themselves for typing.D3, B7, A1, etc., are each individual’s haplotypes. The cells show their phenotypes, the actual proteins expressed on the surface of their cells. Every cell expresses both alleles.
Name the best probable donors of tissues or bone marrow to an individual, and discuss the reasons for your choices.
So a good DR match is the most important thing (Class 2). In terms of Class 1, HLA-A and HLA-B are the most important alleles. An identical twin, followed by a sibling are the best donors. For bone marrow transplantation, where the graft can attack the recipient, we look for matches at A, B, C, DR, and DQ: A 10/10 match is desirable.
Describe the one-way mixed leukocyte reaction (MLR) and discuss its use.
So we create a one-way MLR, in which the cells from the donor are treated (DNA synthesis inhibitors or radiation) to prevent their division (after all, you really want to know, can the recipient recognize the donor MHC). What you then observe is recipient Th cells dividing in response to the donor’s HLA-D (mostly DR, on monocytes). A strong reaction may preclude doing the transplant.
Distinguish between HLA-D and HLA-DR, -DP, -DQ.
HLA-D is sort of a general term for the group of loci that give rise to MHC type II antigen-presenting proteins. It can also refer to a specific locus HLA-DR. HLA-DR HLA-DP and HLA-DQ are the individual loci within the D region of chromosome 6.
Explain the interaction of T cells recognizing HLA-D and T cells recognizing HLA-A or B in the generation of killer T cells. Include the roles of cytokines in your discussion.
In rejection, let’s imagine that what happens first is a few dendritic cells and macrophages from the graft make their way to a host lymph node. There, host Th1 cells recognize foreign HLA-D on the graft cells. Remember, not all cells express HLA-D; the cells which do so are primarily DC and macrophages, of which most grafts have plenty. The Th1 begin to synthesize lymphokines. They also upregulate cell-surface receptors for growth factors like interleukin 2 (IL-2). This is convenient because they stimulate themselves to proliferate (this is the reaction measured in the MLR).The Th1 will also secrete lymphokines (like IFNγ) that attract an M1 macrophage inflammatory response. Meanwhile, CTL in the vicinity are recognizing foreign HLA-A and HLA-B, which are of course also on the DC and macrophages; this recognition is usually insufficient to activate them, though; they also require Th1-derived interleukins as a second signal. Once activated, the CTL become highly cytotoxic; they may proliferate although they don’t have to.
Please describe hyperacute rejection
The graft tissue is rejected almost immediately. There is circulating antibody against the graft's tissue (from a previous, failed graft) or against the graft's residual blood in the tissue's endothelium. Either way, the antibodies attach to the endothelium, activate lots and lots of complement, and thus set off anaphylatoxin release (C3a, C4a, and C5a, remember?) from mast cells that leads to a vasospasm, constricting the vessels and resulting in tissue ischemia. Evidently this can also lead to systemic inflammation unless the tissue is removed pronto.
Discuss how T cells selected to recognize “self + X” also recognize foreign MHC (allorecognition).
Sometimes my T cells will recognize your MHC and it will be similar enough to mine +X that a response will be created. Somewhere between 5-10% of my wbcs recognize your mhc as my mhc plus something. They act as though they are ready to go against you. This is why rejection can be so speedy. It’s a cross recognition type of thing.Best explanation ever.
Give an example of a disease whose incidence is tightly linked to a particular HLA allele. Speculate on the mechanism which might explain the linkage.
An example is ankylosing sponditis, an unlikely-sounding disease involving the chronic inflammation and eventual calcification of the insertions of tendons into bones. 95% of people with this disease have a particular HLA-B allele (B27). If you put human B27 in rats they get the disease too. Whoa.The basic principle is that there's a price paid for the massive genetic variability of the HLA regions. The price is that, eventually, some variant is going to look similar to a reasonably common antigen (there's some suggestion that for ankylosing sponditis it's Klebsiella), and in your immune response to the antigen you're going to develop an autoimmune response to your own tissues.
Compare the roles of cell-mediated and humoral immunity in virus infections with regard to: preventing the infection; controlling spread of viruses in the body; which is responsible for recovery from disease; how each can cause immunopathology.
Humoral immunity may prevent a viral illness, but T cell immunity is necessary for recovery. ►antibody may prevent a virus from ever establishing an infection in the host. ►Once infection has taken place, it will be necessary to kill the infected cells before virus can multiply within them; and that is the role of T cells.
Discuss the role of CTL in recovery from virus infection.
Natural killer (NK) cells have TLR receptors for viral RNA and make dendritic-cell stimulating cytokines in response. Dendritic cells pick up debris and free virus, and process them to peptides. They are presented by the DC on Class II MHC to Th1 cells, and cross-presented on Class I to CTL which, with Th1 help, become activated, circulating killers.Viruses in infected body cells make early products like glycoproteins, and peptides from them are shown at the cell surface on Class I before complete viral particles have been assembled. These cells are then recognized by CTL (remember!CTL are specific for foreign antigen + MHC Class I). In this way the infected cell is killed in the viral eclipse phase, that is, the time between the virus entering the cell and the time large numbers of viruses can be made.
Define “local immunity” and give an example.
Local immunity on the surface that is being invaded can prevent the invasion; this means secretory IgA. !This is why the Sabin (attenuated, live, oral) polio vaccine is so effective; people immunized with it have high levels of IgA in their secretions and do not get colonized by the real virus.
Identify those organisms against which cell-mediated immunity is most effective.
Viruses, fungi, yeasts, intracellular bacteria.
Identify those organisms against which humoral immunity is most effective.
Extracellular bacteria and pathogens.
Give an example of a human and an animal antitoxin; a toxoid; a killed virus vaccine; and a live virus vaccine. Identify the one which produces the longest-lasting immunity. Discuss possible hazards of each type of preparation.
Human antitoxin: IgG against tetanus.Animal antitoxin: also IgG against tetanus.Killed virus vaccine: injected polio (Salk) vaccine.Live virus vaccine: oral polio (Sabin) vaccine.Longest immunity tends to be live virus vaccines (your body produces not just MHC II responses from professional ingester cells but also MHC I responses from your own, infected cells).Hazards:Antitoxin: possibility of complement activation.Killed virus vaccine: I'm not sure, but could potentially cause pain and fever reactions if there was some kind of innate-immune response to the killed virions in solution. Also provides less thorough immunization that live virus vaccine.Live virus vaccine: The obvious one here is that the virus isn't quite attenuated enough not to seriously infect the patient. More of a recurrent problem with immunocompromised people.
State the appropriate times for immunization of children against diphtheria, pertussis (whooping cough), tetanus, polio, and measles. Discuss why live viral vaccines tend to be ineffective in the very young.
Diphtheria, pertussis, tetanus: 15-18 monthsPolio: 2 months, 4 months, 6-18 months, and 4-6 yearsMeasles: 12-15 months, 4 yearsLive viral vaccines tend to be ineffective in the very young because they tend to be destroyed by the mother's circulating IgG before the kid can make antibody to them.
Discuss the use of IgG and IgM antibody titers in the diagnosis of intrauterine and neonatal infections.
(a) IgM: since it's made quickly and goes away quickly, it's a reasonably good touchstone for whether a kid's had a disease lately.(b) IgG: if you measure it once and leave it at that, you don't know whether the level is getting bigger or staying pretty much the same (thus you don't know whether the kid is making a bunch of it due to a recent exposure or whether the kid's already had the disease and still has the antibodies floating around). Need to take a couple of time points and compare them (are they going up or down?). Also, in utero it is the mother’s.
Identify the oral and parenteral polio vaccines by the names of their developers. Discuss their relative advantages and disadvantages, and note which is currently used in the USA.
Currently the parenteral (injected) polio vaccine is used in the US.The injected form is a killed (Salk) vaccine. The rationale for this is that some kids with impaired immune function might actually get sick from reversion of the attenuated live (Sabin) virus, which is given orally, to a virulent state. The rate of this occurring, says Wiki, is about 7,000 times higher in kids with agammaglobinemia than normal children.Oral is, obviously, easier to distribute and administer, particularly in places in which access to healthcare is a problem (it's a four-part vaccine). It's also transmissable-- the immunized kids can infect their friends and family with the (attenuated) virus, which leads to greater spread of protection. It furthermore gives a better protection rate than killed virus (virus shows up on MHC I, not just MHC II proteins). On the other hand, it can also cause polio, mainly in immunocompromised kids.