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Terms in this set (143)

B Cell: (Low maintenance)
-Membrane bound immunoglobulin receptor composed to two heavy chains and two light chains with a variable region (antigen recognition)
-Idiotype (1) = Can recognize unprocessed antigens, but only type of antigenic specificity per cell
-Isotypyes (2) = IgD and IgM
-Can bind two antigens per each immunoglobulin (one on each arm)
-The receptor is flexible at the hinge region (to reach out to secure antigens)
-Can be secreted
-Immunoglobulin has a short membrane binding domain and cytoplasmic tail so a signal transduction complex with long cytoplasmic tails is also present to convey information about the antigen into the cell
-Signal transduction complex: Two Ig-alpha-Ig-beta heterodimers
-Co-factors to the signal transduction complex which lower the threshold to antigen sensitivity (otherwise would need A LOT of antigen): CD 19, CD 20, CD 21

T Cell: (High maintenance)
-Membrane bound T Cell Receptor (TCR) composed of alpha/beta chains (one each)
-Idiotype (1) = Can recognize only small PEPTIDES processed and bound to antigen presenting cells (macrophages, dendritic cells, or B lymphocytes) on MHC
-Isotypes (1) = alpha/beta
-Can bind only one antigen per TCR at a time
-The receptor is rigid
-TCR also has a short membrane binding domain and cytoplasmic tail so a signal transduction complex with long cytoplasmic tails is present to convey information about the antigen into the cell
-Always cell-bound (no secretion)
-Signal transduction complex: CD3

*CD = Cluster of Differentiation
Antigen Independent Stage:
1) Lymphoid stem cell:
-Commits to B cell lineage

2) Pro-B (Progenitor) Cell: (Pro = Not heavy yet)
-Heavy chain gene rearrangement
-Rag expression (required for VDJ rearrangement)
-Tdt expression (randomly adds bases to heavy chain DNA during rearrangement)
-MCH II expression (B cells are APCs so they will expression MHC Class II to present antigens to T helper cells). *Expressed for all stages of maturation and rest of B cell life
-CD19, CD20, CD21, CD40 expression. *Expressed for all stages of maturation and rest of B cell life

3) Pre-B Cell: (Pre = Heavy, but not light yet)
-Light chain rearrangement
-Tdt no longer expressed
-rag expressed until light chain rearrangement is complete
-Heavy chains (mu proteins) waiting for light chain translation in the cytoplasm

4) Immature B Cell: (Heavy and light M, but not D)
-Functional heavy and light chains assemble and are expressed on surface
-Only IgM is expressed on surface (not IgD yet)
-Selection of B cells takes place at this stage. As soon as IgM is expressed on surface it is tested against self-antigens. If reactive to self antigens, apoptosis is initiated. If not, the survival signal is given and the immature B cell is allowed to become a mature B cell and leave the bone marrow

Antigen Dependent Stage:
1) Mature B cell:
-IgM and IgD receptors are expressed on the cell surface following alternative splicing. The B now mature B cell is roaming the periphery for antigen

2) Activated (Blast) B Cell:
-Upon contact with an antigen matching it's idiotype, the B cell becomes activated. At this point, it can terminally differentiate into a plasma cell or become a memory B cell.

3a) Plasma Cell:
-Secrete antibody for a couple of week and then die off

3b) Memory B Cell:
-Long life span with memory of previously encountered antigen
-Antigen stimulation induces class-switching so memory B cell may express surface IgG, IgA, or IgE
-Upon repeated recognition of this antigen, the memory B cell quickly converts to a Plasma cell and begins producing large amounts of antibody
Deficiency of NADPH oxidase (any of the Phox components)
-Without NADPH oxidase, oxygen cannot be reduced to the superoxide anion (a free radical), which is then converted to other reactive oxygen species (e.g. H2O2 via superoxide dismutase).
-Results in failure to generate ROS in lysosome of phagocytes = No respiratory burst!
-Catalase Test (for microbial isolates): Catalase breaks down H2O2 -> H2O + O2. Catalase testing: O2 bubbles seen if +
-In organisms that lack catalase (catalase-), normal metabolic functions will cause an accumulation of H2O2. This H2O2 reservoir can then be converted to ROIs by the host phagocytes to kill the catalase- H2O2-producing bacterium. The immune system will then be able to fight off the infection. Hence the reason why CGD pts are not as susceptible to catalase- bacterial infections.
-Catalase+ bacteria will break down any H2O2 produced through normal metabolism and therefore no H2O2 will accumulate. Subsequently no conversion to ROIs will take place and the host will be susceptible to chronic and recurrent catalase+ bacterial infections (S. aureus, E. coli, and Aspergillus).

Clinical Diagnosis:
-Nitroblue Tetrazolinum (NBT) Dye Reduction Test
-The pts production of superoxide free radical will reduce the NBT to produce a BLUE reaction.
-This can be used to tell if there is a problem with PHOX enzymes, but not how much they are affected.
-A pt with CGD would have a NEGATIVE NBT test: CGD pts lack NADPH oxidase so they cannot make the superoxide free radical. Hence, no reaction -> No blue -> Negative test -> Positive for CGD. If NBT Test = Blue = Positive = No CGD
-Mediated by IgE Abs and mast cells
-Reaction within minutes of re-exposure to antigen
-IgE response is normally protective against parasites (helminths and worms)
otherwise too large to be phagocytosed or killed by other cytopathic mechanisms
-Also the cause of innappropriate allergic/atopic reaction to harmless pollens and dander (IgE response got bored since worm and helminths are not common in developed countries -- allergies are not common in developing countries as IgE is busy dealing with nematodes)

Process of Reaction:
1) First exposure to antigen = Sensitization
2) TH2 response = IL-4 + IL-13 stimulates B cell class switching to IgE
3) B cells production of IgE -> IgE attaches to Fc receptor on mast cells (for a longgggg time)
4) Second exposure to antigen
5) Allergen cross-linking of IgE on mast cell -> mast cell degranulation within minutes (hence, immediate)

Effector Cells:
-Mast cells (mostly in tissues)
-Basophils (mostly in blood)

Activated mast cell (+ basophil) response:
-Promoting an inflammatory response (increased vascular permeability, vasodilation, bronchoconstriction, intenstinal hypermotility with consumed food allergens, inflammation, and tissue damage
-Release of histamine, lipid mediators (PAF, PGD2, LTC4), cytokines (TNF), and enzymes (trypase)

Eosinophil response:
-Recruited by eosinophil chemotactic factor -- arrive late to the scene already activated and cause a lot of damage
-Upon arrival, eosinophils degranulate
-In the case of a parasite, the granules containing cationic proteins kill the parasite and some host cells
-In the absence of a parasite, the contents of the granules damages just host cells and remodeling must take place to repair them

Primary Mediators:
-Pre-made and stored in granules
-Short-lived and not very potent
-Histamine = Smooth muscle contraction, increased vascular permeability
-Heparin = Anticoagulant
-Eosinophil Chemotatic Factor = Recruits eosinophils

Secondary Mediators:
-Made during degranulation
-More potent and last longer, but appear later than primary response
-Lipids are broken down and shuttled through arachidonic acid pathway
-Prostaglandins D2, E2, F2-alpha = Increased smooth muscle contraction and permeability
-Leukotrienes C4, D4, E4 (lipoxygenase pathway) = Increased smooth muscle contraction and permeability
-Leukotriene B4 = Chemotactic for neutrophils
-Cytotoxic type II hypersensitivity
-Abs opsonize RBCs (which happen to be circulating, but is still not considered a Type III) and activate complement, which then deposit a membrane attack complex and lyse the cell
-Results in hemolysis and anemia
-Hemolysis = Premature destruction of RBCs
-Hemolytic anemia arises when bone marrow production of RBCs cannot compensate for RBC loss

Example: Erythroblastosis Fetalis
-Rhesus (Rh) antigen = Surface antigen (RhD) found on the surface of RBCs
-Most people are Rh+
1) Rh- pregnant woman + Rh+ man = Fetus may be Rh+
2) During the first pregnancy fetal Rh+ and maternal Rh- blood do not have contact until the placenta separates at birth (usually....sometimes occurs during aminocentesis, but if only IgM Abs are present, they cannot cross the placenta)
3) At birth, mixing of the fetal and maternal blood stimulates T cell dependent immune response (i.e. becomes sensitized)
4) B cells are stimulated to class switch to IgG, which CAN cross the placenta, and memory B cells are made
5) During subsequent pregnancies with another Rh+ fetus, maternal IgG transported across the placenta cross-reacts with fetal RBCs bearing the Rh antigen. IgG binds to the RBC and leaving the Fc tail available to receptors of cytotoxic cells for ADCC (such as macrophages and NK cells)
6) Complement is activatedand by the IgG and lyses the fetal RBCs
7) Hemolytic anemia (aka hemolytic disease of the newborn) results
8) Can be prevented by treating Rh- mother with Rhogram = human anti-RhD antibody that is given at 28wks gestation and again within 72 hours of birth to passively immunize the mother. The Ab given during pregnancy is NOT IgG (would defeat the purpose) -- instead it is another isotype like IgD. The post birth Rhogam is IgG, which eliminates fetal Rh+ cells before RhD specific immune memory can be generated in the mother. Give this Ab to any Rh- individual following any termination of pregnancy as even a miscarriage counts.

Miscarriages count as a 'first pregnancy' so even for women presenting with their first 'viable pregnancy' they have ALREADY been sensitized
Usually performed for bone marrow donation and living donors, but not usually for cadaver donors (much more important to transplant organ right away than wait for test results).

ABO Blood Typing
-ALWAYS performed because it is easy and can result in hyperacute rejection if there is an ABO incompatibility (as IgM is already formed) -- Would be a Type II cytotoxic hypersensitivity reaction
-Abs to opposing ABO type comes from bacteria that have similar sugars as the ABO glycoprotein (have A antigen on blood cells -> will make B Abs due to bacteria expressing similar antigen)

Microcytotoxicity Test
-Identifies MHC I haplotype using complement (screening test)
-Looks at HLA-A and HLA-B
-Donor cells are mixed with Abs to every allele type to MHC I
-If the donor cell has the allele, Abs bind, complement lyses the cell, dye is taken up and we know what the donor allele is
-If the cell is not lysed, then it does not have the allele specific to that Ab
-Thus, if you get a color type, the donor cell has the allele type you were looking for
-Each cell expresses two alleles as everyone gets one haplotype from mom and one from dad

Mixed Lymphocyte Reaction
-Identifies MHC II
-Looks at HLA-DR
-Irradiate donor cells to inhibit their proliferation, but maintain immunogenicity.
-Add irradiate donor cells to live recipient cells and see if reaction takes place.
-If recipient cells are agitated by donor cells MHC II they will proliferate (to mount a response).
-With the addition of radioactive thymidine, proliferating cells will incorporate it into their newly synthesized DNA and will be radioactive.
-The more radioactivity = More incompatibility.

-Mix serum from recipient with lymphocytes from donor to determine if preformed Abs to donor HLA are there
-Abs can arise from previous pregnancies, transfusions, or transplants
-Called cross-matching