Term
| 3-8 a (i) Describe the structure of an MHC class I molecule, identifying the different polypeptide chains and domains |
|
Definition
| It is a heterodimer made up of one alpha chain and a smaller chain called beta2-microglobulin. The alpha chain consists of three extracellular domains- alpha1, alpha2, alpha3, a transmembrane region and a ctoplasmic tail. Beta2 microglobulin is a single-domain protein noncovalently associated with the extracellular portion of the alpha chain, providing support and stability |
|
|
Term
| 3-8 a (ii) What are the names of the MHC class I molecules produced by humans? Which part of the molecule is encoded w/in the MHC region of the genome? |
|
Definition
| the polymorphic class I molecules in humans are called HLA-A, HLA-B, and HLA-C. The alpha chain is encoded in the MHC region by an MHC I gene. the gene for beta2-miecroglobulin is elsewhere in the genome |
|
|
Term
| 3-8 a (iii) Which domains or parts of domains in MHC I participate in: antigen binding; binding the T-cell receptor; and binding the T-cell co-receptor? |
|
Definition
| The antigen binding site is formed by the alpha1 and alpha2 domains, the ones farthest from the membrane, which create a peptide binding groove. The region of the MHC molecule that binds to the T-cell receptor encompasses the alpha helices of the alpha1 and alpha2 domain thta make up the outer surfaces of the peptide binding groove. The alpha3 domain binds to the T-cell co-receptor CD8 |
|
|
Term
| 3-8 a(iv) Which domains in MHC I are the most polymorphic? |
|
Definition
| The most polymorphic parts of the alpha chain are the regions of the alpha1 and alpha2 domains that bidn antigen and the T-cell receptor, beta2-microglobulin is invariant (same in all individiuals |
|
|
Term
| 3-8 b (i) Describe the structure of an MHC class II molecule, identifying the different polypeptide chains and domains |
|
Definition
| MHC II molecules are heterodimers made up of an alpha chain and a beta chain. The alpha chain consists of alpha1 and alpha2 extracellular domain, a transmembrane region, and a cytoplasmic tail. The beta chain contains beta1 and beta2 extracellular domains, a transmembrane region, and a cytoplasmic tail. the beta chain contains beta1 and beta2 extracellular domains, a transmembrane region, and a cytoplasmic tail |
|
|
Term
| 3-8 b (ii) What are the names of the MHC class II molecules produced by humans? Which part of the molecule is encoded w/in the MHC region of the genome? |
|
Definition
| In humans there are three polymorphic MHC II molecules called HLA-DP, HLA_DQ, and HLA-DR. Both chains of an MHC cII molecule are encoded by genes in the MHC region |
|
|
Term
| 3-8 b (iii) Which domains or parts of domains of MHC II participate in: antigen binding; binding the T-cell receptor; and binding the T-cell co-receptor? |
|
Definition
| antigen binds in the peptide-binding groove formed by the alpha1 and beta1 domains. the alpha helices of the alpha1 and beta1 domains interact with the t-cell receptor. The beta2 domain bind sot the t-cell co-receptor CD4 |
|
|
Term
| 3-8 b (iv) Which domains are the most polymorphic for MHC class II? |
|
Definition
| With the exception of HLA-DRalpha, which is monomorhpic, both the alpha and beta chains of MHC II molecules are polymorphic. Polymorhpism is concentrated around the regions that bind antigen and the t-cell receptor in the lapha1 and beta1 domains |
|
|
Term
| 3-9 a What is the maximum number of MHC molecules that a heterozygous individual could theoretically express? Explain your answer (Ignore possibility of MHC class II molecules composed of chains from different isoforms) |
|
Definition
| There are three MHC I genes in humans (HLA-A, HLA-B, and HLA-C) and they are expressed from both chromosomes. Assuming that each gene is heterozygous, the maximum number of different MHC I alpha chains that could be expressed is 6. As beta2-microglobulin is invariant, this means that six differnt MHC I molecules could be produced. For MHC II molecules, assuming complete heterozygosity and the presence of two functional DRG genes (DRB1 and DRB3, 4, or 5) on both chromosomes, the maximum number of MHC II molecules that could be expressed is 12. The total number of different HLA molecules that can be expressed is 18 |
|
|
Term
| 3-9 b How does this relatively small number of MHC molecules have the potential to bind the huge number of antigenic peptides encountered in the environment, and what features of a peptide determine whether it will be bound by a given MHC molecule? |
|
Definition
| MHC molecules have degenerate binding specificity, which means that one MHC molecule is able to bind a wide range of peptides of different sequence. For all MHC molecules, only a few of the amino acids in the antigen peptide are critical for binding to amino acids int he peptide-binding groove. The critical amino acids in the peptide are called anchor residues; they will be the same or similar in all peptides that bind to a given MHC molecules. The other amino-acid residues in the peptides can be different. The pattern of anchor residues that binds to a given MHC molcule is called the peptide-binding motif. Hence, a very large number of discrete peptides can bind to each MHC isoform, the only constraint being the possession of the correct anchor resides at the appropriate positions in the peptide. MHC I molecules also bind peptides that are typically nine amino acids long, whereas MHC II molecules bind longer peptides with a range of lengths |
|
|
Term
| 3-10 a What is the difference between MHC polygeny and MHC polymorphism? |
|
Definition
| polygeny refers to the presence of multiple genes for MHC I and MHC II molecules in the genome, encoding a set of structurally similar proteins with similar functions. MHC polymorphism is the presence of multiple alleles of most of the MHC I and II genes in the human population |
|
|
Term
| 3-10 b (i) How does polygeny in MHC genes influence the antigens a person's T cells can recognize? |
|
Definition
| Because each individual produces a number of different MHC molecules from their polygenic MHC I and II genes, the t-cell receptor repertoire is not restricted to recognizing peptides that bind to just one MHC molecule. Instead, the t-cell receptor repertoire can recognize peptides with different peptide-binding motifs during an immune response, increasing th eliklihood of antigen recognition and t-cell activation |
|
|
Term
| 3-10 b (ii) How does polymorphism in the MHC genes influence the antigens a person's T cells can recognize? |
|
Definition
| The polymorphism in MHC molecules is localized in the regions affecting T-cell receptor and peptide binding. Thus, a t-cell receptor that recognizes a given peptide bound to variant 'a' of a particular MHC molecule is likely not to recognize the same peptide bound to variant 'b' o fthe same MHC molecule. Polymorhpism also means that the MHC molecules of one person will bind a different set of peptides from those in another person. |
|
|
Term
| 3-11 a describe in chronological order the steps of the endogenous antigen-processing pathway for intracellular, cytosolic pathogens |
|
Definition
| Proteins from pathogens growing in the cytosol are broken down into small peptide fragments in proteasomes. the peptides are transported into the lumen of the endoplasmic reticulum (ER) using TAP (transporter associated with antigen processing) which is a heterodimer of TAP-1 and TAP-2 proteins located in the ER membrane. Peptides bearing the appropriate peptide-binding motif bind to MHC class I molecules already deleivered into the ER. MHC I alpha chains are bound to the chaperone calnexin until beta2-microglobulin binds, and then are bound by the chaperones calreticulin and tapasin until peptide binds. Tapasin binds to TAP-1 positioning the MHC I molecule near the peptide source. MHC I molecules bound to peptide dissociate from the chaperone molecules and progress to the Golgi apparatus for completion of glycosylation and transport tothe cell surface in membrane bound vesicles |
|
|
Term
| 3-11 b (i) what would be the outcome if a mutant MHC class I alpha chain could not associate with Beta2 microglobulin |
|
Definition
| If an MHC I alpha chain is unable to bind beta2-microglobulin, it will be retained in the ER and will not be transported to the cell surface. It will remain bound to calnexin and will not fold into the conformation needed to bind to peptide. Thus, antigens will not be presented using that particular MHC I molecule |
|
|
Term
| 3-11 b (ii) What would happen if the TAP transporter was lacking as a result of mutation |
|
Definition
| If TAP-1 or TAP-2 proteins are mutated and not expressed, then peptides will not be transported into the lumen of the ER. W/out peptide, and MHC I molecule can't complete its assembly and will not leave the ER. |
|
|
Term
| 4-1 a give several properties that distinguish b-1 cells from b-2 cells |
|
Definition
| B-1 cells are activated early during an immune response, do not produce immunological memory, and do not carry out affinity maturation. Individual B-1 cells are polyspecific for antigen; that is, their immunoglobulins will bind to a number of different antigens. They produce primarily antibodies o fthe IgM isotype. In contrast, B-2 cells are activated later in immune responses (owing to the requirement for T-cell help and antigen processing), give rise to immunological memory, and carry out somatic hypermutation. Individual B-2 cells are monospecific for antigen. In addition, B-2 cells can express different isotypes of antibodies through the process of isotypes switching, which involves T-cell help. Bo-1 cells are unable to switch isotype |
|
|
Term
| 4-1 b describe the chemical composition of the antigen recognized by b-1 cells and explain why these antigens are categorized as T-independent (TI-2) antigens |
|
Definition
| The antigens recognized by most B-1 cells are bacterial polysaccharides and other carbohydrate antigens. Helper T cells recognize protein antigens, not carbohydrates and therefore are unable to provide help for B-1 cells |
|
|
Term
| 4-1 c do you think that b-1 cells should be categorized as participants in innate immune respones or acquired immune responses? |
|
Definition
| B-1 cells are probably best associated with innate immune responses because of their rapid resonse to antigen, limited diversity, lack of memory, and polyspecificity |
|
|
Term
| 4-3 Explain how the inability of anergic B cells to enter secondary lymphoid follicles plays a role in eliminating B cells that have antigen receptors specific for soluble self-antigen |
|
Definition
| In order to survive, circulating B cells are required to enter primary follicles where survival signals are delivered by cells in the follicles including follicular dendritic cells. Circulating B cells that fail to enter follicles in secondary lymphoid tissues will die in the peripheral circulation with a 1/2 life of about 3 days. Anergic B cells that enter secondary lymphoid organs are withheld in the t-cell areas adjacent to primary follicles and are thus not permitted to penetrate the primary follicle. As a result, anergic B cells fail to receive the necessary stimulatory signal for survival and permission to proceed to the primary follicle is denied. Instead anergic B cells will undergo apoptosis in the T-cell zone. This is an efficient cleansing mechanism and serves to delete potentially autoreactive B cells from the circulation |
|
|
Term
| 4-4 Identify properties that are shared by anergic B cells and plasma cells and what key property is different? |
|
Definition
| They both have limited life-spans, express decreased levels of IgM on the cell surface and are nonresponsive to antigen and T-cell help, but anergic B cells do not secrete antibody |
|
|
Term
| 4-5 a explain why immunological memory is important in acquired immunity |
|
Definition
| Memory enables faster, more efficient recall responses when antigen is encountered subsequently. this enables the body to get rid of a pathogen before it has time to cause disease |
|
|
Term
| 4-5 b describe how immunoglobulin expressed during a primary immune response differs qualitatively and quantitatively from the immunoglobulin expressed during a secondary immune response |
|
Definition
| Immunoglobulin produced during a primary immune response is primarily IgM, in low concentration and of low affinity for the antigen. Immunoglobulin expressed during a secondary immune response has undergone isotype switching and is often of the IgG isotype. It also has a higher titer, and through somatic hypermutation, will have a higher affinity for its corresponding antigen |
|
|
Term
| 4-6 explain how the two checkpoints in b-cell development correlate with the process of allelic exclusion which ensures that only one heavy-chain locus and on light-chain locus produce functional gene products |
|
Definition
Checkpoint 1 is formation of complex of u heavy chain complexed with surrogate light chain VpreBlambda5, Igalpha and Igbeta. This delivers an important signal to cell verifying functional heavy chain has been made. Triggers cessationj of heavy chain gene rearrangement followed by inactivation of surrogate light chain synthesis. So only one heavy chain locus ends up producing a product.
Checkpoint 2 is when complete B-cell receptor comprising u heavy chains, kapp or lambda light chains, and Igalpha and Igbeta chains is expressed on the B-cell surface. this signals cessation of light-chain rearrangement |
|
|
Term
| 4-7 what would be the consequence if terminal deoxynucleotidyl transferase (TdT) was expressed throughout the whole of small pre-B cell development |
|
Definition
| N nucleotides would be added at the VJ joints of all rearranged light chain genes during gene rearrangement (instead of half), resulting in an increase in immunoglobulin diversity. |
|
|
Term
| 4-8 a discuss the importance of the bone marrow stroma for B-cell development |
|
Definition
| bone marrow stromal cells provide the necessary environment for b-cell development by expressing secreted products and membrane-bound adhesion molecules |
|
|
Term
| 4-8 b what would be the effect of anti-IL-7 antibodies on the development of B cells in the bone marrow and at which stage would development be impaired? |
|
Definition
| If anti-IL-7 antibody were introduced into this environment, developing B cells would be arrested at the late pro-B or pre-B cell stage and would not be able to progress normally to the immature B-cell stage |
|
|
Term
| 4-9 a explain why b cells isolated from a particular b-cell tumor all express the same immunoglobulin |
|
Definition
| A b-cell tumor comprises cells that derive from a single cell that has undergone transformation that resulted in uncontrolled growth. No further maturation of the B cell occurs following transformation. If the B cell has rearranged the heavy and light chain genes prior to transformation, then immunoglobulin will be expressed at the cell surface. Because all of the cells in the tumor belong to the same clone, the immunoglobulin on all of them will be made of the same heavy and light chains |
|
|
Term
| 4-9 b how might the immunoglobulin expressed on pre-b cell leukemia cells be different from that expressed on immature be cells? |
|
Definition
| pre-b cellleukemia is characterized by transformation prior to the rearrangement of light-chain genes. If transformation occurs at the large pre-B cell cell stage, then the immunoglobulin on the cell surface will be composed of u:VpreBlambda5. If transformation occurs at the small pre-B cell stage, then there would be little or no immunoglobulin on the cell surface because surrogate light chain expression is turned off at this stage and the u heavy chains are retained in the endoplasmic reticulum. Normal immature B cells that have not undergone transformation express IgM containing u plus a kappa or lambda light chain |
|
|
Term
| 5-3 a what are the limited number of MHC II cell types |
|
Definition
| Cells that express MHC class II are the professional antigen presenting cells (B cells, macrophages, and dendritic cells, thymic epithelial cells, neural microglia, and activated T cells |
|
|
Term
| 5-3 b Which of the MHC II cell types populate the thymus or circulate through it, and what role do they play in mediating positive and/or negative selection? |
|
Definition
| macrophages, dendritic cells, and thymic epithelial cells. thymic epithelial cells participate in positive selection by presenting MHC I and II molecule with self-peptides to double-positive thymocytes(CD4+/CD8+). Only T cells that have t-cell receptors that can interact with self-MHC are positively selected, thus shaping a Tcell repertoire that is specific for self-MHC molecules. Also help in negative selection for T cell receptors that have high affinity for self MHC/peptides |
|
|
Term
| 5-3 c can you explain why it would be detrimental for noncirculating cells that populate tissues and glands to express MCH II |
|
Definition
| Because those sites w/out circulation are typically MHC II negative and this could bring about the presentation of self-peptides with MHC II that weren't presented in the thymus during negative selection |
|
|
Term
| 5-6 a what is the effect of MHC II deficiency? |
|
Definition
| MHC II deficiency affect the development of CD4 T cells in the thymus. If th ethymic epithelium lacks MHC II, then positive selection of DCr T cells will not take place. CD8 T cells are not affected because MHC I expression is unaffected by this defect |
|
|
Term
| 5-6 b explain why hypogammaglobulinemia is associated with this deficiency |
|
Definition
| In order to produce antibody B cells require t-cell help in the form of cytokines produced by CD4 TH2 cells. Low immunoglobulin levels are attributed to the inability of B lymphocytes to proliferate and differentiate into plasma cells in the absence of TH2 cytokines |
|
|
Term
| 5-8 The benefit of polygeny in MHC I and II genes and the expression of multiple isotypes is the resulting increase in number of potential peptide-binding motifs for antigen presentation to T cells. If more is better, then why hasn't natural selection favored more than three isotypes each for MHC I and MHC II and driven the expansion of polygeny further in the MHC |
|
Definition
| Beyond a certain number of isotypes, the t-cell repertoire will be decreased, owing to the disproportioate increase in negative selection events as the number of different isotypes increases. Each additional isotype will decrease the number of t cells exported to the periphery, compromising the diversity of the t-cell population |
|
|
Term
| Expressed protein products are responsible for "turning off" variable gene rearrangements in B cells. Where in the ontogeny (maturation) of B cells does this occur? |
|
Definition
| This occurs right after the product rearrangement of the heavy chain and light chain, when it is an immature B cell |
|
|
Term
| The large pre-B cell divides into about six cells before any more rearrangement occurs. The resulting six cells then begin light chain rearrangement. therefore, will these six cells have identical antigen specificity? Which is more common among B cells, similar heavy chain rearrangements or similar light chain rearrangements? |
|
Definition
| They have varying antigen specificity since the gene rearrangements occur after the cell division. Heavy chain rearrangements are more likely due to having less likely |
|
|
Term
| In the prenatal period, a subset of B cells known as B-1 cells make mostly IgM receptors and also secrete mostly IgM. The variability of these receptors is also quite low compared to the "normal" B-2 cells we've been learning about. the antibodies of the B-1 cells often can bind to multiple antigens and are therefore known as polyspecific. Why do you think these cells exist? |
|
Definition
| They exist as a initial immune defense due to a lack of memory and their fast response. This is probably meant to be in place until the body can produce more specific B-cells with higher specificity |
|
|
Term
| B cells must have regular contact with a secondary lymphoid follicle in order to survive. those that do not enter follicles may die w/in a few days, those that do enter follicles will die w/in 3-8 weeks unless stimulated by specific antigen. Speculate as to what is going on in a follicle that acts to prolong B-cell life |
|
Definition
| B cells in follicles are changed to centroblasts which in turn become centrocytes. The b cells that make surface immunoglobulins with the highest affinity for the antigen are slected by affinity maturation, which occurs in germinal centers. These germinal center B cells develop into memory B cells. Memory b cells last for a long time, they are much more easily activated on encountering antigen than 'naive' b cells. |
|
|
