User:Eric Martz/MHC Answers

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(New page: ==Answers to Open-Ended Questions about MHC== Here are answers to the [http://molviz.org/antibody/MHC-questions.docx questions provided in a document] with the Major Histocompatibility Com...)
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==Answers to Open-Ended Questions about MHC==
==Answers to Open-Ended Questions about MHC==
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Here are answers to the [http://molviz.org/antibody/MHC-questions.docx questions provided in a document] with the Major Histocompatibility Complex (MHC) tutorial available through [http://molviz.org MolviZ.Org]. Suggestions and feedback to [[Special:Emailuser/Eric_Martz|Eric Martz]].
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Here are answers to the [http://molviz.org/mhc/MHC-questions.pdf questions provided in a document] with the Major Histocompatibility Complex (MHC) tutorial available through [http://molviz.org MolviZ.Org]. Suggestions and feedback to [[Special:Emailuser/Eric_Martz|Eric Martz]].
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<!--1-->Antibody bound to foreign microbes flags them for destruction. This is called "opsonization". Antibody triggers various white blood cells to kill microbes. Antibody bound to viruses can render them non-infectious. Binding of antibody to toxins can neutralize their toxicity. Mothers can give some of their antibodies (primarily IgA) to their babies through their breast milk.
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<!--1-->"Major Histocompatibility Complex". Early studies of tissue grafts between individuals of the same species (allografts) discovered that MHC differences caused the most rapid and intense rejection by the immune system, hence "major". Other genetic differences causes slower, less intense rejection, and were termed "minor histocompatibility" genetic loci. The normal functions of MHC were not discovered until decades later.
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<!--2-->Antibody can cause auto-immune diseases, such as Lupus, rheumatoid arthritis, and Grave's disease. When too much antigen enters the body, antibody:antigen complexes can clog filtration in the kidneys, causing kidney damage called glomerulonephritis.
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<!--2-->All nucleated cells express MHC class I, although the levels of expression vary from tissue to tissue (and a few cell types express undetectable levels). Red blood cells, which lack nuclei, do not express MHC class I. A virus can target any cell type. In order for cytotoxic T cells to detect virus infection, all cell types must express MHC class I.
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<!--3-->People with a rare genetic birth defect called ''agammaglobulinemia'' are unable to make antibodies. They are susceptible to recurrent infections caused by bacteria that do not "hide" inside cells of the host's body: extracellular infections. These include Staphylococci, Streptococci, ''Hemophilus influenzae, Mycoplasma, Pseudomonas'', and ''Vibrio cholerae''. The best therapy is intravenous injection of purified antibodies pooled from healthy donors.
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<!--3-->Only "professional" antigen-presenting cells (APC), such as dendritic cells and macrophages, constitutively express class II MHC. B lymphocytes also express MHC class II, which enables them to receive help from T helper cells. Professional APC phagocytose or endocytose whatever they encounter. B lymphocytes endocytose the specific antigen bound by their antibody receptors, presenting the resulting peptides on their MHC class II to Th cells.
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<!--4-->Immunoglobulin G. (Immunoglobulins are members of a class of proteins called gamma globulins, based on their electrophoretic mobilities.)
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<!--4-->[[Image:Mhc-schematic-sketches.jpg|500px]]
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<!--5-->"Fab" is the Fragment, Antigen Binding. Each IgG molecule has three "arms", two of which are Fab. Fab retains the ability to bind to its cognate antigen. It loses the ability to recruit various immune defense functions, which require the Fc arm, such as opsonization to recruit macrophages and other leukocytes, and activation of complement. However, simply by binding to antigen, Fab may neutralize toxins and decrease the infectiousness of microbes, especially viruses.
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<!--5-->T cytotoxic cells (Tc) express CD8 as a cell membrane receptor. CD8 binds to a specific binding site on MHC class I, facilitating the response of Tc to foreign peptides presented by MHC class I.
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<!--6-->"Fc" is the Fragment, Constant (historically, Crystalline). It is one of the three "arms" of an IgG molecule. When separated by itself, Fc can no longer bind antigen. Thus, Fc loses all of the defense functions of antibody against specific pathogens.
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<!--6-->Protein antigens are synthesized by intracellular parasites such as viruses. Cancer cells also synthesize abnormal proteins. A portion of all cytoplasmic proteins, particularly "worn out" proteins tagged with ubiquitin, are degraded by proteasomes. Peptides generated by proteasomes are transported into the endoplasmic reticulum, and those that fit into the grooves of MHC class I molecules are then carried to the cell surface and presented by the MHC class I molecules.
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Extracellular proteins are taken in by professional antigen-presenting cells and degraded in lysosomes. Peptides from the lysosomes bind to MHC class II, and are then presented on the cell surface.
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<!--7-->Constant domains have the same amino acid sequences for all molecules of a given subtype of antibody, regardless of antigen specificity. Variable domains have different amino acid sequences for each antigen specificity. Within a variable domain, most of the amino acid sequence is a constant framework to enable the domain to fold properly. Only the CDRs are variable. Both constant and variable domains are immunoglobulin domains. They are similar in size, secondary structure (two beta sheets), one disulfide bond between the beta sheets, and in having their amino- and carboxy-termini at opposite ends.
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<!--7-->The peptide-binding groove of MHC class I has closed ends, and can accommodate only peptides of length 8-10 amino acids. In contrast, the groove if MHC class II has open ends, and binds peptides of 13 amino acids up to about 20 amino acids in length.
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<!--8-->The thinnest part functions as a hinge. It enables flexibility, which allows the two paratopes to bind to two epitopes with differences in spacing.
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<!--8-->Each individual has multiple alleles of MHC. These alleles vary in the amino acid sequences in their peptide-binding grooves, thus accommodating a wide range of peptides. In addition, the alpha chains of the MHC class II alleles can assemble with multiple possible beta chains, producing additional variation in the MHC class II grooves.
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<!--9-->An ''epitope'' is the portion of the surface of an antigen molecule that directly contacts bound antibody. A single antigen molecule can have multiple, different epitopes, each recognizable by a different antibody specificity. The ''paratope'' is the surface of the Fab arm of antibody that directly contacts the bound epitope. Each IgG antibody molecule has two Fab's, so two paratopes.
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<!--9-->Each MHC class I groove has sockets that require specific amino acid sidechains pointing down into the groove at specific positions. These are called the peptide's "anchor residues". Thus, all peptides that bind into the groove of a particular MHC class I allele have the same, or similar, anchor residues in the same positions.
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<!--10-->Epitopes of protein antigens are usually discontinuous. That means they are made up of different segments of the antigen's polypeptide chain that come together in the folded antigen protein to form a single epitope. Epitopes are usually fairly flat, but not always. In contrast to epitopes recognized by antibodies, epitopes recognized by T lymphocytes are a continuous peptide fragment of the protein antigen. Such T cell epitopes bind into the gooves of major histocompatibility molecules (MHC), which present the peptides to T lymphocytes. MHC is not involved in the binding of antibody to antigen, but plays a role in activating T helper cells required to activate B lymphocytes to produce antibody in the first place.
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<!--10-->MHC molecules bind peptides that fit their grooves without regard to whether those peptides are from self or foreign proteins. It is the T lymphocytes that decide. T lymphocytes let self proteins pass, but activate immune defenses when foreign peptides are detected. T lymphocytes that recognize self peptides are deleted in the thymus, so they never get out into the body. However, sometimes this T lymphocyte "education" system fails, and then auto-immune disease may occur.
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<!--11-->Your drawing should show two CDR3's in the middle of the paratope, one from the light chain and one from the heavy chain. The CDR3's contribute the most to antigen specificity, since they are the most variable of the CDR's. The CDR3's are flanked by 4 other CDR's, 2 from the light chain and 2 from the heavy chain.
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<!--11-->Viruses and some cancers survive better if their foreign peptides are NOT presented to CD8 Tc cells by MHC class I. Therefore they have evolved schemes to suppress expression of MHC class I. Cells that do not express normal levels of MHC class I may be killed by Natural Killer Cells.
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<!--12-->Flexibility. The images in the tutorial are always rigid.
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<!--13-->Disulfide bonds, which are covalent bonds.
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<!--14-->Antibody binds to antigen by non-covalent bonds, such as hydrogen bonds and salt bridges, and sometimes some hydrophobic interactions. It is important that the epitope and paratope surfaces, which are not completely flat, fit together tightly, without gaps. This is called ''shape complementarity''.
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<!--15-->The analogy is to a single immunoglobulin domain. The two beta sheets are the "bread"; the butter is the hydrophobic core; and the toothpick represents the disulfide bond.
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Current revision

Answers to Open-Ended Questions about MHC

Here are answers to the questions provided in a document with the Major Histocompatibility Complex (MHC) tutorial available through MolviZ.Org. Suggestions and feedback to Eric Martz.


  1. "Major Histocompatibility Complex". Early studies of tissue grafts between individuals of the same species (allografts) discovered that MHC differences caused the most rapid and intense rejection by the immune system, hence "major". Other genetic differences causes slower, less intense rejection, and were termed "minor histocompatibility" genetic loci. The normal functions of MHC were not discovered until decades later.

  2. All nucleated cells express MHC class I, although the levels of expression vary from tissue to tissue (and a few cell types express undetectable levels). Red blood cells, which lack nuclei, do not express MHC class I. A virus can target any cell type. In order for cytotoxic T cells to detect virus infection, all cell types must express MHC class I.

  3. Only "professional" antigen-presenting cells (APC), such as dendritic cells and macrophages, constitutively express class II MHC. B lymphocytes also express MHC class II, which enables them to receive help from T helper cells. Professional APC phagocytose or endocytose whatever they encounter. B lymphocytes endocytose the specific antigen bound by their antibody receptors, presenting the resulting peptides on their MHC class II to Th cells.

  5. T cytotoxic cells (Tc) express CD8 as a cell membrane receptor. CD8 binds to a specific binding site on MHC class I, facilitating the response of Tc to foreign peptides presented by MHC class I.

  6. Protein antigens are synthesized by intracellular parasites such as viruses. Cancer cells also synthesize abnormal proteins. A portion of all cytoplasmic proteins, particularly "worn out" proteins tagged with ubiquitin, are degraded by proteasomes. Peptides generated by proteasomes are transported into the endoplasmic reticulum, and those that fit into the grooves of MHC class I molecules are then carried to the cell surface and presented by the MHC class I molecules.

    Extracellular proteins are taken in by professional antigen-presenting cells and degraded in lysosomes. Peptides from the lysosomes bind to MHC class II, and are then presented on the cell surface.

  7. The peptide-binding groove of MHC class I has closed ends, and can accommodate only peptides of length 8-10 amino acids. In contrast, the groove if MHC class II has open ends, and binds peptides of 13 amino acids up to about 20 amino acids in length.

  8. Each individual has multiple alleles of MHC. These alleles vary in the amino acid sequences in their peptide-binding grooves, thus accommodating a wide range of peptides. In addition, the alpha chains of the MHC class II alleles can assemble with multiple possible beta chains, producing additional variation in the MHC class II grooves.

  9. Each MHC class I groove has sockets that require specific amino acid sidechains pointing down into the groove at specific positions. These are called the peptide's "anchor residues". Thus, all peptides that bind into the groove of a particular MHC class I allele have the same, or similar, anchor residues in the same positions.

  10. MHC molecules bind peptides that fit their grooves without regard to whether those peptides are from self or foreign proteins. It is the T lymphocytes that decide. T lymphocytes let self proteins pass, but activate immune defenses when foreign peptides are detected. T lymphocytes that recognize self peptides are deleted in the thymus, so they never get out into the body. However, sometimes this T lymphocyte "education" system fails, and then auto-immune disease may occur.

  11. Viruses and some cancers survive better if their foreign peptides are NOT presented to CD8 Tc cells by MHC class I. Therefore they have evolved schemes to suppress expression of MHC class I. Cells that do not express normal levels of MHC class I may be killed by Natural Killer Cells.

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Eric Martz

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