Lecture #2 Lymph Nodes Located at points of convergence of lymphatic vessels. Lymph is extracellular fluid which is produced continuously by filtration by the blood-->lymph Afferent lymphatic vessels drain fluid from tissues but also carry lymphocytes that are bearing antigen-->derived from antigen-infected tissues Lymphnodes and spleen are the most highly organized of the 2o lymphoid organs/ in adition to lyoid follicles, they have additional dsitinct regions of T-cell and B cell activity, surrounded by a fibrous capsule. See separation of B cells and T cells into discrete regions B cell follicles Paracortical areas=T cell zone Once the antigen-specific lymphocytes have undergone a period of proliferation and differentiation, they leave the lymph nodes as effector cells through the efferent lymphatic vessel. Are oval structures distributed throughout the body Nodes are linked together by extensive lymphatic vessels. Node surrounded by a connective tissue (fibrous) capsule from which trabeculae protrude centrally. Beneath the capsule is the subcapsular sinus, these channel down and become medullary sinuses Beneath the sinus is the cortical area of the node containing lymphocytes. Afferent and efferent lymphatic vessels Primary lymphoid follicle Secondary lymphoid follicle with germinal center Paracortical area (mostly T cells) Medullary cords (macrophage and plasma cells) Medulary sinus contains the efferent lymphatic vessels, tribeculae and contain phagocytic elements of the macrophage system Germinal centers Prolific proliferation of B cells--> maturation of B cells-->Ab-secreting cells-->terminally differentiated plasma cells Lymphocytes leave GC through blood vessels The Spleen: Two primary functions collects dead blood cells collects antigen from the blood Others: Red pulp-site of red blood cell disposal White pulp-lyumphoctes-surround arterioles In many ways organization of the white pulp is similar to the lymphnode Located in the left upper quadrant of the abdomen. It is supplied by a single splenic artery, which pierces the capsule at the hilum and divides into progressively smaller branches that remain surrounded by protective and supporting fibrous trabeculae. Organization of the White Pulp in the Spleen: 1. Small arterioles are surrounded by cuffs of lymphocytes called periarteriolar lymphoid sheaths, to which are attached the lymphoid follicles, some of which contain germinal centers. 2. PALS and follicles are surrounded by a rim of lymphocytes and macrophages, called the marginal zone. 3.Dense lymphoid tissues constitute the white pulp of the spleen Periarticular lymphoid sheath-made up of T cells Follicles made up primarily of B cells PFZ- Marginal zone- Antibody: Series of repeats of approximately 110 amino acids, each repeat corresponds to a discrete, compactly folded region of protein structure known as a protein domain. Light chain contains 2 and heavy chain contains 4. Amino terminal region of both the heavy and light chain vary greatly between Ab whereas the carboxy terminus of both the heavy and light chains are constant. Hinge region provides flexibility to the molecule. The alpha helix. The N?H of every peptide bond is hydrogen-bonded to the C=O of a neighboring peptide bond located four peptide bonds away in the same chain. (D, E, and F) The beta sheet. In this example, adjacent peptide chains run in opposite (antiparallel) directions. The individual polypeptide chains (strands) in a b sheet are held together by hydrogen-bonding between peptide bonds in different strands, and the amino acid side chains in each strand alternately project above and below the plane of the sheet. (A) and (D) show all the atoms in the polypeptide backbone, but the amino acid side chains are truncated and denoted by R. In contrast, (B) and (E) show the backbone atoms only, while (C) and (F) display the shorthand symbols that are used to represent the a helix and the b sheet in ribbon drawings of proteins (see Panel 3?2B). Ig: Each domain is a barrel-shaped structure in which strands of polypeptide chain (b strands) running in opposite directions (antiparallel) pack together to form two b sheets which are held together by a disulfide bond. The b strands C?a nd C? that are found in the V domains but not in the C domains are indicated by a blue shaded background. The typical 4-strand plus 3-strand (C-region type domain)and 4-strand plus 5-strand (V-region-type domain) arrangements are typical immunoglobulin superfamily domain building blocks, found in a whole range of other proteins that have Ig-like domain. Ig fold approximately 110 aa residues in length that fold independently in a globular motif that is called an Ig domain. Four framework regions(FR1-4), 3 hypervariable regions (HV1,2,3) Haptens: Flexibility aids in interacting with two antigens at a distance from each other. Also enables the Abs to interact with the ab-binding proteins that mediate immune effector mechanisms Lecture #2, pg 19 Abs against gp120 antigen has elongated CDR3 loops that protrude into a recess in the surface of the antigen. The structure of the complex between this antibody and gp120 has not been solved, so the yellow area on the images in the lower panels represents the extent of the CDR regions rather than the actual region of contact between antibody and antigen. Lecture #3 Pg 8 (4th slide) Distinct difference in C( domain, where the fold is unlike that of any other Ig-like domain. The half of the domain that is juxtaposed with the C( domain forms a b sheet similar to that found in other Ig-like domain, but the other half of the domain is formed of loosely packed stands and a short segment of a helix. MHC class I: B2-microglobulin chain is non-covalently associated with the larger alpha chain. B2 mg and g3 domain are Ig-like domains whereas the a1 and a2 are unique. Alpha 1 and alpha 2 domains fold together into a single structure consisting of two segmented a helices lying on a sheet of eight antiparallel beta strands. The folding of the alpha 1 and alpha2 domains creates a long cleft or groove, which is the site at which peptide antigens bind to the MHC molecules. MHC class II: Two transmembrane glycoprotein chains (alpha and beta). Each chain has two domains and the two chains together form a compact four-domain structure similra to that of the MHC class I molecule. A2 and b2 domains have structures similar to the Ig C region domains Each MHC molecule must be able to bind stably to many different peptides. Binding site can bind peptides with high affinity while retaining the ability to bind a wide variety of different peptides Pg 12 (Slide 3) Peptide in the cleft is stabilized at both ends by contacts between atoms in the free amino and carboxy termini of the peptide and invariant sites that are found at each end of the cleft of all MHC class I molecules. Peptides usually 8-10 aa long. The main differences between the allelic MHC variants are found at certain sites in the peptide-binding cleft, resulting in different amino acids in key peptide-interaction sites in the different MHC variants. Lecture #4 Peptide in the cleft is stabilized at both ends by contacts between atoms in the free amino and carboxy termini of the peptide and invariant sites that are found at each end of the cleft of all MHC class I molecules. Peptides usually 8-10 aa long. The main differences between the allelic MHC variants are found at certain sites in the peptide-binding cleft, resulting in different amino acids in key peptide-interaction sites in the different MHC variants. Also, contain Ig-fold domains; CD4 is a single polypeptide and CD8 is composed of 2 peptide; ( and ( that are linked by a disulfide bond Lecture #5 Somatic mutation leads to increased affinity of Ab; repeated immunizations lead also to higher absolute levels of antibody in the blood stream Lecture #6 A B cell rearranges a DJ segment on both alleles. Then there is a single rearrangement of a V segment to a rearranged DJ segment on one allele. If this rearrangement encodes for protein then there is no rearrangement on the second allele. If the first VDJ rearrangement is non-functional (does encode protein) the second allele rearranges a V to the rearranged DJ segment. MHC-peptide being recognized by the 6 hyper variable regions of the TCR alpha and beta chains The ( locus is found within the (-chain locus. If the alpha chain rearranges V-J then the delta locus is lost and the T cell is destined to become a ((( T cell and cannot be a ((( T cell. Structure of an antibody molecule, has two functions-binding to an unlimited no. of antigens using the V region and at the same time the C region binds to a limited number of effector molecules and cells.
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