9. Lymphocyte Development Flashcards
lymphopoiesis is _____ antigen dependent
self
where does lymphopoiesis occur?
primary lymphoid organs
what are the three main branches/outcomes of lymphopoiesis?
- differentiation
- acquisition of antigen recognition (diversity, clonality, development checkpoints)
- proliferation
antibodies serve different functions at different stages of humoral response….explain how this pertains to membrane bound vs secreted Abs.
membrane bound antibodies on B cells recognize antigens to initiate response
secreted Abs neutralize and eliminate microbes and their toxins in the effector phase of humoral immunity
In cell-mediated immunity, the effector function of microbe elimination is mediated by what?
T lymphocytes themselves and by other leukocytes responding to the T cells (the antigen receptors of T cells are involved only in antigen recognition and T cell activation and these proteins are not secreted and do not mediate effector functions)
In antibodies, each light chain is attached to one heavy chain, and the two heavy chains are attached to each other - all by what type of bonds?
disulfide
how many V and C regions does each light chain have? each heavy chain?
light chain: 1 V and 1 C domains
heavy chain: 1 V and 3-4 C domains
which CDR contributes most to antigen binding?
CDR3
the two types of light chains, kappa and lambda, differ in which region? The 5 types of heavy chains (mu, delta, gamma, epsilon, alpha) differ in which region?
C region for both
the antigen receptors of naive B lymphocytes, which are mature B cells that have not yet encountered antigen, are what isotype?
membrane bound IgM and IgD
after stimulation by what do the antigen-specific B cell clones expand and ddifferentiate into progeny that secrete antibodies (some of the progeny of IgM and IgD progeny of the same B cells may produce antibodies of other heavy-chain classes via isotype switching)
antigen and helper T lymphocytes
although heavy chain C regions may switch during humoral immune responses, each clone of B cells maintains its specificity how?
V regions do not change
the strength with which one antigen-binding surface of an Ab binds to one epitope of an antigen is called what?
the affinity of the interaction (affinity increases with repeated stimulation - ie secondary immune response in affinity maturation)
the total strength of binding between antigen and antibody is much greater than the affinity of single antigen-antibody bond and is called what?
avidity of interaction
antibodies produced against one antigen may bind other, structurally similar antigens….this binding to similar epitopes is called what?
cross reaction
what proteins make up the BCR complex?
membrane bound Ig molecules, Igalpha, IgBeta (when BCR binds antigen, Iga and IgBeta transmit signals to the interior of the B cell that initiate the process of B cell activation)
what are myeloma cells and what makes them unique?
tumors of plasma cells and can be propagated indefinitely in tissue culture (but can’t grow in the presence of toxic drug)
Fused cells containing both myeloma and normal B cell nuclei do what?
grow in the presence of drug because normal B cells provide missing enzyme…so can grow just these specific cells that don’t die, called hybridomas (can select a specific clonal line to produce monoclonal antibodies)
what complex of proteins is associated with TCR to transmit some of the signals that are initiated when the TCR recognizes the antigen?
CD3 and zeta proteins (along with TCR make up the TCR complex)
the development of lymphocytes from bone marrow stem cells involves commitment of hematopoietic progenitors to the B and T cell lineage, the ______ of these progenitors, the ________ and expression of antigen receptor genes, and _______events to identify and expand cells that express potentially useful antigen receptors
proliferation, rearrangement, selection
______ interactions define T-lineage in the thymus.
Notch receptor-ligand interactions
selective induction of ________ define B-lineage in bone marrow.
TFs EBF and Pax5
antigen receptors are encoded by several gene segments that are separate from one another in the germline and that do what during lymphocyte maturation?
recombine
what receptors are on the surface of proB and preB cells?
CD19+ (but IgM-)
chromosome translocations and activating point mutations of ____ are found frequently in T-ALL.
Notch-1
chromosome translocations and point mutations that disable ______ are found frequently in B-ALL.
Pax5, EBF
in T cell maturation, which TCR chain is rearranged first?
Beta (preT) (then alpha (immature T))….or gamma/delta before any of that on the proT
which Ig is rearranged first on B cells?
IgH (D-J on proB and V-DJ on preB)…makes IgM first!….then IgL (kappa or lambda on immature B cells)
what enzyme mediates VDJ recombination?
VDJ recombinase (RAG1/RAG2 only expressed in immature B and T lymphocytes
where do gamma/delta T cells localize?
epidermise and epithelium as well as other tissues, but very few and relatively unknown functions
what makes up the pre-BCR complex?
mu chain, surrogate light chains (no variable domain), Igalpha and IgBeta
first checkpoint in B cell development?
- Pre-BCR delivers signals promote the survival and prolif of B lineage cells that have made a productive rearrangement at the IgH locus
○ Selects and expands the pre-B cells that express a functional mu heavy chain (essential component of BCR and pre-BCR)
○ Pre-B cells that make out of frame (nonproductive) rearrangements at the H locus fail to make mu protein, cannot express a pre-BCR or receive pre-BCR signals, and die by apoptosis
pre-BCR and allelic exlusion
- Pre-BCR complex also signals to shut off recombination of IgH genes on the second chromosome, because of which each B cell can express an IgH from only one of the two inherited parental alleles
○ Called allelic exclusion and helps ensure that each cell can only express a receptor of a single specificity
pre-BCR light chain recombination
- Pre-BCR also triggers recombination at the Igkappa light chain locus (the lambda chain is produced only if the recombined K chain locus fails to express a functional protein or if the K chain generates a potentially harmful self-reactive receptor and has to be eliminated via receptor editing.
second checkpoint of B cell maturation
The light chain/mu chain form the complete IgM and delivers signals that promote survival
- Preserves cells that express complete antigen receptors and thus is the SECOND CHECKPOINT during B cell maturation - Signals from receptor also shut off production of the recombinase enzyme and furhter recombination at the unrecombinedlight chain loci - So each B cell produces either one kappa or gamma light chain from one of the inherited parental alleles - Presence of 2 sets of light chain genes simply increases the chance of completing successful gene recombination and receptor expression
immature B cell is the ____ expressing lymphocyte
IgM
what is the final maturation step in B cell maturation?
- Final maturation step involves coexpression of IgD with IgM, which occurs because in any given B cell, the recombined VDJ heavy chain gene exon may be spliced to Cmu exons or Cdelta exons, giving rise to mu or delta mRNA
- Ability of B cells to respond to antigens develops together with the coexpression of IgM and IgD, but we don’t know why we need both
IgM+/IgD+ B cell is the mature B cell - able to respond to antigen in peripheral lymphoid tissues
B cell negative selection
- If immature B cell binds a multivalent antigen in the bone marrow w/high affinity, it may reactivate the VDJ recombinase, undergo additional light-chain V-J recombination, generate a different light chain, and thus change the specificity of the antigen receptor = receptor editing
- Antigens most often found in bone marrow are self antigens that are abundantly expressed throughout the body
- Negative selection may also involve deletion of self-reactive B cell
- Therefore, negative selection eliminates potentially dangerous cells that can recognize and react against ubiquitous self antigens
AIRE
autoimmune regulator - RF responsible for expression of many (but not all) ectopic self antigens in the thymic medulla
autoimmun epolyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED)
human AIRE mutation (so inefficient negative selection and wind up with self-reactive T cells)
- endocrinopathy (addison’s disease, hypoparathyroidism, hypogonadism, Type I DM, pancreas failure)
- mucocutaneous cadidiasis
- alopecia, keratitis
Foxp3 is required for the developent of which cells?
CD4+CD25+ regulatory T cells
mutation:
- enteropathy
- type I DM
- Eczema
Mus = x-linked Hs= immune dysfunction polyendorrinopathy enteropathy x-linked syndrome (IPEX)
