Basic Pathological Mechanisms March 17-19 Flashcards
Which isotype of antibody has two heavy chains, two light chains, four distinct subclasses and crosses the placenta to provide fetal protection?
IgG
Thymus dependent humoral responses are typically associated with which type of molecules?
Proteins
Which marker best defines a cell as a cytotoxic T lymphocyte?
CD8
Viral transformation reduces the MHC molecules on epithelial cells. Which cells are most likely to respond to destroy the infected cells?
Natural killer cells
What is a characteristic structural motif of an antibody molecule?
beta-pleated sheet
Positive and negative selection of T lymphocytes occurs where?
thymus
What is the precursor cell that matures into a mature CD4+ T cell?
an alpha/beta or gamma/delta T cell
What are properties of IgA?
has J chain; has a secretory piece important for transport; the PIG receptor for this molecule is on the basal surface of epithelial cells; has the highest rate of synthesis of all major isotypes
What is the importance of CD28?
T cell activation to produce effector and memory cells
What are properties of adaptive immunity?
clonal distribution of receptors, enhance by prior exposure, immunological memory, vast range of molecular discrimination, and takes a few days to weeks to develop response
Who discovered antibodies?
German physiologist Emil von Behring
Describe innate immunity.
limited range of molecular discrimination; non-clonal distribution of receptors; not enhanced by prior exposure; relatively rapid response (hours)
What is difference between humoral and cell-mediated immunity?
humoral: antibodies
cell-mediated: effector molecules bearing specificity for antigen (TCR)
What are the functions of B cells?
synthesis and secretion of antibodies;
immunological memory;
homing to specific anatomic locations;
presentation of antigens to T cells (co-stimulation of T cells);
cytokine secretion (T cell activation and lymphoid organogenesis)
Describe B cell affinity maturation.
selection within germinal centers (access to follicular B helper T cells)
Describe thymus-dependent humoral responses.
antigens are proteins; class II MHC molecules on B cells present peptide to CD4+ helper T cells; B cells receive help from CD4+ T cells (CD40L on T cell, cytokines released from T cell)
Describe thymus independent humoral responses.
type 1: non-protein with ability to bind TLRs or other innate immune receptors
type 2: antigen with repeating structure (pneumoccocal capsular polysaccharide)
Which humoral response is activate in the absence of all T cells?
TI-1 antigen (polyclonal B-cell activation; repeating epitopes)
What happens when B cells are activated?
antibody secretion by plasma cells; neutralization (prevents bacterial adherence), opsonization, and activation of complement
Describe humoral response to conjugate vaccine.
B cell binds bacterial polysaccharide epitode linked to tetanus toxoid protein; antigen is internalized and processed; presented to T cell; production of antibodies
What interleukin is important in the collaboration of B and T cells?
IL-4
Describe germinal centers.
in secondary lymphoid tissues, such as spleen, lymph node, and Peyer’s patches
composed of B lymphocytes, follicular dendritic cells, and follicular helper T cells
increased expression of Bcl-6; follicular helper cells secrete IL-21
site of class switch recombination, somatic hypermutation, and affinty-based selection responsible for affinity maturation
generates memory B cells and long-lived plasma cells
Describe memory B cells.
are generated from both TD and TI responses
In TD responses, can be generated through germinal center dependent and independent pathways (associated with isotype switching and hypermutation)
TI responses typically have not undergone isotype switching or somatic hypermutation
length of antigen exposure may influence the relative proportions of different types of memory B cells
Describe long-lived plasma cells.
generated in germinal centers
reside in bone marrow
persistence depends on expression of Mcl1 (less antibody diversity compared to memory B cells)
Describe BCR signal transduction.
Tyrosine Kinase receptor
Ligation (combination of multiple BCR receptors) of the BCR activates Src-family kinases (SFK; Lyn, Fyn, Blk) which then phosphorylate the BCR ITAM motifs on Igα and Igβ.
recruitment of SYK and activation of phospholipase C and Bruton’s tyrosine kinase (Btk)
Describe B cell co-receptor activation.
BLys (BAFF) and APRIL; CD19 and PI3K
Describe B cell development.
begins in the bone marrow and continues in the periphery
T/F: the signal transduction pathways elicited by ligation of the BCR are analogous to those initiated by ligation of the alpha-beta TCR?
T
Which isotypes have a J chain? are dimers? are pentameters? which look similar?
IgA and IgM
IgA
IgM
IgG, IgD, and IgE
IgG has how many subclasses?
4
What is the function of antibodies?
neutralization, opsonization, complement activation, activation of FcR-bearing cells; signal transduction
Which immunoglobulin transports across the placenta?
IgG
Which immunoglobulins activate complement?
IgG and IgM
Which tissue contains the highest number of lymphocytes?
intestinal tract (IgA)
Which immunoglobulin predominates in serum?
IgG
T/F: secretory IgA may act extracellularly, intracellularly, and transcellulary?
T
What is the equivalent to the spleen in mucosal immunity?
Peyer’s patches (associated with M cells in intestine)
M cells take up antigen by endocytosis and phagocytosis; antigen is transported across the M cells in vesicles and released at the basal surface; antigen is bound by dendritic cells which activate T cells
T/F: antibodies can be found in serum and on B lymphocyte plasma membranes?
T
Describe constant and variable domains.
each possess two beta sheets
IgA has how many subclasses?
2
T/F: each Ig domain has one variable domain and one to several constant domains?
T
What part of antibody makes contact with antigen?
hypervariable domain
T/F: antibodies link specificity in recognition to intrinsically antigen-nonspecific effector function mediated by Fc regions?
T
T/F: T-cell precursors travel from the bone marrow to develop in the thymus?
T
positive selection (cortex) is to ensure self-recognition (must be able to engage self-MHC), and negative selection (medulla) is to avoid autoreactive (autoimmune) T cells (must not be able to engage self-peptide)
Where do gamma/delta T cell migrate to?
peripheral tissues (epithelial tissues such as the gut)
T/F: once a T cell leaves the thymus it is armed and ready (fully matured)?
F: naive (not yet exposed to foreign antigen)
naive T cells circulate in blood and travel from lymph node to lymph node looking for antigens
What molecule defines cells as T lymphocytes?
CD3 (part of TCR)
Describe TCR.
heterodimeric structure of 2 types: alpha/beta or gamma/delta
Describe CD4.
binds to MHC class II; coactivation by Ick; co-receptor for HIV; secretion of cytokines
Describe CD8.
associated with MHC class I; coativation by Ick (tyrosine kinase); cytotoxic effector cell
Describe CD28.
binds to B7-1 (CD80) and to B7-2 (CD86) which are expressed on professional antigen presenting cells
downstream production of IL-2 (NFAT)
stimulation of CTLA-4 (inhibitory)
What happens following T-cell activation?
proliferation (clonal expansion) and differentiation into an effector T cell and memory T cell
Why is co-stimulation critical in T cell activation?
anergic without it
What inhibits IL-2 production?
cyclosporin A and rapamycin
Describe T cell extravasation and diapedesis.
binding of L-selectin to GlyCAM-1 and CD34 allows rolling; LFA-1 is activated by chemokines bound to ECM (binds to ICAMs: CD54 and CD102) to initiate diapedesis
What is a cell adhesion molecule expressed on T and NK cells?
CD2; ligands are CD48, CD58, and CD59
Describe T cell binding to APCs (dendritic cells)
initially binds through LFA-1/ICAM interaction;
conformational change in LFA-1 increases affinity and prolongs cell-cell contact
Describe features of cytotoxicity.
chromatin condensation, membrane blebbing, DNA fragmentation, cell shrinkage, dilation of ER, cellular fragmentation, and internal enzymatic degradation (APOPTOTIC CELL DEATH)
What are the proteins contained in lytic granules of cytotoxic T cells?
perforin, granzymes (serine proteases), and granulysin
What growth factors cause differentiation of CD4 T cells?
TGF-beta (into Tregs);
IL-12 and interferon gamma (helper 1 T cells)
IL-4 (helper 2 T cells)
What effector molecules are secreted by helper T cells?
type 1: IL-2, interferon gamma, and TNFbeta
type 2: IL-4, IL-5, and IL-10
What type of signaling pathway do cytokines signal with?
JAK/STAT
Describe chemokine signaling.
protein messengers that direct leukocyte traffic with concentration gradients
CC and CXC (GTP-binding proteins)
T/F: gamma/delta T cells are subjected to positive and negative selection?
F
Describe gamma/delta T cells.
secrete interferon gamma and TNF-alpha
secrete granulysin
acquire APC capacity
Describe NK cells.
can have immunoglobulin-like receptors or lectin-like receptors
respond to target cells with reduced MHC-1 expression
interacts with infected cells that express MIC ligands for NKG2D
differentiation is not required for cytotoxic capability (but enhances it)
T/F: Most polysaccharide and lipid antigens can be recognized by T cells?
F
T/F: T-independent responses are relatively simple, whereas T-dependent responses show features such as immunoglobulin isotype switching and affinity maturation?
T
T/F: Polysaccharides and lipids stimulate secretion mainly of IgM antibody?
T
Protein antigens, by virtue of CD40L- and cytokine-mediated helper T-cell actions, induce the production of antibodies of different classes, or isotypes (IgG, IgA, IgE). Isotype switching is induced by cytokines including IFN-γ and IL-4.
What are germinal centers?
areas of proliferating B cells in follicles of secondary lymphoid tissues
The helper T-cells that stimulate these processes in B lymphocytes migrate to and reside in the germinal centers and are called follicular helper T cells (T FH ).
What is the importance of IgE and eosinophils?
Kill parasites and worms (Helminths)
T H 2 cytokines stimulate the production of IgE and activate eosinophils, and thus the response to helminths is orchestrated by T H 2 cells.
T H 2 cells produce IL-4, which stimulates B cells to differentiate into IgE-secreting plasma cells, and IL-5, which activates eosinophils. Eosinophils and mast cells bind to IgE-coated microbes such as helminthic parasites, and function to eliminate helminths. T H 2 cells also induce the “alternative” pathway of macrophage activation, which is associated with tissue repair and fibrosis
What accounts for decline in humoral immune responses in the aftermath of an infection?
apoptosis (does not affect long-lived plasma cells residing in bone marrow or memory cells)
T/F: activated T lymphocytes migrate to the injured tissue?
T
What cytokine is a potent macrophage activator?
Interferon gamma (TH1 subset)
What is the function of TH17 cells?
recruit neutrophils and monocytes, which destroy some extracellular bacteria and fungi and are involved in some inflammatory diseases.
What are generative lymphoid tissues? secondary?
thymus and bone marrow
spleen, lymph nodes, mucosal, and cutaneous lymphoid tissues
