B3.060 Dysregulation of Immune Signaling in Human Disease Flashcards
triad of clinical manifestations for classic Wiskott-Aldrich Syndrome (WAS)
recurrent bacterial and viral infections
extensive eczema
thrombocytopenia/ microplatelets (1/2 volume)
what are WAS patients at risk for later in life
autoimmunity and malignancy
what is the function of WASp
links cell signaling to the actin based cytoskeleton
actin polymerization
what are the segments of WASp
EVH1 BR GBD PPPPP VCA
EVH1 region
binds WIP to keep protein inactive
BR region
basic region, binds to PIP2 and moves protein to immune synapse
GBD region
GTPase binding domain (cdc42)
PPPPP region
proline rich SH3 domain where adaptors bind, required for immune synapse formation
VCA region
verprolin-like, central and acidic regions bind Arp2/3 complex when active, leading to nucleation of actin filaments
what conformational change takes place in the WASp
when GTP-bound cdc42 binds, protein springs open into active conformation
phosphorylation stabilizes
features of classic WAS
50%
absent or truncated WASp
premature terminations/ deletions
features of X-linked thrombocytopenia
mild disease, 50%
mutated, non functional protein, missense mutations
lower quantities, normal size
no autoimmunity
features of X-linked neutropenia
very very rare
missense mutation in GTPase binding domain
no autoinhibitory action of protein
uncontrolled actin polymerization
what would be expected T and B cell counts in a 9 month old with WAS?
normal levels
WASp not involved in initial development of T and B cells
just involved in formation of immune synapse
describe the difference between normal WBCs and WAS patient WBCs on electron microscopy
WAS WBCs lack microvilli due to the lack of actin polymerization
cell surface projections require ability to reorganize actin based cytoskeleton
why might a T cell respond to mitogen, but not to signaling via the T cell receptor using a recall antigen?
mitogen helps collect TCRs on surface via the stimulation of microtubules (no issues with these)
recall antigen doesn’t work because the TCR can’t be independently brought to the surface to recognize antigen due to a lack of actin polymerization in WAS patients
which cell type is thought to be responsible for the development of autoimmunity in WAS patients?
Treg cells
discuss the formation of the immune synapse
takes up to 10 min
can be sustained for several hours
requires reorganization of the actin and microtubule based cytoskeletons
goal of the immune synapse
to provide long term, high quality signaling required for full T cell activations
what is at the very center of the immune synapse/ supramolecular activation cluster (SMAC)
TCR:MHC antigen recognition
what surrounds the TCR:MHC central region of the SMAC
CD28:CD80 costimulation
what surrounds the CD28:CD80 region of the SMAC
LFA1:ICAM1 adhesion
what is in the outermost region of the SMAC
F-actin lamellipodium, CD45, CD44, CD43 (larger molecules)
microclusters of CD28 and TCR
what is the rationale for increased susceptibility to viral infections in WAS patients as it pertains to CD8+ T Cells?
immune synapse cannot form properly, this is needed for directed cell killing
T cell cannot move and release vesicles of granules
how could WAS mutations affect NK cell function?
lack of reorganization of cytoskeleton to facilitate killing functions
how could WAS mutations affect macrophage migration induced by a chemokine?
can’t migrate bc can’t reorganize cytoskeleton (thus no movement)
how does WAS affect cytokine secretion?
cannot direct the release of cytokines to specific cells
what would the lack of a thymic shadow on a CXR indicate?
lack of T cells, but normal B cell numbers
why are Ig levels so low in X-linked SCID patients?
T cells cannot mature
without T cell help, B cells cannot be stimulated to make as many Igs
