Case 13: X-linked Lymphoproliferative Syndrome Flashcards
how does the immune system defeat viruses?
1) elimination of viruses before they are able to enter host cells
2)
identification and destruction of infected host cells that harbor viruses
both innate and adaptive immune systems are used
how does the innate immune system combat viruses?
TLRs sense intracellular
viral particles by identifying prokaryotic nucleic acid fragments within the
host cell
activated TLR induce signaling through interferons regulatory factor (IRF) transcription factors to produce type I interferons = INFα and INF β
INFα and INF β increase lymphocyte retention in the lymph nodes, favoring TH1 differentiation, and
enhancing the cytotoxic effector functions of natural killer (NK) and CD8 T cells
how do NK cells fight viruses?
germline DNA receptors so they are
equipped to react immediately upon the
first encounter with the virus and do not require activation, clonal expansion, and
differentiation into effector cells like the cytotoxic T lymphocytes
NK cells express
receptors that activate or inhibit the cell’s killer activity
inhibitory receptors interact with MHCI molecules to prevent NK cells from attacking healthy cells
what do the granules of NK cells contain?
perforin
granzymes
these induce apoptosis
IFNγ is also released which activated macrophages and polarized naive T cells into TH1 cells
how is a cytotoxic T lymphocyte formed?
a naive virus-specific CD8 T cell is activated to CTL
effector status when its T cell receptor (TCR) recognizes a viral peptide loaded on a
major histocompatibility complex MHCI molecule
CD4 T helper cells are what get activated by MHCII molecules
how do CTL kill cells?
- release of cytotoxic granules
- granule-independent manner via the Gas ligand which engages the death receptor Fas on a host cell and triggers apoptosis
what are NKT cells?
important in the defense against viral infections
they share features of both NK and T cells:
they have CD56 like NK cells but they also have TCR like T cells
these TCRs do not recognize peptides; instead, they identify lipid moieties that are
loaded on an MHC-I-like molecule called CD1
how are NK cells activated?
- MHCI on normal cells is recognized by inhibitory receptors that inhibit signals from activating receptors
- altered or absent mHCI cannot stimulate a negative signal so the NK cell is triggered by signals from activating receptors
- activated NK cell releases granule contents, inducing apoptosis in the target cell
how does the body usually fight EBV?
EBV infects epithelial cells and B cells
its expansion is
usually well controlled by cytotoxic T cells and NK cells
a primary EBV infection
triggers the activation and cell division of B cells infected by the virus
infected B cells express a number of viral antigens that are targets for specific cytotoxic
responses by NK cells and CD8 T cells that keep the proliferation of infected B cells
under control.
usually EBV is asymptomatic and subsides within a few weeks – after acute infection is resolved the virus persists in a latent form in B cells, salivary glands,
and epithelial cells of the nose and throat and can be shed in saliva
if the virus is reactivated, memory cytotoxic T cells will take care of it
so if you have a T cell deficiency, this is usually liked with increased susceptibility to EBV
what are the characteristics of x-linked lymphoproliferative syndrome?
the clinical triad of vulnerability to EBV infections, lymphoma,
and dysgammaglobulinemia
what causes XLP?
in 60-70% of cases, XLP is caused by loss
of function of the signaling lymphocytic activation molecule (SLAM)-associated
protein (SAP), which is encoded by the SH2D1A gene on the X chromosome
what is SAP?
a cytosolic protein expressed in T, NKT, and NK cells
all these cells are important for clearing viral infections!
SAP protein acts primarily as an adaptor molecule
for the SLAM family of receptors, and mediates SLAM signaling
how are SAP and SLAM related?
SAP has an SH2 domain that connects to other proteins
SLAM receptors have an extracellular Ig-like domain and a cytoplasmic tail with ITSM that acts a docking site for SAP
so SAP binds to SLAM; specifically the SH2 domain of SAP binds to ITSM of SLAM at 3 contact sites
what happens when SAP binds to SLAM?
a conformational
change in SAP allows it to recruit FynT
FynT then mediates intracellular
signaling and activation of T, NKT, and NK cells
SAP also blocks inhibitory signals to SLAM from other
SH2 domain-containing protein phosphatases via competitive inhibition
what happens when there is loss of function of SAP?
reduced activity of the SLAM family
of receptors, causing pleomorphic effects on the immune system
where are SLAM receptors found?
dendritic cells, macrophages, NK cells, and B and T lymphocytes
what happens when SLAM receptors are activated on CD8 T cells?
in
CD8 T cells, activation of SLAM receptors augments TCR signaling, T cell proliferation,
IFNγ secretion, and cytotoxic granule release
how are SAP and SLAM in solved in follicular helper T cells?
TFH
cells express CXCR5 and migrate to the T cell zone of the B cell follicle where they
promote germinal center (GC) formation, isotype switching, and B cell responses
to protein antigens.
SAP-deficiency is thought to interfere with the ability of TFH to
stay in the GC and form stable T-B cell contacts.
what is RICD?
RICD = restimulation-induced cell death
SLAM receptors may also regulate excessive T cell activation through RICD
during an exuberant immune response
characterized by excessive pro-inflammatory cytokines, strong T cell stimulation
can result in apoptosis or RICD
RICD acts as a set of breaks on the immune system
to prevent excessive inflammation and lymphoproliferation
what happens to NKT cells if there’s loss of SAP function?
SLAM receptor family signaling is also important for the development of premature NKT cells in the thymus
loss of SAP function, and
SLAM activation leads to reduced numbers of NKT cells in XLP patients
why are XLP patients vulnerable to EBV?
the defective
cytotoxic responses of CD8 T and NK cells, resulting in the persistence of
EBV‑infected cells
B cells in healthy individuals who are infected
with EBV increase expression of the SLAM family member CD48. CD48 interacts
with another SLAM family member on NK cells, CD244, providing an activating
signal that enables the NK cells to kill the infected B cells
signaling via
CD244 is critical in driving NK killing of EBV-infected target cells. Defects in SLAM
signaling due to the SAP deficiency in XLP prevents this process, allowing EBV to
evade the immune system
what is the net effect of XLP?
failure to clear the EBV viruses coupled with defective RICD creates an ongoing
immune stimulus, triggering massive over-proliferation of lymphocytes (lymphoproliferation),
activation of macrophages, and generation of a cytokine storm
or excessive production of inflammatory cytokines such as IFNγ, TNFα, IL-1, IL-2,
and IL-6
overabundance of these cytokines leads to the clinical symptoms
characteristic of fulminant EBV infection that can progress to HLH, including fevers,
cytopenias, and coagulopathy
what is XLP-1 vs. XLP-2?
XLP-1 and XLP-2 are used to distinguish
patients with XLP due to SAP or XIAP mutations, respectively
what does XIAP do?
- XIAP inhibits apoptosis by blocking
the effects of caspases 3, 7, and 9 - activates the mitogen-activated protein
kinase and nuclear factor-κB (NFκB) pathways - necessary for
signaling through the nucleotide-binding and oligomerization domain (NOD) 2
did Nicholas’s history provide any clues to his diagnosis before his presentation
with fulminant infectious mononucleosis?
in retrospect, the family history and the patient’s past medical history provided clues
that he might be affected by XLP. The patient himself had low IgG and recurrent otitis
his uncle and grandfather were affected by some of the manifestations of XLP,
including recurrent lymphoma and aplastic anemia
how can the diagnosis of X-linked lymphoproliferative syndrome be made?
in some patients, family history as well as a classic clinical presentation (fulminant
infectious mononucleosis) provide a strong basis for a clinical diagnosis
often,
however, there is no clear family history and the severe lymphoproliferation cannot
easily be distinguished from other forms of malignant lymphohistiocytosis with
hemophagocytosis.
the molecular defect responsible for most cases of XLP has been
identified as a mutation or deletion of the gene encoding SAP (SH2D1A)
in difficult
cases, a molecular diagnosis is desirable, and PCR analysis of the four exons encoding
SAP can be performed
flow cytometry and Western blotting can be used to identify
patients in whom SH2D1A mutations result in a lack of SAP protein expression
if family history, clinical data, and laboratory data are consistent with a diagnosis of XLP but no defects in SAP can be identified, mutation analysis should be targeted to the BIRC4 (XIAP) gene, using PCR
if a girl presents with fulminant infectious mononucleosis and evidence of
acute EBV infection, what might be the basis of her disease?
In a girl, mutation of an X-chromosome gene such as SH2D1A would be very unlikely
to account for her problem
an autosomal disorder is more probable
if the parents
were related, suspicion of an autosomal defect would be heightened
autosomal
recessive defects that may cause an XLP-like phenotype include ITK deficiency
but also, and more commonly, defects in the cytolytic machinery that result in
hemophagocytic lymphohistiocytosis
nicholas has a 3-year-old brother, Alexander, who has SAP deficiency. what
can be done to prevent the occurrence of disease in this boy?
destruction of Alexander’s bone marrow by radiation or chemotherapy (with busulfan
and cytoxan) followed by administration of HLA-matched marrow from a normal
sibling or unrelated donor would replace all lymphoid precursors with normal
SAP-expressing cells of donor origin
this approach has been used successfully in the
treatment of XLP
