Noah Parmely
Immunology
3/20/2020
Chediak – Higashi Syndrome
Description
Chediak – Higashi syndrome is a complex disease involved in the disruption of
numerous bodily functions. The genetic defect associated with the disease disrupts the
granule release mechanism of all cells which affects more than just the immune system.
Immunologically, neutrophils, CTLs, and NKs are unable to properly destroy pathogen
infected cells. Recurrent infections drastically shorten the lives of those affected and
results in miserable living conditions. The disease is effectively untreatable (p. 130).
Introduction
Chediak – Higashi Syndrome (CHS) is a rare autosomal recessive disorder
which has affected less than 500 patients worldwide. This disorder is a result of a
frameshift mutation occurring on the coding domain for the protein LYST found on
human chromosome 1q42-43 [1]. The first case of CHS was recorded by Antonio
Beguez-Cesar in 1943 [2]. CHS was later named after Chediak and Higashi due to their
contributions toward characterizing the hematological features of the disease [3], [4].
Lysosomal Trafficking Regulator protein (LYST) is a cytosolic scaffold protein
thought to be involved in vesicular transport and fusion events [5]. LYST has been
shown to directly interact with hepatocyte growth factor-regulated tyrosine kinase
substrate (HRS) to facilitate vesicle docking and fusion for exocytosis (Figure 1) [5]. In
the absence of LYST, HRS actively inhibits exocytosis by binding with other vesicle
associated and signaling proteins prohibiting fusion of vesicles with the cell membrane.
Mutations to the LYST gene have been shown to truncate the amino acid sequence,
effectively destroying the chemical and mechanical properties of the protein [6]. As a
result, patients with a LYST mutation often exhibit compromised antigen presentation
capabilities [7] leading to heightened bacterial infection susceptibility. The most
common infections include those involving Staphylococcus and Streptococcus species
which are commonly found on the skin, mucosal surfaces, and in the respiratory tract
[8]. Other manifestations of the disease include impaired chemotaxis of granulocytes
and reduced platelet aggregation [9]. In addition, patients often present with peripheral
neuropathy and clumped melanin granules in the hair and skin (Figure 2) [8], [10]. This
results in a clinical quartet of immunodeficiency, persistent mild bleeding, reduced
neurological functionality, and oculocutaneous albinism.
1
Figure 1: Tchernev VT, Mansfield TA, Giot L, Kumar AM, Nandabalan K, Li Y, Mishra
VS, Detter JC, Rothberg JM, Wallace MR, Southwick FS, Kingsmore SF. The ChediakHigashi protein interacts with SNARE complex and signal transduction proteins. Mol
Med. 2002; 8: 56–64.
2
Figure 2: Patne SC, Kumar S, Bagri NK, Kumar A, Shukla J. Chédiak-higashi
syndrome: a case report. Indian J Hematol Blood Transfus. 2013; 29(2): 80–83.
doi:10.1007/s12288-011-0130-y
Definitive diagnosis of CHS can be established through the observation of
abnormally large granules found in all granule containing cells – most notably
neutrophils, NK cells, and CTLs. This may be supplemented with a genetic analysis
confirming a mutation in the LYST gene of the patient. The large granules are derived
from the coalescence of azurophilic and secondary granules as seen on peripheral
blood smears (Figure 3) [11]. These oversized granules are extremely important when
considering their effects in lymphocytes because they have been shown to impair
cytotoxicity and have been linked to the onset of hemophagocytic lymphohistiocytosis
(HLH) which is a fatal hyperinflammatory disease [12], [13]. Depending on the time of
diagnosis, patients may present in either the ‘accelerated’ phase or in the ‘adult’ phase.
Both phases affect patients at differing rates, and it should be noted that the accelerated
phase typically affects those of a much younger age while being significantly more life
threatening compared to the adult phase.
3
Figure 3: Sánchez-Guiu I, Antón AI, García-Barberá N, et al. Chediak-Higashi
syndrome: description of two novel homozygous missense mutations causing divergent
clinical phenotype. European Journal of Haematology. 2013; 92(1): 49-58.
doi:10.1111/ejh.12203
The accelerated phase affects 85% of CHS patients compared to just 15% for
those presenting in the adult phase. Generally, after exposure to Epstein – Barr Virus
(EBV), patients develop HLH which resembles lymphoma [14]. However, exposure to
EBV is not always necessary for the onset of HLH as the disease can be triggered by
other viral infections [8]. HLH is the defining feature of the accelerated phase of CHS.
Patients who have developed HLH typically present with signs of fever,
lymphadenopathy, liver dysfunction, and bleeding, with an array of other less common
symptoms [8]. HLH is known to have a high mortality rate and is a result of
inappropriate cytotoxic activity resulting in the sustained activation of CTLs and NK cells
[15]. This occurs because CTLs and NKs are unable to clear antigen presenting cells
through secretion of perforin and granzyme containing granules. The release of these
cytotoxic granules is paramount in the cytolysis of target cells. This is because following
the release of perforin, Ca2+ ions react with the C2 domain of perforin, allowing the
protein to interact with the target cell membrane, leading to pore formation [16]. This
pore is required for granzyme B to enter the target cell and initiate caspase dependent
4
apoptosis [17]. Without proper CTL mediated cytotoxic activity, infected cells cannot
secrete the appropriate cytokines to terminate the immune response (Figure 4) [13].
Instead, activated macrophages secrete elevated levels of TNF, IL-6, and IL-18 which
cause a systemic inflammatory response. This ultimately leads to the infiltration of
lymphocytes and additional macrophages into various organs and tissues where they
cause tissue necrosis, organ failure, and hemophagocytosis of bystander hematopoietic
cells [13]. Currently, the only known cure for this disorder is hematopoietic stem cell
transplantation (HSCT), but this treatment is most successful prior to the onset of HLH
and will not alleviate the neurological issues associated with the adult phase of CHS
[18], [19], [20].
Figure 4: Basile GDS, Ménasché G, Fischer A. Molecular mechanisms of biogenesis
and exocytosis of cytotoxic granules. Nature Reviews Immunology. 2010; 10(8): 568579. doi:10.1038/nri2803
The adult phase of CHS is less clinically severe compared to the accelerated
phase, despite HLH development still occurring in some cases. Patients typically
survive into adulthood with lower rates of infection compared to those experiencing the
accelerated phase. Unfortunately, these patients will often develop progressive
5
neurological disorders that may lead to their death. Common disorders include
peripheral neuropathy, parkinsonism, intellectual deficit, balance abnormalities, and
even dementia [8]. These disorders likely stem from defective CHS1 protein found in
both neurons and glial cells [21]. It is still unclear what causes the distinction in severity
between the accelerated and adult phases of CHS, however it has been proposed that
homozygous or bi-allelic mutations to LYST are closely associated with the adult phase
[8]. Treatment of adult phase CHS is geared towards preventative measures. Emphasis
is placed on educating the patient and caregivers on maintaining proper hygiene and
dental care to aid in avoiding bacterial infections. If infection occurs, it is recommended
that antibacterial medication is administered at least twice as long as the standard
recommendation [22]. Additionally, the patient should avoid platelet function interfering
drugs such as aspirin and non-steroidal anti-inflammatory agents and any intramuscular
injections [23]. Furthermore, it is of utmost importance that children who show signs of
CHS are diagnosed early on, so that the patient can be prematurely enrolled in HSCT
protocol and preventative bacterial infection measures can be taken.
Review
Current immunological research of CHS is limited by the disease’s rarity, but so
far has focused primarily on improving the overall survival rate of those susceptible to
HLH while reducing treatment toxicity. This focus has been met with further research
into predicting a patient’s risk of developing HLH, so that premature enrollments into
various treatment protocols are established. By examining the nature of mutations and
the lytic activities of CTLs, the hope is to determine a genotype-phenotype correlation
that would aid in treating those experiencing the more fatal accelerated phase of the
disease [8]. The current hypothesis is that mutations resulting in absent CHS1/LYST
protein coincide with the early onset of the accelerated phase, whereas the adult phase
is typically characterized by partially functional protein mutations. Unfortunately, our
understanding of phenotype prediction is limited as proteins with truncated amino acid
sequences have been seen in patients presenting in both the accelerated and adult
phases [24].
The quintessential treatment for accelerated phase CHS has long been HSCT
with myeloablative conditioning (MAC) due this method’s ability to replenish T-cell
function in as little as two weeks after transplantation [25]. This treatment has been
shown to be the only long-term therapy to improve the 3-year survival rate of CHS
patients presenting in the accelerated phase [26]. Patients who exhibit little to no CTL
cytotoxicity are prime candidates for HSCT because they are at enormous risk of
developing HLH [15], [19]. Unfortunately, the drugs commonly taken during MAC-HSCT
treatment – busulfan, cyclophosphamide, and etoposide – have been shown to coincide
with increased patient mortality, so development of less toxic approaches are being
explored [27].
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The past decade has seen the emergence of reduced-intensity conditioning
(RIC) regiments coupled with HSCT. Compared to MAC, RIC uses reduced levels of
chemotherapy and radiation to destroy host bone marrow cells offering an overall
reduction in transplant-related complications. As a result, the toxicity and mortality of the
treatment is significantly less than that of MAC [28]. A recent study found that the 3-year
probability of survival increased from 43% in patients undergoing MAC-HSCT to 92%
for those undergoing RIC-HSCT. This may be attributed to the monoclonal antibody,
alemtuzumab, used in the RIC regiment, which aids in treating any residual HLH
present at the time of stem cell transplantation [28]. Alemtuzumab recognizes CD52, a
protein expressed on T-cells, NK cells, and other immune cells. These cells are then
quickly dispatched after contact with alemtuzumab (Figure 5) [29]. As a result, patients
who were administered alemtuzumab reported fewer instances of graft-versus-host
disease [28]. Overall, it is recommended that patients undergo RIC-HSCT if the
circumstances allow.
Figure 5: Absolute host lymphocyte counts of patients after treatment with
alemtuzumab. Image adapted from figure 1 of report conducted by Marsh, 2012 [29].
Another new and profound treatment option is umbilical cord blood
transplantation (UCBT). This treatment option has shown to be a promising alternative
stem cell transplantation technique if identical HLA-matched donors are unattainable for
HSCT [30]. UCBT allows for a much greater HLA mismatch at the expense of an
increased susceptibility to infection within 100 days of transplantation due to a delay in
T-cell reconstitution [31]. To alleviate this issue, studies conducted ex vivo have
suggested that T-cell reconstitution can be enhanced through the administration of IL-7.
Interleukin-7 promotes T-cell activation, proliferation, and receptor repertoire broadening
while simultaneously reducing the probability of apoptosis, however a few studies have
7
shown this technique to worsen graft-versus-host disease [32]. In contrast, NK cells of
CHS patients were shown to have restored lytic activity after treatment with IL-2. Upon
exposure to IL-2, fluorescence microscopy showed that the perforin granules within NK
cells were smaller and more evenly distributed throughout the cells, suggesting that IL-2
discourages granule clumping (Figure 6) [33]. Furthermore, IL-2 treatment in vitro
showed that NK cells produced more TNF-α and IFN-ɤ cytokines compared to
untreated NK cells from CHS patients (Figure 7). This finding was tremendous because
it indicated that there may be a way to improve the immune responses of CHS patients
and improve transplant success [33]. Although these levels of cytokine production
remained much lower than that of healthy individuals, this study showed a key
relationship in NK cell biology that may help to advance the treatment options allotted to
CHS patients. And although CHS is extremely rare, it is at least very assuring that our
understanding of the disease improves greatly after each documented case.
Figure 6: Cifaldi L, Pinto RM, Rana I, et al. NK cell effector functions in a ChédiakHigashi patient undergoing cord blood transplantation: Effects of in vitro treatment with
IL-2. Immunology Letters. 2016; 180: 46-53. doi:10.1016/j.imlet.2016.10.009
8
Figure 7: Cifaldi L, Pinto RM, Rana I, et al. NK cell effector functions in a ChédiakHigashi patient undergoing cord blood transplantation: Effects of in vitro treatment with
IL-2. Immunology Letters. 2016; 180: 46-53. doi:10.1016/j.imlet.2016.10.009
9
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12