Introduction

Chediak-Higashi Syndrome (CHS) is a genetic disorder that occurs due to mutations in the CHS1 gene, also known as the lysosomal trafficking regulator (LYST) gene. Symptoms of CHS include excessive bleeding, immune system dysregulation, neuronal impairment, and hypopigmentation (lightening) of the eyes, skin, and hair. As far as the immune system is concerned, there are two phases of CHS: the acute and accelerated phases. In the acute phase of CHS, loss of cytotoxicity occurs, leading to the accelerated phase of CHS.^1,2

What happens in CHS?

CHS is associated with defective synthesis and function of secretory granules due to mutations in the CHS1 (i.e. LYST) gene. The storage vesicles in question are lysosomes (or organelles resembling lysosomes) in various cell types, such as:²

• Melanocytes with melanosomes
• Thrombocytes with dense granules
• Nerve cells containing lysosomal vesicles 
• Neutrophils with granules containing basic azure dyes
• Natural killer cells and antigen-presenting cells like macrophages contain cytotoxic vesicles

Alterations in the LYST gene lead to improper endolysosomal pathways. As a result, lysosomes cannot properly pinch off and fuse, accumulating waste products that cause them to become irregular and large. These non-functional lysosomal granules undergo little to no trafficking, affecting the normal functions of lysosome-containing cells. Therefore, cells with giant lysosomes cannot perform their immune function as normally.³

Physiological consequences of impaired endolysosomal pathways in CHS include:^2,3

• Improper distribution of melanin pigment in melanocytes leads to hypopigmentation
• Lysosomal disorders impair the immune function of natural killer cells
• The cytotoxic potential of T-cells and macrophages will be lost
• Degeneration of nerve cells may lead to cognitive deficits
• Platelet functions, like bleeding time, will be prolonged

How does CHS Impact Cytotoxic T Cells and Natural Killer Cells?

Normally, lysosomes play a key role in immune cells, such as macrophages, cytotoxic T cells (CTLs) and natural killer (NK) cells by performing defensive functions. However, genetic modifications in lysosomal regulating genes (as in the case of CHS) impair their normal defensive behaviours.^1,2

Basic mechanism of CTLs and NK cells

CTLs are CD8 cells which bind antigens like pathogen-associated molecular patterns (PAMPs) through a class I major histocompatibility complex (MHC class I). This binding triggers FasL-Fas receptor complex formation, leading to the release of perforins and granzymes from lysosomes. Perforins make holes in target cells, while granzymes enter target cells to induce cysteine-aspartic proteases (caspases) dependent apoptosis.^4,5 In addition, CTLs also execute cellular killing through signal transduction pathways such as the mitogen-activated protein kinase (MAPK) pathway and the nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) pathway.^6,7 On the other hand, NK cells perform defensive action without MHC-1 molecules. Upon activation, NK cells release the same granzymes and perforins from lysosomal organelles to initiate the same apoptotic pathway.⁸

Disrupted mechanism of CTLs and NK cells in CHS patients

Due to the LYST gene mutation, CTLs and NK cells are unable to release granzymes and perforins from their cytotoxic vesicles into the immunological synapse. Such morphological abnormalities impair basic lysosomal functions, causing trafficking problems, an inability to perform exocytosis, and defective release of cytokines, such as interleukins and tumour necrosis factor alpha. In this way, both CTLs and NK cells lose the ability to clear up extracellular toxins, tumour cells and virus-infected cells.³

Phases of CHS

Next, we will analyse both phases of CHS.

Classic phase

This phase is associated with defective exocytosis of lysosomal granules (e.g., perforins and secretory cytokines) from CTLs and NK cells into the immunological synaptic space. The immune system is not functioning properly, but it remains active. Apart from disrupted defence systems of the body, patients with CHS may experience platelet dysfunction, axonal transport impairment in the neurons, as well as the accumulation of toxic products leading to oxidative stress in nerves.³

Accelerated phase

Persistent accumulation of toxins and recurrent infections activate the immune cells excessively, leading to an outburst of pro-inflammatory cytokines outside the cells. This will cause the inflammation of target and neighbouring cells, a process known as bystander activation. This repeated cycle of hyperactivation and hyperinflammation culminates in the recruitment of phagocytes and innate immune cells (e.g., eosinophils and neutrophils) in the spleen, liver, lymphatic system and bone marrow cells. Consequently, clinical manifestations of CHS include haemophagocytosis lymphohistiocytosis (HLH), swollen lymph nodes, peripheral neuropathy, pancytopenia, as well as an enlarged liver and spleen.⁹

Diagnosis of CHS

Various laboratory techniques can be used to detect immune cell dysfunction in CHS, such as:^10,11

• Microscopic examination – light microscopy reveals giant lymphocytic vesicles in peripheral blood smears, whereas electron microscopy shows ultrastructural details, including trafficking of lysosomal granules
• Molecular tests – sanger sequencing and next-generation sequencing (NGS) are used to detect LYST genetic mutations
• Flow cytometry – used to quantify the population of CTLs and NK cells. Flow cytometry is also used to show the degranulation process and lysosomal trafficking problems
• Chromium release assay – used to measure cytotoxic potential of CTLs and NK cells

Clinical management of CHS

CHS can be managed using the following approach:¹²

• Haemotopoietic stem cell therapy – used to restore the normal innate cytotoxic potential of NKs and CTLs
• Immunosuppressive medications – immunosuppressive drugs are prescribed to control the accelerated phase of CHS. These may include dexamethasone (to curb hyperinflammation), emapalumab (to reduce interferon levels) or etoposide (to suppress hyperinflammation)
• Antimicrobial therapy – antiviral, antibiotics and antifungal medicines are used to alleviate infections in CHS
• Platelet transfusion – used to manage uncontrolled bleeding

FAQs

How are CTLS related to NK cells?

Both cell types are different from each other. Specifically, CTLs require antigen activation to initiate an immune response, whereas NK cells cause direct killing of harmful or cancerous cells.

What are the clinical manifestations of CHS?

Symptoms of CHS include lymphadenopathy, enlarged spleen (splenomegaly), enlarged liver (hepatomegaly), albinism and rapid movement of eyes.

Does neutropenia occur in Chediak-Higashi syndrome?

Yes, it does occur in CHS patients.

Summary

Chediak-Higashi Syndrome (CHS) occurs due to mutations in the CHS1 (i.e. LYST) gene, leading to abnormal trafficking of lysosomal vesicles and the production of giant granules in the nerves and different types of immune cells. In the case of CHS, the most significant lysosomal defects are visualised in cytotoxic T cells (CTLs) and natural killer (NK) cells. Due to the LYST mutation, lysosomal granules fail to polarise and fuse with the plasma membrane, resulting in an insufficient release of perforin and granzymes into the synaptic space. CHS may contribute to the development of hemophagocytic lymphohistiocytosis (HLH).