What causes hemophagocytic lymphohistiocytosis (HLH)?

Updated: Sep 16, 2020
  • Author: Cameron K Tebbi, MD; Chief Editor: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP  more...
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Answer

HLH is characterized by the uncontrolled proliferation of activated lymphocytes and histiocytes secreting a large amount of inflammatory cytokines. HLH can be inherited or acquired; however, all forms of the disease have impaired function of natural killer cells and cytotoxic T cells in common. The genetic form of HCH occurs in families (FHL) and in various inherited immune disorders, including Chédiak-Higashi syndrome 1 (CHS1), Griscelli syndrome 2 (GS2) (mutation in RAB27A), and X-linked lymphoproliferative syndrome (XLP). XLP is caused by a mutation in the SH2D1A gene and is inherited as an X-linked genetic disorder. [60] In most cases of acquired HLH, the immune system is normal and the disease is triggered by an infection, underlying malignancy, immune deficiency disorder, or Kawasaki disease.

As noted above, FHL is a rare, genetically heterogeneous immune disorder with incidence of 0.12-1 cases per 100,000. It is inherited as an autosomal recessive disorder; thus, each sibling has a 25% chance of the disease, 50% are carriers, and 25% remain unaffected. Five genetic loci (ie, FHL1, FHL2, FHL3, FHL4, FHL5) are associated with familial HLH.

Table 1. Genetics in FHL [151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 60, 176, 177] (Open Table in a new window)

Genetic defect/syndrome

Genetic Defect

Protein

Frequency % FHL cases (location)

Mutation Type

Function

FHL1

Unknown (9 gr 21.3-22)

Rare

Pakistan

FHL2

PRF

(10 gr 21-22)

Perforin

20-40%

Often in blacks, Turks, Japanese

>50 deletions, non-sense and missense mutations; heterozygosity for C272T, A91V substitution

Pore-forming protein

FHL3

UNC13D

(17 gr 25)

Munc 13-4

20-30%

Worldwide, Turks, Kurds, US, Europe

>18 deep intronic mutations and large inversion

Vesicle forming

FHL4

STX11

(6 gr 24)

Syntaxin-11

10-20%

Worldwide, Central Europe, Turkey, Saudi Arabia

Variable

Vesicle transport and fusion

FHL5

STXBP2

(19p)

Munc 18-2

5-20%

Worldwide, Italy, UK, Kuwait, Pakistan, North America

Multiple mutations in the syntaxin binding protein Munc 18-2. Impaired binding to syntaxin-11

Vesicle transport and fusion SNARE complex assembly and disassembly

Immune deficiency and albinism

Chédiak-Higashi syndrome

LYST

LYST

Rare

Worldwide

Size function of lytic granules

Griscelli syndrome type II

RAB27A

Rab 27A

Rare

Northern Europe

Vesicle docking, granule movement

Hermansky-Pudlak syndrome Type II

AP3B1

Rare

Worldwide

Vesicle biogenesis, protein sorting

Primary Immune Deficiencies

X-linked lymphoproliferative disease Type I

SH2D1A

SAP

Worldwide

Signal transduction, activation of lymphocytes

X-linked lymphoproliferative disease Type II

BIRC4

XIAP

Worldwide

Inhibition of apoptosis

ITK deficiency

ITK

ITK

Worldwide

T-cell kinase

FHL results in disturbance of regulatory pathways that mediate immune defense and natural termination of immune/inflammatory response. The expressions of genes associated with natural killer cells (NK-cell) functions, innate and adaptive immune responses, proapoptic proteins, and B-cell and T-cell differentiation have been shown to be down-regulated in this disorder. [171]

Some studies suggest the use of perforin expression by peripheral lymphocytes, assessment of the behavior of the 2B4 lymphocyte receptor and NK-cell activity as the bases to identify different subgroups of HLH. [164]

Mutations of MRNA splicing commonly are the underlying molecular defect in patients with FLH3. The Munc 13-4 protein primes the secondary mutation in this gene and can result in defective cellular cytotoxicity. In a study of 31 families with FHL, at least one mutation responsible for splicing error was identified. The deep intronic mutations detected affected regulatory sequences resulting in aberrant splicing. Therefore, the UNC13D mutations appear to lead to splicing errors, which results in common symptomatologies seen in FLH3. [178]

A genomic region (ie, 9gr21) has been linked to FHL1; however, the gene responsible for the specific product or action remains unknown. [159]

In FHL2, gene encoding perforin, which is located on chromosome 10 (ie, 10gr21-21) has been identified. Perforin along with granzyme B are intracellular contents of lysosomal granules in cytotoxic T and NK cells, which are essential for appropriate function of microtubule organizing complex (MTOC). More than 50 mutations of perforin have been described with predominance of blacks, some degree of prevalence in Turkey, and to a lesser extent in Japan. In 62.5% of Japanese patients, the perforin mutation is the 1090-1091delCT and in the remaining 37.5%, 207delC. [155]  In Turkish patients, the perforin mutation often is Trp 374X and results in an early onset of the disease. [170]  In Italian cases, A91V sequence variant is seen with onset of the disease later in life. IN FHL3, the UNC13D gene is located on chromosome 17 (17gr25), which encodes for the production of Munc 13-4 protein is involved. At least 18 separate mutations have been identified. Despite the genetic findings, the course of the disease is identical to those of FHL2. Munc 13-4 protein, a member of the UNC13 family of intracellular protein, is essential for vesicle priming. In patients with FHL3, Munc 13-4 mutation results in defects in the priming of the lytic granules containing perforin and granzymes A and B.

In FHL4, the syntaxin 11 (STX11) gene is located on chromosome 6 (6gr24), which encodes the production of syntaxin 11. A syntaxin mutation finding is not consistent in all affected patients. Although it accounts for 14% of non-FHL1 cases, it is more frequently found in Turkish patients (21%) and is not present in the Japanese cases. [179, 180]

In FHL5, the STXBP2 gene is located on chromosome 19 (19p), which encodes for the protection of Munc 18-2 (ie, syntaxin binding protein 2), and STXBP2 is involved. This protein regulates intracellular trafficking and control of SNARE complex assembly and disassembly, thus exocytosis machinery. [181, 182]

Most reported cases, as expected, are consanguineous families and are due to homozygous missense mutations. The mutation has been reported in Turkish, Saudi Arabian, and central European countries.

HLH can occur in the absence of a genetic mutation or factors and conditions associated with genetic predisposition/alteration or consanguinity. Although the data is sparse, secondary HLH likely has by far greater incidences than FLH. [183]

The most common causes of secondary HLH are as follows [19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 184, 185, 186, 187, 188, 189, 190] :

  • Infections (viral, bacterial, parasitic and fungal)

    • Epstein-Barr virus

    • Cytomegalovirus

    • Human herpes virus 8 (HHV8)

    • HIV

    • Mycoplasma mycobacteria

    • Leishmania

    • Plasmodium candida

    • Cryptococcus

    • Kala Azar

  • Immunosuppression - After organ transplantation

    • Cancer

    • T-cell lymphoma

    • Leukemias

  • Metabolic disorders

    • Lysinuric protein intolerance

    • Multiple sulfatase deficiency

    • Wolman disease

  • Autoimmune disorders - Systemic lupus erythematosus

  • Macrophage activation syndrome - Still disease


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