1. Hemophagocytic Lympho Histiocytosis
BY: Alireza Shafiei
Allergist and Clinical Immunologist
Assistant Professor of Tehran University of Medical Sciences
Bahrami Hospital

2. Introduction:
In practice, distinction between primary and secondary HLH is not essential for the initial diagnosis and management.
Primary HLH, also called familial hemophagocytic lymphohistiocytosis (FHL), refers to HLH caused by a gene mutation:
FHL1 , FHL2 , FHL3 , FHL4, FHL5 ,GS2 (RAB27A) ,HPS2 ,XLP1,XLP2 ,BLOC1S6 ,CD27 , ITK , MAGT1 (XMEN) ,SLC7A7, XIAP (BIRC4)
Secondary (sporadic, acquired) HLH has generally been used to describe those without a known familial mutation; adults; and those for whom a clear trigger of the HLH episode has been identified (eg, viral illness, autoimmune disease, lymphoma).

5. Understanding the pathogenesis of hlh
T lymphocytes play an essential role in the induction of the disease manifestations of HLH
The granule-dependent cytotoxic pathway is a rapid, powerful, and iterative mechanism to mediate killing of virus infected cells as well as tumor cells
Although T cell-mediated recognition leads to T cell activation and clonal expansion, lymphocytes deficient in cytotoxic function fail to kill the infected cells.
Elimination of APCs provides an important negative feedback to limit T cell- mediated immune responses.

6. Understanding the pathogenesis of hlh
In the absence of effective cytotoxicity, APCs continue to stimulate CTLs,
which produce high quantities of cytokines (e.g., INF-γ), thus inducing macrophage activation.
The sustained macrophage activation results in tissue infiltration and production of high levels of IL-6, IL-18, and TNF-α, which cause tissue damage and play a major role in the clinical manifestations of the disease.
Activated macrophages phagocytose bystander hematopoietic cells (hemophagocytosis).
Activated lymphocytes and macrophages infiltrate various organs, resulting in massive tissue necrosis and organ failure

7. Immunologic Abnormalities
most patients with HLH exhibit impaired cytotoxic function of NK cells and CTLs, coupled with excessive activation of macrophages .
Excessive cytokine production by macrophages, NK cells, and CTLs is thought to be a primary mediator of tissue damage
The normal elimination of activated macrophages by NK cells and CTLs occurs through the process of perforin-dependent cytotoxicity.
NK cells and CTLs lyse target cells in a series of steps that include formation of an immunologic synapse; creation of a pore in the macrophage membrane; and delivery of cytolytic granules into the macrophage.

8. Immunologic Abnormalities
Hemophagocytosis  In addition to antigen presentation and cytokine production, macrophages can also phagocytize host cells.
Hemophagocytosis refers to the engulfment (literally "eating") of host blood cells by macrophages.
Hemophagocytosis alone is neither pathognomonic of, nor required for, an HLH diagnosis.
Cytokine storm: The persistent activation of macrophages and NK cells and CTLs that occurs in patients with HLH leads to excessive cytokine production (cytokine storm) by all of these cells.
It is thought that the excessive cytokines are ultimately responsible for multiorgan failure and the high mortality of the syndrome

9. Definition
Excessive uncontrolled activation and proliferation of T cells and macrophages
Cytokine storm
Hyperinflammation

10. Cytokine Storm Spectrum of Cytokine-Induced Disease SIRS Genetic HLH
Acquired HLH
Macrophage activation syndrome
Severe sepsis
Normal response to infxn
Systemic Inflammatory Response Syndrome

17. Helminthic infections Unknown gene mutations
Causes of HLH
Perforin deficiency
Helminthic infections
Munc 13-4 deficiency
Fungal infections
Syntaxin 11 deficiency
Bacterial infections
HLH
Munc 18-2 deficiency
Viral infections
Unknown gene mutations
Medications
Immune deficiencies
Autoimmune diseases
Malignancy

20. Immunodeficiency syndromes
Griscelli syndrome – Griscelli syndrome (GS) type 2 is caused by mutations in RAB27A, which encodes a GTP binding protein. GS2 is characterized by hypopigmentation, immune deficiency, thrombocytopenia, and/or neurologic defects.
●Chediak-Higashi syndrome – Chediak-Higashi syndrome (CHS) is caused by mutations in CHS1/LYST.
CHS is characterized by partial oculocutaneous albinism, neutrophil defects, neutropenia, and neurologic abnormalities

21. Immunodeficiency syndromes
X-linked lymphoproliferative disease – X-linked lymphoproliferative disease type 1 (XLP1) is caused by mutations in SH2 domain protein 1A (SH2D1A), which encodes an activator of NK and T cells.
XLP2 is caused by mutations in X-linked inhibitor of apoptosis (BIRC4); the encoded protein protects cells from apoptosis.
XMEN disease – X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease is another immunodeficiency syndrome with EBV-associated malignancies and rarely HLH
Interleukin-2-inducible T cell kinase (ITK) deficiency – These patients, like those with XLP and XMEN deficiencies, are unable to control EBV infections. They have a variety of lymphoproliferative diseases, lymphomatoid granulomatosis, HLH, and dysgammaglobulinemia.

22. Immunodeficiency syndromes
CD27 (TNFRSF7) deficiency – Missense mutations that reduce expression of CD27 have been associated with a syndrome of severe EBV infections associated with HLH, Hodgkin lymphoma, uveitis, and recurrent infections [49].
Hermanski-Pudlak syndrome – Hermansky-Pudlak syndrome (HPS) is a rare disorder characterized by oculocutaneous albinism and platelet storage pool deficiency. Several responsible gene mutations have been identified: HPS1, AP3B1 (HPS2), HPS3, HPS4, HPS5, HPS6, DTNBP1 (HPS7), BLOC1S3 (HPS8), and BLOC1S6 (PLDN).

26. XLP1 is commonly associated with:
Lymphoma
hypogammaglobulinemia,
aplastic anemia,
vasculitis,
gastrointestinal inflammation.
XLP2 is associated :
atypical/mild HLH-like episodes,
inflammatory bowel disease,
recurrent infections,
uveitis,
fistulating skin disease,
granulomatous hepatitis,
granulomatous,
lymphocytic interstitial lung disease.
CD70 deficiency, CD27 deficiency, ITK deficiency, and MAGT1 all share a strong predisposition to lymphoma.