Hemophagocytic L ympho - PowerPoint Presentation

Slide1

Hemophagocytic Lympho Histiocytosis

BY:

Alireza

Shafiei

Allergist and Clinical Immunologist

Assistant Professor of Tehran University of Medical Sciences

Bahrami

Hospital

Slide2

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).

Slide3

Slide4

Slide5

Understanding the pathogenesis of hlhT lymphocytes play an essential role in the induction of the disease manifestations of HLHThe 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.

Slide6

Understanding the pathogenesis of hlhIn 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

Slide7

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.

Slide8

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. H

emophagocytosis

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

Slide9

Definition

Slide10

Cytokine StormSpectrum of Cytokine-Induced DiseaseNormal response to infxn

SIRS

Severe sepsis

Macrophage activation syndrome

Acquired HLH

Genetic HLH

Systemic Inflammatory Response Syndrome

Slide11

Slide12

Slide13

Slide14

Slide15

Slide16

Slide17

Causes of HLHHLHPerforin deficiencyMunc 13-4 deficiency

Syntaxin 11 deficiency

Munc 18-2 deficiency

Unknown gene mutations

Immune deficiencies

Malignancy

Autoimmune diseases

Viral infections

Bacterial infections

Fungal infections

Helminthic

infections

Medications

Slide18

Slide19

Slide20

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

Slide21

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

.

Slide22

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

).

Slide23

Slide24

Slide25

Slide26

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,

hypogammaglobulinemia

,

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.

Slide27

Slide28