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761Strippoli, et al: Pathogenesis of MAS

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Review

Reaching the Threshold: A Multilayer Pathogenesis ofMacrophage Activation SyndromeRaffaele Strippoli, Ivan Caiello, and Fabrizio De Benedetti

ABSTRACT. Macrophage activation syndrome (MAS) is a potentially fatal complication of rheumatic diseases.The condition is considered part of secondary hemophagocytic lymphohistiocytoses (HLH). Thereare similarities in genetic background, pathogenesis, and clinical and laboratory features withprimary HLH (p-HLH). We describe findings in mouse models of secondary HLH, comparing themwith models of p-HLH and the cellular and molecular mechanisms involved, and relate them torecent findings in patients with secondary HLH. A multilayer model is presented in whichbackground inflammation, infections, and genetics all contribute in different proportions and inseveral ways. Once the “threshold” has been reached, inflammatory cytokines are the final effectors,independent of the interplay between different upstream pathogenic factors. (First Release April 152013; J Rheumatol 2013;40:761–7; doi:10.3899/jrheum.121233)

Key Indexing Terms:MACROPHAGE ACTIVATION SYNDROME JUVENILE IDIOPATHIC ARTHRITISHEMOPHAGOCYTIC LYMPHOHISTIOCYTOSES ETIOLOGY

From the Division of Rheumatology, IRCCS Ospedale PediatricoBambino Gesù, Rome, Italy.R. Strippoli, MD, PhD, Division of Rheumatology, IRCCS OspedalePediatrico Bambino Gesù; Integrin Signaling Laboratory, Department ofVascular Biology and Inflammation, Centro Nacional de InvestigacionesCardiovasculares (CNIC), Madrid, Spain; I. Caiello, BS; F. De Benedetti,MD, PhD, Division of Rheumatology, IRCCS Ospedale PediatricoBambino Gesù.Address correspondence to Dr. R. Strippoli, IRCCS Ospedale PediatricoBambino Gesù, Division of Rheumatology, Piazza S. Onofrio 4, 00165Rome, Italy. E-mail: [email protected] for publication January 31, 2013.

The term macrophage activation syndrome (MAS) iscommonly used to identify a potentially life-threateningcomplication of rheumatic diseases1,2,3. It usually occurs inthe context of systemic juvenile idiopathic arthritis (s-JIA),but also, albeit more rarely, in adult-onset Still disease,systemic lupus erythematosus, or Kawasaki disease.

MAS is characterized by high fever, lymphoadeno-megaly, hepatosplenomegaly, pancytopenia, and coagulo-pathy, and may proceed to multiple organ failure.Biochemical abnormalities include increased hypofibrino-genemia, hypertriglyceridemia, and increased levels ofsoluble CD25, ferritin, and inflammatory cytokines.

Although the term MAS is commonly used, particularlyby rheumatologists, the condition has recently been linkedto secondary hemophagocytic lymphohistiocytosis (HLH).Indeed, similarities in clinical and laboratory features,genetic background, and pathogenesis with primary HLHare becoming more evident. The term rheumatologic-HLH(rheuma-HLH or r-HLH) has been recently proposed4.

Primary HLH (p-HLH) is caused by mutations of genes

coding for proteins involved in granule exocytosis, includingperforin, Munc13-4, syntaxin11, and Munc18-25. In theabsence of a genetic cause or familial inheritance, secondaryHLH occurs in response to infections, associated withmalignancies (particularly lymphoma), or in the context ofrheumatic disease (MAS/r-HLH). Studies in patients withp-HLH, as well as in murine models of p-HLH6,7,8,9,10,11,support the hypothesis that a defective cytotoxic CD8+ Tcell response and an alteration of the antigen-presenting cell(APC)–CD8+ T cell crosstalk leads to defective silencing ofthe immune response and abnormal T cell activation2,3,6,9,12.The end result of this process is uncontrolled production ofproinflammatory cytokines by macrophages and T lympho-cytes, leading to organ damage and hematologic altera-tions13,14. Indeed, characteristic of HLH, although notnecessary for the diagnosis, is the presence of macrophagesphagocyting blood cells in liver or bone marrow15.

In this review, we describe findings in mouse models ofsecondary HLH, comparing them with models of p-HLHand the cellular and molecular mechanisms involved, andrelate them to recent findings in patients with secondaryHLH.

Animal models of primary and secondary HLH Murine models of p-HLH have been generated by genedeletion or gene mutation of the murine orthologs of thegenes involved in human p-HLH, including perforin,Munc13-4, and Rab27a6,7,8,10,11. Perforin deleted (prf–/–)mice are the most studied. These mice do not spontaneouslydevelop HLH-like symptoms, but they show featurescharacteristic of HLH after infection with a noncytopathic

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virus, lymphocytic choriomeningitis virus (LCMV)6. Theydevelop fever, splenomegaly, pancytopenia, hypertriglyceri-demia, and hypofibrinogenemia, and die within 2 weeks.Histological analysis reveals activated lymphohistiocyticinfiltrates, bone marrow hypoplasia, and hemophagocytosis.Serum cytokine profiles are also very similar to those ofhumans with p-HLH. Mice harboring nonfunctionalmutations of Unc13d (murine ortholog of the humanMunc13-4) behave normally in pathogen-free conditions;upon infection with LCMV they develop an HLH-likephenotype with reduced platelet counts, splenomegaly,neutrophilia, and macrophage infiltration with bone marrowhemophagocytosis7. After LCMV infection, mice deficientfor Rab 27a, a protein that colocalizes with Munc13-4,develop a mild decrease in hemoglobin and in plateletcounts, neutrophilia (and not neutropenia), increasedferritin, splenomegaly, and liver hemophagocytosis, withnegligible lethality8.

These models based on genetic alterations in the granuleexocytic pathway are models of p-HLH and thereforerepresent tools to investigate cellular and molecular mechanisms of diseases caused by genetic mutations.However, the findings may not be directly translated to thesetting of secondary HLH triggered by infections orpresenting in the context of rheumatic diseases. Four modelsof secondary HLH have been published in the last year, ofwhich 2 are triggered by living pathogens (Table 1).

A model of secondary HLH caused by Epstein-Barr virus(EBV) infection has been obtained using humanized mice.Human hematopoietic CD34+ cells are introduced into

immunodeficient mice, thus rebuilding a “humanized”immune system. Infection of these mice with EBV inducesa condition resembling EBV-associated HLH in humans,with thrombocytopenia and hemophagocytosis. By 10weeks postinfection, two-thirds of the infected mice dieafter exhibiting high and persistent viremia, leukocytosis,anemia, and thrombocytopenia16. Chronic typhoid feverfollowing infection with Salmonella enterica has beenproposed as a model of secondary HLH17. In this experi-mental model, an acute response is followed by a chronicinflammatory disease characterized by anemia, thrombo-cytopenia, reduced lymphocytes, increased neutrophils andmonocytes, hypofibrinogenemia, hyperferritinemia, fever,and hepatosplenomegaly. Hemophagocytic macrophageswere found in bone marrow and spleen.

A third model of secondary HLH has been described, inwhich normal mice develop an HLH-like syndrome uponrepeated stimulation with the dinucleotide CpG. CpGmimics bacterial and viral DNA and is a synthetic ligand ofToll-like receptor-9 (TLR-9)18. This model of secondaryHLH caused by infections is based on repeated CpGadministration in genetically normal mice in the absence ofunderlying chronic inflammation. It is characterized byleukopenia, anemia, thrombocytopenia, splenomegaly,hyperferritinemia, and liver necrosis due to microthrom-bosis. Neither mortality nor hemophagocytosis wasobserved. However, in the absence of interleukin 10(IL-10), these mice show hemophagocytosis and die,supporting the antiinflammatory role for IL-10 in thissetting.

762 The Journal of Rheumatology 2013; 40:6; doi:10.3899/jrheum.121233


Table 1. Murine models of secondary hemophagocytic lymphohistiocytosis (HLH) are compared with the prototypical model of primary HLH (prf–/– miceinfected with LCMV).

Primary SecondaryLCMV in PRF1 EBV HM Salmonella Repeated CpG IL-6TG

–/– enterica Dinucleotide

Genetics of cytotoxic pathway Perforin –/– Normal Normal Normal NormalTrigger LCMV EBV S. enterica CpG LPS/Poly:ICBackground inflammation No No No No YesLethality Yes 2 weeks Yes 10 weeks No No Yes one weekSplenomegaly Yes Yes Yes Yes Yes*Thrombocytopenia Yes Yes Yes Yes YesLeukocytes Neutropenia Lymphocytosis Leukocytosis Lymphopenia NeutropeniaAnemia Yes Yes Yes Yes YesFerritin increase Yes** Not reported Yes Yes YesLDH increase Yes*** Not reported Not reported Not reported YesFibrinogen Decreased Not reported Mild decrease Normal Not reportedIL-6 Increased Not reported Not reported Increased IncreasedIL-1ß Not detected Not reported Not reported Not reported IncreasedIFN-γ Increased Increased Not reported Increased Increased*Hemophagocytosis Yes Yes Yes No NoRescue upon T CD8+ depletion Yes Not reported Not reported No Not reportedRescue upon IFN-γ blockade Yes Not reported Not reported Yes Not reported

* Strippoli, et al, unpublished. ** Pachlopnik Schmid, et al, 2009. *** Jessen, et al, 2011. LCMV: lymphocytic choriomeningitis virus; PRF: perforin; EBV:Epstein-Barr virus; HM: humanized mouse; TG: transgenic; LDH: lactate dehydrogenase; IFN: interferon; LPS: lipopolysaccharide.



Lastly, a model of secondary HLH has been generated inIL-6 transgenic mice (IL-6TG)19. IL6TG mice express highlevels of IL-6 and do not present obvious signs of inflam-matory disease. However, when challenged with TLRligands, they show increased mortality, with increasedferritin and soluble CD25, as well as decreases in platelet,neutrophil counts, and hemoglobin levels; hemophago-cytosis was not found. This model provides informationabout the development of HLH triggered by TLR ligandsmimicking infections, in the presence of high levels of IL-6(a cytokine that is markedly increased in patients withs-JIA20), in mice with normal cytotoxic pathways.Therefore, these mice represent a model of secondary HLHin the context of rheumatic disease (MAS/r-HLH).

Cellular agentsCell types that have been thought to play a pathogenic rolein HLH include CD8+ T lymphocytes, natural killer (NK)cells, and macrophages.

Murine models of p-HLH provide clear evidence for arole of CD8+ T lymphocytes in p-HLH. In prf–/– mice,depletion of CD8+ T lymphocytes stops disease activity6. Inmodels of p-HLH, CD8+ T cells producing high levels ofinterferon-γ (IFN-γ) are found6,7,8. An increase in viralantigens by APC appears to be responsible for theabnormal CD8+ T lymphocyte activation9. To date, nodefinitive information is available on the role of CD8+ Tcells in the salmonella and EBV humanized mouse modelsof secondary HLH or in the IL-6TG model ofMAS/r-HLH17,19. However, a marked increase in CD8+ Tcells is reported in the EBV humanized mouse model16.CD8+ T lymphocytes are increased only marginally, andmore importantly, are dispensable in the repeated CpGmodel of secondary HLH18. This difference suggests thatthe involvement of CD8+ T cells might be different inp-HLH versus secondary HLH. However, IFN-γ-producingCD8+ T lymphocytes have been found in the livers ofchildren with HLH secondary to infections or MAS/r-HLH,supporting the hypothesis of a pathogenic role of these cellsin humans with secondary HLH21. Studies of CD8+ T cellactivity from patients with MAS/r-HLH did not yield clearabnormalities. Therefore, the role of T cells in MAS/r-HLHis far from being defined and this may represent a differencecompared to p-HLH.

The pathogenic role of NK cells in all forms of HLHremains unclear. NK cells are dispensable for HLHdevelopment in prf–/– mice and in the repeated CpG modelof secondary HLH6,18. However, in a murine experimentalsetting of IFN-γ-increased serum levels, NK cell differen-tiation was impaired, suggesting that abnormal IFN-γ levels,which can be found in many HLH murine models, mayblock NK cell maturation22. Defective NK cytotoxicity is ahallmark of p-HLH, being the consequence of mutations ofgenes involved in cytotoxic pathways. An imbalance of NK

cell subpopulations (decrease in the CD56+ subset) and adefective cytotoxic activity have been found in some s-JIApatients with MAS/r-HLH3,23,24. Reduced levels of perforinexpression have been reported in NK cells from patientswith s-JIA who are susceptible to MAS/r-HLH24. NK cellnumber and cytotoxic activity are reduced duringMAS/r-HLH, and this was related to impaired response toIL-1825,26. Although IL-18 enhances NK functions, such asresponse to TLR and IFN-γ production, high and persistentlevels of this cytokine were found to be correlated withincreased NK cell apoptosis in systemic autoimmunediseases, including rheumatoid arthritis27. Taking theseobservations together, it is not clear whether abnormalitiesof NK cells during MAS/r-HLH play a primary role orwhether they are secondary to high levels of cytokines andother abnormal stimuli. Moreover, it is unclear whether andhow other functions of NK cells, such as cytokineproduction (i.e., IFN-γ), are affected during MAS/r-HLH.

Although macrophage hemophagocytosis is consideredhighly specific for MAS/r-HLH, the pathogenic role ofmacrophages is a matter of debate. Macrophages have beenproposed to have a causal role, to be secondarily activated,or even to have antiinflammatory activity2. Although cellsstaining positive for CD68, a macrophage cell marker, areincreased during the development of HLH in prf–/– mice, acausal role of macrophages in the pathogenesis of HLH wasnot established in this experimental model6. On the otherhand, nonlymphoid cells are highly expanded and may playa role in the production of IFN-γ in the repeated CpG modelof secondary HLH18. Macrophages have been demonstratedto produce IFN-γ under different kinds of stimuli28,29.Macrophages producing TNF-α and IL-6 have been foundin livers of patients with HLH secondary to infections orMAS/r-HLH21. A characteristic of MAS/r-HLH is thepresence of macrophage-expressing CD163, which is tradi-tionally correlated with antiinflammatory scavenger activityof fully differentiated macrophages30. Liver biopsies ofpatients with HLH secondary to infections or MAS/r-HLHalso show infiltrating CD68+ macrophages, which are oftenconsidered highly proinflammatory21. Immunohisto-chemistry of bone marrow aspirates from patients withMAS/r-HLH in s-JIA shows similar numbers of CD68+ andCD163+ macrophages (Bracaglia and Strippoli, unpub-lished data). However, the phagocytic activity andproduction of inflammatory cytokines by macrophages frompatients with MAS/r-HLH in s-JIA have not been reported.The observation of a synergy in monocyte/macrophageactivation between IL-6, a cytokine involved in s-JIA, andTLR ligands in inflammatory cytokine production19

(Strippoli, et al, unpublished data) supports the pathogenicrole of macrophages in the generation of an exaggeratedinflammatory response contributing to the development ofovert r-HLH.

While CD8+ T lymphocytes appear to play a major role





in p-HLH, murine models of secondary HLH, as well as theavailable data from patients with MAS/r-HLH, do notprovide clear evidence of a role of NK cells or CD8 Tlymphocytes. However, defective cytotoxicity, as shown bydecreased NK activity in patients with r-HLH, may suggesta role for these 2 cell types, but more studies are required toclarify their contribution.

A multilayer model of MAS/r-HLH pathogenesisBased on the data from animal models of primary andsecondary HLH and from patients with MAS/r-HLH, it isreasonable to hypothesize that multiple factors, at differentlevels, contribute to the development of MAS/r-HLH inpatients with s-JIA (Figure 1).

High disease activity may contribute to hyperresponse toan infectious trigger (as occurs in a significant proportion ofpatients with MAS/r-HLH). Evidence in vitro and in vivopoints to a major role for high levels of IL-619,31, at least forTLR ligands. In general, genetic predisposition to highresponse to pathogen-associated molecular patterns bypattern recognition receptors might be involved. Highdisease activity may also contribute to functionallydefective cytotoxic activity. Albeit with some interpatientvariability, defective perforin expression, defective NKcytotoxic activity, and/or defective NK cell numbers havebeen shown in patients with active disease with or withoutactive MAS/r-HLH23,26. A potential role of increased IL-18

level and abnormal IL-18 receptor response has beensuggested26,32,33.

Concerning genetic background, recent evidencesuggests a potential role of the same genes involved inp-HLH. One study showed heterozygosity for low-pene-trance variants of perforin in some patients withMAS/r-HLH24; another reported the association between aspecific Munc13-4 haplotype and development ofMAS/r-HLH in patients with s-JIA34. To our knowledge, noinformation is available on other genes involved in p-HLH.One could hypothesize that hypomorphic variants in each ofthese genes, as well as in other unknown genes of thecytotoxic pathways, may contribute. The genetic back-ground may also affect the intensity of the response to TLRligands. A recent report demonstrated an association of aninterferon regulatory factor-5 (IRF-5) polymorphism withsusceptibility to MAS/r-HLH in Japanese patients withs-JIA35. IRF-5 is one of the transcription factors thatmediate TLR signaling. Although this observation needsconfirmation in white subjects, it points to an additionalpotential contribution of the genetic background.

When one considers the entire spectrum of HLH, therelative contribution of the factors described above may bevariable in different forms (Figure 2). In p-HLH, loss offunction mutations are sufficient to cause development ofHLH even in the apparent absence of infectious triggers.Most deaths caused by the H5N1 avian influenza are



Figure 1. Multilayer model of pathogenic events leading to the development of macrophage activationsyndrome/rheumatologic-hemophagocytic lymphohistiocytosis (MAS/r-HLH). Genetic factors and eventsrelated to disease activity may combine to reach the threshold for MAS/r-HLH in the presence of an infectioustrigger (i.e., viral infection). NK: natural killer cells; TLR: Toll-like receptor; IL: interleukin; PAMP:pathogen-associated molecular patterns; IFN: interferon.



associated with HLH features, suggesting that some infec-tious triggers might be sufficiently strong to cause HLH,with little, if any, contribution from genetics or from apreexisting inflammatory status4. Other infectious triggersare known to be associated with development of HLH (i.e.,Leishmania, EBV); however, this occurs in a smallpercentage of infected patients, suggesting a relevant contri-bution of the genetic background. In MAS/r-HLH, subtlegenetic defects and the inflammatory status, with variablecontribution from each one of these factors, create a patho-physiological environment in which, as a consequence of aninfectious stimulus of moderate/mild “strength,” theactivation of macrophages and T cells may reach thethreshold for clinically full-blown HLH. All forms of HLHhave common clinical and laboratory features. UncontrolledT cells and macrophage activation fuels a cytokine stormthat is eventually responsible for the clinical features.Exaggerated levels of inflammatory cytokines are thus thefinal effectors, independent of the interplay betweendifferent upstream pathogenic factors.

Potential therapeutic targetsIdentification of the key agents in the cytokine storm mightprovide the rationale for novel therapies. In s-JIA, 2cytokines have emerged: IL-1 and IL-6. However, their rolein the development and progression of MAS/r-HLH ispoorly understood. Evidence in IL-6TG mice supports thehypothesis that the high levels of IL-6 in s-JIA mightcontribute to triggering MAS/r-HLH. In vitro studies havealso shown that IL-6 can lead to TLR-mediated signaling inmonocytes, inducing increased production of inflammatorycytokines, including IL-1β19. Even if neutralization of IL-6has proven to be effective in a significant portion of patients

with s-JIA, some MAS/r-HLH episodes were reported in theclinical trial with tocilizumab. Their relation with drugexposure and their severity remain to be clarified31. WhileIL-6 is increased both in prf–/– mice and in the repeatedCpG model of secondary HLH, its role in progression andmaintenance has never been tested using blockingantibodies6,18,36. With the exception of a recent report on asingle patient with adult-onset Still disease with a favorableoutcome, no information on the response to tocilizumab inMAS/r-HLH or in other HLH syndromes is available37.

In gene profiling of patients with s-JIA, increasedexpression of components of the IL-1 and TLR pathwayshas been identified38,39, and IL-1 blockade with anakinra iseffective in a significant proportion of patients. Reportssuggest also that administration of anakinra is effective intreatment of established MAS/r-HLH38,40,41,42. However,initiation of anakinra treatment has occasionally beenassociated with triggering of MAS/r-HLH43. Moreover,IL-1 blockade is not effective in mice harboring nonfunc-tional mutations of Unc1344. More information is needed tofully understand the role of IL-1 and the potential of IL-1blockade in MAS/r-HLH42. An IL-1–IL-6 synergy may behypothesized in patients with s-JIA exposed to infections.IL-1 induces IL-6 production from a variety of celltypes45,46,47. IL-6 strengthens TLR ligand-induced IL-1βproduction by peripheral blood mononuclear cells(Strippoli, et al, unpublished data), and blockade of IL-1may affect biological effects of IL-6 in multiple myeloma48.

Although its role in s-JIA has not been investigated,IFN-γ levels are increased in mouse models of both primaryand secondary HLH, including the MAS/r-HLH in IL-6TGmice6,8,9,16,18 (De Benedetti, unpublished data). However,the increase is variable in the different models, with levels



Figure 2.A model of hemophagocytic lymphohistiocytosis (HLH) pathogenesis. The threshold of HLH triggering may be reachedthrough severe defects in the granule exocytic pathway, as in most cases of primary HLH, or by abnormally strong infectioustriggers, as in the HLH-like syndrome (because of H5N1 infection). In macrophage activation syndrome/rheumatologic-hemo-phagocytic lymphohistiocytosis (MAS/r-HLH), background inflammation, infections, and genetics all contribute in differentproportions and in various ways.



being generally higher in the models of p-HLH. In modelsof p-HLH, neutralization of IFN-γ reduces biochemicalabnormalities, reduces tissue infiltrates, and preventsdeath6,8; in the nonlethal repeated CpG model of secondaryHLH it reduces hematological abnormalities18. In addition,systemic chronic exposure to IFN-γ is sufficient to causecytopenia and hemophagocytosis in mice49. Nevertheless,IFN-γ appears less effective, and another inflammatorycytokine, TNF-α, acquires pathogenic relevance whenprf–/– mice are challenged with murine cytomegalovirus, acytopathic virus29. In the repeated CpG model ofsecondary HLH, leukopenia and hyperferritinemia were IFN-γ-independent18. Information on the effect of IFN-γneutralization is not available in other models of secondaryHLH, including in IL-6TG mice. CD8+ T cells are thesource of IFN-γ in p-HLH models. In the repeated CpGmodel of secondary HLH, a myeloid cell population mayplay a role in IFN-γ production18. The source of IFN-γ in theIL-6TG models of MAS/r-HLH is still to be determined.IFN-γ-producing CD8+ T lymphocytes are present in theliver of children with HLH secondary to infections orMAS/r-HLH21. Thus biological inhibition of IFN-γ as wellas the IL-18/IL-18BP system, which plays a major role inIFN-γ production and is unbalanced in patients with HLH,may be a new frontier in the treatment of both primary andsecondary HLH50.

There is some evidence suggesting efficacy of IL-1inhibition in overt MAS/r-HLH, supporting a role of IL-1 inmaintaining MAS/r-HLH. While there is still no solid infor-mation on the role of IL-6 in overt MAS/r-HLH, data fromanimals suggest that IL-6 may contribute to triggering it.Some data point to major involvement of IFN-γ in p-HLH;however, a comprehensive analysis of the levels and thesignature of this cytokine in patients with MAS/s-HLH isstill needed. Incidentally, increased levels of neopterin, amarker of IFN-γ activation, have been reported in 5 patientswith MAS/r-HLH; this finding needs confirmation in alarger number33. A better understanding of the interplaybetween these cytokines might allow identification of themost suitable therapeutic target, to dampen as rapidly aspossible the cytokine storm leading to multiple organdamage in patients with severe MAS/r-HLH.

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