Hemophagocytic Syndromes and Infection

, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

Disclosures

Emerging Infectious Diseases. 2000;6(6) 

In This Article

Pathophysiology

Phagocytosis of blood cells and their precursors is a hallmark of hemophagocytic syndromes. Hemophagocytosis is achieved mostly by monocytes, macrophages, and nitro-blue tetrazolium reduction by monocytes from patients with HLH is approximately six times that of control monocytes[40]. Splenic macrophages from patients with HLH exhibit an activated phenotype with increased expression of MHC class I and II molecules and increased M-CSF receptor expression[41]. Phagocytosis of platelets in HLH may be enhanced by increases in anti-platelet immunoglobulin (Ig) G, which has been reported in parvovirus B19-associated HLH[42].

Figure 2.

Schematic representation of possible immunopathologic mechanisms in infection-associated hemophagocytic lymphohistiocytosis (HLH). In Epstein-Barr virus (EBV)-associated HLH, infection of T lymphocytes results in clonal proliferation, with production of high levels of activating cytokines. Elaboration of TNF-alpha and other cytokines causes fever and systemic illness. TNF-alpha and IFN-gamma production contributes to macrophage activation with resulting hemophagocytosis, as demonstrated by the ability of anti-TNF-alpha and anti-IFN-gamma antibodies to attenuate hemophagocytosis. The immunopathology of infection with nonviral pathogens is less well understood, but may be related to exaggerated production of TNF-alpha and IFN-gamma in response to infection. TNF-alpha = tumor necrosis factor-alpha; IFN-gamma = interferon-gamma; IL-1 = interleukin-1; IL-2 = interleukin-2; IL-6 = interleukin-6; IL-18 = interleukin-18; sFasL = soluble Fas ligand; T = T-lymphocyte; M = macrophage; EBV = Epstein-Barr virus.

Excessive activation of monocytes in HLH may be due to stimulation by high levels of activating cytokines. High levels of interferon-gamma (IFN-gamma)[43,44,45], soluble interleukin-2 receptor[43,46], tumor necrosis factor-alpha (TNF-alpha[44,47,48] interleukin-1[49], and interleukin-6[43] have been demonstrated, suggesting that elaboration of activating cytokines by T-helper cells promotes activation of macrophages in this disease (Figure 2). Higher levels of IFN-gamma correlate with poor clinical outcome in children with virus-associated HLH[45,49].

Recently, oversecretion of interleukin-18 by monocytes in patients with HLH has been described[50]; interleukin-18 production may further enhance TNF-alpha production by T-lymphocytes and NK cells, as well as induce Fas ligand expression on lymphocytes, which enhances their cytotoxic effect. Serum levels of soluble Fas ligand, which can trigger apoptosis in such Fas-expressing tissues as the kidney, liver, and heart, also appear to be increased in HLH[51].

The exact mechanisms by which abnormal cytokine elaboration by T lymphocytes results in HLH remain unclear. However, data from patients with EBV-associated HLH, as well as HLH associated with EBV-positive T-cell lymphomas, may be instructive. Although T lymphocytes lack the putative EBV receptor CD21, the presence of episomal EBV genome in T-cell lymphomas[52,53] and T lymphocytes from patients with virus-associated HLH is well described[54,55]. EBV-positive T-cell lymphomas appear to elaborate TNF-alpha more frequently than either EBV-positive B-cell lymphomas or EBV-negative T-cell lymphomas[53].

Lay and colleagues induced the expression of CD21 in T-lymphoma cell lines and subsequently infected these cells with EBV. High levels of TNF-alpha, IFN-gamma, and IL-1alpha were secreted by these cells after EBV infection; when the lymphocytes were co-cultured with monocytes, enhanced phagocytosis by monocytes was observed. The enhanced phagocytosis was eliminated by the addition of antibodies against TNF-alpha and IFN-gamma[53].

The clonal expansion of EBV-infected T lymphocytes has been demonstrated in both EBV-associated HLH[55,56,57] and EBV-positive T-cell lymphoma[53] by the presence of homogeneous viral terminal repetitive sequences. EBV-infected cells stain positive for such T-lymphocyte markers as CD45RO and T-cell receptor-ß[54,55]. Clonality of infected T lymphocytes is further suggested by the finding of monoclonal rearrangements of the T-cell receptor-ß gene in EBV-associated HLH[58].

The distinction between the monoclonal proliferation of T lymphocytes seen in EBV-associated HLH and EBV-positive T-cell lymphomas may describe extremes of a spectrum of disordered T-lymphocyte proliferation and cytokine elaboration following EBV infection of T lymphocytes. Elaboration of such viral proteins as LMP1, essential to the immortalization of EBV-infected B-lymphocytes, may affect EBV infection of T lymphocytes, although studies suggest otherwise[59]. It is also unclear whether clonal proliferation of T lymphocytes occurs in HLH associated with pathogens other than EBV. The fact that these syndromes seem more likely to resolve with control of the underlying infection suggests that this may not be the case. The apparent utility of cyclosporin A in HLH[60,61,62] and the morphologic similarity of the liver disease seen in HLH to acute graft rejection in transplant patients[1] lend further credence to the role of lymphocytes as central to the pathogenesis of HLH.

The pathophysiology of infection-associated HLH following infection with nonviral pathogens may also be related to production of high levels of activating cytokines by host lymphocytes and monocytes. The relative frequency of association between infecting organisms (e.g., Mycobacterium tuberculosis, Salmonella Typhi, and Leishmania sp.) that trigger a TH1 immune response and reactive hemophagocytic syndromes might suggest that the syndromes result from a poorly regulated or inappropriate TH1 response to intracellular pathogens. However, Tsuda and colleagues found no evidence of a marked shift towards a TH1 cytokine profile in patients with HLH associated with nonviral infections[63].

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