Pathogenesis of Secondary Hemophagocytic Lymphohistiocytosis

National Institute Of Allergy And Infectious Diseases

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Abstract

HLH occurs due to profound immune dysregulation and hypercytokinemia. Primary HLH (pHLH) develops in infants due to inherited defects in cytotoxicity, or as recently identified, dysregulated inflammasome activation. Its pathogenesis is driven by robust, dysregulated T-cell activation and IFNγ production and is fatal without SCT. Gain-of-function variants in the NLRC4 inflammasome can also cause recurrent HLH through dramatic IL18 production. In secondary HLH, which occurs more commonly in adults, disease causing mechanisms are unknown, but it can be triggered by infections, malignancy, or autoimmune disease. In children with systemic juvenile idiopathic arthritis (sJIA)-triggered sHLH, the IFNγ-IL18 axis is also implicated in its pathogenesis, suggesting a common pathway in all HLH. Retrospective studies of sHLH cohorts have been unable to confirm these findings due to missing data, inconsistent sampling, and lack of follow-up. We have used well-characterized cohorts of HIV patients with mycobacterial-IRIS, which can cause sHLH, to investigate if a common pathway is involved in these individuals. Specifically, we compared patients with mycobacterial-IRIS meeting sHLH (HLH-IRIS) to individuals with IRIS (without HLH) and non-IRIS people with HIV and mycobacterial infections. Those with HLH-IRIS had worse clinical outcomes. Longitudinal analysis of biomarkers and T-cell phenotypes identified a unique immune profile in HLH-IRIS which resembled pHLH, with prominent activation of the IFNγ-IL18 axis and an expansion of activated (CD38+HLADR+) CD4+ and CD8+ T-cells coinciding with a depletion of Tregs. CXCL9 and sCD25 reflected disease activity and could be used to guide treatment response. Genetic testing further supported this overlap with pHLH as there was an enrichment of protein-altering variants in HLH-associated genes in IRIS patients, and we are currently evaluating the functional impact of these variants which could provide the first evidence implicating specific genetic risk factors that predispose to IRIS. To corroborate these findings in another hyperinflammatory cohort, through a collaboration with NCI, we performed similar analyses in patients with Kaposi sarcoma herpesvirus (KSHV)-inflammatory syndromes, which clinically resemble HLH. In this population, we identified a prominent IL18 signature with only subtle increases in IFNγ. This dramatic IL18 production (driven by inflammasome activation in myeloid cells) resembles the immune profile of sJIA-triggered sHLH and contrasts with the predominantly IFNγ profile (hyper-activated T-cells with low Tregs) found in pHLH and HLH-IRIS. These findings suggest that differential activation of the IFNγ-IL18 axis from different etiologic triggers could produce unique immune profiles due to differences in pathogenesis that could be utilized to improve diagnosis and treatment. To further expand on these findings to other etiologies of sHLH, we begun a clinical translational research program to recruit, study, and clinically manage patients with this hyperinflammatory syndrome. Our HERCULES clinical trial is actively recruiting and has enrolled over 20-patients over the last year. The hypothesis is that a shared pathophysiology is involved amongst all etiologies of HLH which centers on the IFNγ-IL18 axis, and we are investigating the immunopathogenic mechanisms of this syndrome with the goal of identifying targeted pathways that can be inhibited in future therapeutic clinical trials. More specifically, our goals are (1) to investigate inherited and acquired mechanisms of immune dysregulation in sHLH focusing on pathways already implicated in pHLH (inflammasome activation in myeloid cells, lymphocyte cytotoxicity, dysregulated T/NK-cell populations); and (2) to prospectively characterize the longitudinal course of this dynamic inflammatory process by monitoring biomarkers, immunophenotypes, and treatment outcomes. This program aims to study a neglected, diverse hyperinflammatory patient population and it has the potential to expand our understanding of hyperinflammatory mechanisms on a broad scale. Currently, we are also evaluating the immune profile of patients with cancer receiving chimeric antigen receptor (CAR) T-cell therapy. Treatment with CD22 CAR T-cells specifically can develop HLH-like reactions, now termed immune effector-cell HLH-like syndrome (IEC-HS), which lead to adverse outcomes and greater mortality. Mechanisms of inflammation are also unknown as are optimal treatment options. We have already linked increased IL-18 and more specifically free IL-18 to the onset of IEC-HS and are working to describing on the cellular implications resulting from this increase.