Macrophage Activation Syndrome in SJIA - Alexei Grom
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Macrophage Activation Syndrome (MAS) is caused by excessive activation and multiplication of macrophages and cytotoxic T cells, leading to massive inflammation. In MAS, these immune cells overproduce cytokines that cause a "cytokine storm" and the macrophages begin destroying normal blood cells. This can cause a sudden drop in blood cell counts and become life-threatening. MAS shares similarities to hemophagocytic lymphohistiocytosis, a genetic disease where cytotoxic cells cannot properly kill infected cells. MAS most commonly occurs in systemic juvenile idiopathic arthritis and is diagnosed based on signs of infection, low blood cell counts, high ferritin levels, and liver dysfunction. Treatment involves high-dose corticosteroids,
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Macrophage Activation Syndrome in SJIA - Alexei Grom
- 1. Macrophage Activation Syndrome in SJIA Alexei Grom, MD Cincinnati Children’s Hospital Medical Center
- 2. Macrophage Activation Syndrome • Caused by excessive activation and multiplication of predominately two types of immune cells • cytotoxic CD8+ T cells and • macrophages • Excessive activation of these cell leads to massive inflammation that might be life-threatening
- 3. Normal macrophages • a type of white blood cells that engulfs and destroys microbes and other foreign substances in a process called phagocytosis
- 5. Macrophages in MAS • Overly activated • Start phagocytosing and destroying normal blood cells (such as red blood cells, neutrophils and platelets) • Destruction of these blood cells leads to a sudden drop in their numbers and might be life-threatening
- 7. Normal cytotoxic T cells • A cytotoxic T cell (also known CD8+ T-cell or killer T cell) is a T lymphocyte (another type of white blood cells) that kills cancer cells, and cells that are infected (particularly with viruses)
- 9. MAS is a cytokine storm
- 10. MAS is a cytokine storm • Immune cells communicate with each other by sending various “chemical signals” called cytokines • some cytokines cause inflammation • some cytokines reduce inflammation • In MAS, there is excessive activation and multiplication of macrophages and cytotoxic T cells that produce too much cytokines that cause inflammation
- 11. MΦ Proposed Mechanisms of Macrophage Activation in Hemophagocytic Syndromes 11 CD8+ IFN-γ GM-CSF MΦ MΦ MΦ MΦ MΦMΦ MΦ Mo TNF-α IL-6 IL-1 IL-18 M-CSF CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ MΦ
- 12. MAS and Hemophagocytic Lymphohistiocytosis • striking clinical similarities between MAS and hemophagocytic lymphohistiocytosis • hemophagocytic lymphohistiocytosis is a genetic disease in which cytotoxic cells have decreased ability to kill cells infected with viruses • Mouy R, et al. J Pediatr 1996;129:750
- 13. Annual Reviews
- 14. MΦ Proposed Mechanisms of Macrophage Activation in Hemophagocytic Syndromes 14 CD8+ IFN-γ GM-CSF MΦ MΦ MΦ MΦ MΦMΦ MΦ Mo TNF-α IL-6 IL-1 IL-18 M-CSF CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ MΦ CD8+ CD8+
- 15. Cytolytic Defects in FHLH Cytolytic cells cause destruction of target cells by delivering granules that contain proteins such as perforin and granzymes 15 death Infected Cell Effector Cell (NK Cell) Granzyme B Fusion Priming Munc13-4 Munc18-2 Syntaxin 11 Rab27a Nucleus Perforin
- 16. Signs and Symptoms Macrophage Activation Syndrome
- 17. Macrophage Activation Syndrome • Patients look very ill, run high fevers • Laboratory abnormalities: • Sudden drop in hemoglobin, platelet and neutrophil counts • Very high serum ferritin • Impaired liver function • Increased liver enzymes (Ast, Alt) • Decreased ability to make proteins involved in blood coagulation (such as fibrinogen) leading to bleeding Silverman ED, et al. J Pediatr 1983;103:872. Hadchouel M, Prieur AM, and Griscelli C. J Pediatr 1985;106:561.
- 19. MAS in Pediatric Rheumatology • Has been reported in association with almost any rheumatic disease • By far, most common in systemic JIA • About 80% of reported cases occurred in association with systemic JIA • SLE, Kawasaki disease • Prevalence of “overt MAS” in systemic JIA is ~10% Sawney, et al. Arch Dis Child 2001;85:4210 • Evidence of subclinical MAS in a subgroup of systemic JIA patients with active systemic disease (~30%) Bleesing, et al. Arthritis Rheum 2007;56:965 Behrens, et al. J Rheumatol 2007:34:1133
- 20. Laboratory monitoring for signs of MAS • Cell blood count • Ferritin • Liver enzymes • Fibrinogen • Soluble IL2Rα • Soluble CD163
- 22. Established Treatments of MAS • High dose corticosteroids • Cyclosporine A • Anakinra in some patients • Etoposide in most difficult cases
- 23. Treatments under investigation • Biologics neutralizing INF-gamma (anti-IFN γ antibodies) • Biologics neutralizing IL-18 (recombinant IL18BP) • Jak-Stat inhibitors
Editor's Notes
- Hemophagocytic syndromes are characterized by an uncontrolled expansion of activated CD8 cells that secrete proinflammatory cytokines such as interferon gamma and granulocyte-macrophage colony-stimulating factor. These cytokines cause monocytes to differentiate into macrophages, which then release proinflammatory cytokines, thus causing an exaggerated, cyclical cascade. Persistent activation of macrophages leads to massive increase in proinflammatory cytokines. The mechanism leading to expansion of activated macrophages is not clear. One possible hypothesis for uncontrolled expansion of T cells is a defect in cytolytic function. Reference: Grom AA. Macrophage activation syndrome. In: Cassidy JT, Laxer RM, Petty RE, Lindsley CB, eds. Textbook of Pediatric Rheumatology. 6th ed. Philadelphia, PA: Saunders Elsevier; 2011:674-681.
- Hemophagocytic syndromes are characterized by an uncontrolled expansion of activated CD8 cells that secrete proinflammatory cytokines such as interferon gamma and granulocyte-macrophage colony-stimulating factor. These cytokines cause monocytes to differentiate into macrophages, which then release proinflammatory cytokines, thus causing an exaggerated, cyclical cascade. Persistent activation of macrophages leads to massive increase in proinflammatory cytokines. The mechanism leading to expansion of activated macrophages is not clear. One possible hypothesis for uncontrolled expansion of T cells is a defect in cytolytic function. Reference: Grom AA. Macrophage activation syndrome. In: Cassidy JT, Laxer RM, Petty RE, Lindsley CB, eds. Textbook of Pediatric Rheumatology. 6th ed. Philadelphia, PA: Saunders Elsevier; 2011:674-681.
- This figure denotes the cytolytic pathway and potential mutations that may be involved. The activity of cytolytic cells is mediated by release of cytotoxic granules that contain proteins such as perforin and granzymes.1 On recognition of the target cells, the cytolytic cells reorganize the cytoskeleton and the microtubule (MT)-organizing center moves toward the site of contact between the cytolytic cell and the target cell, which is called the “immunologic synapse.”2 Cytolytic granules move along the MTs and degranulate at the point of contact.1,2 Perforin is a key cytolytic protein that acts by inserting itself in the membrane of the target cell and delivers content of granules to the target cell.1 References: Ravelli A, Grom AA, Behrens EM, Cron RQ. Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment. Genes Immun. 2012;13(4):289-298. Filipovich AH. Hemophagocytic lymphohistiocytosis and other hemophagocytic disorders. Immunol Allergy Clin North Am. 2008;28(2):293-313.
- Hemophagocytic syndromes are characterized by an uncontrolled expansion of activated CD8 cells that secrete proinflammatory cytokines such as interferon gamma and granulocyte-macrophage colony-stimulating factor. These cytokines cause monocytes to differentiate into macrophages, which then release proinflammatory cytokines, thus causing an exaggerated, cyclical cascade. Persistent activation of macrophages leads to massive increase in proinflammatory cytokines. The mechanism leading to expansion of activated macrophages is not clear. One possible hypothesis for uncontrolled expansion of T cells is a defect in cytolytic function. Reference: Grom AA. Macrophage activation syndrome. In: Cassidy JT, Laxer RM, Petty RE, Lindsley CB, eds. Textbook of Pediatric Rheumatology. 6th ed. Philadelphia, PA: Saunders Elsevier; 2011:674-681.