Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder of the immune system in which affected individuals develop a hyperactive yet defective response to specific challenges, including infection with viruses and other pathogens. Under normal circumstances, specialized cells of the immune system known as “T lymphocytes” and “natural killer (NK)” cells control infections by secreting chemicals called “cytokines” (which recruit and activate immune cells), and releasing toxic granules (which act like “bullets” to kill infected cells as well as some of the normal immune cells that are responding to the infection). The T lymphocytes and NK cells in patients with HLH have a problem producing or releasing the toxic granules (i.e. the bullets), but they secrete pro-inflammatory cytokines at normal or even increased levels. When an individual with HLH becomes infected, his or her immune cells do not properly clear the infected and/or activated cells, but they continue to produce copious amounts of cytokines. As a result, the immune system becomes over-activated, with T lymphocytes and NK cells proliferating excessively and infiltrating multiple organs, such as the liver, spleen, bone marrow and brain. The T and NK cells can damage these tissues, leading to organ dysfunction and often death.
HLH is proposed to occur in two forms. One form is known as “primary” HLH. This is an inherited form of the disease that typically occurs in infancy or early childhood. A second form, known as “secondary” HLH, occurs in older children and adults. It is not thought that this latter form is inherited. Rather, it is believed that secondary HLH results from a temporary dysregulation of the immune system that occurs as the result of an infection, certain types of cancer or specific autoimmune diseases. It is estimated that primary HLH affects around 1 in every 50,000 live births. Currently, the incidence of secondary HLH is not known. In primary HLH, defective genes are inherited from both parents or from the mother alone. Since 1999, several genes have been identified as causing primary HLH. Remarkably, each of these genes functions in the same biologic pathway that is responsible for the production and release of toxic granules by T and NK cells onto infected or activated cells that serve as the targets to be killed.
Historically, most patients with primary HLH and many with secodary HLH died. Fortunately, as information about the biologic basis of HLH evolved, so has its treatment. Current HLH treatments involve the use of immunosuppressive medications such as steroids and cytotoxic chemotherapies, which function to temporarily kill activated T and NK cells as well as other cells of the immune system. For patients with primary HLH, the only curative treatment is bone marrow transplantation, where the genetically defective immune system is replaced with a normal immune system from a healthy donor. Thanks to improved recognition and treatment, it is now possible to cure about 60-70% of HLH patients. Nonetheless, current treatment approaches are associated with serious side effects such as infection and a significant proportion of patients die due to active HLH or the complications resulting from its treatment.
As can be appreciated, great strides have been made in understanding and treating HLH. However, many questions remain unanswered. Specifically, how can we best translate the information on HLH genetics into novel treatments that are more effective and less toxic than current approaches? Are abnormalities in these same genes responsible for the development of secondary HLH? Future studies of human HLH patients and the creation and investigation of relevant animal models will provide insights into these important yet unanswered questions.Dr. Kim Nichols
Sean Fischel Connect Inc. was started to honor the memory of my son, Sean Michael Fischel, who lost his life after battling a rare disease called HLH (hemophagocytic lymphohistiocytosis). Our hope is to keep Sean’s light shining in the hearts of others. Our mission is for the charitable purpose of supporting children’s health and well being, encouraging them to connect and appreciate the impact they have on others and to raise awareness and funding for the research and treatment of childhood diseases.