HLH: The Autoimmune Cancer

HLH is a scary and unpredictable disease, targeting infants straight out of the womb and adolescents out of the blue.

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HLH is very rare, affecting around one in 100,000.

What if there was a disease that mirrored cancer, but you couldn’t tell what it was until it struck? Now, that would be something to look out for. Cancer is the abnormally rapid division of our cells caused by a mutation, most frequently forming tumors. The recovery process is arduous, often requiring months or even years of chemotherapy and radiation treatments. Hemophagocytic lymphohistiocytosis (HLH) is a combination of two biological phenomena: it attacks our bodies at a rapid pace and uses our own white blood cells to override it.

HLH is an immunodeficiency disorder where one’s white blood cells attack one’s body from within. More specifically, HLH targets macrophages, NK-cells, and cytotoxic T-lymphocytes. Macrophages are cells that eat pathogens through phagocytosis. NK-cells and cytotoxic lymphocytes both kill pathogens, the cytotoxic lymphocytes by first recognizing pathogens with specific proteins on their cell membranes.

HLH was first discovered around 75 years ago by scientists R. Bodley Scott and A.H.T. Robb-Smith. They discovered that HLH resulted in abnormalities with erythrocytes, a type of red blood cell that is responsible for giving blood its dark red color and transporting oxygen during circulation. It wouldn’t be until two decades later that HLH was given its name and considered a viral infectious disease. However, the disease still managed to perplex doctors in the 20th century, and the survival rate remained a mere four percent.

HLH can be contracted in two ways: inherited and acquired. Inherited HLH is due to a mutation in the STX11 gene, which produces the syntaxin-11 protein. These proteins are responsible for cell exocytosis—the excretion of waste from the cell—as well as “cell-mediated killing,” maintaining homeostasis using attacking mechanisms. When the gene is mutated, however, white blood cells do not know when to attack and instead target any organ they can find. The liver and spleen are usually affected, often becoming enlarged due to infection and inflammation upon diagnosis. At this point, the bone marrow will continue to create more blood cells to fight the existing blood cells, which have now become pathogens. This vicious cycle continues until the white blood cells are clustered around the body due to crowding, similar to a malignant tumor.

Acquired HLH results from a trigger, usually viral, such as the Epstein-Barr virus (EBV), organ transplant cross-contamination, or blood transfusions. EBV is a subset of the herpes virus and can spread through salivation, sexual contact, or the sharing of blood. EBV is considered the most deadly trigger because while it may become latent, it never truly disappears in the body. The reappearance of EBV can be triggered by external environmental factors, such as stress, before it starts attacking the body once again. The more immune disorders one has, the lower one’s chances of surviving HLH.

HLH is very rare, affecting around one in 100,000. Furthermore, the symptoms are very similar to those caused by thousands of other diseases. Thus, it is not uncommon for doctors to misdiagnose children in the early stages of HLH with other joint diseases and rheumatic fever, oblivious to their future symptoms. The only sure way to diagnosis HLH is to conduct blood cell counts. A person with HLH exhibits characteristics such as low red blood cell count, anemia, a deprivation of oxygen, and blood cell buildup in the bone marrow. At this point, doctors may analyze a patient’s liquid bone marrow to confirm the diagnosis.. Once confirmed, treatment may begin.

The most common treatment for HLH is chemotherapy, which lasts from about two weeks to two months, depending on the severity. Afterward, the patient is prepared to receive a bone marrow transplant with new stem cells to replace the damaged and diseased stem cells in the existing bone marrow. This ensures that the presence and severity of HLH are kept to a minimum, should it resurface at all.

As we look into the future, scientists are looking to gene therapy, a revolutionary field of science brought into the spotlight by Nobel Prize Winners Jennifer Doudna and Emmanuelle Charpentier with CRISPR technology. CRISPR is a gene-editing therapy that allows scientists to get into the nitty-gritty of DNA genome structures and alter them. This could potentially reverse genetic mutations, which may in turn slow down the symptoms of disease. There has also been increasing support for the use of anti-cytokine drugs, anti-inflammatory substances used to reduce swelling inside the body. By minimizing the internal reactions of the body, these drugs ensure that the body takes fewer blows from the autoimmune response.

HLH is a frightening and unpredictable disease, targeting infants straight from the womb and adolescents out of the blue. HLH can also occur in adults, though those forms of HLH are typically acquired and milder. However, advances in understanding the causes of HLH will allow us to better understand not only HLH, but autoimmune diseases overall. With stem cell research and increased knowledge regarding our body’s offensive and defensive mechanisms, scientists can develop solutions to increase the survival rate of HLH and improve the quality of life for people with the disease.

This article is a tribute to Sriyans Shakya, a survivor of HLH.