Hodgkin lymphoma begins when a specific type of immune cell, a B cell, undergoes genetic changes that prevent it from dying when it normally should. These transformed cells, called Reed-Sternberg cells, are the hallmark of the disease. No single cause explains every case. Instead, a combination of viral infection, genetic susceptibility, immune dysfunction, and possibly environmental exposures work together to trigger it.
How Normal B Cells Become Cancerous
Your immune system constantly produces B cells in structures called germinal centers, located inside lymph nodes. These B cells undergo rapid mutation as part of normal immune function, testing out different antibody configurations to find ones that work against infections. B cells that produce faulty or nonfunctional antibodies are normally eliminated through a process called apoptosis, or programmed cell death.
In Hodgkin lymphoma, something goes wrong with this quality control. Researchers have found that Reed-Sternberg cells carry a high load of mutations in their antibody genes, often resulting in completely nonfunctional antibodies. Under normal circumstances, these defective cells would be destroyed. But a key signaling pathway called NF-κB becomes permanently switched on, rescuing them from death. In roughly one-quarter of patients studied, this happens because of mutations in a gene called IκBα, which normally keeps NF-κB in check. When IκBα is damaged or deleted, NF-κB runs unchecked, allowing the defective B cells to survive and multiply.
The Role of Epstein-Barr Virus
Epstein-Barr virus (EBV), the virus behind mononucleosis, is present in the tumor cells of roughly 40 to 50% of Hodgkin lymphoma cases. One study using tissue analysis found EBV in the Reed-Sternberg cells of 48% of patients. The virus has a well-documented ability to make B cells immortal, preventing them from dying as they normally would.
EBV accomplishes this partly through the same pathway that drives non-viral cases. A viral protein called LMP-1 activates NF-κB by promoting the breakdown of IκBα, the molecule that normally keeps NF-κB suppressed. So whether the trigger is a genetic mutation or a viral protein, the end result is the same: the cell’s self-destruct mechanism gets disabled. EBV also appears to interfere with the immune system’s ability to recognize and destroy infected cells, giving the cancerous cells additional cover.
Not everyone who catches EBV develops Hodgkin lymphoma. Most people are infected with the virus by adulthood without any long-term consequences. The virus likely acts as one contributing factor among several, pushing already-vulnerable cells past a tipping point.
How Reed-Sternberg Cells Protect Themselves
One of the strangest features of Hodgkin lymphoma is that the actual cancer cells make up only about 1 to 2% of the tumor mass. The rest is a dense mix of immune cells that the Reed-Sternberg cells actively recruit and manipulate to create a protective environment.
Reed-Sternberg cells release chemical signals that attract specific types of immune cells. They pull in macrophages and mast cells, draw in neutrophils, and, critically, recruit a type of immune cell called regulatory T cells. Regulatory T cells normally prevent the immune system from attacking the body’s own tissues. By surrounding themselves with these cells, Reed-Sternberg cells effectively build a shield against immune attack. The tumor essentially hijacks the body’s immune regulation to protect itself.
Genetic Susceptibility and Family History
Your genes play a measurable role in whether you develop Hodgkin lymphoma. Having a first-degree relative (parent, sibling, or child) with the disease increases your risk roughly threefold. The risk is even higher within families when the disease strikes young. A Swedish study of 3.5 million people found that having a parent with Hodgkin lymphoma was associated with a 7.2-fold higher risk in their children, while having a sibling with it raised the risk 8.8-fold.
Much of this inherited risk traces to a region of the genome involved in immune function, specifically the HLA system, which helps your immune cells distinguish between your own tissue and foreign invaders. Different HLA gene variants either raise or lower the risk depending on whether EBV is involved. For EBV-positive Hodgkin lymphoma, carrying the HLA-B*37 variant nearly quadruples the risk, while HLA-A*01 roughly triples it. For EBV-negative cases, different variants like HLA-DRB1*15/16 are associated with a more modest increase of about 1.6-fold. Some variants are protective: carrying HLA-A*02 cuts the risk of EBV-positive disease roughly in half.
These patterns reinforce the idea that how your immune system handles (or fails to handle) EBV and other challenges is central to whether Hodgkin lymphoma develops.
Age and the Bimodal Pattern
Hodgkin lymphoma has an unusual age pattern with two distinct peaks. The first and larger peak hits adults between ages 21 and 30, with a median diagnosis age of around 20. The second peak occurs in people over 70. This bimodal distribution is one of the disease’s most recognizable features, and the two peaks likely reflect different underlying biology. Young adult cases are more often the nodular sclerosis subtype and tend to occur in the mediastinum (the area between the lungs), while cases in older adults are more frequently mixed cellularity or EBV-positive.
Immunosuppression and HIV
A weakened immune system significantly raises the risk of Hodgkin lymphoma. People living with HIV are 5 to 26 times more likely to develop the disease than HIV-negative individuals, making it the fifth most common cancer in this group. The connection makes biological sense: a compromised immune system is less capable of controlling EBV and less effective at identifying and destroying abnormal B cells before they proliferate.
Interestingly, HIV-associated Hodgkin lymphoma often develops not at the lowest point of immune function but during partial immune recovery, such as after starting antiretroviral therapy. This suggests the relationship between immune surveillance and the disease is more complex than simple suppression.
Autoimmune Conditions and Chronic Inflammation
Several autoimmune diseases are associated with a meaningfully higher risk of Hodgkin lymphoma. A large Scandinavian study found that people with sarcoidosis had 14 times the risk of the general population. Systemic lupus erythematosus carried a nearly sixfold increase, and rheumatoid arthritis roughly tripled the risk. Sjögren syndrome and immune thrombocytopenic purpura were also linked to elevated risk, though the numbers were too small to calculate a precise odds ratio.
The common thread appears to be chronic immune activation. Autoimmune diseases keep the immune system in a state of persistent stimulation, which increases the number of B cells cycling through germinal centers and raises the chances that one will acquire the right combination of mutations to escape normal cell death. Family history of certain inflammatory conditions also matters: having a relative with sarcoidosis or ulcerative colitis was associated with a modest but statistically significant increase in risk.
Environmental Exposures
The evidence linking specific chemicals to Hodgkin lymphoma is less definitive than the viral and genetic evidence, but some associations have emerged. A pooled analysis of studies from the U.S. and Canada found that exposure to certain organophosphate insecticides, particularly terbufos, was associated with roughly 2.5 times the risk. For people diagnosed at younger ages (40 or under), exposure to the insecticides dimethoate and malathion also showed elevated risk. One Canadian study found a sixfold increase associated with the herbicide dichlorprop and a fivefold increase with chlorpyrifos.
However, a large international study of agricultural workers examining 22 active ingredients and 13 chemical groups found no statistically significant associations with Hodgkin lymphoma. The inconsistency across studies suggests that if pesticide exposure plays a role, it may be limited to specific compounds, specific exposure levels, or people with other predisposing factors. Environmental exposures are unlikely to be a primary driver for most cases.
Putting the Pieces Together
Hodgkin lymphoma is not caused by any single factor. The disease develops when a B cell that should have been eliminated instead survives, typically because the NF-κB pathway gets permanently activated. EBV can flip that switch through its own proteins. Genetic mutations can do it independently. Inherited variations in immune genes determine how well your body controls EBV and how effectively it polices abnormal cells. Immunosuppression from HIV or other causes removes another layer of defense. Autoimmune conditions create an environment of chronic immune stimulation that increases the odds of something going wrong.
For any individual patient, the disease likely results from several of these factors converging. A person with certain HLA gene variants who contracts EBV during adolescence and has a family history of the disease carries substantially more risk than someone with none of those factors, even though each one alone might never have been enough.