Immunotherapy, a revolutionary approach to treating diseases like cancer and autoimmune disorders, works by modifying or enhancing the immune system’s activity. However, because it fundamentally alters how the immune system functions, immunotherapy can sometimes lead to unintended consequences such as triggering autoimmune diseases.
The immune system is designed to distinguish between what belongs in the body (self) and what does not (non-self). Autoimmune diseases occur when this distinction fails, causing the immune system to attack healthy tissues. Immunotherapy often involves boosting or redirecting immune responses—such as activating T cells more strongly or blocking inhibitory pathways that normally keep immunity in check. While these actions help fight cancer cells or regulate harmful inflammation, they can also inadvertently activate autoreactive immune cells that target normal tissues.
One common mechanism behind immunotherapy-induced autoimmunity is related to **immune checkpoint inhibitors** (ICIs). These drugs block proteins like PD-1, PD-L1, and CTLA-4 that act as brakes on T cell activation. By releasing these brakes, ICIs unleash a powerful anti-tumor response but may also cause T cells that recognize self-antigens to become active. This can result in various autoimmune side effects affecting organs such as skin, gut, liver, endocrine glands—and even the nervous system where conditions like autoimmune encephalitis may develop due to inflammation triggered by autoreactive T cells attacking brain tissue.
Another factor contributing to autoimmunity during immunotherapy is **molecular mimicry**, where antigens shared between tumor cells and normal tissues confuse the immune system into attacking both. For example, certain proteins found on melanoma cells resemble components of nerve tissue; thus an immune response against melanoma might cross-react with nerves causing neuropathies characterized by loss of myelin insulation around nerves.
In therapies involving engineered T cells such as CAR T-cell therapy—a form of treatment where patient’s own T cells are modified to better recognize cancer—there is a risk of excessive cytokine release known as cytokine release syndrome (CRS). This “cytokine storm” floods the body with inflammatory molecules like interleukin-6 and tumor necrosis factor-alpha which can disrupt normal tissue function and provoke systemic inflammation including neurotoxicity through blood-brain barrier breakdown. Such intense inflammatory states may precipitate or worsen autoimmune phenomena.
The risk factors for developing autoimmunity from immunotherapy include:
– The type of therapy used: Dual checkpoint blockade tends to have higher rates of adverse autoimmune events than single-agent treatments.
– Patient characteristics: Female sex has been associated with increased susceptibility.
– Immune environment: Certain baseline levels of cytokines or specific “immunotypes” reflecting how balanced one’s immune cell populations are might predict who develops complications.
Despite these risks, advances in understanding have led clinicians to develop strategies for managing immunotherapy-induced autoimmunity without completely abandoning treatment benefits. These include early recognition through monitoring symptoms closely; using corticosteroids or other immunosuppressants temporarily; targeting specific cytokines involved in inflammation; and tailoring therapies based on individual patient profiles.
Interestingly enough, while some forms of immunotherapy cause unwanted autoimmunity by overactivating immunity against self-tissues unintentionally—in other contexts researchers are designing *precision* immunotherapies aimed at *treating* existing autoimmune diseases themselves by selectively modulating pathogenic parts of the immune response without broadly suppressing it.
In summary:
Immunotherapies enhance or redirect our natural defenses but carry an inherent risk: they can break down tolerance mechanisms protecting us from attacking ourselves. This leads some patients receiving treatments like checkpoint inhibitors or CAR-T cell therapy into developing new-onset autoimmune conditions ranging from mild skin rashes up through severe neurological syndromes caused by brain inflammation. The underlying causes involve unleashed autoreactive lymphocytes due either directly from removing inhibitory signals on their activation pathways—or indirectly via molecular mimicry between tumors and healthy tissues—and systemic inflammatory cascades driven by excessive cytokine production during treatmen