Lymphocytes are white blood cells central to the adaptive immune system, recognizing and eliminating pathogens. When a significant infection occurs, the immune system activates these cells, causing them to undergo physical changes. The term “atypical lymphocytes” refers to these transformed cells, which have altered their appearance under the stress of fighting a strong infection, signaling an active immune response.
Identifying Atypical Lymphocytes
When viewed on a peripheral blood smear, a typical, quiescent lymphocyte is small, characterized by a dense, round nucleus that occupies most of the cell volume. The cytoplasm surrounding the nucleus is usually minimal and pale blue. This morphology changes significantly when the cell is activated to become an atypical lymphocyte.
Atypical lymphocytes are noticeably larger than their resting counterparts as they increase their cellular machinery to fight infection. Their nucleus may appear irregular, indented, or lobulated, rather than smoothly round, and the internal chromatin structure can become less condensed. The cytoplasm becomes far more abundant and often stains a vibrant, dark blue—a feature known as basophilia. These activated cells are sometimes referred to as Downey cells.
Common Causes for Their Appearance
The presence of atypical lymphocytes indicates a “reactive” state, meaning these cells are actively responding to a foreign antigen, most commonly from a viral infection. These cells are primarily activated cytotoxic T-lymphocytes, responsible for directly killing infected body cells. The appearance of these cells is a sign that the body is effectively mounting an aggressive defense against a specific invader.
Infectious Mononucleosis, caused by the Epstein-Barr Virus (EBV), is the most recognized cause of a high percentage of atypical lymphocytes in the blood. The vigorous immune battle against EBV-infected B-cells drives the activation of these cells, often resulting in a mononucleosis-like illness. Cytomegalovirus (CMV) infection is another common viral cause that frequently triggers the appearance of these morphologically altered cells in the bloodstream.
Certain other infections also prompt this strong immune activation, including Toxoplasmosis, a parasitic infection, and various forms of viral Hepatitis. In the acute, early phase of Human Immunodeficiency Virus (HIV) infection, before the disease progresses, atypical lymphocytes can appear alongside a flu-like syndrome. Additionally, these reactive cells have been observed in patients fighting other viral illnesses, such as influenza and even SARS-CoV-2 infection, further illustrating their role as general markers of an immune system under attack.
Lymphocytes can also appear temporarily following immunizations, in response to certain drug reactions, or in the setting of some autoimmune disorders. Regardless of the specific trigger, their presence signifies an immune system currently engaged in warfare, producing a diverse population of cells tailored to neutralize the perceived threat.
Clinical Significance and Interpretation
The finding of atypical lymphocytes usually occurs during a routine Complete Blood Count (CBC) with a manual differential. The mere presence of a small percentage of these cells may hold little clinical significance, as the immune system is constantly encountering and reacting to environmental antigens. However, when the percentage is significantly elevated, it serves as an important signal to the healthcare provider that an underlying condition requires investigation.
Interpreting this finding necessitates combining the blood test results with the patient’s symptoms and overall clinical picture. Atypical lymphocytes are reactive and temporary, meaning they reflect the body’s normal, self-limiting response to an infection. The cells are typically heterogeneous, showing a wide range of sizes and shapes, which is a hallmark of a polyclonal, or reactive, immune response.
In rare cases, the presence of atypical cells can raise suspicion for a malignant condition, such as leukemia or lymphoma. However, in malignant disorders, the abnormal cells often look more uniform or monomorphic, unlike the varied appearance of reactive cells. If the patient’s symptoms and other laboratory parameters suggest a common viral cause, follow-up testing, such as specific antibody tests for EBV or CMV, is generally performed to confirm the diagnosis.