MLAB 1415- Hematology Keri Brophy-Martinez Nonmalignant Lymphocyte Disorders

Review Lymphs originate primarily from bone marrow and thymus Secondary organs include spleen, lymph nodes, tonsils, and Peyer’s patches in GI tract

Review Pluripotent Stem cell Lymphocyte Stem cell B-cell T-cell 3 general populations B- lymphs: 10-20 % T-lymphs: 60-80% NK: < 10%

Introduction Important to differentiate benign conditions associated with lymphocytosis from malignant lymphoproliferative disorders How? Presence of heterogeneous reactive lymphs Positive serological test for antibodies against infectious organisms Absence of anemia and thrombocytopenia All of above favor a benign diagnosis

Introduction Majority of disorders affecting lymphocytes are acquired Hallmark: reactive lymphocytosis Reactive process Congenital disorders Defect is found within lymphocytic system

Lymphocytosis Excess of lymphocytes in the blood. Absolute lymphocyte count (ALC) > 4.8 x 109 /L in adults Relative count > 35-45% Self-limited Reactive process is due to infection or inflammatory conditions B and T cells involved Lymphocytes develop in response to antigenic stimulation. They become “activated”

“Activated” Lymphocytes Reactive lymphocyte - transformed or benign lymph Similar terms are transformed lymph, atypical lymph, virocyte, immunoblast, plasmacytoid, Downey cell What causes them? Once stimulated by infection or inflammatory condition, lymphs enter various stages of activation Morphologically heterogeneous population presents signs of activation: Large irregular shape Cytoplasmic basophilia Vacuoles Azurophilic granules can be present and are thought to contain pore-forming proteolytic enzymes and serine proteases with pro-apoptotic activity.

Activated Lymph Characteristics Normal Lymph Size 9-30 µm 8-12 µm N:C ratio Decreased High Cytoplasm Abundant Colorless to dark blue Azurophilic granules Can scallop the RBCs Scant Colorless to light blue Nucleus Elongated, irregular Round Chromatin Coarse to moderately fine Coarse Nucleoli Absent to distinct Absent

ID the Activated Lymphs..

Causes of Reactive Lymphocytosis Infectious mononucleosis (IM) Toxoplasmosis Cytomegalovirus (CMV) Infection

Infectious mononucleosis (IM) Caused by the Epstein-Barr Virus (EBV) which enters the body via saliva (“kissing disease”) EBV Pathophysiology EBV attaches to B lymphs causing the lymph to express an activation marker that stimulates B-lymphocyte growth factor. The virus is incorporated into the lymph genome making the cell express viral proteins on the cell membrane and immortalizes the line of EBV-lymphs. Activated cytotoxic T-lymphs are released to inhibit the activation and proliferation of EBV infected lymphs. These are the characteristic Reactive Lymphs. Clinical symptoms Classic triad: fever, pharyngitis and lymphadenopathy Dysphagia (difficulty swallowing) General malaise Fatigue Spleen is enlarged and nodes are firm but not tender or warm Generally seen in children and young adults (14-24 yrs old)

Lab features of IM CBC Relative lymphocytosis Peaks at 2-3 weeks of infection, remains elevated for 2-8 weeks Leukocyte count 12-25 x 109/L Peripheral smear Reactive lymphocytes , historically referred to as a Downey cell with irregular cytoplasmic border, increased cytoplasm and dark blue edge around the periphery of the cytoplasm. >20% reactive lymphs Serologic test Heterophil antibody test (i.e Monospot)

Causes of Reactive Lymphocytosis Toxoplasmosis Infection with intracellular protozoan Toxoplasma gondii Acquired infections in children and adults due to ingestion of oocysts from cat feces or undercooked meat Can be transmitted via placenta

Causes of Reactive Lymphocytosis Cytomegalovirus (CMV) Infection Belongs to herpes family Endemic worldwide Acquired through transfusions, sexual contact and close contact Can be transmitted across placenta Poor prognosis for immunocompromised individuals who contract virus

Immune Deficiency Disorders Impaired function of one or more of the components of the immune system: T, B, or NK lymphocytes Decreased lymphocyte count Body unable to mount an adaptive immune response Can be acquired or congenital

Acquired Deficiencies Acquired immune deficiency syndrome (AIDS) Infection with a retrovirus, human immunodeficiency virus type-1 (HIV-1) Transmission through sexual contact or contact with blood and/or blood products Binds CD4 antigen on helper T lymphocytes which results in cell lysis