MLAB 1415- Hematology Keri Brophy-Martinez

1. MLAB 1415- HematologyKeri Brophy-Martinez Chapter 20: Nonmalignant Lymphocyte Disorders

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

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

4. Characteristic Cell • 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.

5. Antigen-stimulated lymphocytes pg. 129 • Reactive or Atypical: Atypical is widely used; however, connotes abnormal or malignant • Downey Cell: obsolete term for reactive lymph and immunoblasts • Immunoblasts: • large cells with prominent nucleoli • fine clear chromatin • dark purple-blue cytoplasm • preparing for or engaged in mitosis in response to stimulus • Plasmacytoid lymphs: • daughters of B immunoblasts • Eccentric nucleus with moderate amount of deep blue cytoplasm • Plasma Cell • Fully differentiated B cell • Eccentric nucleus with “cartwheel appearance” with large amount of basophilic cytoplasm • Perinuclear clearing (Golgi apparatus) • Releases Ig

6. Reactive Lymph Characterisitcs

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

8. 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

9. 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”

10. Causes of Reactive Lymphocytosis • 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 by receptor CD21 which causes it to express the activation marker CD23 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 lymphadenpathy • 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)

11. 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)

12. 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

13. 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

14. Causes of Reactive Lymphocytosis • Infectious lymphocytosis • Affects children • Viruses include adenovirus, coxsackie A and Bordetella pertussis • Leukocytosis and lymphocytosis occur in first week of illness then return to normal

15. Lymphocytopenia • Absolute lymphocyte count< 1.0 x 109/L • Causes • Decreased production or increased destruction of lymphocytes • Changes in lymphocyte circulation patterns • Corticosteroid therapy • Other unknown causes • Refer to page 411, table 20-4

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

17. 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

18. Congenital Deficiencies • Decrease in lymphocytes and impairment in either cell-mediated immunity (Tcells), humoral immunity(Bcells) or both • Lymphocytes appear normal on ps

19. Congenital Deficiencies • Severe Combined immunodeficiency Syndrome • Major qualitative immune defects involving both humoral and cellular immune functions • Fatal by 2 years if untreated by bone marrow transplant or gene therapy • Wiskott-Aldrich Syndrome • Patients have recurrent infections due to immunodeficiency (decreased CD8 T-lymphs), thrombocytopenia and eczema