Exposure to antigen through a break in the skin or mucosa results in antigen being taken up by an antigen-presenting cell and carried via lymphatic channels to the nearest lymph node. Lymph channels course throughout the body except for the brain and the bones. Lymph enters the node through the afferent vessel and leaves through an efferent vessel. Because antigen-presenting cells pass through lymph nodes, they present antigen to lymphocytes residing there. Lymphocytes in a node are constantly being replaced by antigen-naïve lymphocytes from the blood. They are retained in the node via special homing receptors. B cells populate the lymphoid follicles in the cortex; T cells populate the paracortical regions. When a B cell encounters an antigen to which its surface immunoglobulin can bind, it stays in the follicle for a few days and forms a germinal center where the immunoglobulin gene is mutated in an effort to make an antibody with higher affinity for the antigen. The B cell then migrates to the medullary region, differentiates into a plasma cell, and secretes immunoglobulin into the efferent lymph.

When a T cell in the node encounters an antigen it recognizes, it proliferates and joins the efferent lymph. The efferent lymph laden with antibodies and T cells specific for the inciting antigen passes through several nodes on its way to the thoracic duct, which drains lymph from most of the body. From the thoracic duct, lymph enters the bloodstream at the left subclavian vein. Lymph from the head and neck and the right arm drains into the right subclavian vein. From the bloodstream, the antibody and T cells localize to the site of infection.

Lymphadenopathy may be caused by infections, immunologic diseases, malignancies, lipid storage diseases, or other disorders of uncertain etiology (e.g., sarcoidosis, Castleman’s disease; Table 46-1). The two major mechanisms of lymphadenopathy are hyperplasia, in response to immunologic or infectious stimuli, and infiltration, by cancer cells or lipid- or glycoprotein-laden macrophages.

TABLE 46-1: Diseases Associated with Lymphadenopathy
  1. Infectious diseases
    1. Viral—infectious mononucleosis syndromes (EBV, CMV), infectious hepatitis, herpes simplex, herpesvirus 6, varicella-zoster virus, rubella, measles, adenovirus, HIV, epidemic keratoconjunctivitis, vaccinia, herpesvirus 8
    2. Bacterial—streptococci, staphylococci, cat-scratch disease, brucellosis, tularemia, plague, chancroid, melioidosis, glanders, tuberculosis, atypical mycobacterial infection, primary and secondary syphilis, diphtheria, leprosy
    3. Fungal—histoplasmosis, coccidioidomycosis, paracoccidioidomycosis
    4. Chlamydial—lymphogranuloma venereum, trachoma
    5. Parasitic—toxoplasmosis, leishmaniasis, trypanosomiasis, filariasis
    6. Rickettsial—scrub typhus, rickettsialpox, Q fever
  2. Immunologic diseases
    1. Rheumatoid arthritis
    2. Juvenile rheumatoid arthritis
    3. Mixed connective tissue disease
    4. Systemic lupus erythematosus
    5. Dermatomyositis
    6. Sjögren’s syndrome
    7. Serum sickness
    8. Drug hypersensitivity—diphenylhydantoin, hydralazine, allopurinol, primidone, gold, carbamazepine, etc.
    9. Angioimmunoblastic lymphadenopathy
    10. Primary biliary cirrhosis
    11. Graft-versus-host disease
    12. Silicone-associated
    13. Autoimmune lymphoproliferative syndrome
    14. IgG4-related disease
    15. Immune reconstitution inflammatory syndrome (IRIS)
  3. Malignant diseases
    1. Hematologic—Hodgkin’s lymphoma, non-Hodgkin’s lymphomas, acute or chronic lymphocytic leukemia, hairy cell leukemia, histiocytic and dendritic cell neoplasms, amyloidosis
    2. Metastatic—from numerous primary sites
  4. Lipid storage diseases—Gaucher’s, Niemann-Pick, Fabry, Tangier
  5. Endocrine diseases—hyperthyroidism
  6. Other disorders
    1. Castleman’s disease (giant lymph node hyperplasia)
    2. Sarcoidosis
    3. Dermatopathic lymphadenitis
    4. Lymphomatoid granulomatosis
    5. Histiocytic necrotizing lymphadenitis (Kikuchi’s disease)
    6. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease)
    7. Mucocutaneous lymph node syndrome (Kawasaki’s disease)
    8. Familial Mediterranean fever
    9. Severe hypertriglyceridemia
    10. Vascular transformation of sinuses
    11. Inflammatory pseudotumor of lymph node
    12. Congestive heart failure

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