Primary Lymphatic Organs

The primary lymphoid organs, also referred to as central lymphoid/lymphatic organs, are the tissues responsible for the production of lymphoid cells from progenitor cells, incuding the bone marrow and the thymus. In the bone marrow, hematopoietic stem cells progress to become oligopotent progenitors (in the case of lymphocytes, the common lymphoid progenitor). B lymphocytes stay and undergo processes for differentiation before migrating to the secondary lymphoid organs (such as lymph nodes). The progenitor cells that are to become T lymphocytes proceed to the thymus for further maturation.

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Overview

Immune system

  • The immune system provides defense (immunity) against invading pathogens ranging from viruses to parasites. The components of the immune system are interconnected by blood and the lymphatic circulation.
  • 2 overlapping lines of defense:
    • Innate immunity (nonspecific), involving the following cells:
      • Natural killer cells
      • Monocytes/macrophages
      • Dendritic cells
      • Neutrophils, basophils, eosinophils
      • Tissue mast cells
    • Adaptive immunity (based on specific antigen recognition) involves the following cells:
      • T and B lymphocytes (derived from lymphoid organs)
      • Antigen-presenting cells

Lymphatic system

The lymphatic system (lymph vessels, lymph fluid, and lymphoid organs) is part of the body’s immune system.

  • Lymphoid organs:
    • Primary: 
      • Locations where lymphocytes develop from progenitor cells (initial formation)
      • Include the bone marrow and thymus
    • Secondary: 
      • Sites where lymphocytes undergo activation, proliferation, and additional maturation
      • Include the spleen, lymph nodes, and MALT (i.e., tonsils)
  • Lymphatic vessels and ducts:
    • A network, similar to the blood vessels, that extend throughout the human body.
    • Connect lymphoid organs and transport interstitial fluid (lymph) 
    • Play crucial roles in immune response and fluid balance
Anatomy of the lymphatic system

Anatomy of the lymphatic system:
Includes the primary (bone marrow, thymus) and secondary (spleen, lymph nodes, and MALT) lymphoid organs
Lymphatic vessels convey lymph to the larger lymphatic vessels in the torso, transporting fluid back to the venous circulation.

Image: “Anatomy of the Lymphatic System” by OpenStax. License: CC BY 4.0

Bone Marrow

Anatomy

Bone marrow is the spongy tissue found in the medullary canals of long bones and cavities of the cancellous bones. 

  • Red bone marrow:
    • Hematopoietic/blood-forming
    • Located in flat bones (skull, sternum, vertebrae, scapulae, and pelvic bones) and epiphysis of long bones (femur, tibia, humerus)
  • Yellow bone marrow:
    • Nonhematopoietic
    • Located in diaphysis of long bones
Red and yellow marrow portions of the bone

Bone marrow:
Cross section showing the red and yellow marrow of the bone

Image: “619 Red and Yellow Bone Marrow” by OpenStax College. License: CC BY 3.0

Main Functions

  • Primary site of blood cell formation (by the 5th month of gestation)
  • Breakdown of old RBCs (into bilirubin, iron, globin) via macrophages and reuse of iron
  • Storage of fat through adipocytes

Structures

  • Hematopoietic:
    • Hematopoietic stem cells (HSCs) are multipotent cells with the ability to self-renew and differentiate to all hematopoietic lineage cells.
    • HSCs → multipotent progenitor cells (MPPs) → oligopotent progenitors:
      • Common lymphoid progenitor cells (CLPs)
      • Common myeloid progenitor cells (CMPs)
    •  CMPs and CLPs develop into lineage-restricted progenitors and, through stages, eventually become effector cells or differentiated cells:
      • CMP → granulocytes, monocytes, megakaryocytes, erythrocytes
      • CLP → lymphocytes (T progenitor cells go to the thymus)
  • Nonhematopoietic: structures that provide a microenvironment that supports the differentiation of hematopoietic cells and proliferation of blood cells:
    • Bone cells
    • Marrow stroma
    • Sinusoids

Thymus

Anatomy

  • Encapsulated bilobed primary lymphoid organ 
  • Located in the anterosuperior mediastinum
  • Development and growth:
    • Arises from the 3rd and 4th pharyngeal pouches (endoderm)
    • Thymic lymphocytes arise from the mesoderm.
    • 12 g at birth, reaches maximum weight at puberty (30–40 g)
    • After puberty, it undergoes involution (lymphoid parenchyma is replaced by adipose tissue).

Main function

The main function of bone marrow is to act as the site of T-cell differentiation and maturation (from the bone marrow, progenitor cells go to the thymus).

General structure

  • With dense connective tissue capsule
  • Divided into 2 asymmetrical lobes (right is larger):
    • Each lobe of the thymus has smaller lobules separated by trabeculae (fibrous septa extending from the outer capsule).
    • Each lobule contains a:
      • Cortex
      • Medulla

Functional regions

  • Cortex:
    • Outer part of the lobule (dark)
    • Area where the bone marrow–derived cells (CD4–, CD8–) enter.
    • Contains dense groups of developing immature T cells/thymocytes (with variable sizes and rare mitoses)
  • Medulla: 
    • Lighter-staining central area of the lobule
    • Loosely arranged
    • As T cells mature, they migrate from the cortex toward the medulla.
    • Contains:
      • Mature lymphocytes (less numerous)
      • Hassall’s, or thymic, corpuscles: whorls of squamous-appearing epithelial cells (remnants of degenerating cells and cytokeratins) 
  • The corticomedullary junction contains antigen-presenting cells, dendritic cells, and macrophages.

Vasculature

  • Arterial blood supply is from the internal thoracic arteries. 
  • Venous blood drains into the brachiocephalic and internal thoracic veins.
  • Blood vessels enter and exit the thymus through trabeculae.
  • The thymus contains only efferent lymphatics that end up carrying the mature lymphocytes from the thymus.

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Clinical Relevance

  • Acute lymphoblastic leukemia: hematologic malignancy with uncontrolled proliferation of lymphoid precursor cells. Acute lymphoblastic leukemia/lymphoma (ALL/LBL), the most common form of cancer affecting children, is characterized by increased lymphoblasts. The disease causes replacement of normal marrow by lymphoblasts, which eventually go into circulation and infiltrate other organs. Clinical presentation consists of fatigue, bleeding, fever, and infections that are related to the anemia, thrombocytopenia, and lack of functional WBCs. Diagnosis is by peripheral blood smear and bone marrow biopsy examination showing lymphoblasts. Management is mainly chemotherapy administered in phases. 
  • Thymoma: rare thymic neoplasm often discovered incidentally on imaging. Thoracic symptoms occur because of effects on the adjacent organs (can cause shortness of breath, cough, phrenic nerve palsy, superior vena cava syndrome). The most common paraneoplastic syndrome associated with a thymoma is myasthenia gravis.
  • DiGeorge syndrome: condition caused by a microdeletion at location q11.2 of chromosome 22. In DiGeorge syndrome, there is defective development of the 3rd and 4th pharyngeal pouches, leading to thymic and parathyroid hypoplasia (causing T-cell immunodeficiency and hypocalcemia, respectively). Conotruncal anomalies present as congenital heart defects. Diagnosis is via clinical findings, laboratory tests (showing reduced T cells and low calcium), echocardiography, and genetic analysis. Treatment can include calcium supplementation, prophylactic antibiotics, surgery, and thymus or hematopoietic cell transplantation. 

References

  1. Haynes, B.F., Soderberg, K.A., Fauci, A.S. (2018). Introduction to the immune system. In: Jameson, J., et al. (Eds.), Harrison’s Principles of Internal Medicine, 20th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=192284326
  2. Mescher, A.L. (Ed.). (2018). The immune system & lymphoid organs. In: Junqueira’s Basic Histology: Text and Atlas, 15th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2430&sectionid=190282111
  3. Scoville, S., Caligiuri, M.A. (2021). The organization and structure of lymphoid tissues. In: Kaushansky, K., et al. (Eds.), Williams Hematology, 10th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2962&sectionid=252523494

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