Notes on Organs of the Immune System (Lymphoid Tissues, Primary/Secondary, Recirculation)

Adaptive immunity and lymphoid organization

• Adaptive immunity is mediated by lymphocytes mainly found within lymphoid organs.
• Lymphocytes arise from stem cells in the bone marrow.
• Lymphocytes mature within primary lymphoid organs: T cells and B cells.

Primary vs secondary lymphoid organs

• T cells mature within the Thymus.
• B cells mature within gastrointestinal lymphoid tissues, bone marrow, or the bursa of Fabricius, depending on animal species.
• If newly developed lymphocytes have receptors for self antigens that could potentially cause tissue damage, they are killed before they can leave primary lymphoid organs (negative selection).

From primary to secondary lymphoid organs

• Mature lymphocytes leave the primary lymphoid organs to reside in secondary lymphoid organs, where their role is to encounter and respond to foreign antigens.
• Major secondary lymphoid organs: lymph nodes, spleen, bone marrow, and Peyer’s patches within the intestine.

Three-group model of lymphoid organs

• The lymphoid organs can conveniently be divided into three groups based on their role in the development and functioning of lymphocyte populations.

Evolutionary comparisons of lymphoid tissues

• Across species, the distribution and existence of primary/secondary lymphoid tissues vary:
  • Thymus, GALT (gut-associated lymphoid tissue), Spleen, and Bone marrow are common themes, but birds have Bursa of Fabricius as a unique primary lymphoid organ;
  • Other vertebrates show variations in where B and T cell maturation occurs.
• The slide set illustrates thymus, GALT, spleen, and bone marrow across species (e.g., lamprey, fish, frog, chicken, mouse) to highlight evolutionary differences in lymphoid organ localization.

Major lymphoid tissues: internal and surface organs

• Internal lymphoid organs: Thymus, Bone marrow, Spleen, Lymph nodes, Salivary glands, Respiratory tract, Intestine, Mammary glands.
• Surface lymphoid organs: Urogenital system and related mucosal interfaces.

Differences between primary and secondary lymphoid organs (summary)

• Origin: Primary organs arise from early germ layers (ectoderm/endoderm vs mesoderm specifics vary by organ).
• Time of development: Primary organs develop early in embryonic life; secondary organs later in fetal life.
• Persistence: Primary organs tend to involute after puberty; secondary organs persist in adults.
• Response to antigen: Primary organs are generally unresponsive; secondary organs are fully reactive.
• Examples:
  • Primary: Thymus, bursa (in birds), some Peyer’s patches.
  • Secondary: Spleen, lymph nodes.

Thymus: structure and function

• The thymus is a primary lymphoid organ where T cells mature.
• Thymus structure includes a cortex and a medulla within thymic lobules.
• Cells involved:
  • Proliferating thymocytes (immature T cells) in the cortex.
  • Macrophages, cortical epithelial cells, and medullary epithelial cells.
  • Blood vessels and a capsule with subcapsular region; trabeculae.
• Hassall's corpuscles are characteristic in the medulla.
• Thymic hormones: Thymosins, thymopoietins, thymic humoral factor, thymulin (a zinc-containing peptide), thymostimulins.

Thymus: macroscopic and age-related notes

• Thymus weight and distribution (cortex vs medulla) vary with prenatal and postnatal age.
• In the dog and other mammals, the thymus shows changes in weight and composition from newborn through adulthood.
• Effects of adult thymectomy: It takes up to a year for full immune consequences to become apparent due to prolonged survival of circulating T cells.

Congenital athymia and animal models

• Nude athymic mice and X-linked (e.g., Mexican hairless dog, XOLOITZCUINTLE) animals lack a functional thymus.
• Nude mice demonstrate the necessity of the thymus for normal immune function; skin grafts on nude mice show lack of rejection due to deficient cell-mediated immunity.

Bursa of Fabricius (avian primary lymphoid tissue)

• Bursa of Fabricius is a primary lymphoid organ in birds that activates B cells via bursin (a Bursa-derived hormone).
• Infectious bursal disease virus damages the Bursa and reduces antibody production; cellular immunity is less affected.
• Photomicrography shows the bursal structure at different developmental stages.

Peyer’s patches and intestinal lymphoid development

• Ileal patches (IPP) in lambs reach maximal size before birth and form the largest lymphoid tissue by about 6 weeks of age.
• IPPs are sites of B cell proliferation; removal of IPPs in lambs leads to B cell deficiency.
• In many species, Peyer’s patches serve as primary lymphoid tissue (group I mammals) or secondary lymphoid tissue (group II mammals); about 80–90% are primary in ruminants, pigs, horses, dogs, and humans; some primates, rabbits, and rodents show different patterns.
• Large ileal Peyer’s patch in some group I mammals regresses around 1 year of age.

Bone marrow as a primary lymphoid tissue

• In group II mammals, bone marrow serves as the B cell source.
• Normal canine femoral bone marrow shows megakaryocytes; bone marrow acts as a site for B cell development in many species.

Secondary lymphoid tissue: lymph nodes

• Lymphatics are open-ended vessels returning extravascular fluid from peripheral tissues to the heart via blood.
• Lymph nodes are distributed along lymphatics and act as filtering stations.
• Lymph node sections and nodes in canines include suprapharyngeal, lateral retropharyngeal, parotid, caudal mediastinal, cranial mediastinal, superficial cervical, middle mediastinal, mandibular, prescapular, axillary, popliteal, and deep cervical nodes.
• Structure:
  • Cortex: follicular aggregates of B lymphocytes surrounded by a T cell-rich paracortex.
  • Follicles may be primary or secondary; mantle zones surround germinal centers.
  • Medullary cords provide a framework for medullary sinuses containing macrophages and plasma cells.
• Blood and lymph supply:
  • Lymph enters via afferent lymphatics into the subcapsular sinus and percolates through the node to the medullary sinus, exiting via efferent lymphatics.
  • The node has arterial and venous blood supply; lymphocytes can enter via high endothelial venules (HEVs).
• High Endothelial Venules (HEVs) and conduits:
  • HEVs allow lymphocyte entry from blood into the node.
  • Conduits connect the subcapsular sinus to the perivenular space around HEVs, enabling sampling of soluble antigens by dendritic cells.
• Conduits: composed of loosely attached fibro-reticular cells around collagen bundles; dendritic cell processes sample antigen content within conduits.

The spleen: a secondary lymphoid organ

• Spleen architecture includes red pulp and white pulp with distinct zones.
• White pulp structures include PALS (periarteriolar lymphoid sheaths, mostly T cells), B-cell corona, germinal centers; red pulp contains splenic cords and sinuses; marginal zone and central arterioles are key features.
• The spleen is in open communication with blood (no direct lymphatic drainage), which aligns with its role in filtering blood-borne antigens.

Immune responses in secondary lymphoid organs

• Immune response to intravenous antigen: the primary response occurs in lymph nodes or spleen; however, in a secondary response, most antibodies are produced in the bone marrow.

Mucosa-associated lymphoid tissue (MALT)

• MALT includes:
  • Gastrointestinal tract: GALT
  • Bronchial tissue: BALT
  • Nasal region: NALT
  • Conjunctiva: CALT
  • Skin: SALT

The Common Mucosal System and antigen sampling

• The mucosal immune system coordinates responses across mucosal sites.
• Antigens are sampled by M cells in the dome of Peyer’s patches and transported to dendritic cells.
• Lymphocytes traffic between mucosal sites and systemic compartments:
  • Antigen encounters in the gut can influence immune responses at distant mucosal sites like the mammary gland and respiratory tract.
• The Peyer’s patch acts as a gateway for mucosal immune responses, driving IgA-producing B cells and mucosal T cell responses.

Lymphocyte recirculation and immune surveillance

• Lymphocytes continually recirculate through the body via blood and lymphatic vessels.
• Immune surveillance involves naive lymphocytes entering lymph nodes and secondary lymphoid tissues via HEVs, becoming primed upon antigen encounter, and returning as effector or memory cells.
• Recirculation routes:
  • Naïve lymphocytes typically recirculate through various lymph nodes via the blood and lymphatic system.
  • Antigen-specific lymphocytes recirculate from mucosal sites (gut and respiratory tract) back to distant sites such as the mammary gland to contribute to passive immunity for neonates.
• Clinically, recirculation explains why localized infections can influence systemic responses and why neonatal passive immunity is linked to maternal mucosal immune activation.

Immune surveillance and homing receptors

• Lymphocytes know their location in the circulation through the expression of vascular addressins on HEVs that interact with lymphocyte homing receptors, guiding them to appropriate tissues.

Key takeaways and summary points

• All lymphocytes arise from a bone marrow stem cell.

• B-cell maturation occurs in the avian bursa of Fabricius and in other anatomical locations in mammals.

• T-cell maturation occurs in the thymus.

• B cells mediate humoral immunity; T cells undertake cell-mediated immunity (CMI).

• T and B cells compartmentalize in lymphoid tissue.

• The spleen has no lymphatic drainage but is continuous with the blood circulation.

• Lymphocytes can be morphologically small (naïve or memory cells) or larger (lymphoblasts) when activated.

• Plasma cells are a terminal stage of B-cell differentiation and secrete immunoglobulin.

• Lymphocytes carry unique surface molecules enabling detection by antisera through flow cytometry, immunofluorescence, or immunohistochemistry.

• Lymphocytes continually recirculate throughout the body via lymphatic and blood vessels.

• Clonal selection theory posits genetic antigen specificity in lymphocytes and clonal expansion upon antigen encounter.

• Lymphocyte recirculation enables immune surveillance for antigens across the body.

• Lymphocytes express vascular addressins on HEVs, guiding homing receptor interactions and tissue localization.

• Recirculation from gut and respiratory tract to the mammary gland contributes to passively acquired immunity for neonates.

• Abbreviations:

  • CMI = Cell-Mediated Immunity
  • HEV = High Endothelial Venule

Overview of the integrated view of lymphoid tissues

• Primary lymphoid organs generate and educate lymphocytes (thymus for T cells; bone marrow for B cells in most mammals; Bursa of Fabricius in birds; Peyer’s patches can function variably as primary or secondary depending on species).
• Secondary lymphoid organs (lymph nodes, spleen, MALT) function as sites for antigen encounter, initiation of adaptive immune responses, and generation of effector and memory cells.
• Mucosal immunity is integrated through MALT and the common mucosal system, linking local antigen sampling to systemic immunity and neonatal protection via maternal transfer.

Clinical relevance highlights

• Thymectomy in adults shows delayed immune compromise due to persistence of mature T cells.
• Nude mice and other athymic models illustrate the necessity of T-cell development for proper cellular immunity and graft rejection.
• Bursa of Fabricius integrity is crucial for robust humoral immunity in birds; damage reduces antibody production.
• Peyer’s patches and IPPs are critical for B cell maturation; their absence leads to B cell deficiency in certain species.
• Lymph node architecture (cortex, paracortex, germinal centers) underpins efficient antigen presentation, B-T cell interactions, and humoral responses.

End of notes