HDM-24 ILS-2 Gross Anatomy and Development of Lymphoid Tissues PDF

Year I: HDM ILS-2: Gross Anatomy and Development of Lymphoid Tissues Sherese Richards MD. Associate Professor Biomedical Education: Anatomy 09/30/2024 S. Richards MD.  Course...

Year I: HDM ILS-2: Gross Anatomy and Development of Lymphoid Tissues Sherese Richards MD. Associate Professor Biomedical Education: Anatomy 09/30/2024 S. Richards MD.  Course References  Required:  Histology: A Text and Atlas: With Correlated Cell and Molecular Biology, 8e  Chapter 14 : Section on Overview of the Immune and Lymphatic Systems  Moore KL, Dalley AF, Agur AMR. Clinically Oriented Anatomy. 8th ed. Lippincott Williams & Wilkins; 2018.  Chapters 2-9: Sections on relevant regional lymphatics  Recommended:  Gray's Anatomy for Students, Fifth Edition Chapter 5  Netter FH. Atlas of Human Anatomy. 7th ed. Elsevier; 2019.  Gilroy AM, Macpherson BR, Johnson AL, Schunke M, Schulte E, Schumacher U. Atlas of Anatomy. 4th ed. Thieme; 2020. 09/30/2024 S. Richards MD.  Learning Objectives 1. Identify the major components of the lymphatic system and differentiate primary vs. secondary lymphatic organs including bone marrow, thymus vs. spleen and lymph nodes. 2. Describe the embryological development of lymphoid tissues and organs, including the thymus, spleen, and lymph nodes. 3. Describe the gross anatomy, blood supply and venous drainage of lymphoid tissues and organs, including the bone marrow, thymus, spleen, and lymph nodes. 4. Explain the physiological and clinical importance of the lymphatic vessels 5. Describe the microscopic and histological features of the lymphoid tissues and lymphatic vessels 6. Describe the organogenesis of the lymphatic vessels and how remodeling is manipulated in cancer 7. Describe the principle and applications of lymphangiograms S. Richards MD 3 Lymphatic System Overview  Groups of cells, tissues, and organs responsible for monitoring body surfaces and internal compartments to combat foreign microorganisms, transformed cells, and other harmful substances.  Lymphocytes most important cells of the lymphatic system:  They differentiate and mature in the primary lymphatic organs: B lymphocytes in the bone marrow T lymphocytes in the thymus  Enter the blood or lymphatic vessels to colonize secondary lymphatic organs and tissues (spleen). 09/30/2024 S. Richards MD.  Secondary Lymphatic Tissues  Secondary lymphatic tissues:  Spleen  Lymph nodes and aggregations of lymphatic nodules  Diffuse lymphatic tissues: Tonsils; appendix; bronchus-associated lymphatic tissue (BALT) in lungs; gut-associated lymphatic tissues (GALT) in the gastrointestinal tract; and mucosa-associated lymphatic tissue (MALT) throughout the genitourinary system (e.g. bladder).  Lymph: fluid removed from ECF of the connective tissues. Flows in lymphatic vessels to lymph nodes interspersed along the superficial lymphatic vessels (associated with the skin and superficial fascia) and deep lymphatic vessels (associated with main arteries).  Lymphatic vessels empty into the blood returning into large veins.  The thoracic duct is the largest lymphatic vessel. 09/30/2024 S. Richards MD.  Spleen It is relatively delicate and considered the most vulnerable abdominal organ. Located in the left upper quadrant (LUQ), or hypochondrium of the abdomen, protected by the inferior thoracic cage The spleen develops from the mesoderm (mesenchyme) of the dorsal mesogastrium during the fifth to sixth week. Appears as a small bud that later expands and differentiates into its mature structure. Associated with the developing stomach, and its vascularization is primarily established by branches from the celiac trunk. 09/30/2024 S. Richards MD.  Spleen Associated posteriorly with the left 9th–11th ribs The relations of the spleen are as follows: Anteriorly: the stomach Posteriorly: the left part of the diaphragm, which separates it from the pleura, lung, and ribs 9–11 Inferiorly: the left colic flexure Medially: the left kidney The anterior and superior borders of the spleen are sharp and notched, whereas its posterior (medial) end and inferior border are rounded When it is hardened and enlarged (splenomegaly) it moves inferior to the left costal margin and can be palpated when the person takes a deep breath. Blood supply splenic artery (celiac trunk) and vein (portal vein) Lymphatic drainage: pancreaticosplenic lymph nodes en route 09/30/2024 to the celiac nodes S. Richards MD.  Spleen The spleen filters blood and initiates adaptive immune responses to blood-borne antigens The largest lymphatic organ (clenched fist) in the upper left quadrant of the abdomen and has a rich blood supply. No direct connection with lymph circulation but gathers antigens and pathogens directly from the bloodstream. Contains large numbers of lymphocytes and specialized vascular spaces or channels, a meshwork of reticular cells and reticular fibers, and a rich supply of macrophages and dendritic cells. Monitors the blood immunologically, as the macrophages and dendritic cells of lymph nodes monitor the lymph. 09/30/2024 S. Richards MD.  Spleen Enclosed by a dense connective tissue capsule from which trabeculae extend into the parenchyma of the organ Large quantity of blood that is expelled periodically into the circulation by smooth muscle in its capsule and trabeculae The connective tissue of the capsule and trabeculae contains myofibroblasts -contractile cells that produce connective tissue fibers. The hilum on the medial surface is the site for the passage of the splenic artery and vein, nerves, and lymphatic vessels. The lymphatic vessels originate in the white pulp near the trabeculae and constitute a route for lymphocytes leaving the spleen. Most of the spleen consists of splenic pulp, divided into two functionally and morphologically different regions based on gross appearance: White pulp: inner thick accumulation of lymphocytes surrounding an artery Red pulp: surrounding large number of RBCs filtered and degraded. 09/30/2024 S. Richards MD.  Bone Marrow  The marrow cavity in spongy bone contains bone marrow.  Red bone marrow: consists of blood cells in different stages of development and a network of reticular cells and fibers that serve as a supporting framework for the developing blood cells and vessels  Red marrow: does not increase proportionately with bone growth  Yellow marrow: when the rate of blood cell formation diminishes in adults and the marrow tissue consists mostly of fat cells  In response to appropriate stimuli, such as extreme blood loss, yellow marrow can revert to red marrow  In the adult, red marrow is normally restricted to the spaces of spongy bone in a few locations, such as the sternum and the iliac crest  Diagnostic bone marrow samples and marrow for transplantation are obtained from these sites.  The bone marrow is supplied mainly by nutrient arteries 09/30/2024 S. Richards MD.  Thymus Development  Develops bilaterally from the third pharyngeal pouch (endoderm)  Starts with invagination of the epithelium that grows caudally into the mediastinum of the chest then disconnects.  Common lymphoid progenitor (CLP) cells from the bone marrow destined to become immunocompetent T cells invade the epithelial rudiment and occupy spaces between the epithelial cells.  The thymus is fully formed and functional at birth.  Persists as a large organ until about the time of puberty, when T-cell differentiation and maturation are reduced and most of the lymphatic tissue is replaced by adipose tissue (involution).  In some infants, the thymus may compress the trachea. 09/30/2024 S. Richards MD.  Thymus  A primary lymphoid organ located in the inferior part of the neck and the anterior part of the superior mediastinum  Flat gland with flask-shaped lobes that lies posterior to the manubrium and extends anterior to the fibrous pericardium.  After puberty, the thymus undergoes gradual involution and replaced by fat.  The rich arterial supply of the thymus:  Anterior intercostal and anterior mediastinal branches of the internal thoracic arteries.  The veins of the thymus drain into:  Left brachiocephalic, internal thoracic, and inferior thyroid veins.  The lymphatic vessels of the thymus drain into:  Parasternal, brachiocephalic, and tracheobronchial lymph nodes. 09/30/2024 S. Richards MD.  Lymphatic Nodes  Lymph nodes filter lymph along the pathway of lymphatic vessels and initiate adaptive immune responses to antigens.  Small, bean-shaped, encapsulated lymphatic organs.  Range in size from about 1 mm (barely visible with the naked eye) to about 1–2 cm  Positioned along lymphatic vessels and filters the lymph on its way back to the blood vascular system.  Access to the antigens that enter the organism through the epithelia or tissues drained by lymphatic vessels.  Activate antigen-specific lymphocytes that undergo proliferation and differentiation into effectors cells.  Although widely distributed throughout the body, lymph nodes are concentrated in certain regions, such as the axilla, groin, neck, and mesenteries. 09/30/2024 S. Richards MD.  Lymphatic Nodes  Cortex  Outer portion (except at hilum)  Superficial Cortex (Nodular): Contains B cells in lymphatic nodules (primary and secondary)  Deep Cortex (Paracortex): Rich in T cells; thymus- dependent region  Lymphatic Sinuses: Lymph percolates through, allowing immunosurveillance  Medulla  Inner portion of the lymph node  Medullary Cords: Contain B cells, macrophages, dendritic cells, plasma cells  Medullary Sinuses: Channels that converge at the hilum, draining into efferent lymph vessels  Reticular Cells/Fibers: Form the structural framework 09/30/2024 S. Richards MD.  Lymphatic Nodes  Capsule:  Dense connective tissue surrounding the node  Trabeculae:  Dense connective tissue extending from the capsule  Forms a framework within the node  Reticular Tissue:  Composed of reticular cells and fibers  Creates a fine supporting meshwork throughout the node  Reticular meshwork consists of mesenchymal origin cells, reticular fibers, and ground substance  Afferent Lymphatic Vessels:  Convey lymph toward the node  Enter at various points on the convex surface of the capsule  Efferent Lymphatic Vessels:  Convey lymph away from the node  Leave at the hilum (concave surface)  Hilum also serves as the entrance/exit for blood vessels and nerves 09/30/2024 S. Richards MD.  Lymphatic Nodes  The reticular meshwork of the lymph node contains several types of cells that perform different functions in generating immune responses.  Reticular Cells:  Synthesize and secrete type III collagen (reticular fibers)  Form a supportive stroma in lymphatic tissue  Attract lymphocytes and dendritic cells via chemokine production  Dendritic Cells (DCs):  Highly efficient antigen-presenting cells (APC)  Present antigens to T cells using MHC I and MHC II molecules  Localized in T cell-rich areas of the lymph node  Macrophages:  Phagocytic and antigen-presenting cells  Less efficient APCs compared to dendritic cells  Specialize in endocytosis and digestion of foreign materials  Follicular Dendritic Cells (FDCs): This silver preparation shows the connective tissue capsule (top), subcapsular  Retain antigen-antibody complexes on their surface for long periods sinus, and the superficial cortex of the lymph node (bottom). The reticular fibers (arrows) form an irregular anastomosing network throughout the stroma of the  Do not present antigens (lack MHC II molecules) lymph node. Note elongated oval nuclei of reticular cells (arrowheads), which are in intimate contact with reticular fibers in the sinus.  Interact with B lymphocytes in germinal centers 09/30/2024 S. Richards MD.  Lymphatic Nodes  ~ 800 lymph nodes scattered throughout body, located deep and superficially, grouped according to regions drained  Cervical (occipital, submental, preauricular, submandibular, internal jugular, supraclavicular)  Infraclavicular  Axillary, pectoral  Mediastinal (peritracheal, thymic region)  Epi- or supratrochlear and brachial  Upper abdomen (splenic, hilar, celiac, porta hepatis)  Lower abdomen (iliac, paraaortic, retroperitoneal, mesenteric, abdominal, NOS)  Inguinal and femoral  Popliteal 09/30/2024 Lymph node regions S. Richards MD.  Lymphatic Vessels  Function of LV:  Fluid balance: excess ISF is returned to systemic circulation  Immunity: transfer lymph and antigens to secondary lymphoid organs  Digestion: Lipid absorption in GI via lymphatic capillaries termed lacteals  Clinical significance of LV:  Obstruction: resulting in lymphedema  Spread of infection  Clinical significance of LN:  Palpable lymph nodes (lymphadenopathy) in several disease states Lymphadenopathy of right neck  Primary site of cancer (hematological) from spread of oral cancer.  Secondary sites of cancer, use LVs for metastasis 09/30/2024 S. Richards MD.  Lymphatic Vessels  General drainage scheme: Important to understand drainage patterns for cancer metastasis and certain infections  Superficial LVs: drain mostly skin and normally follow venous vessels  Deep LVs: drain superficial LVs and internal organs and normally follow arteries and deep veins  Both superficial and deep LVs traverse lymph node groups as they course proximally (get closer to the heart)  LVs communicate freely with one another and with veins in many aspects of the body, consequently ligation of a trunk may have only transient effects on fluid dynamics 09/30/2024 S. Richards MD.  Lymphatic Vessels  Distribution pathway (drainage path) of lymphatic vessels:  Lymph capillaries -> Lymphatic vessels -> lymphatic trunks -> lymphatic ducts -> subclavian veins  Lymphatic plexuses: network of anastomosing lymphatic capillaries in a tissue  Collecting LVs aka lymphatic vessels: drain as afferent vessels into lymph nodes, exit as efferent vessels Unnamed  Lymphatic trunks: 9 named trunks  Lymphatic ducts: 2 named ducts Right lymphatic duct and (left) thoracic duct drain into right and left subclavian veins respectively. Note, these veins are blood vessels, not LVs  Malfunctioning of lymphatic vasculature results in impaired lymphatic Thoracic Duct (left side): into left return termed lymphedema and results in compromised immune subclavian vein (drains most of body) Right Lymphatic Duct: into right function subclavian vein (drains upper right portion of body and right side of head/neck) 09/30/2024 S. Richards MD.  Lymphatic Vessels Abdomen, pelvic, lower limbs Head and Neck, right side Head and Neck, left side Arm, axilla, breast Arm, axilla, breast Right side left side Thorax, breast, Thorax, breast, trachea, lungs, trachea, lungs, mediastinum heart mediastinum heart 09/30/2024 S. Richards MD.  Lymphatic Vessels  LVs begin as blunt-ended anastomosing lymphatic capillaries that form plexuses of microscopic vessels within tissues/ blood capillaries to help drain excess ISF to form lymphatic fluid:  Capillaries have special flap valves that allow fluid uptake, collagen threads that anchor capillary in tissue, preventing vessel collapse  Lymphatic fluid aka lymph (w/ or w/o antigens) taken up in vessels and then along the way, through LNs  Antigens remain trapped within LNs, induce adaptive (B and T cell) immune responses  Along the way lymph is collected into consecutively wider vessels, then eventually returned into systemic blood circulation near heart.  Circulation is one way: from tissues to heart  LVs are absent from: CNS, eyeball, and compact 09/30/2024 S. Richards MD. bone.  Lymphatic Vessels  Anatomic Features of LVs:  Lymph capillaries:  Single layer, overlapping, oak-leaf-shaped lymphatic endothelial cells (LECs)  Lack b.m. and smooth muscle cells (SMCs)  Bound to ECM of interstitium via anchoring filaments (AF), prevents vessel collapse under conditions of high interstitial pressure  Discontinuous cell-cell junctions form flap valve that controls fluid movement, open in response to increased ISF pressure (fluid accumulation in tissue), allowing ISF to enter capillary  Lymph (collecting) vessels:  Lined with endothelium w/ b.m., larger, internal semi-lunar valves control fluid movement, SMCs, connected by continuous zipperlike junctions  Lymph ducts:  Lined with endothelium, internal valves that control fluid movement, 1 or 2 layers of SMC 09/30/2024 S. Richards MD.  Lymphatic Vessels Lymphatic vessel distinguished from blood capillary by irregular shape, walls composed of lymphatic endothelial cells, usually lacks continuous basement membrane, conspicuous valves Appear similar to veins but lymphatic vessels contain few lymphocytes and no 09/30/2024 RBC S. Richards MD. 09/30/2024 S. Richards MD.  Lymphatic Vessels Development  Development of Lymphatic Vessels:  Vein endothelial cells dissociate, sprout in response to VEGF-C, aggregate to form lymph sacs; additional sprouting of sacs produces lymphatic primary plexus (network):  Prospero homeobox protein 1 (PROX1) master transcriptional regulator drives lymphangiogenesis during development  Vascular endothelial growth factor receptor-3 (VEGFR-3) on endothelial cells drives LEC proliferation and migration in response to VEGF-C  Myeloid cells produce cytokines that regulate lymphatic vascular morphogenesis to form larger vessels 09/30/2024 S. Richards MD.  Lymphatic Vessels Remodeling  Remodeling of Lymphatic Vessels  In cancer, inflammatory conditions, and response to injury, pre-existing LVs undergo remodeling (lymphangiogenesis):  In cancer:  Tumor cells and immune cells in tumor micro- environment produce lymphangiogenic growth factor VEGF  VEGF acts proximal and distal to draining LN promoting lymphangiogenesis  Facilitates metastasis of primary tumors to secondary sites  VEGF axis is pharmacologically targeted in cancer by mAb-based therapies that block interaction between VEGF and its receptor 09/30/2024 S. Richards MD.  Clinical Correlation: Lymphangitis  Clinical Correlation: Lymphangitis: inflammation of lymphatic vessel due to infectious or noninfectious (obstruction)  Most commonly develops after cutaneous inoculation of microorganisms that invade the lymphatic vessels and spread toward the regional lymph nodes.  Organisms may invade lymphatic vessels directly through a skin wound or an abrasion or as a complication of a distal infection.  Streptococcus pyogenes: skin  Staphylococcus aureus: skin  Pasteurella multocida: dog bite  Sporothrix schenckii: thorns, slivers 09/30/2024 S. Richards MD.  Clinical Correlation: Lymphedema  Clinical Correlation: Lymphedema: defined as abnormal accumulation of ISF and fibroadipose tissues (arm or leg) resulting from injury, infection, or congenital abnormalities of lymphatic system.  Manifests when lymphatic load exceeds transport capacity of lymphatic system, allowing filtered fluid to accumulate in interstitium.  Persistent accumulation of lymphatic fluid promotes proliferation of adipocytes and deposition of collagen fibers in ECM and around capillary and collecting lymphatics.  Commonly caused by removal / damage to LN during cancer diagnosis/treatment  Ineffective flow or obstruction can lead to lymph stasis à edema, inflammation, tissue hypoxia, tissue fibrosis and a variety of diseases 09/30/2024 S. Richards MD. Post- breast cancer Tx Elephantiasis  Lymphatic Vessels  Clinical Imaging: Lymphangiogram  a specialized imaging technique for visualizing LNs and LV, which cannot normally be visualized using routine X-ray or MRI. To perform, a contrast medium is injected into lymphatic vessel, imaging is collected by fluoroscopy or MRI.  Indication:  Assessment of cancer metastasis  Effectiveness of cancer treatment  Assessment of lymphedema  Plan surgical procedures, e.g. lymphovenous bypass 09/30/2024 S. Richards MD.  Spleen Rupture  Spleen Rupture and Splenectomy  Repair difficulty: Ruptured spleen repair is challenging.  Splenectomy: Often performed to prevent fatal bleeding.  Subtotal splenectomy: Partial removal can result in rapid regeneration.  Total splenectomy: Generally no severe effects in adults; liver and bone marrow take over functions.  Risks: Increased susceptibility to bacterial infections post- splenectomy.  Splenomegaly (Spleen Enlargement)  Causes: Granulocytic leukemia, hypertension, hemolytic or granulocytic anemias.  Size: Can enlarge up to 10 times its normal size.  Detection: Enlarged if palpable below left costal margin.  Treatment: Splenectomy may be necessary in severe cases. 09/30/2024 S. Richards MD.  Accessory Spleens & Splenosis  Accessory Spleens  Development: May form near the splenic hilum prenatally.  Locations: Tail of pancreas, gastrosplenic ligament, infracolic compartment, mesentery, or near ovaries/testes.  Prevalence: Common, usually one present.  Size: Typically small (1 cm), can range from 0.2 to 10 cm.  Clinical significance: Important to identify during splenectomy to avoid persistence of symptoms (e.g., splenic anemia).  Splenosis  Definition: Autoimplantation of ectopic splenic tissue.  Cause: Can occur after splenic rupture, tissue spreads into peritoneum, omentum, or mesenteries. 09/30/2024 S. Richards MD.