LYMPHATIC SYSTEM Petr Vaňhara https://cz.pinterest.com/pin/353180795752366013/ LECTURE CONTENT • Principles of immune response - Innate and acquired immunity - Humoral and cellular immunity • Structures essential for development and activation of immune cells - Lymphatic circuitry - Lymphatic follicles - Lymph nodes - Spleen - Thymus - MALT • Development of lymphatic system Immune system Lymphatic system Cardiovascular & hematopoietic systems IMMUNE SYSTEM Immunity = self defense - Epithelial: epithelial barriers equipped with antimicrobial substances - Innate: complement, macrophages and neutrophils, natural killers - Acquired: T and B lymphocytes Clinical relevance - Autoimmune disorders - Immunodeficiency EPITHELIAL IMMUNE RESPONSE EPITHELIUM OF RESPIRATORY PASSAGES Foreign organism Released chemicals Injured skin Phagocyte Inflamed tissue Phagocyte leaving vessel Phagocyte engulfing organisms • Chemotaxis and extravasation of leukocytes, mostly neutrophils, monocytes and dendritic cells to the site of inflammation motifolio.com EPITHELIAL INFLAMMATORY RESPONSE • Pro-inflammatory cytokines - interleukins (e.g. IL-1, IL-8) - TNFa, TGFb - interferons • Other signaling molecules - prostaglandins - GM-CSF, M-CSF and many others EPITHELIAL IMMUNE RESPONSE Activation of immune response Damage-associated molecular patterns (DAMPs) DENDRITIC CELLS • „professional“ antigen presentation = activation of immune cells with high efficiency • antigen processing – MHC II • cytokine production • component of monocyte-macrophage system • lymphatic organs, epithelia, connective tissue TCR recognizing antigen presented in MHC complex is eesential for activation of T-cells https://doi.org/10.3389/fimmu.2019.00093 DENDRITIC CELLS LYMPHOCYTES • „Clusters of differentiatinon“, CD • Surface molecules constituting immunophenotype • Molecular signaling regulating immune response • Clinically relevant in diagnostics and therapy 1. Antigen presentation and activation of B-cells Bacterium Antigen of Bacterium Engulfed Bacterium Antigen of BacteriumMatching B cells Non- matching B cells 2. Activated B-cells proliferate and expand 3. Most of B-cells differentiate to plasma cells, some will convert to memory cells Memory B cell Second exposure to the same bacteria activates this cell to rapidly produce plasma cells Plasma cells Antibody Antigen of Bacterium Phagocyte Phagocyte Inactivated bacterium motifolio.com ANTIBODY (HUMORAL) RESPONSE ANTIBODY (HUMORAL) RESPONSE ANTIBODIES • Immunoglobulins • Large proteins with defined structure capable of binding antigens • Variable and constant regions • Fc region bound by Fc reseptor on immune cells ANTIBODIES • Genome rearrangements leading to generation of unique antibody transcripts (>10 billions) • V(D)J recombination during development • Isotype switching ANTIBODIES • Five principal classes • IgG: most common (>75%), soluble, stable • IgA: in exocrine secretions, mucosa • IgM: natural immunity, activator of complement • IgE: activator of mast cells • IgD: B-cells activators ANTIBODIES • IgE: activator of mast cells 1. Antigen presentation and activation of T- cells 2. T-cells differentiate to cytoxic Tc cells, memory t cells or regulatory cells 3. Cytotoxic Tc eliminate abnormal cells Infected cell Killer T cell seeking new target Released toxic protein Killer T cell Toxic protein Memory T cell Future exposure to the same antigen activates this to rapidly produce killer T cells Virus Cell Phagocyte Matching T cell Antigen of virus Non-matching T cells motifolio.com CELLULAR RESPONSE CELLULAR RESPONSE MONOCYTE-MACROPHAGE SYSTEM • mononuclear phagocytic system, reticuloendothelial system • originate in bone marrow: monoblasts → monocytes • after extravasation → macrophages • irregular surface (hallmark of phagocytosis) • numerous lysosomes • Golgi apparatus and rER • long-living cells (months) • phagocytosis (large particles) MONOCYTE-MACROPHAGE SYSTEM • monocytes (circulation) • macrophages (histiocytes) of c.t. • Kupffer cells (liver) • osteoclasts (bones) • microglia (CNS) • alveolar macrophages (lungs) • macrophages and dendritic cells (lymphatic organs, epithelia, c.t.) • Langerhans cells (skin) • mesangial cells (kidney) DOI: 10.1038/ki.1992.369 MHC PROTEINS • Major histocompatibility complex • Activation or attenuation of T-cell response • Peptide display • MHC I: all nucleated cells and platelets • MHC II: antigen presenting cells • (MHC III: structurally similar ti MHC I and II, but with rather unknown function in immune respone) T-lymphocytes • paracortical zone of lymph nodes • white pulp of spleen (periarteriolar sheath) • interfollicular regions in other lymphatic organs (tonsils) B-lymphocytes • lymphatic follicles and medullary cords of lymph nodes • Spleen follicles and marginal zone of white pulp • lymphatic follicles in other organs B- AND T- LYMPHOCYTES IN HUMAN BODY doi: 10.3791/58305 INNATE AND ACQUIRED IMMUNITY ACQUIRED IMMUNITY Histology: - Leukocytes - Lymphatic organs Lymphocytes Antigen presenting cells LYMPHATIC ORGANS Development of lymphocytes and APC: Primary lymphatic organs • bone marrow • thymus Secondary lymphatic organs • lymph nodes • spleen • MALT including tonsils and appendix Tissues • blood • lymph • epithelia • connective tissues LYMPHATIC CIRCULATION Lymph vessels Histology • Lymph capillaries - Thin walled, blunt ended vessels with irregular lamina basalis - Anchoring filaments, tiny valves • Lymph vessels - T. intima – endothelium and subendothelial c.t. - T. media - few layers of smooth muscle cells - T. adventitia - collagen c.t. • Similar to small veins • Valves derived from t. intima • Open to d. thoracicus and d. lymphaticus dx. → v. subclavia (at v. jugularis int.)Function • Collect interstitial fluid • Microenvironment for lymphocyte development and maturation • Lipid transport (chylomicrons) LYMPHATIC CIRCULATION Lymph capillaries Guyton and Hall Textbook of Medical Physiology LYMPHATIC CIRCULATION Lymph flow is unidirectional https://doi.org/10.1113/JP272088 Lymph composition • Contains similar concentration of ions to plasma, but lower levels of proteins • Lipid-rich lymph from intestine - chylus • Immune cells • Volume in the circulation ca. 1L (2-2.5L new lymph from interstitial fluid per day) Mescher LYMPHATIC ORGANS Central (primary): • thymus • bone marrow – also hematopoietic organ Peripheral (secondary): • encapsulated – lymph node, spleen • mucosa associated lymphoid tissue – MALT • tonsils • lymphatic follicles in mucosa of hollow organs Folliculus, nodulus lymphaticus) - non-encapsulated aggregates of reticular conective tissue and lymphocytes - peripheral lymphatic organs - mucosa of hollow organs (GIT, respiratory, urinary, reproductive system) - primary – prior any contact with antigen - secondary – stimulated by antigen - pale germinative center - dark mantle zone LYMPHATIC FOLLICLE • reticular connective tissue + lymphocytes Tanaka, FujitaRoss, Romrell Mescher LYMPHATIC (LYMPHORETICULAR) TISSUE • C.t. capsule containing hilus with vessels • parenchyma = lymphoreticular tissue (reticular c.t. and lymphocytes): • cortex (lymphatic follicles and sinuses) (B-cells) • medulla (cords and sinuses) (B-cells) • paracortical region (T-cells) • sinuses: subcapsular (marginal), perifollicular (cortical), medullary • Littoral cells – lining of sinuses, phagocytosis LYMPH NODE (nodus lymphaticus, lymphonodus) LYMPH NODE (nodus lymphaticus, lymphonodus) Gartner, Hiatt LYMPH NODE CIRCULATION (BLOOD AND LYMPH) lymphatic follicles medulla cortex LYMPH NODE (NODUS LYMPHATICUS, LYMPHONODUS) subcapsular sinus lymphatic follicle Krstic LYMPH NODE (NODUS LYMPHATICUS, LYMPHONODUS) Medullary cords and sinuses Lymph node from lung hilus with dust (carbon) deposits LYMPH NODE MEDULLA • Plasma cells in medullary cords • High endothelium post-capillary venules – extravasation of leukocytes from blood to lymph node parenchyma Mescher LYMPH NODE MEDULLA Medullary cords and sinuses • C.t. capsule and trabecules • Parenchyma = pulp • white (lymphoid) - periarteriolar lymphatic sheath - PALS - Malpighian bodies - follicles) • red (non-lymphoid) - cords of Billroth - venous sinuses • marginal zone between lymphoid and non-lymphoid regions in the spleen SPLEEN (LIEN) Ross, Romrell SPLEEN (LIEN) SPLEEN (LIEN) Impregnation white pulp Sobotta SPLEEN (LIEN) mesothelium capsula lienis trabecule SPLEEN (LIEN) White pulp SPLEEN (LIEN) a. centralis 45 White pulp Ross, Romrell SPLEEN (LIEN) Red pulp red pulp venous sinuses Mescher SPLEEN (LIEN) • Venous sinuses of red pulp • Removal of abnormal erythrocytes Ross, Romrell Fawcett, Jensh SPLEEN (LIEN) • Venous sinuses of red pulp • Removal of abnormal erythrocytes Ross, Romrell Fawcett, Jensh SPLEEN (LIEN) Venous sinus Reticular cell Cells in circulation Ross, Romrell SPLEEN (LIEN) • a. lienalis • aa. trabeculares • aa. centrales • arteriolae penicillatae • (arteriole of the pulp, sheated arteriole) • venous sinuses • veins of the pulp • vv. trabeculares • v. lienalis Leeson, Leeson, Paparo SPLEEN BLOOD CIRCULATION Fawcett, Jensh SPLEEN – OPEN AND CLOSED CIRCULATION SPLEEN AND LYMPH NODE IN ANTIGEN RECOGNITION Lymph filter Blood filter Lymph node Spleen • c.t. capsule • parenchyma: cortex and medulla • epithelial reticulum and T-cells • Hassall bodies (corpuscles) Mescher THYMUS medulla cortex THYMUS (YOUNG 55 Cortex: • T-cell proliferation, acquisition of immunocompetence • positive selection (functional TCR → survival) • hemato-thymic barrier (endothelium + basal lamina + cell of cytoreticlum) • prevents premature contact with antigens THYMUS (CORTEX) • negative selection – prevention of autoimmune reaction • overall survival 2-3% • cytoreticulum • hemato-thymic barrier absent Hassal bodies in medulla THYMUS (MEDULLA) • positive: CD4+ CD8+ • tissue-restricted antigens (TRAs) T-CELL SELECTION THYMUS (INVOLUTION) • incomplete encapsulation by connective tissue • aggregations of lymphatic tissue (follicles) covered by epithelium of crypt • crypts – deep and branched invaginations lined by epithelium • reticulated epithelium ▪ t. palatina – stratified squamous e. ▪ t. lingualis – stratified squamous e. ▪ t. pharyngea – pseudostratified columnar e. ▪ t. tubaria – pseudostratified columnar e. TONSILS Sobotta TONSILLA PALATINA TONSILLA PALATINA Mescher TONSILLA PALATINA reticulated epitheliumlymphatic follicle TONSILLA PALATINA Gll. Weberi crypt TONSILLA LINGUALIS 66 TONSILLA LINGUALIS 67 Gll. Weberi TONSILLA LINGUALIS TONSILLA PHARYNGEA DEVELOPMENT OF LYMPHATIC SYSTEM • Development starts at week 5 • Origin unclear, presumably from mesenchyme or as outgrowths of primitive endothelium • Week 6-9, six primary lymph sacs from local dilatations 1. Two jugular (junction of the subclavian veins with the v. precardinales (→ v. jugularis int.) 2. Two iliac lymph sacs near the junction of the iliac veins with the v. postcardinales 3. Single retroperitoneal lymph sac 4. Single cisterna chyli dorsal to the retroperitoneal lymph sac DEVELOPMENT OF LYMPHATIC SYSTEM • Lymph vessels grow from lymph sacs • jugular: head, neck, thorax, upper limbs • iliac: trunk, lower limbs • retroperitoneal and cisterna chyli: intestine • Development of lymphatic ducts • left and right thoracic duct connecting c. chyli and jugular sacs • anastomoses • D. thoracicus: caudal part of right thoracic duct, cranial part of left thoracic duct • D. lymhaticus dx.: cranial part of right thoracic duct DEVELOPMENT OF LYMPHATIC SYSTEM • Development of lymph nodes • lymph sacs (except for c. chyli) are invaded by mesenchymal cells and constitute apparent clusters of lymph nodes • B-cell compartments (follicles) develop around birth, lack germinative centers (naive) • lymph nodes develop along lymph vessels by similar mechanism DEVELOPMENT OF TONSILS AND THYMUS • Tonsilla palatina • second pharyngeal pouch (fossa) • Tonsilla pharyngea, tubaria and lingualis • aggregation of lymph nodules in the nasopharyngs, by opening of tuba auditiva or lingual root • Thymus • third pharyngeal pouch DEVELOPMENT OF THYMUS • Thymus • third pharyngeal pouch DEVELOPMENT OF THYMUS trachea thymus sternum and ribs esophagusVertebral cartilageVertebral cartilage Week 8 DEVELOPMENT OF SPLEEN • Dorsal mesentery of stomach • Mesodermal origin (coelomic epithelium) DEVELOPMENT OF SPLEEN Spleen Stomach LiverPancreas Gl. suprarenalis sin. Week 8 Thank you for attention Questions? Comments? pvanhara@med.muni.cz Special thanks to CellCartoons.net