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Histology of the immune (lymphoid, lymphatic) system • Jeanne Adiwinata Pawitan • Dept. of Histology • FMUI Jeanne A Pawitan Immune system • Cells of the immune system • Bone marrow (myeloid tissue) • Diffuse lymphoid system ° Diffuse lymphoid tissue ° Lymph (lymphoid) nodules • Lymphoid organs - capsule Jeanne A Pawitan Immune system – defense mechanism • Function: protection >< foreign elements ° Foreign macromolecules ° Invasive microorganisms • Viruses • Bacteria • Others ° Transformed cells Jeanne A Pawitan Defence mechanism (Martini) • Non specific defenses ° ° ° ° ° Physical barriers Phagocytes (M, neutro, eosinophils, monocytes) Immunological surveillance: NK cells Interferons, complement system Inflammatory responses, fever • Specific defenses – specific immunity –specific immune response ° Innate (human >< animal disease, except AIDS) ° Acquired Jeanne A Pawitan Immune response • Specific recognition system (specific immune system) ° Recognize self >< non self ° Component • Cellular (lymphocytes B, T) • Soluble (Ig) • Nonspecific (innate) effector system (non specific immune system) ° Amplifies – function – specific system Jeanne A Pawitan Nonspecific immune system • Soluble component ° Complement proteins (cytokines): lymphokinesmonokines: interleukines (ILs), interferons (IFNs), tumor necrosis factors (TNFs), transforming growth factors (TGFs), hematopoietic colony-stimulating factors (CSFs) • Cellular component – phagocytes: ° Blood: neutrophils, eosinophils, monocytes ° Tissue: macrophages (alveolar macrophages, Kupffer’s cells, synovial cells – joint cavities, perivascular microglial cells – CNS) Jeanne A Pawitan Bone marrow (red) – myeloid tissue • Location: ° central (marrow, medullary) cavity – long bones ° Interstices (trabeculae) – spongy/cancelous bones • Soft, gelatinous, highly vascular – cellular tissue • Function: hemopoiesis – 5th month prenatal • LM: ° vascular compartment (A., V., sinusoids) ° Intervening spaces • hemopoietic compartments – meshwork - islands of hemopoietic cells • Adventitial reticular cells, reticular fibers Jeanne A Pawitan Bone marrow cells • Hemopoietic cells ° Blood cells – various stages ° Macrophages – destroyed • Nuclei – erythrocytes precursors • Malformed cells • Excess cytoplasm • Adventitial reticular cells ° By age 20 – adult: cytoplasm - accumulate fat • ≈ adipose cells – large – reduce hemopoietic compartment • yellow marrow Jeanne A Pawitan Diffuse lymphoid system • Non-encapsulated • Location: ° Lymphoid organs ° Mucosa (lamina propria) – mucosa associated lymphoid tissue (MALT) • Digestive system (Gut ALT): Peyer’s patches • Respiratory system (Bronchus ALT) • Urinary system • Occur as ° Diffuse lymphoid tissue = localized lymphocyte infiltration ° Lymphoid nodules (lymphonodulus) Jeanne A Pawitan Diffuse lymphoid tissue • Consists of ° Stroma • Reticular fibers – silver impregnation • Reticular cells of mesenchymal origin – some are phagocytic ≈ fixed macrophages ° Lymphocytes ° Free macrophages ° Plasma cells Jeanne A Pawitan Reticular cells • Shape: elongate – stellate • Nucleus: ovoid – euchromatic • Cytoplasm: ° Scanty ° Acidophilic ° Contains • RER – few • Golgi complex – moderate-well developed • Fine filaments – bundles – at periphery Jeanne A Pawitan Lymph (lymphoid, lymphatic) nodule, lymphonodulus – lymphoid follicles • =circumscribed-spherical/ovoid-closely packed-lymphocytes • In diffuse lymphoid tissue • Location: ° ° ° ° Lymph node –cortex Spleen – white pulp Tonsils Lamina propria (MALT): Peyer’s patches, etc. Jeanne A Pawitan Lymph nodule • = primary nodule • Consists of ° Germinal center = secondary nodule = ovoid area – contains: larger, pale-staining cells • Less densely populated pole – light region/zone • Densely populated pole – dark region/zone ° ‘cap’ = corona, cortex, mantle – small lymphocytes – densely packed – facing less dense pole - directed toward • Marginal sinus • Red pulp • Epithelium (MALT) Jeanne A Pawitan Germinal center – diff. B limphocytes- IgG • Dendritic (stellate) cells, dendritic macrophages ° ° ° ° • • • • • • Silver method Cellular framework Radiating processes – desmosomes Non phagocytic, bind Ag – Ag presenting – activate T lymphocytes Flattened reticular cells – desmosomes: outer boundary Lymphoblast – actively proliferating Lymphocytes: large, medium, small - esp.dark region Transition to plasma cells Plasma cells (scarce, except in tonsils) Macrophages – ↓toward dark region Jeanne A Pawitan Gut-associated lymphoid tissue • Isolated lymphoid follicles • Peyer’s patches – aggregates – ileum ° Lymphoid follicles • B cells • T cells – looser – surrounding B Cells • Numerous APC – surrounding B cells ° Simple columnar epithelium M (microfold) cells – capture Ag present their epitopes to lymphocytes ° Afferent lymph vessels (-), ° Efferent lymph drainage (+) ° Received small arterioles capillary bed high endothelial lined venules (HEVs) ° Lymphocytes entering Peyer’s patches have homing receptors – specific for HEVs of GALT Jeanne A Pawitan Bronchus-associated lymphoid tissue • ≈ Peyer’s patches – walls – bronchus – esp. bronchi-bronchiole bifurcate • Epithelial cover: pseudostratified ciliated columnar epithelium with goblet cells M cells • Afferent lymph vessels (-) • Efferent lymph drainage (+) • Rich vascular supply HEVs ° Possible systemic and localized role in immune response ° Lymphocytes entering BALT have homing receptors for HEVs of BALT • Cells: mostly B cells, also APC, T cells Jeanne A Pawitan Lymphoid organs • • • • Thymus (primary lymphoid organ) Lymph nodes (lymphonodus) Spleen (lien) Tonsils (tonsila) Jeanne A Pawitan Thymus • Location: superior mediatinum – anterior of great vessels (aorta) • After puberty – involution (atrophy) → adult – adipose cells • 2 lobes • Encapsulated – dense-irregularcollagenous connective tissue septa (trabecula) – lobes incomplete lobules Jeanne A Pawitan Thymus - lobules • Cortex – darker ° Epithelial reticular cells – endodermally derived – type I, II, III ° T lymphocytes (thymocytes): immunologically incompetent competent ° Macrophages • Medulla – confluent – lighter ° Epithelial reticular cells – endothelially derived- type IV, V, VI ° Lymphocytes – less than in cortex Jeanne A Pawitan Thymus – vascular supply • Small arteries – capsule – trabecula corticomedullary junction – capillary beds cortex - continuous capillary ° Thick basal lamina ° Sheath – epithelial reticular cells type I (occluding junction) – blood-thymus barrier medulla – small venules – veins - out Jeanne A Pawitan Thymus – histophysiology • Cortex: ° T cells proliferate – surface markers – maturation capable to recognize • Self MHC molecules • Self epitopes incapable - detroyed ° Epithelial reticular cells type I, II • Test the ability of T cells: have MHC molecules Epitopes • Produce hormones maturation of T cells Thymosin Thymopoietin Thymulin Thymic humoral factor Jeanne A Pawitan Maturation of T cells • Role of extrathymic hormones ° Suprarenal, gonads – adrenocorticosteroids T cell number in thymic cortex↓ ° Thyroid – thyroxin stimulate epithelial reticular cells - thymulin↑ ° Pituitary – somatotropin promotes T cell development in thymic cortex Jeanne A Pawitan Lymph node • Location: interposed in the path of lymph vessels-esp. ° Neck, axila, groin ° Along major vessel ° body cavities • Functions: ° Filter – remove • Bacteria • Foreign substances Jeanne A Pawitan Lymph node • Small, soft, Ø < 3 cm • Capsule – fibrous connective tissue (thickened at hilum) - trabeculae adipose tissue • Convex: afferent lymph vessels – valves • Concave = hilum: A., V., efferent lymph vessels – valves ← medulla Jeanne A Pawitan Lymph node - sinuses Sinuses: network – stellate reticular cells – macrophages – endothelial-like simple squamous epithelium – migratory lymphoid cells Course: Afferent lymphatic vessels • Subcapsular sinus • Cortical (paratrabecular) sinuses • Medullary sinuses Efferent lymphatic vessels Jeanne A Pawitan Lymph node • Histologically: ° Cortex – antigen-presenting follicular dendritic cells • Primary lymphoid nodules (virgin B & memory B cells) • Secondary nodules (with germinal centers) – antigenic challenge B memory & plasma cell ° Paracortex – Thymus dependent zone ° Medulla Jeanne A Pawitan Lymph node -paracortex • Cells ° Mostly T cells ° APC comes (from outside) – presents epitope-MHC II complex to T helper Th – is activated – proliferates width of paracortex ↑ ° Activated Th medullary sinuses out to area of antigenic activity • Postcapillary venules = high endothelial venules (HEVs) - cuboidal ° endothelial cells - signaling molecules ° Rolling lymphocytes – selectins >< signaling molecules firmly bound – diapedesis – out to lymph node parenchyma Jeanne A Pawitan Lymph node - medulla • Trabeculae – from hilum • Medullary cords ° Network – reticular fiber – reticular cells ° Cells • Lymphocytes – migrating from cortex medullary sinuses • Plasma cells • Macrophages Jeanne A Pawitan Lymph node - vascularization • Artery (hilum) trabeculae medulla medullary cords ° Capillary beds in medulla ° Cortex – cortical capillary beds postcapillary venules (paracortex) vein hilum Jeanne A Pawitan Lymph node – histophysiology • Lymph - foreign particulate matter lymph node – macrophages-phagocytosis = filter • Site of antigen recognition ° APC – antigen (from outside) lymph node – lymphocytes presentation of epitopeMHC complex ° Ag – trapped by follicular dendritic cells recognize by lymphocytes Jeanne A Pawitan Lymph node – histophysiology • B lymphocytes – recognize Ag activated primary lymphoid nodule proliferates –diff B memory, plasma cells - secondary lymphoid nodule ° B memory (some)– stay in cortex ° B memory, plasma cells leave cortex medullary cords • Plasma cells (10%)– medulla - Ab medullary sinuses • Plasma cells medullary sinuses bone marrow – Ab • B memory out to secondary lymphoid organs 2nd exposure - prompt and potent secondary response Jeanne A Pawitan Spleen (lien) • • • • Largest lymphoid organ Upper left quadrant – abdominal cavity Intraperitoneal – visceral peritoneum Function: ° ° ° ° ° Proliferation B, T cells Ab formation – blood-borne Ag inactivation Elimination of Ag, bacteria, particles, etc. Filtering blood – destroying old erythrocytes Hemopoietic (fetal) – adult – when needed Jeanne A Pawitan Spleen (lien) • Convex surface • Concave surface – hilum – capsulethickened ° Arteries – nerve fibers (in) ° Veins – lymph vessels (out) • Dense – irregular connective tissue – capsule - occasional smooth muscle cells – trabeculae into the organ Jeanne A Pawitan Spleen (lien) • Histology ° Network – reticular fibers – reticular cells – attached to capsule trabeculae – blood vessels ° Fresh - cut - parenchyma • Grey area = white pulp • (Marginal zone – 100 μm wide – between white – red pulp) • Surrounding red area = red pulp (splenic cords of Billroth) Jeanne A Pawitan Spleen (lien) – blood supply • Splenic artery - hilum branching trabecular arteries ( 0.2mm) central arteries – periarterial lymphatic sheath (PALS) ° Radiating - slender blood vessels red pulp (recur) marginal sinuses – marginal zone ° branching penicillar arteries – red pulp: • Pulp arteriole • Sheated arteriole – Schweigger-Seidel sheath – macrophages) • Terminal arterial capillaries – splenic sinuses • Veins of the pulp splenic vein portal vein Jeanne A Pawitan Closed circulation – open circ. • Closed circulation ° Endothelial lining: terminal arterial capillaries –continuous - sinuses • Open circulation ° Terminal arterial capillaries – red pulp sinuses • Combination of both Jeanne A Pawitan Spleen (lien) – white pulp • Central arteriole • PALS: ° T lymphocytes ° Frequently: lymphoid nodules (B cells) – germinal center = antigenic challenge central arteriole - periphery Jeanne A Pawitan Spleen (lien) – marginal zone • Cells ° ° ° ° Plasma cells T, B lymphocytes Macrophages Interdigitating dendritic cells (antigen presenting cells, APC) • Marginal sinuses (vascular channels: interendothelial spaces 2-3 μm) – esp. surrounding lymphoid nodules particulate matter – free access to parenchyma Jeanne A Pawitan Spleen (lien) – marginal zone-events • APC – search for Ag in blood • Macrophages – attack microorganism in blood • Circulating B, T lymphocytes in blood stream – enter the white pulp • Lymphocytes – contact with interdigitating dendritic cells – if the epitope-MHC complex is recognized immune respons in white pulp Jeanne A Pawitan Spleen (lien) – red pulp • sponge ° Spaces = splenic (venous) sinuses (sinusoids) • Endothelial lining – fusiform staves of a barrel • Between endothelial cells - spaces - 2-3 m • Surrounded by reticular fibers (continuous with splenic cords) – thin strands ┴ longitudinal axis • Have a discontinuous basal lamina ° Sponge material = splenic cords of Billroth • Reticular fibers (collagen III) – loose network – interstices permeated by extravasated blood • Stellate reticular cells – isolate coll III from blood >< platelet reaction to coll >< coagulation • Macrophages particularly numerous near sinusoids Jeanne A Pawitan Spleen –histophysiology • Macrophages ° Marginal sinuses – macrophage rich ° Periphery of splenic sinuses Phagocytosis Ag, bacteria, particulate matter, etc Old erythrocytes Less fkexible (old, malaria) –cannot penetrate spaces between endothelium Surface coat: sialic acid residue (-) galactose moieties exposed – induced phagocytosis Jeanne A Pawitan Spleen –histophysiology • Lymphocytes -Ag challenge white pulp ° B memory cells, plasma cells – lymphoid nodules ° T cells (various subcategories) – PALS • marginal sinuses ° Site of Ag challenge ° Circulating pool of lymphocytes ° Plasma cells • Some stay in marginal zone Ab marginal sinuses • Most bone marrow – Ab bone marrow sinuses Jeanne A Pawitan Tonsils: palatine, pharyngeal, lingual • Incompletely encapsulated • Aggregates of lymphoid nodules • Guard the entrance of oral (oro) pharynx • Exposed to ° Airborne Ag ° Ingested Ag • Reaction to Ag ° Forming lymphocytes ° Mounting immune response Jeanne A Pawitan Palatine tonsils • Location ° Boundary of oral cavity-oral pharynx ° Between palatoglossal –palatopharyngeal folds • Deep aspect - fibrous capsule • Surface – stratified squamous nonkeratinized epithelium dips into crypts (10-12) - contain ° Desquamated epithelial cells ° Dead leucocytes, bacteria, other Ag substances ° Food debris • Inside – tonsilar parenchyma ° Lymphoid nodules – many with germinal centers = B cell formation Jeanne A Pawitan Pharyngeal tonsil • Location: roof of nasal pharynx • Capsule – incomplete, thinner vs palatine • Surface: pseudostratified ciliated columnar epithelium – interspersed with patches of stratified squamous epithelium pleats = shallow longitudinal infoldings ° Ducts of seromucous glands base pleats • Inside = palatine tonsil • Inflamed adenoid Jeanne A Pawitan Lingual tonsil (several) • Location: dorsal surface of posterior 1/3 of tongue • Superficial – stratified squamous nonkeratinized epithelium – single cript ° Ducts of seromucous minor salivary glands base of crypt • Capsule – flimsy • Inside = palatine tonsil Jeanne A Pawitan