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HISTOLOGY NOTES: ----------------------------------------------------------------------Trachea ? Pseudostratified columnar ciliated (PCC) epithelium with goblet cells, mucoserous (mixed) glands ? C-shaped cartilages, smooth trachealis muscles dorsally Bronchus ? PCC epithelium with goblet cells, mixed glands ? Plates of cartilage and smooth muscle bundles mixed Bronchiole ? Columnar ciliated and secretory Clara cells, no goblet cells, no glands ? Smooth muscle only Respiratory bronchiole ? Cuboidal ciliated cells, alveoli in walls with type I and II cells Alveoli ? Mixture of many type I (squamous, gas exchange) and few type II (great, surfactant-secreting) epithelial cells ? Abundant surrounding capillaries Major Intracellular Organelles (Be able to recognize on electron micrographs): Lysosome ? Lysosomal storage diseases (e.g., Tay-Sachs and many others) ? Few to hundreds/cell, round to irregular shape ? Surrounded by unit membrane ? Contains electron dense hydrolytic enzymes ? Degradation of phagocytosed materials and cell turnover ? Particularly abundant in neutrophils, macrophages, and liver parenchymal cells ? Specific granules of granulocytes and acrosome of spermatozoon are specialized lysosomes. Peroxisome ? Abnormal in X-linked adrenoleukodystrophy and Zellweger syndrome ? Round ? Surrounded by unit membrane ? Contain urate oxidase, D-amino acid oxidase, catalase ? Involved in beta-oxidation of fatty acids ? Particularly abundant in liver parenchymal cells Mitochondrion ? Abnormal mitochondria seen in Kearns-Sayre syndrome, MERRF, MELAS, Leigh syndrome, and Lebers disease ? Few to hundreds/cell, usually elongated ? Have outer membrane and inner membrane ? Cristae are shelf-like projections from inner membrane. They increase surface area. They are tubular in mitochondria in steroidogenic tissues, e.g., Leydig cells, adrenal cortex, corpus luteum. ? Have dense bodies in matrix ? Site of oxidative phosphorylation, ATP synthesis ? Particularly abundant in muscle tissue, transporting epithelia, liver parenchymal cells, secretory cells (e.g., pancreatic acinar cells)

Endoplasmic Reticulum (ER) ? Anastomosing plates and sheets of unit membranes, surrounding flattened lumina ? Are either smooth (without attached ribosomes, SER, drug detoxification and steroid synthesis) or rough (with attached ribosomes, RER, protein synthesis for secretion). ? Contain enzymes and work bench for protein synthesis and steroid synthesis ? RER often extremely abundant, especially in liver parenchymal cells, pancreatic acinar cells, goblet cells, glandular cells, plasma cells, motor neurons (as Nissl substance), i.e., cells that secrete proteins and glycoproteins invariably have a lot of RER. ? SER often abundant in liver parenchymal cells (drug detoxification), steroidogenic cells, and striated muscles as sarcoplasmic reticulum Golgi Apparatus ? 5-10 flattened, unit membrane-bound sacs and numerous, smaller membrane-bound vesicles ? Few to many/cell ? Often intermediate between RER and secretory granules in secretory cells ? Curved structure with convex (cis-face, forming face) toward RER and concave (trans-face, maturing face) toward secretory granules ? Contain glycosyltransferases and other enzymes for finishing and packaging secretions initially synthesized in RER and destined for secretion ? Involved in formation of lysosomes ? Abundant in neurons, plasma cells, protein secreting cells, goblet cells, epididymal epithelium Nucleus ? Present in most cells, except RBCs, 4-8m in diameter, often round but variable shape ? Surrounded by double unit membrane (nuclear envelope) with pores to allow passage of macromolecules synthesized in nucleus (e.g., m-RNA and r-RNA) into cytoplasm ? Contains most of genome in DNA strands ? Chromatin can be darkly stained, condensed, inactivated (heterochromatin) or lightly stained, decondensed, active (euchromatin) ? Contains nucleolus in synthetically active cells Nucleolus ? Present in many cells actively engaged in protein synthesis ? Can be absent, when present often 1/nucleus ? Location of cistrons for synthesis of r-RNA ? Has fibrous central component (chromatin) and granular peripheral components (r-RNA precursors) ? Prominent in liver parenchymal cells, motor neurons, many embryonic cells, Sertoli cells, early stages of RBCs and WBCs in bone marrow, etc. The Junctional Complex and Components Junctional Complex ? Seen as terminal bars in light microscope ? Specialized for firm cell-cell adhesion between epithelial cells ? Usually (but not always) located on the apical boundary between cells, near the luminal (apical) or free surface of the epithelium. ? Passes all the way around the apical surface of adjacent cells in a belt-like fashion ? Isolates the luminal compartment from the lateral compartment between cells and the deeper regions of an organ, below the basement membrane

? Consists of (from apical to basal) a zonula occludens (tight junction), zonula adherens (adhesive junction), and a macula adherens (desmosome) Zonula Occludens ? Point of fusion of outer leaflets of plasma membrane ? Forms hydrophobic barrier between lumen and lateral intercellular compartment ? Seen as wavy line of freeze-fracture etch preparations ? Prevents passage of materials from lumen to lateral compartment and vice versa ? Passes all the way around the apical crown of a cell in a belt-like fashion ? Can have several levels of leaflet fusion, producing redundant barrier. ? Well developed in intestinal epithelium (preventing digestive enzymes from breaking down cells). Important component of blood-brain and blood-testis barrier. Zonula Adherens ? Most commonly found just deep to the zonula occludens ? Belt-like, similar in this regard to the zonula occludens ? Outer leaflets now diverge, leaving 15-20 nm intercellular gap ? Site of intercellular adhesion ? Inner leaflets of membranes associated with actin-rich (presumably reinforcing or motile) microfilaments Macula Adherens (Desmosome) ? Most commonly found just deep to the zonula adherens ? Macular (spot-like) rather than zonular ? Adhesive function ? Intercellular gap 15-20 nm, with central lamina of adhesion (?) protein ? Dense plaques cemented to inner (cytoplasmic) face of membrane ? Tonofilaments (bundles of intermediate filaments rich in keratin) insert into these dense plaques ? Hemidesmosomes anchor the basal surface of some epithelial cells to the basement membrane Gap Junction (Nexus) ? Often a component of junctional complex, allows intercellular communication ? Consists of six protein subunits arranged around an aqueous channel ? Adjacent cells often have patches of gap junction on their apposed surfaces, creating aqueous channels for passage of water, ions, small regulatory molecules, e.g. cAMP, between cells ? Also present between many other cell types, e.g. cardiac muscle cells, neurons, lens, etc. Lymphoid Tissue and Organs Scattered Lymphocytes and Lymphoid Tissue ? B-cell function abnormal in Brutons agammaglobulinemia ? T-cell function abnormal in DiGeorge syndrome and AIDS ? Widely scattered free lymphocytes or small aggregates of lymphocytes ? Particularly abundant in skin, respiratory system, gastrointestinal tract, and urogenital system Lymph Nodules ? Are larger aggregates of lymphocytes ? Can have germinal centers ? Consist of lymphocytes, plasma cells, and macrophages ? Sites of lymphocyte differentiation into plasma cells Palatine Tonsils

? Often inflamed in children ? Abundant lymph nodules in pharynx on either side of root of tongue ? Associated with stratified squamous unkeratinized epithelium covering tonsillar crypts Peyers Patches ? Collections of lymph nodules in GI tract ? Most abundant in ileum Vermiform Appendix ? Inflammation and infection leads to appendicitis ? Collections of lymph nodules in cecal diverticulum ? Associated with simple columnar cecal epithelium with many goblet cells Lymph Nodes ? Become enlarged during infections and neoplastic diseases ? Widely distributed, numerous in neck, mediastinum, axilla, inguinal region, mesenteries, and along major blood vessels ? Dedicated to immune surveillance of lymph ? Encapsulated with trabeculae projecting deep into organ away from capsule ? Many afferent lymphatic (valved) vessels distributed peripherally ? One (or a few) efferent lymphatic vessel drains organ at hilus ? Arteries and veins enter and exit at hilus ? Lymph percolates in through afferent vessels, into subcapsular sinuses, around germinal centers, and is collected in medullary sinuses which empty into hilar efferent vessel(s) ? Cortex contains primary (inactive, darker) follicles and secondary follicles (active, lighter germinal centers). The germinal centers contain many B-cells, plasma cells, macrophages, and a few T-cells ? Paracortical regions are richer in T-cells ? Medulla contains medullary cords of closely packed lymphocytes, plasma cells, macrophages, and medullary sinuses that carry lymph into efferent lymphatic(s). Thymus ? Congenital absence leads to DiGeorge syndrome and reduced T-cells ? Found in neck close to the thyroid ? Lobulated, each lobule has cortex and medulla ? Site of T-cell maturation ? Contains many endodermally derived (inferior branch of pharyngeal pouch III) reticular epithelial cells, joined by desmosomes ? Reticular epithelial cells create microenvironment conducive to Tcell differentiation ? Medulla characterized by hyaline aggregates of effete reticular epithelial cells called Hassalls corpuscles Spleen ? Enlarged in hemolytic anemias, e.g., sickle cell anemia ? Only intraperitoneal lymphoid organ, closely associated with fundus of stomach ? Encapsulated by dense CT capsule with trabeculae projecting toward center of organ and covered by mesothelium ? Consists of white pulp and red pulp ? Dedicated to immune surveillance of the blood and phagocytosis of effete RBCs ? Red pulp contains many sinusoids and entrapped blood ? White pulp contains central artery surrounded by periarterial lymphoid sheath (PALS) ? PALS and adjacent marginal zone rich in T-cells

? Germinal centers are located peripheral to the PALS and are richer in B-cells The Mononuclear Phagocyte System (MPS) Common Feature of All Cells in MPS ? Derived from bone marrow ? Highly migratory ? Dedicated phagocytes ? Surface markers include Fc receptors, Il-2 receptors, and complement receptors ? Secrete many immunomediators including Il-1, Il-6, TNF, interferon, CSF, and erythropoietin ? Play key role in inflammation MPS Family Members ? Monocytes (in blood, precursors of many macrophages) ? Pulmonary, pleural, and peritoneal macrophages ? Histiocytes ? Macrophages of lymph nodes and spleen ? Kupffer cells (hepatic sinusoids) ? Osteoclasts ? CNS microglia ? Cutaneous Langerhans cell ? Multinuclear giant cells (Langhans cells) in inflammation Tissues Specialized for Contraction General Features ? Cells specialized for forceful and repeated contraction. ? Unusually high concentration of the contractile proteins actin and myosin. ? Contain contraction regulatory proteins such as calmodulin, troponin, and tropomyosin. ? Striated varieties (skeletal and cardiac muscle), the muscle proteins are arranged in highly organized arrays called sarcomeres, allowing for my forceful and rapid contraction. ? Energy stored in ATP drives the conformational changes in proteins and energizes movement. Myoid Cells ? Similar to smooth muscle but usually isolated or in thin layer ? Surround seminiferous tubules, epididymal tubules near testis, and acini of mammary glands and sweat glands. ? Often exist as single, stellate cells deep to the epithelial basement membrane Smooth Muscle ? One nucleus/cell, centrally place, not striated ? Make up a major component of wall of many visceral organs (except heart) and wall of blood vessels ? Often closely associated with CT fibroblasts in wall of organ ? Controls diameter of lumen, blood pressure, motility of organ ? Calcium diffuses into cell and binds to calmodulin ? Calmodulin activates ATPase in myosin heads ? Myosin moves with respect to actin to generate force Skeletal Muscle ? Duchenne muscular dystrophy and myasthenia gravis have direct effects on skeletal muscle. ? Many nuclei/cell, peripherally placed, cells long and large, unbranched, striated. Skeletal muscle fibers are an anatomic syncytium. ? Epimysium is CT capsule around entire gross muscle ? Perimysium is CT capsule around fascicles of muscle

? Endomysium is collection of fibroblasts that surround individual muscle fibers (cells) and bind them together into coherent mass. ? Muscle fiber (cell) contains many myofibrils and is surrounded by a sarcolemma (muscle cell membrane) ? Sarcolemma has deep surface invagination called T(transverse)-tubules that carry action potential depolarization deep into sarcoplasm ? Each myofibril consists of many sarcomeres attached end to end ? Fewer mitochondria/cell than cardiac muscle Sarcomere Structure and Contraction ? Sarcomere extends from Z-line to Z-line ? Sarcomere has thin (actin-rich) filaments inserting in Z-lines and thick (myosin-rich) filaments intercalated between thin filaments. ? M-line marks middle of sarcomere and thick filaments ? A-band represents extent of thick filament myosin aggregatesremains constant regardless of state of contraction ? I-band represents region of only thin filaments - Shortest at maximal contract - Intermediate at resting length - Longest when stretched ? H-band is in middle of sarcomere, on either side of M-line. Length varies with contraction in same way that I band does ? Myosin heads project away from thick filaments and latch on to thin filaments ? During contraction, conformational change in myosin head causes thin filaments to ratchet past thick filaments, moving Z-lines closer together, shortening sarcomere, shortening myofibrils, shortening muscle fibers, and causing entire gross muscle to contract. ? In stretched muscle, there is minimal overlap between thick and thin filaments. Thus, H band is broadest here. ? Sarcoplasmic reticulum (SR) concentrates calcium and surrounds myofibrils. ? T-tubule adjacent to two terminal cisternae of SR at triads (located at A-I junction) by gap junctions ? Depolarization wave (from motor end plate) passes along sarcolemma, down T-tubules, and triggers release of calcium from SR ? Calcium binds to troponin, causes conformation change in tropomyosin, and exposes myosin head binding sites of actin. ? Myosin heads bind, change conformation, and pull actin filaments closer to M-line, bringing Z-lines closer together and shortening sarcomeres Cardiac Muscle ? One nucleus/cell, centrally placed, cells small and branched, striated ? Individual cells firmly adherent and connected by gap junctions at intercalated discs, meaning that cells are in ionic communication and act in a coordinated fashion. Cardiac muscle is not anatomically syncytial. ? Sarcomeres similar to those in skeletal muscle and work essentially the same way ? There is a T-tubule, located over Z-lines, but it is associated with less extensive SR cisternae. ? More mitochondria/cell than skeletal muscle Frequently Tested Clinical Conditions Related to Histology/Cell Biology Kartagener Syndrome ? Male, infertility, URI, situs inversus ? Cilia and flagella defective, lack dynein arms Duchenne Muscular Dystrophy

? Young male, muscle weakness, elevated CPK ? Dystrophin defects lead to defective attachment of contractile apparatus to cell membrane. Myasthenia Gravis ? Female in 20s, weakness first in ocular muscles, progressive ? Autoantibodies to acetylcholine receptor Achondroplasia ? Autosomal dominant inheritance, apparent at birth ? Long bones of limbs shortened and bowed, depressed nasal bridge. Prominent forehead ? Defective fibroblast growth factor-3 receptor Cystic Fibrosis ? Autosomal recessive inheritance, most common in Northern Europeans ? Chronic URI, wheezing, digestive difficulties, increased salt in sweat ? Abnormal transmembrane conductance regulator Tay-Sachs Disease ? Autosomal recessive, most common in Ashkenazi Jews, French-Canadians ? Blindness, mental retardation, accumulation of ganglioside GM2 ? Lysosomal defect in hexosaminidase A Hereditary Spherocytosis ? Autosomal dominant in most common form ? Loss of spectrin leads to round, fragile RBCs and hemolytic anemia Hurler Syndrome ? Autosomal recessive ? Coarse fascies, opaque cornea, mental retardation, excretes dermatan sulfate and heparan sulfate in urine ? Lysosomal defect in alpha-L-iduronidase Marfan Syndrome ? Autosomal dominant ? Long limbs, hyperextensibility of digits, associated with aortic aneurysm ? Defective fibrillin Osteogenesis Imperfecta (type I) ? Multiple fractures, blue sclera, hearing and dental problems ? Abnormal type I collagen Brutons Agammaglobulinemia ? Male infant, repeated infections, nearly normal CBC ? B-cells absent so there are no plasma cells DiGeorge Syndrome ? Newborn to young infant with fungal infections, craniofacial anomalies, and tetany, reduced PTH ? T-cells lacking due to thymic hypoplasia Collagen Types General ? Most abundant protein in the human body. ? Linear tropocollagen molecule consists of three _-chains wrapped around one another ? Types depend on different combinations of different _-chains and more subtle biochemical differences Type-I ? Abnormality leads to osteogenesis imperfecta (type I) ? Bones, tendons, fascia, organ capsules ? Striated fibers, ranging from thin to very thick Type-II ? Hyaline and elastic cartilage, nucleus pulposus, vitreous body ? Thin fibrils

Type-III ? Abundant in lamina propria, liver, spleen, bone marrow ? Forms reticular (argyrophilic) fibers Type-IV ? Abundant in basement membranes ? Associated with laminin and heparan sulfate ? Forms fine filaments not visible in light microscope Type-V ? Wide distribution, small amounts ? Surrounds smooth and skeletal muscle ? Binds other fibrous collagens together Type-VI ? Not abundant (except in cornea) ? Associated with types-I and III ? Structural role unclear Type-VII ? In basement membranes, especially in skin ? Anchoring function in basement membranes Type-VIII ? Associated with endothelial cell basement membranes ? Present in basement (Descemets) membrane of corneal endothelium Type-IX ? Found in cartilage ? Involved in assembly of type-II collagen fibrils Type-X ? Confined of cartilage ? Adjacent to hypertrophic chondrocytes in developing bone ? May play role in calcification Odds and Ends All Steroidogenic Tissues are similar in electron micrographs ? Prominent lipid droplets (stored cholesterol esters) ? Abundant SER (enzymes for steroid biosynthesis) ? Mitochondria with tubular cristae (produce ATP for steroid biosynthesis) ? Examples: - Adrenal cortex (largest lipid droplets in zona fasciculata) - Corpus luteum - Thecal cell of ovarian follicle - Leydig cells All Protein-Secreting Cells are similar in electron micrographs ? Prominent nucleolus (for synthesis of r-RNA precursors) ? Abundant RER (for assembly of polypeptide chains ? Abundant Golgi apparatus (for glycosylation and packaging of secretion granules) ? Many mitochondria (for ATP for protein synthesis and vesicle transport) ? Membrane-bound granules for secretion (often called zymogen granules) ? Examples: - Plasma cells (secrete immunoglobulins) - Motor neurons (secrete neurotransmitters) - Pancreatic acinar cells (secrete digestive enzymes) - Salivary glands - Lacrimal glands - Mammary glands - Cells in parathyroid (secrete PTH) - Chief cells in gastric glands (secrete pepsinogen) - Adenohypophysis (secrete trophic hormones, e.g. LH, TSH, FSH)

Important Characteristics of Bone Marrow Cells ? Most primitive stem cells are rarest, largest, have pale staining weakly basophilic cytoplasm, large uncondensed nuclei, and multiple nucleoli ? Myeloblasts have large, uncondensed nuclei, several nucleoli and lack nonspecific azurophilic) granules ? Promyelocytes have large, uncondensed nuclei, several nucleoli, and azurophilic granules ? Myelocytes have large, uncondensed nuclei, usually one nucleolus, and azurophilic granules and specific (neutrophilic, eosinophilic or basophilic) granules ? Metamyelocytes have condensed, lobulated nuclei and both types of granules ? Mature cells have fully condensed and lobulated nuclei and a predominance of specific granules ? Proerythroblasts are large, round cells with several nucleoli and basophilic agranular cytoplasm ? Basophilic erythroblast are smaller than proerythroblasts, nucleus more condensed, nucleoli less prominent, cytoplasm intensely basophilic due to numerous polyribosomes for hemoglobin synthesis ? Polychromatophilic erythroblasts have further nuclear condensation and accumulation of acidophilic cytoplasmic hemoglobin, less cytoplasmic basophilia that previous stage ? Orthrochromatic erythroblasts (normoblasts) have further nuclear condensation, acidophilic cytoplasm because hemoglobin has replaced free polyribosomes ? Once nucleus is extruded, you have mature RBC ? Reticulocytes are RBCs with remnants of basophilic polyribosomes in cytoplasm They normally represent 1-2% of peripheral RBCs. Elevations suggest hemolytic anemias