Lecture 11: Immune System and Lymphoid Organs

Histology Stanley Shostak
BioSc 1450 Spring 05

Lecture 8b. Immune System and Lymphoid Organs

Protective surface mechanisms

lysozyme: antibacterial enzyme in tears and saliva; acidic environment of stomach and vagina;

non-specific tissue defences

inflammation: (chronic or acute) vascular changes including capillary dilation, enhanced permeability and increased blood flow resulting in production of fibrin-rich inflammatory exudate; migration neutrophils and later macrophages; phagocytosis enhanced by immunological mechanisms; destroyed tissue replaced by capillary-rich granulation tissue; slowly replaced by fibroblast proliferation and collagen deposition; formation avascular and acellular fibrous scar;
complement: cascade activated by classical pathway (involving antigen-antibody complexes) or alternative pathway (direct activation by invader); initiate vascular changes (dilation and increased permeability), cell lysis, opsonization (coating invader with complement; enhancing phagocytosis), chemotaxis, and activation.

specific immune responses

antigen: any foreign substance recognized by immune system
autoimmune reactions: normal body components act as antigen

monocytes-macrophage: phagocytic

complement, neutrophils, macrophages frequently employed in destruction of antigen

immuno surveillance and anticancer activity

Anatomy

without permanent structure
isolated cells and spurious nodules
loosely organized (no capsule) structures but permanent peripheral lymphoid tissue

MALT: mucosa associated lymphoid tissue = non-encapsulated aggregations in gastrointestinal, respiratory and other tracts, sometimes GALT (gut associated lymphoid tissue = aggregated lymph nodules of ileum) BALT (bronchiolar-associated lymphoid tissue)

aggregated lymph nodules

tonsils (considered encapsulated in G&H) forming tonsillar ring: palatine, pharyngeal, lingual.

with organized structures capsular lymphoid organs

lymph nodes
thymus

spleen

Types of immunity corresponding to types of lymphocytes

cell-mediated immunity: T lymphocytes function as cytotoxic cells directly killing abnormal body cells (mediated by T helper and T suppressor cells)
humoral immunity: mediated by B cells (may require T helper and T suppressor cells)

antigen presenting cells (APCs): various types including macrophages and B lymphocytes activate T cells; take up immunogens; reduce to epitope, and present it on surface to lymphocyte in conjunction with MHC (=HLA) class II complex

surface immunoglobulin (sIg) on B cells

T cell receptor (TCR) on T cells

gene rearrangement and splicing mRNA: DNA splicing generates enormous diversity of receptor structures

lymphocytes

T lymphocytes = vast majority in circulation, periarteriolar, medullary portions of lymphnodes and spleen. B lymphocytes = minority in circulation, nodular and cortical; not in thymus except possibly medulla.
short microvilli much more numerous on B lymphocytes than on T lymphocytes

must be capable of moving throughout body; must encounter specific antigen to which they are responsive.

lg lymphocytes: activated, on way to tissue where they will become plasma cells

natural killer (NK) cells: some lg lymphocyte (or unique class); azurpophilic granules containing acid hydrolases = large granular lymphocytes (LGL).

T lymphocytes pan-T cell markers (CD2, CD3 and the T cell receptor); can only recognize antigen bound to MHC protein

immunologically immature; migrate from bone marrow to thymus; proliferate; acquire surface markers; develop into thymus- (T-)dependent lymphocytes; = naive lymphocytes yet to make contact with antigen; cells with ability to react to ones own normal, constituents (self antigens destroyed or suppressed > self tolerance; populate peripheral lymphoid tissue (lymph nodes, MALT; spleen); resume circulation (route terminates upon encountering appropriate antigen)
T_H: T helper cells = CD4 cells secrete interleukins; activate B cells to produce antibody; regulate cytotoxic T cell function and activation of macrophages > chronic granulamatous inflammatory response (delayed-type hypersensitivity)

T_H1: prefenetially activate macrophages
T_H2: activate B cells
Suppressor/cytotoxic cells

T_C: Cytotoxic T cells = CD8 cells: kill virus-infected and malignant cells; require T_H cells for activation, proliferation and function
T_S: Suppressor T cells = CD8 cells:

B lymphocytes: can recognize some soluble antigens (lipopolysaccharides of bacterial cell walls and polysaccharides) independently.

Bursa of Fabricius (= bone-marrow equivalent cells of mammals)
naive mature B lymphocytes: most circulating

memory cells: have high affinity receptors for antigen (sIg) and produce IgM earlier

exposure to antigen in peripheral lymphoid tissue > clonal proliferation (synthesize imunoglobulin of same antigen specificity but of more than one class) > antibody secretion by B cells and plasma cells and accumulation of B memory cells

antibodies: immunoglobulins: glycoproteins that bind to specific antigens IgG
IgA
IgD
IgM
IgE

activation generally requires T helper cells responding to same antigen

primary immune response: antigen encountered for first time; most B cells of activated clone mature into plasma cells producing IgM; some become memory cells long-lived, circulating memory cells are able to respond quickly to subsequent challenge with same antigen secondary immune response: antibody production during subsequent challenge more rapid, of greater magnitude and produces IgG

Antigen presenting cell (APC) [note: may be B lymphocytes as well as members of macrophage-monocyte-dendritic cell system]

interdigitating cell of lymph node, of thymus: probably derived from circulating monocytes of macrophage-monocyte system: numerous long branched cytoplasmic extensions extend between surrounding lymphocytes; nucleus deeply indented with dispersed chromatin; lysosomal granules and phagosomes; take up and process antigen to form capable of being recognized by T lymphocytes; presentation at plasma membrane

follicular dendritic cells of lymph node

Dendritic cells (= Langerhans cells) of epidermis; APC migrates from site of antigen uptake to regional lymph nodes; become paracortical interdigitating dendritic cell

Plasma cell: clock (cart wheel) face clumped chromatin of round nucleus; prominant nucleolus; perinuclear halo = negative golgi due to well-developed golgi apparatus; deeply basophilic cytoplasm; antibody promptly secreted (not stored) from lymphocyte; successive waves of cell division in medullary cords of lymph nodes to plasmablast

maturation requires several signals:

sIg: surface immunoglobulin of naive B cell simultaneous activation and clonal expansion of T_H cells interleukins 2, 4, 5 & 6 and interferon gamma: secretion by T_H cells function in medullary cords of lymph nodes, white pulp of spleen, supporting tissues of mucosal surfaces (lamina propria) & bone marrow antigens T cell-dependent antigens: T_H cell-secreted interleukins
T cell-independent antigens: hi MW polymers with simple repeating structures; induce cross-linking of cell surface receptors surface antigens immunoglobulins exhibited on surface (sIg) of naive mature B lymphocyte: specificity a function of random rearrangement of genes encoding variable region of immunoglobulin; binding signals clonal development

T cell receptor (TCR): resembles sIg; produced by random DNA rearrangements

major histocompatibility (MHC) antigens = human leucocyte antigen (HLA): present antigen to T lymphocyte; bind small peptide fragments of non-self (and self) protein; complex moved to surface becomes accessible to T lymphocyte with appropriate receptor

Class I: present on surfaces of all cells in body except erythrocytes, APCs, macrophages and B cells; present non-self proteins synthesized intracellularly (viral proteins); activating cytotoxic T lymphocytes;

Class II: normally present only on APCs, some macrophages and B lymphocytes, immunologically-activated T lymphocytes; bind peptide products of phagocytosis and lysosomal breakdown of exogenous proteins (bacterial products) recognized by T_H cells; followed by activation of B lymphocytes

Class III: associated with certain diseases

surface antigens defined by the CD system; epitope: chemical formation of antigen; cluster of differentiation = CD system of nomenclature flow cytometry: T and B lymphocytes express different CD antigens or combinations at different stages of maturation and activation Thymus: A nested organ; hemopoiesis also occurs in fetus

Parenchyma: lymphocytes and epithelial cells provide mechanical supporting framework

lymphocytes and, in cortex, envelop lymphocytes and perform nurse function; promoting T cell differentiation, proliferation and subset maturation;

epithelial cells: lg, pale stained nuclei, eosinophilic cytoplasm, prominent basement membranes; typical desmosomes; bundles of intermediate filaments; also secrete different hormones: thymulin, thymopoietin and thymosin alpha 1 and variety of humoral factors regulating T cell maturation and proliferation; continuous layer of thymic epithelial cells resting on basement membrane lines capsule and septa; also forms sheaths around blood vessels--barrier to entry of antigenic material = blood-thymus barrier of cortex.

cortex: highly cellular; deeply basophilic; fine epithelial framework; blood-thymic barrier

medulla: less cellular; relatively coarse and bulky (eosinophilic) epithelial framework (compared to cortex); thymic corpuscles (Hassalls) eosinophilic lamellated structures = degenerate epithelial cells; reticular (epithelial) cells isolate from cortex

Stroma

capsule: thin, CT;

interlobular septa: short; terminate at cortico-medullary junction;

blood vessels radiate into substance from interlobular septa, branching at cortico-medullary junction

post-capillary venules: in cortico-medullary region; have specialized cuboidal endothelium similar to that of high endothelial venules of lymph node; allows passage of lymphocytes into and out of thymus

cortical capillaries: continuous endothelium type; fascia occludentes (blood-thymic barrier)

medulla and septal capillaries: fenestrated

no afferent lymphatics.

involution: by fatty infiltration and lymphocyte depletion (results in collapse of epithelial framework)

Lymph nodes: interrupt course of lymph draining back to gen. circulation

contain most lymphocytes; interposed along larger regional vessels of lymph vascular system; occur in groups where lymphatics converge: neck, axilla, groin, lung hila and para-aortic areas.

Anatomy

hilum (notch on a bean) in cavity of node; efferent lymphatic vessels drain from hilum > thoracic duct or right lymphatic duct

arteries enter through hilum; lymphocytes enter mainly via arteries (10% through afferent lymphatics except in mesenteric lymph nodes where 30% enter throuh afferents);

post-capillary venules in paracortex: site of migration of lymphocytes into sinuses; have cuboidal endothelium = high endothelial venules (actually low cuboidal endothelium); have complementary adhesion molecules; golgi apparatus, secrete glycolipids and glycoporteins.

veins leave through hilum

nonspecific filtration of particulate matter and microorganisms from lymph:

phagocytic activity of macrophages prevents exogenous material from reaching general circulation

immunological accessory cells:

macrophages; APC, and cells with non-specific effector functions; part of monocyte-macrophage system; reach lymph node through lymph

stromal cells: supporting tissue; reticulum; dense in cortex except in follicular areas; traverse sinuses and completely invested by lymph-endothelial cells; laid down by fibroblasts; macrophages Îare draped over the whole reticular meshwork

lymph-endothelial cells (phagocytic for particulate material from afferent lymph) and fibroblasts constituting lymph node supporting framework; nonimmunologically-specific process.

parenchyma: population of lymphocytes

open meshwork of reticulin fibers providing support for ever changing population of lymphocytes

Functional compartments

network of lymphatic sinuses

lined lymphatic endothelium; continuous lumen afferent and efferent lymphatic vessels; sinus macrophages: large; supported by reticulum strands; engulf particles, soluble antigens and other debris from afferent lymph; some APCs; cortical lymphocytes may also sample antigen directly as it percolates through the node.

blood vascular compartment

lined by vascular endothelium; microcirculation of node; high endothelial venules allow lyphocytes entry to sinuses

interstitial compartment

lined by both lymph-endothelium and vascular endothelium on opposite sides; circulating lymphocytes which recognize antigen remain; those that do not leave within a few hours > general circulation through efferents.

3 functional domains populated by different types of lymphocytes

B lymphocytes in superficial cortex; associated with predominantly humoral immunological response

T lymphocytes in paracortical region never arranged as follicles; associated with predominantly cytotoxic immunological response

B lymphocytes and plasma cells in medullary cords involved in immunoglobin synthesis

Special histology

cortex: highly cellular; densely packed lymphocytes;

capsule & trabeculae: dense collagenous tissue afferent lymphatic vessels: pierce capsule diagonally; valves prevent regurgitation subcapsular sinus: beneath capsule; phagocytic cells with highly irregular veiled cell surface = veiled cells; probably precursors of interdigitating cells of paracortex. outer (superficial) cortex dominated by B lymphocytes, mainly naive and memory cells; blast transformation: cell enlarge and increase cytoplasmic RNA prior to cell division > lymphoblast of germinal center = follicle center cells lymphoid follicles: primary if germinal center not present; secondary if germinal center present germinal centers: site of B lymphocyte proliferation; partially encircled by flattened, immunological accessory cells:
germinal center bordering cells ([cup-shaped region] incomplete superficially): may prevent entry T cells into germinal center tingible body macrophages: numerous lysosomes; ingested cellular remnants cap region: follicular dendritic cells: retain antigen on surface; appear continuous with germinal center bordering cells marginal zone macrophages: phagocytic cells situated within follicular interstitium beneath subcapsular sinus

natural killer (NK) cells: in follicles ; resemble large lymphocytes; surveillance for tumors and virus-infected cells

lymphocyte corona: concentration T_H cells + various types: cortical sinuses:labyrinth of channels; pass toward medulla adjacent to trabeculae; extend into node inner cortex = paracortical zone; dominated by T lymphocytes of helper and cytotoxic/suppressor subsets; rejoin circulation 6 to 16 hrs later; > lymphoblasts: expanded clones of activated T lymphocytes; paracortical reaction: expansion paracortical zone due to proliferation T lymphocytes; dissiminated to peripheral sites no lymphoid follicles

interdigitating cells: veiled cells of subcapsular sinuses may be precursors

macrophages: cytoplasm packed with lipid and nuclear debris

post-capillary venules: high endothelial cells promote (allow) lymphocytes to move through wall

medulla: less cellular; continuous with hilum medullary sinuses: network of broad interconnected lymphatic channels; classical macrophages located on traversing reticulin fibers
medullary cords: extensions of cortex; between medullary sinuses; dominated by plasma cells: lg, pale stained nucleus with prominent nucleolus, and plasmablast Spleen:
production immunological responses aginst blood-borne antigens; removal particulate matter and effect blood cells; in fetus, important site of hemopoiesis; function may resume in adult in certain disease states; functions taken over by bone marrow and liver in event of spleenectomy
Note: no periarteriolar lymphoid sheaths or marginal sinuses in human spleen

capsule with short septa extending into organ; thickened in hilum

hilum: continuous with supporting tissue ensheathing larger blood vessels

parenchyma(70%): major constituent = two constituent (red and white pulp): swiss cheese; permeated by broad, interconnected venous sinuses (30%).

white pulp: lymphoid aggregations embedded in matrix of red pulp; 5 to 20% spleen mass; function resembles that of paracortex and superficial cortex of lymph nodes;

spleenic artery: breaks up into major branches entering hilum; numerous arterioles; covered in some species by periarteriolar lymphoid sheaths; in humans T lymphocytes (mainly T_H) concentrated around arterioles; B lymphocytes follicles adjacent to central arterioles.

central arterioles: relatively tall endothelium, 1 to 2 layers smooth muscle, give rise to capillaries; end by splitting into penicillar arterioles in red pulp.

capillaries: high endothelium; pericytes; give rise to collateral capillaries.

collateral capillaries: split off central arteriole; enter marginal zone; lo endothelium, no pericytes.

small lymphatics: arise in the T lymphocyte areas; form network around arterioles; continue to hilum; drain into adjacent lymph nodes

follicles: B cells; germinaal centers;

mantle zone = corona;

marginal zone: broader than mantle; less densely packed by large lymphocytes;

marginal sinue (in rat)

perivascular rims: small areas around arteries containing lymphocytes and plasma cells; analogous to medulla of lymph node

red pulp: bulk of organ; highly vascular; supported by extremely loose meshwork of reticulin fibers;
penicillar arteries: last branches after arterioles branch from smaller arteries usually at right angles; give rise to capillaries which tend to arise at right angles; >

spleenic capillaries of red pulp: have standard endothelium; terminate into sheathed capillaries;>

sheathed capillaries [SC]: cylindrical arrangement of mononuclear phagocytes; blood leaves capillaries and enters red pulp (parenchyma)

spleenic parenchyma [open circulation] populated by capillaries and macrophages as well as a cuff of lymphocytes immediately surrounding capillaries; removed particulate matter and effect RBCs (cannot negotiate slits into sinuses; aged cells accumulate immunoglobulin; may facilitate phagocytosis via Fc receptors on macrophages);>

splenic (venous) sinuses: interconnected network; lined by elongated, spindle-shaped, flattened endothelial cells parallel to long axis of sinus; = stave cells; resting on

basement membrane interrupted by numerous narrow slits;

reticulin fibers arranged circularly, continuous with reticulin meshwork of parenchyma;

blood from parenchyma squeeze between stave cells and narrow slits through walls of sinus; drain into tributaries of splenic vein > hepatic portal vein

nonfiltering (area) parts of red pulp parenchyma: patches or parenchyma devoid of capillaries; greater proportion of T and B lymphocyes and mononuclear phagocytes; adjacent to blind-ended and bulb-shaped sinuses with endothelial cells possessing antigens of high endothelial venules (sometimes considered part of lymphoid [white] tissue)

perilymphoid = perifollicular zone (zone of red pulp immediately surrounding T and B lymphoid masses: devoid of sinuses; sparse reticulin meshwork; also contains sheathed capillaries: cylindrical arrangement of mononuclear phagocytes; blood leaves capillaries and enters red pulp; sluggish flow may enhance interaction of blood cells, antigens and antibodies.

last revised: 02-01-05