Lymphatic System

Lymphatic vessels 1lymphoid organs Thymus Bone marrow 2lymphoid organs Lymph nodes Adenoids Tonsils Spleen Appendix SALT ALT BALT

A! "unctions 1! #emove excess interstitial $uid 2! Transport o% dietary lipids &! Speci'c immunity (as compared to non)speci'c immunity*

Lymph organs and tissues

+rimary (re,uired %or stem cell immunocompetance* i! red marrow produces all lymphoid precursor cells -ut also .educates. B)lymphocytes ii! thymus .educates. pre)Tlymphocytes %rom -one marrow/ ma0ing mature T)lymphocytes! ost active until pu-erty!

PRIMARY LYMPHOID ORGANS

+rimary lymphoid organs are where lymphocytes arise and mature in the a-sence o% antigenic stimuli! They are the -one marrow and thymus! Bone marrow: the so1 tissue in the hollow center o% -ones Source o% all hematopoietic progenitor (stem* cells/ site o% B cell maturation post)-irth in mammals!
hematopoietic stem cell stromal stem cell 2 secretes cyto0ines %or the stimulation o% B) cell maturation

Thymus
Bilo-ed organ Located in the anterior mediastinum o% the thoracic cavity anterior to the trachea and heart and great vessels and posterior to sternum! Site where lymphoid cells undergo maturation and education into T cells prior to release into the circulation! This process allows T cells to develop the important a3ri-ute 0nown as sel%)tolerance! 4specially important in new-orn -a-ies without a thymus a -a-y5s immune system collapses and the -a-y will die 6radually enlarges during childhood A1er pu-erty it undergoes a process o% involution resulting in a reduction in the %unctioning mass o% the gland! 7t continues to %unction throughout li%e/ however!

A! Stroma 1! capsule 2! tra-eculae (strands o% connective tissue into parenchyma* a! lo-ules (outer cortex 8 inner medulla* &! 7nterdigitating dendritic cells 2 ma0e organ %rameowr0 contri-ute to growth 8 maturation o% thymocytes

B! +arenchyma 1! cortex a! immature T lymphocytes 7mmature lymphoid cells enter the cortex/ where they proli%erate/ mature/ and move to the medulla/ %rom where mature T lymphocytes enter the circulation! 9urse cells 2 thymic epithelial cells with long mem-rane extensions :ortical epithelial cells 2 %orm networ0 -y long interconnecting cytoplasmic extensions

2! medulla a! T lymphocytes enter venules -! ;assall<s corpuscles 2 eosinophilic solid

:! ;istophysiology 1! T lymphocytes originate in -one marrow 2! involution a1er pu-erty a! parenchyma replaced -y %at &! A7=S virus 0ills helper T cells

Secondary Lymphoid >rgans

+eripheral lymphoid organs? lymph nodes/ spleen/ tonsils/ adenoids/ and lymphoid tissue associated with other organ systems (gut/ s0in/ mucosa*! Along the vessels o% lymphatic system control the ,uality o% immune responses @ell organiAed 8 encapsulated 2 Spleen 8 Lymph nodes =iBused 8 unencapsulated aggregation o% lymphoid tissues 2 ALT

=iBerences among the various lymphatic tissues signi'cantly aBect the %orm o% immunity and relate to how antigens are ac,uired -y these organs 2 lymph nodes are 'lters o% lymph/ spleen is a 'lter o% -lood/ and mucosal associated lymphatic tissues ac,uire antigens -y transcytosis to lymphoid tissue %rom the .external. environment across specialiAed %ollicle)associated epithelial cells

This drawing simpli'es structures and connections o% secondary lymphatic tissues where antigen may most eCciently direct immune responses! ultiple 0nown and un0nown %actors intrinsic to the microenvironments o% lymph node/ spleen and mucosa associated lymphatic tissue (here ALT is represented -y +eyer5s patches* in$uence whether a .peripheral. or .mucosal. type o% response occurs! The drawing also indicates that these tissues are integrated with each other and the rest o% the individual through vascular and lymphatic connections and a system o% lymphocyte recirculation! icroenvironmental structures in the drawing are identi'ed -y the sym-ols -elow

4ncapsulated 8 -ean shaped containing lymphocytes/ macrophages 8 =:<s in a reticular networ0 "ilter lymphatic $uidD Sites o% Ag presentation 8 cell traCc "irst organiAed lymphoid structure to encounter Ag<s that enter tissue spaces
Cortical nodules (follicles)

Lymph 9odes

Cortex

Medullary sinuses

Functions o s!ruc!ura" e"emen!s o "ym#h no$es

Subcapsular Sinus

Lymphatic system ) a series o% vessels which drain and 'lter the tissue $uids! Lymph enters the node via aBerent lymphatics/ passes through the sinuses lined with macrophages and leaves via eBerent lymphatic (ultimately all drain into the portal vein*!

Lymphocytes enter the node primarily %rom the -lood via ;4E and leave via eBerent lymphatics! =:s migrating %rom tissue enter the node into the T cell areas! B cells entering nodes %rom -lood must cross the T rich area in transit to the B cell rich areas thus optimiAing T)B cooperation! The B cell rich areas contain mature/ resting B cells organiAed into structures around %ollicular dendritic cells (primary %ollicles*!

A! 6ross Anatomy 1! -ean shaped/ with hilus 2! aBerent 8 eBerent lymphatics &! located throughout -ody along lymphatics B! Stroma 1! capsule 2! tra-eculae &! reticular '-ers

:! +arenchyma 1! su-capsular sinus a! diagnostic %eature 2! cortex a! lymph nodulesF%ollicles 1* B lymphocytes -! inner cortex F paracortex 1* T lymphocytes c! intermediate F tra-ecular sinuses &! medulla a! medullary cords (B cells* -! medullary sinuses

+arenchyma ) three components? G cortex G paracortex G medulla G :ortex (B cell area* +rimary %ollicle s (lymphocytes / mostly resting B cells/ macrophages 8 "=:<s* Ag challange Secondary %ollicles 2 contains germinal center (discrete lymphoid compartments where B%ce""s undergo division/ isotype switching and memory development*

B cells via ;4Es 7n lymph node 7n %ollicles

Stimulated B cells ) proli%erate and remain in the node! Activated B cells within the lymphoid %ollicles ) follicle centre cells centroblasts (cells with cleaved nuclei) centrocytes (cells with larger more open nuclei and several nucleoli ) to paracortex 8 medullary sinuses immuno-lasts plasma cellsFmemory cells The pale staining central area o% a secondary %ollicle ) germinal centre ) surrounded -y a mantle Aone o% small/ naive B cells and a %ew T cells Hnstimulated B cells ) return to the general circulation!

B cells alone are not a-le to mount immune responses! They are assisted -y accessory cells? G sinus macrophages (highly phagocytic* G tingi-le -ody macrophages (ingest cellular de-ris in germinal centres* G marginal Aone macrophages (%ound -eneath the su-capsular sinus* G %ollicular dendritic cells

B cell differentiation in the germinal center

mature B cell bacteria helper T cell

Centrobla+t
D"%* ZON

!CL"## #$ITCH % CO&BIN"TION !#O&"TIC H'( %&)T"TION

LIGHT ZON

FDC

centrocyte

Memory B cell Plasma B cell

apoptosis anergic

+aracortex (T cell area* contains lymphocytes and accessory cells along with supporting cells! predominant site %or T cells within the lymph node! The various types o% T cell enter the node %rom the -lood via the ;4Es! @hen activated they %orm lympho-lasts/ which divide to produce a clone o% T cells responding to a speci'c antigen! Activated T cells then pass into the circulation to reach peripheral sites! Accessory cells? 7nterdigitating cells are numerous in the paracortex and act as Ag)presenting cells!

edulla comprised o%? G large -lood vessels G medullary cords G medullary sinuses The medullary cords are rich in plasma cells/ which produce Athat pass out o% the node via the eBerent lymphatic! Macrophages are also numerous within the medulla! Lymph passes into the node through the aBerent lymphatic into the marginal sinus/ though the cortical sinuses to reach the medullary sinuses -e%ore leaving via the eBerent lymphatic!

+articulate ma3er in the lymph is removed -y macrophages! Antigens are ta0en up -y antigen presenting cells and these %acilitate the speci'c immune response! Less than 1IJ o% lymphocytes enter the node in the lymph/ the large maKority entering %rom the -lood via the ;4Es! 7n%ectionFAg challenge "i1y %old increase in lymphocytes in eBerent lymph vessel than in aBerent lymph vessel (@hyL*

Spleen? de'nition(s*
a highly vascular ductless organ that is located in the le1 a-dominal region near the stomach or intestine o% most verte-rates and is concerned with 'nal destruction o% red -lood cells/ 'ltration and storage o% -lood/ and production o% lymphocytes

Spleen

PALS

Two distinct components o% the spleen ) red pulp and the white pulp #ed pulp ) large num-ers o% sinuses and sinusoids 'lled with -lood ) responsi-le %or the 'ltration %unction o% the spleen! @hite pulp ) aggregates o% lymphoid tissue ) responsi-le %or the immunological %unction o% the spleen!

aKor %unctions? G7t is responsi-le %or the destruction o% old red -lood cells (#B:s*D G7t is a maKor site %or mounting the immune response! "ilters -lood ) Blood entering the spleen travels through progressively smaller arterioles until it is deposited in the red pulp/ where the #B:s are processed! Surrounding the arterioles is a sheath o% lymphoid cells/ which ma0e up the periarteriolar lymphoid sheath (PALS)! The inter%ace -etween +ALS and -lood is a region o% intense phagocytic activity and sets the stage %or immune responses! The immune reactivity o% the spleen is especially eBective %or dealing with -lood)-orne antigens such as -acteria!

INSID& TH& SPL&&N

Re$ #u"#
;as a complex system o% -lood vessels within it/ arranged to Red %acilitate removal o% old or pulp damaged red -lood cells %rom the circulation! A small proportion o% splenic -lood $ow passes through more rapidly without undergoing 'ltration!

'h(!e #u"#

"apsule ra!ecula Vascular sinusoids Primary follicle Margin Whit alzone e Periarterial pulp lymphatic sheath (PALS) Germinal center Vein Artery

Red pulp

:ontains T cells/ B cells and accessory cells! Similar with lymph node structure in many respects! +urpose ) to mount an immunological response to antigens within the -lood +resent in the %orm o% a periarteriolar lymphoid sheath ) contains B cell %ollicles and T cells! At the edge o% the T Aone ) marginal Aone ) larger lymphocytes and antigen presenting dendritic cells are located!

A! Stroma 1! capsule 2! tra-eculae &! reticular '-ers B! +arenchyma F Splenic +ulp 1! white pulp 2! red pulp &! splenic artery a! tra-ecular arteries -! central arteries 1* +ALS c! splenic sinusoids d! tra-ecular veins e! splenic vein

:! @hite pulp 1! +ALS a! T lymphocytes =! #ed pulp 1! splenic cords a! B8T lymphocytes -! reticular cells c! plasma cells d! macrophages 2! splenic sinusoids

4! ;istophysiology 1! lymphocyte production a! white pulp 2! erythrocyte removal a! macrophages &! immune de%ense a! B and T cells -! macrophages Mcleanses the -loodN Msimilar %unctions carried out -y liver/ other lymph organsN

M)*OSA%ASSO*IAT&D LYMPHOID TISS)& +MALT,

9onencapsulated su-mucosal lymphoid nodules and diBuse lymphocytic in'ltrates in the su-mucosa o% intestinal and respiratory tracts consists o% aggregates o% lymphocytes/ macrophages/ =:s/ and other accessory cells Sca3ered throughout the lamina propia in the gut @or0 collectively with regional lymph nodes and spleen to produce B) and T)eBector cells which lodge in lamina propria and in intraepithelial locations wherever there is mucosa 9asopharyngeal lymphatic tissues (ie tonsils and adenoids in man*/ -ronchus associated lymphatic tissues/ +eyer5s patches/ appendix and isolated %ollicles in intestitinal mucosae Eary with regard to type o% sur%ace epithelium (stati'ed s,uamous/ ciliated columnar/ or a-sorptive columnar* and relative proportions o% T) and B)cells All have . . cells in their %ollicle associate epithelium ucosal lymphatic tissues ampli%y development o% commi3ed B)cells %or secretory 7gA responses to enviromental antigens and programs certain environmental antigens %or systemic tolerance induction which does not eBect production o% B)cells commi3ed to 7gA secretion! . ucosal. tolerance is mani%ested -y antigen)speci'c suppression o% delayed cutaneous hypersensitivity and reduced 7g6 expression Large population o% anti-ody)producing plasma cells (%ar more than plasma cells in the spleen/ lymph nodes/ and -one marrow com-ined*

G)T%ASSO*IAT&D LYMPHOID TISS)& +GALT,

>uter mucosal epithelial layer contains so)called (n!rae#(!he"(a" "ym#hocy!es +I&Ls,lamina propria/ lies under the epithelial layer/ contains large num-ers o% B cells/ plasma cells/ activated T; cells/ and macrophages in loose clusters! Su-mucosal layer -eneath the lamina propria contains +eyer<s patches/ nodules o% &I2OI lymphoid %ollicles Large aggregates o% 6ALT have distinct B cell %ollicles and T cell areas! Antigen presenting accessory cells are also present! Lymphocytes %orm domed %ollicles o% B cells surrounded -y T cells! +eyer5s patches %acilitate the generation o% an immune response within the mucosa! B cell precursors and memory cells are stimulated -y Ag in +eyer5s patches! :ells pass to the mesenteric lymph nodes where the immune response is ampli'ed! Activated lymphocytes pass into the -lood stream via the thoracic duct! These cells then home in the gut and carry out their 'nal eBector %unctions! ;4Es are not present in +eyer5s patches! 9o aBerent lymphatics and no medullary cords %or local accumulation o% plasma cells

Some epithelial cells have complex micro%olds in their sur%aces! Pnown as M (multifenestrated) cells/ $a3ened epithelial cells lac0ing the microvilli/ they collect Ag (endocytose and transport various materials without lysomal degradation*! cells have a deep invagination/ or poc0et/ in the -asolateral plasma mem-raneD this poc0et is 'lled with a cluster o% B cells/ T cells/ and macrophages! Q Luminal antigens are endocytosed into vesicles that are transported %rom the luminal mem-rane to the underlying poc0et mem-rane! Q The vesicles then %use with the poc0et mem-rane/ delivering the potentially response)activating antigens to the clusters o% lymphocytes contained within the poc0et! Q cells are located in so)called (n$ucti.e s(!es/sma"" re0(ons o a mucous mem-rane that lie over organiAed lymphoid %ollicles! Q Antigens transported across the mucous mem-rane -y within these lymphoid %ollicles! cells can activate B cells

Q The activated B cells diBerentiate into plasma cells/ which leave the %ollicles and secrete the 7gA class o% anti-odies

ORGANI1ATION OF GALT
M cell follicle#associated epithelium lymphatic net(or) 'illi

high endothelial 'enule

lamina propria Peyer%s follicular $" cellspatch & cells in domed follicle centro!last gut lumen & cells

Tonsil anatomy
+haryngeal tonsils +alatine tonsils Lingual tonsils Aggregations o% lymph nodules

"rom human anatomy text

Tonsils
A! aggregations o% lymph nodules B! incompletely encapsulated :! crypts

Tonsils
=! +alatine tonsils 1! pharynx 2! strati'ed s,uamous epithelium &! crypts 4! +haryngeal tonsils 1! pharynx 2! +S:: "! Lingual tonsils 1! -ase o% tongue 2! strati'ed s,uamous epithelium &! one crypt

:ells o% SALT include 0eratinocytes/ Langerhans cells (immature =:s %ound in s0in*/ intraepiethelial T cells/ and melanocytes! ononuclear phagocytes in perivenular locations in the super'cial dermis Langerhans cells %orm a continuous epidermal meshwor0? they capture Ag/ then migrate to draining lymph nodes/ where they act as Ag)presenting cells! The maKority o% T cells are %ound in the dermal layer o% s0in! +assenger leu0ocyte that initiates allogra1 reKection via antigenF:lass 7 ;: expression is also a Lan0erhans ce""/ and removal o% the cell or a-lation o% the aBerent lymphatics prevents sensitiAation The epidermis also contains intraepidermal lymphocytes, similar to the intraepithelial lymphocytes o% ALT in that most o% them are :=RS T cells/ many o% which express T)cell receptors/ which have limited diversity %or antigen! Q These intraepidermal T cells are well situated to encounter antigens that enter through the s0in and may play a role in com-ating antigens that enter through the s0in! Q The underlying dermal layer o% the s0in contains sca3ered :=OT and :=RS T cells and macrophages! Q ost o% these dermal T cells were either previously activated cells or are memory cells!

S2IN%ASSO*IAT&D LYMPHOID TISS)& +SALT,

SALT