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IMS: Microanatomy > Lymphoid Organs > Flashcards

Lymphoid Organs Flashcards

1
Q

Diffuse Lymphoid Tissue

A

CT with abundant unorganized lymphocytes but no nodules.

Ex:

lamina propria

airways

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2
Q

Isolated Lymphoid Nodules

A

Organized spherical clusters of tightly packed lymphocytes.

  • Composed mainly of B-cells
  • Occurs in two forms:
    • Primary nodules: small inactive B-cells
    • Secondary nodules: activated proliferating B-cells in lighter germinal center
      • Indicates that an Ab-producing immune response is occurring
  • Temporary structures not always present in the same site
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3
Q

Aggregated Lymphatic Nodules

A

Large group of nodules that are reliably present in specific locations.

Ex:

Appendix

Peyer’s patch in ileum of small instestine

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4
Q

MALT

A

Mucosal-associated Lymphoid Tissue

  • Found in the lamina propria of hollow organs

GALT - gut-associated

BALT - bronchus-associated

NALT - nasal-associated

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5
Q

Lymphocyte Development

A
  1. Originates in bone marrow from pluripotential hematopoietic stem cells
  2. Differentiates in primary lymphoid organs
    • B-cells in bone marrow
    • T-cells in thymus
    • Ag independent
  3. Leave as naÏve lymphocytes and migrate to secondary lymphoid tissues/organs
  4. Activation occurs in an Ag-dependent manner
    • Results in blast transformation
      • Enlargement
      • Clonal proliferation
      • Differentiation
        • Effector cells
        • Memory cells
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6
Q

Thymus Embryology

A
  • Develops from endoderm of 3rd pharyngeal pouch
  • Two thymic primordia migrate into thorax
  • Fuse to form bi-lobed organ located below sternum
  • Initially composed only of Thymic Epithelial Cells (TECs) aka epithelial reticular cells (ERCs)
    • Have elongated processes connected via desmosomes
    • Become stromal cells of thymus
  • Precursor T-cells migrate into thymus and push in between TECs
  • Functional at birth
  • Involutes at puberty
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7
Q

Thymus Anatomy

A
  • Capsule: thin layer of dense irregular CT with collagen type I and reticular fibers
  • Septa: sheets of CT that extend inward from capsule
    • Divides thymus into lobules
    • Carry major blood vessels into lobules
  • Cortex: dark-staining outer region of each lobule
    • Contains relatively more lymphocytes than medulla
    • Also containes TECs and macrophages
  • Medulla: pale inner region
    • Continuous throughout the whole organ
    • Contains more TECs, thymic dendritic cells, macrophages and fewer thymocytes than cortex
  • Blood Vessels: capsule → septa → corticomedullary boundary → capillaries
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8
Q

Thymocyte Maturation

A
  • Surface markers change as cells mature
  • TCR development
  • Become commited to particular T-cell linage
    • Helper vs cytotoxic
  • Undergo two selective processes:
    • Positive selection
    • Negative selection
  • More than 95% die by apoptosis and phagocytized by macrophages
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9
Q

Thymocyte Migration Path

A
  • Leave bone marrow and enter thymus via HEV at the corticomedullary boundary
  • Migrate to outermost cortex
  • Migrate back towards corticomedullary boundary
  • Enter medulla
  • Leave via post-capillary venules at corticomedullary junction or via lymphatics
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10
Q

Thymocyte Surface Markers

A
  1. Enter thymus as double negative cells
  2. Become double positive cells (CD4+, CD8+)
  3. Develop TCR and CD3
  4. Become single positive cells (either CD4 or CD8)
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11
Q

Blood Thymus Barrier

A

Developing thymocytes must be shielded from Ag exposure while in the cortex to prevent apoptosis/anergy.

Barrier formed by:

  • Continous layer of Type I TECs just beneath capsule joined by tight junction
  • Double layer of Type 3 & 4 TECs joined by tight junctions at the corticomedullary boundary
  • Basal lamina of TEC’s
  • Capillary endothelial cells joined by tight junctions
  • Basal lamina of endothelial cells
  • Perivascular space containing CT cells and fibers

Blood-thymus barrier is leakier in the medulla.

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12
Q

Thymocyte Selection

A

Positive Selection

  • Occurs in cortex
  • Double positive thymocytes must bind to self MHC molecules on TECs
    • Binding results in positive “to live” signal
    • Cells that cannot bind die by neglect
  • Eliminates thymocytes that are unable to bind self-MHC (~95-99%)

Negative Selection

  • Occurs primarily in the medulla (also the cortex under certain conditions)
  • Eliminates thymocytes that are specific for self-antigens
  • Binding of thymocytes to Ag on dendritic cells, medullary TEC’s, and macrophages results in apoptosis
    • Medullary APC’s show promiscuous antigen expression
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13
Q

TEC

Characteristics

A
  • Found in both cortex and medulla
  • Poorly phagocytic
  • Pale cells with euchromatic nucleus
  • Long thin cytoplasmic processes
  • Connected to one another via desmosomes
  • Some also connected via tight junctions
  • Tonofibrils composed of cytokeratin tonofilaments by EM
    • Characteristic of epithelial cells
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14
Q

TEC

Functions

A
  • Structural support
  • Secrete chemokines
    • Attract pre-cursor thymocytes
    • Ex. Thymus-expressed chemokine (TECK)
  • Secrete cytokines
    • Induce thymocyte maturation
    • Ex. Stromal cell-derived factor-1 (SDF-1)
  • Creates seperate microenvironments within the thymus
  • Contributes to blood-thymus barrier
  • Form Hassall’s corpuscles in the medulla
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15
Q

TEC

Classification

A

Cortical TECs

  • Type I TECs
    • Forms sheets of cells joined by tight junctions
    • Lines inner surface of capsule and covers CT septa
    • Contributes to blood-thymus barrier seperating cortex and extra-thymic environment
  • Type II TECs (Thymic Nurse Cells)
    • Long processes connected by desmosomes
    • Forms a network throughout cortex
    • Surrounded by clusters of thymocytes
    • Secrete factors that influence thymocyte development
    • Participate in positive selection
  • Type III TECs
    • Forms continuous layer at corticomedullary boundary
    • Connected by tight junctions
    • Contribute to barrier between cortex and medulla

Medullary TECs

  • Type IV TECs
    • Forms layer just beneath type III TECs at the cortico-medullary boundary
    • Joined to one another and type III TECs by tight junctions
  • Type V TECs
    • Stellate cells connected by desmosomes
    • Forms meshwork throughout medulla
    • Participates in negative selection
  • Type VI TECs
    • Arranged in concentric layers to form Hassall’s corpuscles
      • Center may become calcified, keratinized, or necrotic
    • Produce a variety of cytokines
      • Thymic stromal lymphopoietin (TSLP) which activates thymic denritic cells which then activate TReg
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16
Q

Tingible Body Macrophages

A

Cytoplasm contains dark-staining apoptotic bodies (tingible bodies) from dead thymocytes.

May have large lysosomes that are PAS+ = also called PAS cells.

May act as APCs in negative selection.

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17
Q

Thymic Dendritic Cells

A
  • Found in the medulla
  • Functions as APCs in negative selection
  • Bone-marrow derived
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18
Q

Thymic Involution

A

Age Involution

Functional at birth → largest at puberty → begins to involute after puberty.

Some functional thymic tissue remains throughout life.

Adipose tissue fills in involuted areas.

Accidental Involution

Early or accelerated involution can occur due to:

Steroid hormones

Severe infections

Chronic illness

Severe stress

Ionizing radiation

Delayed Involution

Can be induced in animals with castration which prevents high levels of steroid hormones at puberty.

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19
Q

DiGeorge Syndrome

A

Congenital Thymic Aplasia

  • Congenital malformation of structures derived from 3rd and 4th pharyngeal pouches
  • Thymus underdeveloped or absent
  • Immunocompromised
  • Many die young due to infection
  • Congenital heart defects also present
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20
Q

Myasthenia Gravis

A
  • Autoimmune disease with Ab against Ach receptors at NMJ of skeletal muscles
  • ~ 75% of patients also have thymic abnormalities
    • Hyperplasia
    • Thymoma
  • May begin in the thymus where some stromal cells ectopically express AchR
  • Therapeutic thymectomy sometimes performed
21
Q

Lymph Node Anatomy

A
  • Encapsulated
  • Receives lymph via numerous afferent lymphatic vessels which enter the convex surface
  • Lymph exits via efferent lymphatic vessels at the hilus
  • Blood vessels enter and exit at the hilus
  • Interior organized into 3 concentric layers:
    • Cortex
    • Paracortex
    • Medulla
22
Q

LN Cortex

A
  • Outermost region immediately deep to subcapsular lymphatic sinus
  • Darkly basophilic due to abundant lymphocytes
  • Has 2 components:
    1. Lymphoid nodules
      • spherical/ovoid structures
      • Contains mainly B-cells
      • Thymus-independent regions
    2. Internodular cortex
      • Region between nodules
      • Contains mainly T-cells
      • Thymus-dependent regions
23
Q

LN Paracortex

A
  • Lies deep to cortex
  • Contains no lymphoid nodules
  • Dark-staining
  • Contains mainly T-cells
    • Thymus-dependent region
  • Contains HEVs which deliver most of the lymphocytes to a node
24
Q

LN Medulla

A
  • Central portion of the LN
  • Lighter staining due to many lymphatic sinuses
  • Has 2 components:
    1. Medullary sinuses (light staining)
    2. Medullary cords (dark staining)
      • Forms continuous network which completely surrounds each medullary sinus
  • At the hilus there is no cortex or paracortex so the medulla is in direct contact with the capsule
25
Q

Lymphoid Nodules (Follicles)

A

Found in LN and other secondary lymphoid organs.

Areas to which B-cells preferentially migrate.

Contains smaller numbers of:

Follicular dendritic cells, macrophages, and few T-cells.

26
Q

Primary Nodules

A
  • Stains uniformly dark
  • Contains small inactive B-cells
  • Develop into secondary nodules when activated B-cells proliferate within them
  • Regress to primary nodules when immune response is over
27
Q

Secondary Nodules

A
  • Sites where activated B-cells are dividing and maturing as part of a humoral immune response
    • Somatic hypermutation
    • Affinity maturation
    • Class switching
    • Maturation of plasmablasts and memory B-cells
  • Have two components:
    • Germinal center
      • light-staining central region
      • site where B-cell proliferation and maturation occurs
    • Cap/Mantle/Corona
      • Dark staining peripheral region
      • Contains small inactive lymphocytes that get pushed to the edge of the nodule by rapidly dividing B-cells
28
Q

Germinal Centers

A

Well-developed germinal centers can be subdivided into a dark zone and light zone.

Activated B-cells move from dark zone to light zone.

Dark Zone

  • Usually nearest to the T-cell region in paracortex
  • Site of intense proliferation of activated B-cells
    • Many mitotic figures
  • Dividing B-cells in the dark zone called centroblasts
    • Centroblasts undergo somatic hypermutation and Ab affinity maturation

Light Zone

  • Centroblasts migrate into light zone and then known as centrocytes
  • Rate of mitosis decreases
  • Centrocytes interact with follicular dendritic cells (FDCs)
29
Q

Follicular Dendritic Cells

(FDCs)

A
  • Stromal cells of lymphoid nodules
    • Only found there
  • Have long cytoplasmic processes with a beaded appearance
  • Are not derived from PHSC
  • Do not process Ag, therefore, are not technically APCs
  • FDCs bind Ag-Ab complexes via Fc receptors
    • Presents complexes to activated B-cells
    • Binding triggers FDCs to deliver a rescue signal
    • TH cells supply a second rescue signal
  • Important in B-cell selection and affinity maturation
30
Q

Plasmablasts

A

Activated B-cells which survive selection develop into either plasmablasts or memory B-cells.

  • Plasmablasts are Ab-producing B-cells
  • Leave germinal centers and differentiate into plasma cells
31
Q

Plasma Cells

A
  • Produce Ab for several weeks then die
  • Within a lymph node, plasma cells are most abundant in medullary cords
  • Most plasma cells leave the node via efferent lymphatics
  • Are returned to the blood and distributed to tissues/organs
  • Old plasma cells may contain large eosinophilic Russel bodies = Russel body cells
    • Russel bodies are swollen cisternae of RER filled with Ab
32
Q

Lymphatic Circulation

Within LN

A

Afferent lymphatic vessels → subcapsular sinus → trabecular sinuses → medullary sinuses → efferent lymphatic vessel.

  • Afferent lymphatics
    • Carry lymph to the nodes
    • Lymph nodes are the only organs that have afferent lymphatics
    • Valve prevents backflow
  • Subcapsular sinus
    • One continuous space which lies just deep to the capsule
    • Seperates capsule from cortex
    • Receives lymph from afferent lymphatics
  • Trabecular sinuses (aka intermediate sinuses)
    • Receive lymph from subcapsular sinus
    • Each trabecular sinus surrounds a trabecula
    • Short, straight, and few in number
  • Medullary sinuses
    • Receive lymph from trabecular sinuses
    • Pass through the medulla of the node
    • Very numerous
    • Irregular in shape
    • Unite at the hilus to form the efferent lymphatic vessel
    • Surrounded by medullary cords
  • Efferent lymphatic
    • Leaves node at the hilus
    • Valves prevent backflow
    • The efferent vessel of one node typically becomes the afferent vessels of next node in the chain

Intra-nodular channels (subcapsular, trabecular, medullary):

  • Lack valves
  • Have discontinuous endothelium
    • Highly permeable
  • Have stroma within lumen which attaches to capsule and trabeculae
    • Composed of reticular cells and reticular fibers
    • Physically traps particulate Ag in the lymph
    • Also supports parenchymal cells
    • Have fixed macrophages which adhere to the stroma and phagocytize Ag

Efferent lymphatics gradually unite into large lymphatic vessels that deliver filtered lymph back to blood by emptying into large veins at base of the neck.

33
Q

Lymphocyte Entry into LN

A
  • Most lymphocytes enter LN via blood through high endothelium venules (HEVs)
    • Located in the paracortex
    • Have cuboidal to columnar endothelial cells
  • Some enter via afferent lymphatics
34
Q

Lymph Node

Typical Immune Response

A
  1. Arrival of antigen
    • Ag picked up by lymphatic capillaries and carried to nearby LN arriving via afferent lymphatic
    • 3 forms of Ag
      • Free antigen
      • As part of Ag-Ab complex
      • Bound to APC
  2. Arrival of lymphocytes
    • Most arrive via HEV’s and migrate from paracortex to T or B cell regions within LN
    • “Homing” occurs in response to chemokines secreted by stromal cells
      • IDCs in T-cell zones attract T-cells
      • FDCs in follicles attract B-cells
    • T-cells tend to remain in paracortex or internodular cortex
    • B-cells migrate to lymphoid nodules in cortex
  3. Lymphocyte activation, blast transformation, and replication
    • Most responses start in paracortex where APCs activate naïve T-cells
    • Activated TH cells divide and migrate towards cortex to B-cell zone
    • TH cells activate B-cells with similar Ag specificity
    • Small foci of activated B-cells proliferate outside of nodules
    • After several days, activated B-cells migrate into primary nodules, divide rapidly, and form secondary nodule.
    • Activated B-cells differentiate into plasmablasts or memory B-cells
    • Activated lymphocytes remain within LN for several days due to loss of sphingosine-1-phosphate (S1-P) receptors during activation (shut-down phase)
      • S1-P receptors required for exit from LN & thymus
      • Lymphocytes migrate up gradient of S1-P which is higher in circulating lymph than in nodal parenchyma
      • Re-express receptors after several days and can exit
    • Plasmablasts migrate to medullary cords or exit node
    • Memory B-cells remain in mantle of GC or migrate with memory T-cells to medullary cords/efferent lymphatics
    • Lymphadenopathy occurs due to retention and replication of activated T & B cells
35
Q

Langerhans Cells

A
  • Immature dendritic cell found in the skin
  • Within lymphatic vessels, develop sheet-like cytoplasmic projections called “veils” and are called veiled cells
  • Within lymph node, changes shape and becomes interdigitating dendritic cells (IDCs)
    • Localize in T-cell zones and helps activate T-cells
36
Q

Reactive Node Morphology

A

Most immune responses involve both cell-mediated (T-cells) and humeral responses (B-cells) but in some cases one type of response predominates.

  • If Ab production predominates:
    • Node shows follicular hyperplasia
    • Minimal paracortex hypertrophy
    • Ex. Rheumatoid arthritis
  • If cell-mediated response predominates:
    • Node shows paracortical hyperplasia
    • Few secondary nodules develop
    • Ex. Viral infections
37
Q

Other Causes of Lymphadenopathy

A
  • Microbial infection within the node
    • Yersinia pestis replicates within lymph nodes
      • Causes bubonic plague
    • Swollen, black LN called bubo
  • Primary malignancies of the lymphocytes of the node
    • Ex. cancers such as Hodgkin’s lymphoma
  • Replication within the node of metastatic malignant cells
  • Malignant nodes are usually slow-growing and non-tender
38
Q

Lymphocyte Recirculation

A

Lymphocytes are the only type of leukocytes which recirculate via lymph and blood.

  • Leave LN via efferent lymphatics → large veins → secondary lymphoid organs and lymphoid tissues via arterial system
    • Naïve lymphocytes recirculate to any secondary lymphoid organ
    • Effector cells usually recirculate to site of infection/inflammation via chemokines
    • Memory lymphocytes return to the type of lymphoid tissue where they first encountered Ag
39
Q

Splenic Functions

A
  1. Filters Ag from blood and initiates immune responses
    • Occurs within the white pulp
      • Lymphoid region
      • Basophilic & darker in H&E due to lymphocytes
      • Paler in fresh sections due to fewer RBC’s
  2. Destroys senescent RBC’s
    • Occurs in red pulp
      • Non-lymphoid region
40
Q

Splenic Anatomy

A
  • Covered in mesothelium d/t intraperitoneal location
  • Thick capsule of dense irregular CT
    • Contains some contractile myofibroblasts
  • Trabeculae of CT extends inward from capsule
  • Stroma consists of reticular fibers and reticular cells
    • Found in both red and white pulp
    • Provides support
    • Produces chemokines which attract T & B cells
  • Hilus where blood vessels enter and leave & efferent lymphatics leave
41
Q

Splenic

White Pulp

A
  • Many seperate areas of white pulp scattered throughout spleen
  • Each organized around a central artery
  • Has two structural components:
    1. Periarteriolar lymphatic sheath (PALS)
      • Forms cylindrical sheath of lymphocytes around each central artery
      • Composed mainly of T-cells
        • Thymus-dependent region
      • Contains dentritic cells which activate T-cells
    2. Lymphoid nodules
      1. Embedded in the PALS
      2. B-cell region
      3. Primary vs secondary
      4. Nodules often push central artery to edge of white pulp
  • Often not possible to see exact boundary between PALS and nodule
42
Q

Splenic

Red Pulp

A

Has 2 structural components:

  1. Splenic sinuses (aka venous sinuses or sinusoids)
    • Highly permeable sinusoidal capillaries
    • Contains blood, not lymph
  2. Splenic cords (Bilroth’s cords)
    • Regions of parenchyma that surrounds splenic sinuses
    • Sites where old RBC’s destroyed
43
Q

Marginal Zone

(MZ)

A
  • Several layer of reticular fibers and flattened cells that surrounds each area of white pulp
  • Acts as interface between red and white pulp
  • Mixed cell population (T-cells, B-cells, DCs, several types of macrophages)
  • Marginal zone B-cells
    • Seperate subpopulation of B-cells specialized to detect blood-borne viruses and bacteria
    • Rapidly become IgM-producing plasma cells without T-cell help
  • Supplied by side braches arising from central arteries
  • Traps antigens and presents to lymphocytes
44
Q

Splenic Circulation

A

Spleen has both open and closed circulatory systems.

splenic artery (enters hilus) →

capsular arteries →

trabecular arteries →

central artery (WP) with side branches which open in marginal zone →

splenic cord (red pulp) →

penicillar arterioles →

aquires a sheath of macrophages = sheathed capillary →

open circulation in splenic cords of red pulp →

cells re-enter between endothelial cells of splenic sinuses →

pulp veins →

trabecular veins →

capsular veins →

splenic vein (exits hilus) →

hepatic portal vein

45
Q

Splenic Sinuses

A
  • Main type of vessel in red pulp
  • Wide & highly permeable
  • Spindle-shaped endothelial cells
    • Long axis parallel to vessel
    • Large lateral gaps common
      • Easy for most blood cells to cross sinusoidal wall
      • Old RBCs less flexible and get stuck
  • Discontinuous basement membrane organized into hoops
    • Encircles the sinus
    • Stains with silver stain or PAS
  • Reticular cell processes form an incomplete layer around each sinus
    • Make reticular fibers which are part of basement membrane hoops
  • No stroma
46
Q

Splenic Immune Response

A
  • Side branches of central arteries open into marginal zone delivering blood with:
    • T & B lymphocytes
      • T-cells migrate from MZ into PALS
      • Follicular B-cells migrate from MZ into lymphoid nodules
    • APCs carrying processed Ag
      • APCs migrate into white pulp especially PALS
    • Soluble Ag
  • Naïve T and B cells leave via efferent lymphatics and recirculate
  • APCs activate T-cells in PALS
  • Activated T-cells migrate to edge of nodule and help activate follicular B-cells
  • Activated B-cells undergo blast transformation producing germinal center of secondary nodule
  • Plasmablasts leave nodules and differentiate into plasma cells
    • Plasma cells most abundant in splenic cords
47
Q

Red Pulp Function

A
  1. Destruction of old RBCs
    • Senescent RBCs lose flexibility and tend to fragment as they are pushed between endothelial cells of splenic sinuses
    • Macrophages can also recognize changes in RBC membranes
      • Binding of auto-Ab to band 3
      • Transfer of PS from inner to outer leaflet
      • Cleavage of sialic acid from carbohydrate side chains of membrane glycoproteins exposing terminal mannose
  2. Breakdown of hemoglobin:
    • Macrophages break down hemoglobin into AA, iron, and heme
    • Heme converted to biliverdin and iron
    • Biliverdin converted to bilirubin and carried to liver
      • Liver converts bilirubin to bilirubin glucuronide and secretes into duodenum as part of bile
    • Iron bound to transferrin and carried to bone marrow
48
Q

Splenomegaly

A

Enlarged spleen

Has many diverse causes including:

  • Diseases with excessive RBC destruction
    • Hereditary spherocytosis
    • Sickle cell anemia
    • Spleen enlarges due to congestion of splenic cords with defective blood cells
  • Certain lysosomal storage diseases
    • Phagocytic cells throughout the body accumulate indigestible substrates due to lack of a normal lysosomal enzyme

IMS: Microanatomy (16 decks)

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