Histology of Lymphoid Tissue

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Lines of Immune Defense

1. Non-specific protection via:

• Keratin in skin.

• Mucous in respiratory & GI tracts.

• Acid in vagina.

2. Acute Inflammation via

• Emigration into tissues by neutrophils (911) & monocyte-macrophages (garbage men).

3. Immune System via

• Defense against specific targeted agents (a specific response for a specific insult).

Lymphatic Tissue Exists as

1. Individual diffuse cells (lymphocytes).

2. Aggregations of lymphocytes (10 & 20 nodules).

3. Aggregations of nodules (tonsils, Peyer's patches).

4. Lymphatic organs (nodes, spleen, thymus).

Lymphatic tissue as a filter

Lymphatic tissues monitor various fluid tissue compartments for the presence of foreign antigens:

1. Interstitial fluid via diffuse tissue.

2. Lymph via lymph nodes.

3. Blood via spleen & secondarily by liver.

Reticular Fibers

• Lymphocytes of lymphatic tissue are supported by reticular cells & fibers.

• Reticular cells are mesodermally derived fibroblasts specialized for the synthesis & maintenance of the framework of reticular fibers.

• The exception is the thymus that has reticular epithelial cells derived from the 3rd & 4th pharyngeal arch endoderm.

Antigen-Presenting Cells

• Antigen-presenting cells (APC) occur in most tissues.

• They ingest foreign antigens, partially digest them, return selected portions to their cell surface & present them to lymphocytes, thereby activating them.

• APC have ramifying cell processes that increase their surface area to interact with other cells & antigens.

• This branching morphology is the basis for their descriptive name, dendritic antigen-presenting cells.

APC Examples

• Macrophages derived from monocytes.

• Epithelial Langerhans cells of the skin.

• Dendritic cells of lymphoid organs.

• B lymphocytes.

• Epithelial reticular cells of the thymus.

• Microglia.

Antigen Processing

Antigen processing is a necessary step in the immune reaction, as most antigens do not act directly on lymphocytes.

Lymphocytes: 20-50%

White Wlood Cells

• Large nuclear to cytoplasmic ratio.

• Thin rim of blue cytoplasm.

• Many functionally different type B lymphocytes differentiate in bone marrow & mediate humoral immunity, a process that requires the presence of immunoglobulins in the blood.

• T lymphocytes differentiate in the thymus & mediates cellular immunity, a process that requires living cells as opposed to immunoglobulins.

B and T cells

• Both T & B cells have immunologic memory.

• Once exposed to an antigen, lymphocytes undergo mitosis and some form:

Effector cells

• B cells differentiate into plasma cells & produce antibodies.

Memory cells

• Remain quiescent until they encounter the antigen again & can mount a rapid & vigorous response.

B Lymphocytes

• B lymphocytes when stimulated by antigen proliferate & differentiate into plasma cells that produce antibodies.

• Found in mammary glands, epithelia, spleen, lymph nodes.

• Lymphocyte maturation was originally studied in a gut-associated organ called the Bursa of Fabricious & is the origin of the designation of B lymphocyte.

Cytokines

• Cytokines are non-antigen specific soluble factors that are made by or act on elements of the immune system.

• Cytokines produced by lymphocytes are called lymphokines.

• When T cells are stimulated by antigen-antibody complex they produce lymphokines.

• Interleukins are signaling molecules that regulate the immune response or mobilize & activate macrophages & granulocytes.

• There are at least 10 different interleukins.

Lymphocyte Response

When a pathogen invades, lymphocytes respond in 3 ways:

1. B cells secrete antibodies that bind to the pathogen, signaling its degradation by macrophages & other cells.

2. Cytotoxic C cells recognize & kills the cells infected by the pathogen.

3. Helper T cells independently recognize the pathogen & secrete protein factors (lymphokines) that stimulate growth and responsiveness of B cells and macrophages, thus greatly strengthening the power of the response.

Lymphocyte Rolling and Adhesion

• Initial rolling adherence of a circulating lymphocyte to the epithelium of a high endothelial venule is mediated by selectins.

• Stronger adhesion is mediated by integrins that enable the cell to stop rolling & migrate out between endothelial cells.

B cell Activation

• When resting B cells are activated by antigen to proliferate and mature into antibody secreting cells, they produce and secrete antibodies.

• The antibodies have a unique antigen-binding site, which is the same as that of the original membrane-bound antibodies that served as antigen receptors.

Primary Humoral Response

In primary humoral immune response, macrophages ingest & digest bacteria.

• Insert a polypeptide of the bacteria into their plasmalemma that serves as an antigen.

• B & helper T lymphocytes bind to the antigen.

• Helper T cells release cytokines that activate B cells to proliferate.

• This results in many more B cells responding to the antigen.

• B cells produce & release large amounts of specific antibody.

Secondary Humoral Response

• In 2nd encounter with the same antigen: Fab binds to antigen.

• Fc binds to receptors on macrophage.

• This greatly facilitates uptake & destruction of bacteria.

• Secondary response is, therefore, more rapid & efficient, resulting in a 10-100 fold increase in circulating antibody.

Antibodies

(=immunoglobulins) are circulating plasma glycoproteins that interact specifically with antigenic determinants (molecular domains of the antigen). 5 classes:

IgG:

Most abundant. Crosses the placenta & protects newborn against infection.

IgA:

The main antibody in milk (colostrum), tears, saliva, nasal, bronchial, intestinal & prostatic secretions & vaginal fluids. It is resistant to several enzymes & thus protects against proliferation of microorganisms in bodily fluids.

IgM:

Dominate in early immune responses. Along with IgD is found on surface of B cells. Both membrane-bound & circulating forms occur.

IgE:

Has great affinity for receptors on mast cells & basophils. When the antigen that elicited formation of the IgE is encountered again, the antigen-antibody complex on the surface of the mast cell triggers degranulation & a consequent allergic reaction.

IgD:

Less well understood. Involved in B cell differentiation.

Antibody-Activated Phagocytosis

• An IgG-antibody-coated bacterium is efficiently phagocytosed by a macrophage or neutrophil, which has cell surface receptors able to bind the IgG molecules.

• The binding of the antibody-covered bacterium to the receptors activates the phagocytic process.

T Cells

• T lymphocytes occur as several types, most lymphocytes in the blood (80%) are T lymphocytes.

• Helper T cells - regulate activity of T & B cells positively.

• Secrete lymphokines.

• Suppressor T cells - regulate T & B negatively.

• Cytotoxic T cells (killer T cells, natural killer cells) kills other cells including tumor cells, virus-infected cells & foreign grafts.

• Null cells - may represent circulating stem cells.

• T cells act directly without secreting antibodies.

• They have surface receptors that recognize antigens on the surface of other cells.

• They secrete lymphokines when stimulated by antigen.

• T cells are able to recognize & bind to cells containing viruses or parasites.

• Activated by binding, they secrete perforin, a chemical that makes holes in the target cell.

• This causes the cell to lyse & its fragments are ingested by macrophages.

• If a foreign graft is introduced, T cells wandering through the area recognize it as nonself & bind to it.

• They release a cytokine that diffuses to capillaries where it induces great numbers of lymphocytes to migrate thru the vessel wall to join in the rejection reaction.

• Their combined efforts result in rejection of the graft.

B and T Cell Differentiation

• All lymphocytes arise in bone marrow & B cells leave the marrow as mature cells but T cells differentiate further in the thymus.

• Bone marrow & the thymus are called central lymphoid organs.

Peripheral lymphoid organs include:

• Spleen, Lymph nodes, Solitary nodules, Tonsils, Appendix, and Peyer's patches.

Peripheral Lymphoid Tissue

• The epithelial barrier of the respiratory & GI tracts are not totally effective in screening out pathogens, therefore lymphatic tissue provides surveillance at these sites.

• MALT - mucosa associated lymphoid tissue.

• BALT - bronchi associate lymphoid tissue.

• GALT - gut associated lymphoid tissue including: tonsils nodules in esophagus, Peyer's patches in ileum, lymphoid aggregates in large intestine, and appendix.

Clonal Selection Theory

• An antigen activates only those lymphocyte clones that are already committed to respond to it.

• A cell is committed to respond if its cell surface receptors recognize the antigen.

• All cells within a clone have the same receptor.

• The immune system consists of millions of different lymphocyte clones, hundreds of which may be activated by a particular antigen.

• B & T cells respond in a similar way.

• The immune system functions on a "ready- made" rather than a "made-to-order" principle.

Lymphatic Tissue

• These are non-encapsulated clusters of lymphocytes associated with the respiratory & GI tracts.

• Diffuse lymphatic tissue occurs in the lamina propria.

• These effect local responses to antigens in tissue fluid.

• Nodular lymphatic tissue (lymphatic nodules) are temporary structures of B cells that usually disappear in 2 weeks.

Lymphatic Nodules

• Lymphatic nodules are aggregations of lymphocytes.

• Primary nodules - no light central region (germinal center).

• These are virgin nodules that are present in the absence of exposure to antigen, ex. during intrauterine life or animals born & kept under sterile conditions.

• Secondary nodules - appear after birth (exposure to antigens).

• Capsule of reticular cells, cap, corona or mantle of densely aggregated lymphocytes & light staining germinal center (GC).

• GC is a mixture of multiplying & differentiating B cells primarily & their plasma cells & a few scattered T cells.

• This is the most important site of B cell production & antibody formation.

• Tertiary nodules are aggregations of T cells without a germinal center in the inner paracortex of lymph nodes.

Aggregated Nodules

• Tonsils.

• Appendix.

• Peyer's patches.

• Waldeyer's tonsillar ring: pharyngeal (pseudostratified ciliated columnar) and palatine (stratified squamous).

• Lingual tonsils are partially encapsulated with epithelial inpocketings.

Peyer's Patches

• Opposite to mesentery.

• Located in the mucosa of the ileum.

• M cells are specially differentiated absorptive cells covering Peyer's patches.

• M cells sample antigens present in the intestinal lumen of the mother & transport them to underlying lymphocytes that enter the circulation & come to reside in the lamina propria where they originated & develop into plasma cells & produce antibodies.

• Lymphocytes can be deposited in the CT near mammary glands & the plasma cells will produce secretory IgA which will cross the mammary gland epithelium & be incorporated into the milk & thus protect the newborn from intestinal antigens previously encountered by the mother.

• Secretory IgA.

• IgA binds to a transmembrane receptor on the nonluminal surface of the secretory epithelial cell.

• The receptor-IgA complexes are ingested via RME, transferred across the cell cytoplasm in vesicles & secreted into the lumen via exocytosis.

• In the lumen, the receptor & antibody are cleaved releasing the antibody.

Lymph Nodes

• Lymph nodes are a series of in-line filters.

• All tissue fluid derived from lymph is filtered by at least one node before returning to the circulatory system.

• Lymphocytes can enter nodes via afferent lymphatics or high endothelial venules.

• Most enter via high endothelial venules.

• Lymph nodes (500/body) are 1mm-1cm encapsulated generally bean shaped structures with a cortex, medulla & hilus (where efferent lymphatics are located).

• Lymph nodes have 3 compartments: vascular, lymphatic & interstitial.

Lymph Flow

• Lymph enters & flows through:

• Afferent lymphatics.

• Subcapsular sinus.

• Cortical (intermediate) sinuses.

• Trabecular sinuses.

• Medullary sinuses.

• Efferent lymphatics.

• Lymphocytes & monocyte-macrophages can move in & out of the blood circulation at high endothelial venules & thus gain access to the interstitial compartment.

B and T Cell Maturation

• B cells primarily mature in the cortex clustered in lymphoid follicles.

• T cells primarily mature in the paracortex.

• Many types of lymphocytes, both B & T, enter a node via high endothelial venules & leave via efferent lymphatics.

• Lymphocytes then enter the bloodstream where they cycle through a secondary lymphoid organ.

• Antigen presenting cells include interdigitating dendritic cells that present to T cells in paracortex & follicular dendritic cells that activate memory cells in a germinal center of lymphoid follicles.

Flow of Antigens

• Antigens, accessory cells & lymphocytes can enter via afferent lymphatics or high endothelial venules.

• Antigens & lymphocytes enter the interstitial compartment and encounter B cells in the cortex & T cells in the paracortex along with antigen presenting cells.

• Proliferation ensues followed by nodule formation & plasma cell formation with production of antibodies.

• They depart via efferent lymphatics to the general circulation.

• Most lymphocyte recirculation occurs at lymph nodes.

• Through recirculation, locally stimulated lymphocytes (ex. an infected finger) from satellite lymph nodes inform other lymphoid organs to prepare for a generalized immune response against infection.

• This continuous recirculation of lymphocytes results in a constant monitoring of all parts of the body by cells that inform the immune system of the presence of foreign antigens.

Lymph Node Anatomy

• Outer cortex - B cells in nodules.

• Inner (paracortex) - T cells.

• Medulla - lymphocytes, plasma cells & macrophages.

Spleen

• Lies between left ribs 9-11.

• Filters blood for old, damaged RBC & foreign antigens.

• Can be removed since its function can be taken over by liver & bone marrow.

• Has a delicate capsule & can rupture & release considerable amount of blood into the abdominal cavity.

Primary Functions

1. Filters blood & removes old cells through slits in sinusoids & a large population of macrophages.

2. Concentrating platelets. Up to 1/3 of platelets are stored here & can be rapidly released.

3. Antibody production. Very good at detecting quite low levels of antigen in blood. B cells are activated in white pulp, move to red pulp & return to circulation.

When fresh spleen is viewed with the naked eye, there are white areas called white pulp & surrounding red pulp composed of splenic cords of Bilroth situated between fenestrated sinusoids.

Splenic Circulation

• Splenic arteries.

• Trabecular arteries.

• Central or white pulp arteries occupy an eccentric position within the periarterial lymphoid sheath (PALS) composed of T lymphocytes.

• Peripheral to the PALS are nodules of B cells.

• After leaving the PALS, arteries are straight, pencillar arteries within the red pulp.

• These end as capillaries that deliver blood to sinusoids by the open circulation model.

• A marginal zone, mostly of APS & macrophages between white & red.

Open vs Closed Splenic Circulation

• Open circulation - capillaries open to parenchyma of red pulp with its numerous macrophages and then squeeze between slits in sinusoids where cytofiltering occurs.

• Closed circulation - obsolete concept.

White vs Red Pulp

White pulp:

• T cells in PALS around central artery B cells around PALS Marginal zone with APS & macrophages.

Red pulp:

• Plasma cells Macrophages Lymphocytes

Notes on Thymus

• Thymus: Primarily an organ of infancy & early childhood.

• By the 5th decade it is only 10g.

Origin of Thymus

Dual embryonic origin:

• Lymphocytes from bone marrow.

• Epithelial reticular cells (ERC) from endoderm of 3rd & 4th pharyngeal pouches.

Composition of Thymus

• T cells.

• Epithelial cells.

• reticular cells.

• Macrophages.

• Occasional B cells.

• Medulla has Hassall's corpuscles (degenerate ERC).

T-cells in Thymust

• T cells develop in cortex & are shielded from antigens because:

• Lacks afferent lymphatics.

• Have a blood-thymus barrier.

• Many macrophages.

• T cell progenitors migrate to thymic cortex & mature.

• Only those with self tolerance survive & undergo clonal expansion via mitosis.

• The others undergo clonal deletion via apoptosis (programmed cell death).

• Mature T cells move to the medulla & thence to the general circulation.

Function of Thymus

• Primary function is to generate T cells & develop self tolerance.

• T cells are seeded out & populate different lymphoid sites where they proliferate.

• Most T cells are not immunocompetent in the thymus but become immunocompetent in blood, lymph or interstitial fluid.

• T cells originate in bone marrow but proliferate & develop self tolerance in the thymus.

• Developing T cells are immunologically naive & need to be sheltered from the cruel world during their delicate period.

• Only a small minority of cells in the thymus reach maturity & these have developed self tolerance.

Blood-Thymus Barrier

Blood-thymus barrier occurs in the cortex and consists of:

• Endothelium & BL of thymic capillaries.

• Connective tissue.

• Epithelial reticular cells.

Additional Reading:

Basic Histology

1. Introduction to Histology
2. Basic Cell Physiology
3. Actin, Microtubules, and Intermediate Filaments
4. Mitochondria, Nucleus, Endoplasmic Reticulum, Golgi
5. Epithelium (Epithelial Tissue)
6. Connective and Adipose Tissue
7. Types of Cartilage
8. Osteogenesis
9. Nervous Tissue
10. Muscle Tissue
11. Cardiovascular System
12. Blood and Hematopoiesis
13. Lymphoid Tissue
14. Digestive Tract I: Oral Cavity
15. Digestive Tract II: Esophagus through Intestines
16. Liver, Pancreas, and Gall Bladder
17. Respiratory System
18. Integument
19. Urinary System
20. Endocrine System
21. Male Reproductive System
22. Female Reproductive System
23. Eye and Ear

Medical Images

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