lymphatic system

2. Lymphatic System

Definition

The lymphatic system consists of:

• Groups of cells

• Tissues

• Organs

Function:

• Monitor body surfaces and internal fluid compartments

• React to harmful substances

3. Main Cells of the Lymphatic System

Lymphocytes

• Definitive cell type of the lymphatic system

• Effector cells in immune responses against harmful substances

4. Components of the Lymphatic System

Important lymphatic tissues and organs:

• Diffuse lymphatic tissue

• Lymphatic nodules

• Lymph nodes

• Spleen

• Bone marrow

• Thymus

These lymphatic organs and tissues are collectively called the immune system.

Lymphatic Vessels

• Connect parts of the lymphatic system to the blood vascular system

5. Sites of Lymphocyte Development

Lymphatic tissues are sites where lymphocytes:

• Proliferate

• Differentiate

• Mature

Lymphocyte “Education”

Occurs in:

• Thymus

• Bone marrow

• Gut-associated lymphatic tissue (GALT)

Purpose:

• Lymphocytes become immunocompetent

• They learn to distinguish:

  • Self → molecules normally present in the body

  • Nonself → foreign molecules

6. Antigen

Definition

An antigen is:

Types of Antigens

Antigens may be:

• Soluble substances

  • Foreign proteins

  • Polysaccharides

  • Toxins

• Infectious organisms

• Foreign tissues

• Transformed (cancerous) cells

Antigen Processing

• Most antigens must be processed by immune cells before other immune cells can respond.

7. Exposure to Pathogens

The body is constantly exposed to:

• Pathogenic organisms

• Infectious microorganisms

• Toxins

• Foreign cells

• Foreign tissues

Additionally:

• Normal cells may transform into cancer cells, appearing foreign to the immune system.

8. Types of Immune Defenses

Immune responses are divided into:

1. Nonspecific (Innate) immunity

2. Specific (Adaptive) immunity

These represent the two lines of immune defense against foreign invaders and transformed cells.

9. Nonspecific (Innate) Immunity

Characteristics

• Preexisting

• Nonspecific defenses

• Represents the first line of defense against microbial invasion.

Components of Innate Immunity

1. Physical Barriers

Prevent entry of organisms:

• Skin

• Mucous membranes

2. Chemical Defenses

Destroy invading microorganisms:

• Low pH

3. Secretory Substances

Examples:

• Thiocyanate in saliva

• Lysozymes

• Interferons

• Fibronectin

• Complement in serum

Function:

• Neutralize foreign cells

4. Phagocytic Cells

Examples:

• Macrophages

• Neutrophils

• Monocytes

5. Natural Killer (NK) Cells

10. Specific (Adaptive) Immunity

When It Occurs

• Activated when nonspecific defenses fail

Characteristics

• Targets specific invaders

• Initiated by initial contact with a specific antigen

Immune Memory

Adaptive immunity often leads to immune memory.

Genetic Basis

Adaptive immunity develops through:

• Random somatic rearrangements of genes encoding:

  • Immunoglobulins

  • T-cell receptors (TCRs)

11. Activation of Lymphocytes

During adaptive immune responses:

• B lymphocytes

• T lymphocytes

become activated to destroy invading organisms.

12. Types of Specific Immune Responses

1. Humoral Immune Response

• Produces antibodies

• Antibodies are proteins

• Function:

  • Mark invaders for destruction by other immune cells

2. Cellular Immune Response

Targets:

• Transformed cells

• Virus-infected cells

Destroyed by:

• Specific “killer” cells

13. Immune System Activation

After invasion by bacteria or other pathogens:

1. Immune system becomes activated

2. Inflammatory response occurs

3. Pathogens are destroyed

4. Long-term immune memory is generated

Cells of the Lymphatic System

1. Overview

Cells of the immune system consist of:

• Lymphocytes

• Supporting cells

These cells together make up the cells of the immune system.

2. Types of Lymphocytes

There are three major types of lymphocytes:

1. B cells

2. T cells

3. Natural Killer (NK) cells

3. Supporting Cells of the Immune System

Supporting cells interact with lymphocytes and have important roles in:

• Presentation of antigens to lymphocytes

• Regulation of immune responses

Types of Supporting Cells

• Monocytes

• Macrophages

• Neutrophils

• Basophils

• Eosinophils

• Reticular cells

• Dendritic cells

• Follicular dendritic cells

• Langerhans’ cells

• Epithelioreticular cells

4. Role of Epithelial and Stromal Cells

Specialized epithelial and stromal cells provide the environment for immune reactions by:

• Secreting specific substances

• Regulating:

  • Cell growth

  • Cell migration

  • Activation of effector cells

  • Activation of supporting cells

5. Organization of Supporting Cells

Structure

Supporting cells in lymphatic organs are organized into loose meshworks.

Reticular Cells and Reticular Fibers

In:

• Lymph nodules

• Lymph nodes

• Spleen

Reticular cells and reticular fibers produced by these cells form elaborate meshworks.

Cells Located in These Meshworks

• Lymphocytes

• Macrophages

• Dendritic cells

• Follicular dendritic cells

• Other immune system cells

These cells also exist in loose connective tissue of the body.

6. Langerhans’ Cells

Location

• Found only in the middle layers of the epidermis

Function

• Carry out surveillance and defense

7. Epithelioreticular Cells

Location

• Found in the thymus

Function

• Form the structural meshwork of thymic tissue

Important Feature (Exam Point)

Despite their name:

• They do NOT produce reticular fibers

• They are NOT related to reticular fibers

8. Identification of Cells in Lymphatic Tissue

Different lymphatic tissue cells are identified by surface markers called:

Cluster of Differentiation (CD) Markers

General Characteristics of Lymphocytes

Definition

• Circulating lymphocytes are the chief cellular constituents of lymphatic tissue.

Circulating Pool

• Most lymphocytes (≈70%) in blood or lymph form a circulating pool of immunocompetent cells.

Circulation Cycle

Lymphocytes:

1. Exit systemic circulation

2. Enter lymphatic tissues

3. Perform immunologic surveillance

4. Return to systemic circulation

Main Circulating Population

The circulating population mainly consists of:

• Long-lived mature lymphocytes

• Mainly T cells

• Capable of:

  • Recognizing foreign antigens

  • Responding to foreign antigens

These cells move from one lymphatic tissue site to another.

2. Non-Circulating Lymphocyte Population

About 30% of lymphocytes:

• Do not circulate between blood and lymphatic tissues.

These include:

• Short-lived immature cells

• Activated lymphocytes destined for specific tissues

Migration

These cells:

• Leave capillaries

• Migrate into tissues, especially:

  • Connective tissue under the respiratory epithelium

  • Connective tissue under the gastrointestinal epithelium

  • Connective tissue under the urogenital epithelium

  • Intercellular spaces of epithelia

3. Major Types of Lymphocytes

Three functional types:

1. T lymphocytes

2. B lymphocytes

3. Natural Killer (NK) cells

Important Exam Point

The classification of lymphocytes is independent of morphological (size) characteristics.

4. T Lymphocytes (T Cells)

Differentiation

• Differentiate in the thymus

Proportion

• 60–80% of circulating lymphocytes

Function

• Involved in cell-mediated immunity

Lifespan

• Long life span

Surface Markers

T cells express:

• CD2

• CD3

• CD5

• CD7

• T-cell receptors (TCRs)

Subclassification

Based on presence or absence of:

• CD4

• CD8

5. Helper T Cells (CD4⁺ T Cells)

Characteristics

• Express CD4 marker

Subtypes

Divided based on cytokine secretion:

TH1 Cells

Produce:

• Interleukin-2 (IL-2)

• Interferon-γ (IFN-γ)

• Tumor necrosis factor-α (TNF-α)

Function

Interact with:

• Cytotoxic CD8⁺ T cells

• NK cells

• Macrophages

Role

Important for controlling intracellular pathogens, including:

• Viruses

• Certain microorganisms

TH2 Cells

Produce:

• IL-4

• IL-5

• IL-10

• IL-13

Function

Interact with:

• B lymphocytes

Role

• Initiate antibody-mediated immune responses

• Target extracellular pathogens

6. Cytotoxic T Lymphocytes (CD8⁺ T Cells)

Marker

• Express CD8

Function

Kill target cells such as:

• Virus-infected cells

• Cancer-transformed cells

• Cells infected with intracellular microorganisms

• Parasite-infected cells

• Transplanted cells

7. Regulatory (Suppressor) T Cells

Function

• Suppress immune responses to:

  • Foreign antigens

  • Self antigens

Mechanism

They influence activity of other immune cells.

Example Regulatory T Cell Markers

• CD4

• CD25

• FOXP3

FOXP3 indicates expression of forkhead family transcription factors.

Effects

Regulatory T cells can:

• Reduce ability of T lymphocytes to initiate immune responses

• Suppress B-cell differentiation

• Regulate erythroid cell maturation in bone marrow

Another suppressor T-cell type:

• CD8⁺ CD45RO⁺ T lymphocyte

9. B Lymphocytes (B Cells)

Differentiation

B cells differentiate in bursa-equivalent organs in mammals:

• Bone marrow

• GALT

Function

Participate in humoral immunity by producing:

• Antibodies (immunoglobulins, Ig)

These are immune proteins circulating in the blood.

Proportion

• 20–30% of circulating lymphocytes

B-Cell Receptors (BCRs)

B cells express:

• Membrane-bound immunoglobulins

• Called B-cell receptors (BCRs)

Function:

• Serve as antigen-specific binding sites

Immunoglobulin Changes During Maturation

During differentiation:

• Immature B cells → express IgM

• Mature B cells → express IgD

MHC Expression

B cells express:

• Major histocompatibility complex II (MHC II) molecules

CD Markers of B Cells

• CD9

• CD19

• CD20

Natural Killer (NK) Cells

1. Definition

Natural killer (NK) cells:

• Are neither T cells nor B cells

• Are specialized to kill certain types of target cells

2. Type of Immunity

NK cells are part of:

Nonspecific (innate) immunity

3. Origin

NK cells develop from:

Common lymphoid progenitor (CLP) cell

This is the same progenitor that gives rise to B cells and T cells.

4. Proportion in Blood

NK cells constitute:

5–10% of circulating lymphocytes

5. Thymus and TCR Expression

NK cells:

• Do NOT mature in the thymus

• Do NOT express T-cell receptors (TCRs)

6. Target Recognition

NK cells are genetically programmed to recognize:

• Virus-infected cells

• Tumor (transformed) cells

7. Mechanism of Killing

NK cells kill target cells similar to cytotoxic CD8⁺ T lymphocytes.

After recognizing a transformed cell, NK cells:

1. Become activated

2. Release:

   • Perforins

   • Granzymes (fragmentins)

Role of Perforins and Granzymes

Perforins

• Create channels (pores) in the target cell plasma membrane

Granzymes

• Cause fragmentation of DNA

8. Result of NK Cell Action

These processes lead to:

• Apoptosis
  or

• Lysis of the target cell

9. Regulation of NK Cells

NK cell activity is regulated by:

Natural Cytotoxicity Receptors (NCRs)

Regulation occurs through:

• Activating NCRs

• Inhibiting NCRs

These receptors are located on the surface of NK cells.

10. NK Cell Markers (CD Markers)

Specific markers of NK cells include:

• CD16a

• CD56

• CD94

Lymphocyte Development and Differentiation

1. Antigen-Independent Differentiation (Primary Lymphatic Organs)

Lymphocytes first undergo antigen-independent differentiation in primary lymphatic organs.

Primary (Central) Lymphatic Organs

In humans and other mammals:

• Bone marrow

• GALT (gut-associated lymphatic tissue)
  → together called bursa-equivalent organs

• Thymus

Function of Primary Lymphatic Organs

In these organs lymphocytes:

• Differentiate into immunocompetent cells

• Become genetically programmed to recognize a single antigen

This process is called:

Antigen-independent proliferation and differentiation

After becoming immunocompetent, lymphocytes:

• Enter blood or lymph

• Are transported throughout the body

• Become dispersed in connective tissues

2. Antigen-Dependent Activation (Secondary Lymphatic Organs)

Lymphocytes undergo antigen-dependent activation in secondary lymphatic organs.

Secondary (Peripheral) Lymphatic Organs

These include:

• Lymphatic nodules

• Lymph nodes

• Tonsils

• Spleen

Structure of Effector Lymphatic Tissue

In these tissues:

• Immunocompetent lymphocytes

• Plasma cells (derived from B cells)

• Macrophages

organize around:

• Reticular cells

• Reticular fibers

to form effector lymphatic tissues and organs.

Result of Antigen-Dependent Activation

T and B lymphocytes differentiate into:

• Effector lymphocytes

• Memory cells

Immune Responses to Antigens

1. Initial Response: Inflammation

The initial response to an antigen is:

Inflammation

The inflammatory response is a nonspecific defense.

Antigen may be:

• A foreign molecule

• A pathogenic organism

Actions During Inflammation

The inflammatory response may:

1. Sequester the antigen

2. Digest it with enzymes from neutrophils

3. Phagocytose and degrade it in macrophages

Macrophage degradation may lead to:

➡ Presentation of antigen fragments to immunocompetent lymphocytes

This triggers a specific immune response.

Specific Immune Responses

Specific immune responses are classified into:

1. Primary immune response

2. Secondary immune response

2. Primary Immune Response

Definition:

The first encounter of the body with an antigen.

Characteristics

• Lag period of several days

• Antibodies detected are mostly IgM

• Initial response initiated by one or a few B lymphocytes

After this response:

• Some antigen-specific B lymphocytes remain as memory cells

3. Secondary Immune Response

Characteristics:

• More rapid

• More intense

• Higher levels of antibodies (usually IgG)

Reason:

Presence of memory B lymphocytes already programmed for that antigen.

Types of Specific Immune Responses

There are two major types:

1. Humoral (antibody-mediated) immunity

2. Cell-mediated immunity

Humoral Immunity

Definition

Humoral immunity is mediated by:

Antibodies

Source of Antibodies

Produced by:

• B lymphocytes

• Plasma cells derived from B lymphocytes

Cell-Mediated Immunity

Mediated By

Specific T lymphocytes

Function

T cells attack and destroy:

• Virus-infected cells

• Foreign cells

TCR–CD3 Complex

The TCR–CD3 complex:

• Contains TCR α and β chains

• Associated with CD3 molecules

Function

When TCR binds antigen presented on MHC:

1. Signal transmitted through CD3

2. T cell becomes activated

3. T cell secretes interleukins

4. T cells divide and differentiate

Activation of T and B Cells — Exam Notes

1. Activation of T Cells

Requirement for Activation

Activation of T cells requires costimulatory signals.

Both:

• Helper T cells (CD4⁺)

• Cytotoxic T cells (CD8⁺)

require two stimulatory signals for:

• Full activation

• Differentiation

• Proliferation

2. Two Signals Required for T-Cell Activation

First Signal

The first signal is produced by:

Interaction of:

• T-cell receptor (TCR)

• CD4 or CD8 molecules

with the:

Antigen–MHC complex

Second Signal (Costimulatory Signal)

The second signal is the costimulatory signal.

It results from interaction between:

• Membrane molecules on T cells

• Molecules on antigen-presenting cells (APCs)

Important Costimulatory Interactions

1⃣ CD28 (T cell) ↔ B7 / CD86 (APC)

2⃣ CD40 (APC) ↔ CD40L / CD154 (T cell)

3. Activation of Helper T Cells (CD4⁺)

When a helper CD4⁺ T lymphocyte recognizes an antigen:

• The TCR binds to antigen–MHC II complex

If the costimulatory signal is present:

➡ The helper T cell becomes activated

Result

Activated helper T cells release:

Cytokines

4. Cytokines

Definition

Cytokines are:

• Immune signaling proteins

• Biologic modulators of immune responses

Cytokines Produced by CD4⁺ T Cells

The cytokines secreted by helper T cells are called:

Interleukins (ILs)

Function of Interleukins

Interleukins stimulate:

• T cells

• B cells

• NK cells

to:

• Differentiate

• Proliferate

5. Activation of Cytotoxic T Cells (CD8⁺)

When a cytotoxic CD8⁺ T lymphocyte (CTL) recognizes:

Antigen–MHC I complex

the TCR binds to it.

If a costimulatory signal is present (CD40–CD40L interaction):

➡ The CTL becomes activated.

Activated CTL Functions

Activated CTLs:

• Release cytokines

• Stimulate cell proliferation

• Destroy abnormal host cells

Examples of target cells:

• Virus-infected cells

• Transformed (cancer) cells

Some CTLs may destroy target cells without costimulatory signals.

6. MHC Restriction of T Cells

Cytotoxic T Cells

CD8⁺ T cells are MHC I restricted

Meaning:

They recognize antigens presented by MHC I molecules.

Helper T Cells

CD4⁺ T cells are MHC II restricted

Meaning:

They recognize antigens presented by MHC II molecules.

7. MHC Molecules and Antigen Recognition

MHC I

Interacts with:

• TCR

• CD8 molecules

Present on:

• Target cells

Function:

Allows cytotoxic T cells to recognize:

• Virus-infected cells

• Transformed cells

MHC II

Interacts with:

• TCR

• CD4 molecules

Found on:

Antigen-presenting cells (APCs) such as:

• Macrophages

Function:

Present antigens to helper T cells.

8. Activation of B Cells

For B lymphocytes to become activated and differentiate into plasma cells:

➡ They must interact with helper T lymphocytes.

Antigen Recognition by B Cells

Each B lymphocyte recognizes:

• One specific antigen

Two Signals Required for B-Cell Activation

Signal 1

Interaction between:

• B-cell receptor (BCR)

• Antigen

The antigen is then:

• Internalized by receptor-mediated endocytosis

• Antigen fragments are displayed on MHC II molecules

Signal 2

Provided by helper T cells.

Interaction involves:

• CD40 (B cell)

• CD40L / CD154 (helper T cell)

This interaction completes B-cell activation.

9. Differentiation of Activated B Cells

Activated B lymphocytes differentiate into:

1⃣ Plasma cells

2⃣ Memory B cells

10. Plasma Cells

Function

Plasma cells:

• Synthesize and secrete antibodies

During differentiation:

• B cells switch from producing membrane BCRs to soluble antibodies.

11. Memory B Cells

Memory B cells:

• Respond more rapidly to future encounters with the same antigen.

12. Antigen–Antibody Complex

The antibody produced by plasma cells binds the antigen forming:

Antigen–antibody complex

These complexes can be eliminated by:

• NK cells

• Macrophages

• Eosinophils

13. Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)

Definition

In ADCC, antibodies direct immune cells to kill target cells.

Mechanism

IgG antibodies:

• Bind to target cells

Immune cells recognize the Fc region of IgG using:

Fc receptors

Cells possessing Fc receptors include:

• NK cells

• Macrophages

• Neutrophils

• Eosinophils

Result

Binding of antibody-coated cells leads to:

• Apoptosis

• Lysis of the target cell

14. Complement System

If the antigen is a bacterium:

The antigen–antibody complex can activate:

Complement system

Complement proteins bind bacteria and promote:

• Phagocytosis by macrophages

Complement-bound cells can also be targets of ADCC.

15. Cell-Mediated Immune Response

Main Cells

Cytotoxic CD8⁺ T lymphocytes (CTLs)

Function

Target and destroy:

• Virus-infected cells

• Transformed cells

16. CTL Killing Mechanism

After antigen recognition:

1⃣ CTLs undergo clonal expansion

2⃣ Differentiate into effector killer cells

Cytotoxic Proteins Released

CTLs release:

Perforins

Granzymes

Perforins

• Form pores in the target cell membrane

• Increase membrane permeability

Granzymes

• Enter target cell through perforin pores

• Activate caspases

• Induce apoptosis

17. Fate of CTLs After Killing

After killing the target cell:

• Most CTLs undergo apoptosis

• Some become memory cells

18. Regulatory (Suppressor) T Cells

Markers

Regulatory T cells are:

CD4⁺ CD25⁺ FOXP3⁺ T lymphocytes

Origin

• Originate in the thymus

Proportion

• About 5% of total T-cell population

Functions

Regulatory T cells:

• Suppress immune responses of other lymphocytes

• Maintain immunological self-tolerance

• Prevent autoimmune diseases

Cytokines Produced

Regulatory T cells secrete:

• IL-10

• Transforming growth factor-β (TGF-β)

TGF-β strongly suppresses proliferation of:

• T effector cells

• B effector cells

Cytokines

Definition

Cytokines are:

• Soluble polypeptide molecules

• Produced mainly by activated T lymphocytes

Function

Cytokines affect:

• T cells

• B cells

• Monocytes

• Macrophages

• Antigen-presenting cells

Cytokines vs Growth Factors

Both are similar, but differ in:

➡ Target cell populations

21. Cytokines as Chemical Messengers

Cytokines act as:

Chemical messengers between immune cells

They can act:

• Autocrine → on the same cell

• Paracrine → on neighboring cells

Communication with Other Systems

Cytokines also communicate with:

• Central nervous system

• Endocrine system

• Hemopoietic system

Cytokine Receptors

Cytokines act through specific receptors.

Cells regulated by cytokines therefore possess:

Cytokine receptors

22. Interleukins

Source

Interleukins are synthesized mainly by:

• Helper CD4⁺ T lymphocytes

To a lesser extent by:

• Monocytes

• Macrophages

• Endothelial cells

Function

Interleukins promote:

• Growth

• Differentiation

of:

• T cells

• B cells

• Hematopoietic cells

Antigen-Presenting Cells (APCs)

APCs interact with helper CD4⁺ T lymphocytes to facilitate immune responses.

The interaction between most antigens and antibodies alone is not sufficient to stimulate immune responses.

The antigen must be:

• Broken into small peptide fragments
• Presented with MHC II molecules
• Displayed to helper CD4⁺ T lymphocytes

Antigen can also be processed as part of the B-cell activation pathway.

APCs and the Mononuclear Phagocytic System (MPS)

Most APCs belong to the mononuclear phagocytic system (MPS).

APCs include:

• Macrophages
• Perisinusoidal macrophages (Kupffer cells) of the liver
• Langerhans’ cells in the epidermis
• Dendritic cells of spleen and lymph nodes

Two APCs that do not belong to the MPS:

• B lymphocytes
• Type II and Type III epithelioreticular cells of the thymus

Antigen Processing by APCs

To present antigen to helper T cells:

1. The APC endocytoses the antigen

2. The antigen is degraded into peptides (18–20 amino acids)

3. In the endosomal compartment, peptides bind to MHC II molecules

4. The antigen–MHC II complex is transported to the cell membrane

5. The complex is displayed on the APC surface

Additional Functions of Macrophages

Besides acting as APCs, macrophages have other important immune functions.

They:

• Endocytose and partially degrade protein and polysaccharide antigens before presenting them with MHC II to CD4⁺ T cells

• Digest pathogenic microorganisms through lysosomal activity together with helper CD4⁺ T lymphocytes

• Secrete multiple cytokines, including:
– Lymphokines
– Complement components
– Interleukins
– Acid hydrolases
– Proteases
– Lipases

Activated Macrophages

Activated macrophages destroy phagocytosed bacteria and foreign antigens.

After contact with antigen, macrophages undergo activation processes with functional and morphological changes.

Classically Activated Macrophages (M1 Macrophages)

Activated by:

• Interferon-γ (IFN-γ)

Characteristics:

• Increase in cell size
• Increased lysosomes
• Increased cytoplasmic vacuoles

Functions:

• Highly phagocytic
• Strong ability to lyse ingested pathogens and foreign antigens

They promote:

• Inflammation
• Destruction of extracellular matrix
• Apoptosis

Alternatively Activated Macrophages (M2 Macrophages)

Activated by:

• Interleukins

Functions:

• Downregulate inflammation
• Promote rebuilding of extracellular matrix
• Stimulate cell proliferation
• Promote angiogenesis

Macrophage Role in Removing Foreign Materials

Macrophages help sequester and remove foreign materials and organisms that:

• Do not provoke an immune response
• Are ingested but not digested

Foreign Body Giant Cells

When macrophages cannot eliminate foreign material, they may fuse together.

This forms multinucleated giant cells called:

Langerhans’ giant cells

Function:

• Isolate pathogens or foreign materials from the body.

Diffuse Lymphatic Tissue and Lymphatic Nodules

Diffuse lymphatic tissue and lymphatic nodules:

• Guard the body against pathogenic substances
• Are the site of the initial immune response

Location

Diffuse lymphatic tissue is commonly found in the:

• Alimentary canal
• Respiratory passages
• Genitourinary tract

These areas contain accumulations of lymphatic tissue that are not enclosed by a capsule.

Diffuse Lymphatic Tissue

Lymphocytes and other free immune cells are located in the:

• Lamina propria (subepithelial connective tissue)

This form of lymphatic tissue is called:

• Diffuse lymphatic tissue
or
• Mucosa-associated lymphatic tissue (MALT)

It is called MALT because it is associated with mucous membranes.

Function

Cells of diffuse lymphatic tissue are strategically positioned to:

• Intercept antigens
• Initiate an immune response

After Antigen Exposure

After contact with antigen:

1. Cells travel to regional lymph nodes

2. They undergo proliferation and differentiation

3. The progeny return to the lamina propria

These returning cells function as:

• Effector B lymphocytes
• Effector T lymphocytes

Importance of Diffuse Lymphatic Tissue

Its importance in protecting the body from antigens is shown by two findings:

1. Presence of Plasma Cells

Large numbers of plasma cells are present, especially in the:

• Lamina propria of the gastrointestinal tract

This indicates local antibody secretion.

2. Presence of Eosinophils

Large numbers of eosinophils are frequently observed in the:

• Lamina propria of the intestinal tract
• Lamina propria of the respiratory tract

This indicates:

• Chronic inflammation
• Hypersensitivity reactions

Lymphatic Nodules in the Alimentary Canal

1. General Features of Lymphatic Nodules

• Lymphatic nodules are usually found in structures associated with the alimentary canal, including:

  • Tonsils

  • Ileum

  • Vermiform appendix

• General distribution

  • Usually dispersed singly in a random manner.

• In the alimentary canal, some aggregations of nodules occur in specific locations.

Aggregations of Lymphatic Nodules

1. Tonsils

Location & Arrangement

• Tonsils form a ring of lymphatic tissue at the entrance of the oropharynx.

Types of Tonsils

1. Pharyngeal tonsils (adenoids)

   • Located in the roof of the pharynx.

2. Palatine tonsils

   • Located on either side of the pharynx

   • Positioned between the palatopharyngeal and palatoglossal arches

3. Lingual tonsils

   • Located at the base of the tongue

✔ All tonsils contain aggregates of lymphatic nodules

Histological Structure of Palatine Tonsils

• Consist of dense accumulations of lymphatic tissue.

• Located in the mucous membrane.

Epithelium

• Covered by squamous epithelium.

Tonsillar Crypts

• The epithelium dips into underlying connective tissue.

• This forms numerous tonsillar crypts.

✔ Walls of crypts contain numerous lymphatic nodules

Lymphatic Drainage of Tonsils

• Tonsils do NOT possess afferent lymphatic vessels.

• Lymph drains from tonsillar lymphatic tissue via efferent lymphatic vessels.

2. Peyer’s Patches

Location

• Found in the ileum (distal portion of the small intestine).

Structure

• Consist of numerous aggregations of lymphatic nodules.

Cells Present

• Contain:

  • T lymphocytes

  • B lymphocytes

Additional Nodules

• Numerous isolated single (solitary) lymph nodules occur along:

  • Large intestine

  • Small intestine

3. Vermiform Appendix

Origin

• Arises from the cecum.

Histology

• Lamina propria heavily infiltrated with lymphocytes.

• Contains numerous lymphatic nodules.

Mucosa-Associated Lymphatic Tissue (MALT)

Naming Principle

• Diffuse lymphatic tissue and lymphatic nodules are named according to the region or organ in which they appear.

Types

1. GALT (Gut-Associated Lymphatic Tissue)

• Found in the alimentary canal.

2. BALT (Bronchus-Associated Lymphatic Tissue)

• Found in the bronchial tree.

3. MALT (Mucosa-Associated Lymphatic Tissue)

• Includes:

  • GALT

  • BALT

Distribution of MALT

• Diffuse lymphatic tissue and lymphatic nodules occur in many regions of the body, for example:

  • Female reproductive tract

• Present where the mucosa is exposed to the external environment.

Important Exam Point

✔ All lymphatic nodules enlarge after encounters with antigen.

Lymph Nodes

Definition

• Lymph nodes are small, encapsulated organs that filter lymph.

• Located along the pathway of lymphatic vessels.

General Characteristics

• Shape: small bean-shaped organs

• Type: encapsulated lymphatic organs

Size

• Range from about 1 mm (barely visible with unaided eye)

• Up to 1–2 cm in their longest dimension

Function

• Serve as filters through which lymph percolates on its way to the blood vascular system.

Distribution

• Widely distributed throughout the body

• Concentrated in certain regions:

  • Axilla

  • Groin

  • Mesenteries

Lymphatic Vessels of the Lymph Node

Two types of lymphatic vessels serve the lymph node:

1. Afferent Lymphatic Vessels

• Convey lymph toward the lymph node

• Enter at various points on the convex surface of the capsule

2. Efferent Lymphatic Vessels

• Convey lymph away from the lymph node

• Leave at the hilum

Hilum

• Depression on the concave surface of the node

• Serves as entrance and exit for blood vessels and nerves

Transport of Activated Lymphocytes

• Activated lymphocytes remain in the lymph node to:

  • Proliferate

  • Differentiate

• They are carried to the lymph node primarily by blood vessels.

Supporting Elements of the Lymph Node

1. Capsule

• Dense connective tissue

• Surrounds the lymph node

2. Trabeculae

• Also dense connective tissue

• Extend from the capsule into the substance of the node

• Form a gross supporting framework

3. Reticular Tissue

• Composed of:

  • Reticular cells

  • Reticular fibers

• Forms a fine supporting meshwork throughout the remainder of the organ.

Composition of Reticular Meshwork

• Cells of mesenchymal origin

• Reticular fibers

• Ground substance produced by those cells

Cells of the Reticular Meshwork

The reticular meshwork of the lymph node contains several cell types that perform functions in immune responses.

General Morphology

Cells appear:

• Stellate or elongated

• Have oval euchromatic nuclei

• Contain small amounts of acidophilic cytoplasm

They are capable of taking up dyes and colloidal materials.

Using immunocytochemistry and transmission electron microscopy, several cell populations are identified.

Types of Cells in the Reticular Meshwork

1. Reticular Cells

• Indistinguishable from typical fibroblasts

Functions

• Synthesize and secrete type III collagen (reticular fibers)

• Produce associated ground substance forming the stroma.

Structural Role

• Elongated cytoplasmic processes wrap around bundles of reticular fibers

• This isolates these structural components from lymphatic tissue parenchyma.

Additional Functions

• Express surface molecules

• Produce substances that attract:

  • T cells

  • B cells

  • Dendritic cells

2. Dendritic Cells (DCs)

Origin

• Bone marrow–derived antigen-presenting cells (APCs)

Function

• Monitor the local environment for foreign substances

• Process antigens

• Present antigens to antigen-specific T cells

Efficiency

• More efficient in antigen presentation than other APCs

Antigen Presentation

• Can present virtually any protein antigen

• Presented on:

  • MHC I

  • MHC II

Surface Molecules

• Express exceptionally high levels of MHC II

• Express costimulatory molecules needed for T cell activation

Location in Lymph Node

• Usually found in T lymphocyte–rich areas

3. Macrophages

Functions

• Phagocytic cells

• Antigen-presenting cells

Molecules Expressed

• MHC I

• MHC II

• Costimulatory molecules

Comparison with Dendritic Cells

• Lower levels of MHC II and costimulatory molecules

• Therefore less efficient APCs than dendritic cells

Major Capability

• Very high capacity for endocytosis and digestion of internalized materials

4. Follicular Dendritic Cells (FDCs)

Morphology

• Have multiple thin, hair-like branching cytoplasmic processes

Location

• Processes interdigitate between B lymphocytes in germinal centers

Antigen Handling

• Antigen–antibody complexes adhere to cytoplasmic processes

• Attachment occurs via antibody Fc receptors

Antigen Retention

• Antigen can remain on the cell surface for:

  • Weeks

  • Months

  • Years

Important Characteristic

• Antigen is not endocytosed (unlike macrophages)

APC Status

• Not antigen-presenting cells

• Reason: lack MHC II molecules

Thymus

Definition

• The thymus is a lymphoepithelial organ located in the superior mediastinum.

General Characteristics

Location

• Superior mediastinum

• Anterior to the heart and great vessels

Shape

• Bilobed organ

Developmental Process

1. The epithelium invaginates.

2. The thymic rudiment grows caudally as a tubular projection of endodermal epithelium into the mediastinum.

3. The advancing tip proliferates.

4. It eventually becomes disconnected from the branchial epithelium.

Cellular Origin of T Cells

• Common lymphoid progenitor (CLP) cells from the bone marrow:

  • Migrate to the thymus.

  • Develop into immunocompetent T cells.

  • Invade the epithelial rudiment.

  • Occupy spaces between epithelial cells.

✔ As a result, the thymus becomes a lymphoepithelial organ.

General Architecture of the Thymus

Capsule

• The thymus has a thin connective tissue capsule.

Trabeculae

• Trabeculae extend from the capsule into the parenchyma.

Contents of Capsule and Trabeculae

They contain:

• Blood vessels

• Efferent lymphatic vessels (but NOT afferent lymphatic vessels)

• Nerves

Connective Tissue Components

In addition to collagen fibers and fibroblasts, the connective tissue contains variable numbers of:

• Plasma cells

• Granulocytes

• Lymphocytes

• Mast cells

• Adipose cells

• Macrophages

Thymic Lobules

• Trabeculae divide the thymus into thymic lobules.

Important Exam Point

• These are NOT true lobules.

Structure

Each lobule consists of:

• Cortical caps

• Covering portions of the continuous inner medullary tissue

Histologic Appearance

• In some sections the cortical cap and medullary tissue resemble a lymphatic nodule with a germinal center, which may confuse identification.

Thymic Parenchyma

• Contains developing T cells within an extensive meshwork formed by epithelioreticular cells.

Thymic Cortex

Location

• Outer portion of the parenchyma

Staining

• Markedly basophilic in H&E preparations

Reason

• Presence of closely packed developing T lymphocytes with intensely staining nuclei.

Thymocytes

• Developing T lymphocytes are called thymocytes.

Cellular Organization

• Thymocytes occupy spaces within a meshwork of epithelioreticular cells.

Other Cells

• Macrophages are dispersed among cortical cells.

Origin and Development of T Cells

• Developing T cells arise from CLPs originating in bone marrow.

• During development in the thymus:

  • CLP-derived cells pass through several developmental stages.

  • These stages are identified by expression of different CD molecules.

Epithelioreticular Cells

Characteristics

• Have features of both:

  • Epithelial cells

  • Reticular cells

Function

• Provide the framework for developing T cells.

Comparison with Other Lymphatic Organs

• In other lymphatic tissues:

  • Framework = reticular cells + reticular fibers

• In the thymus:

  • Reticular connective tissue cells and reticular fibers are absent

Epithelial Features

Epithelioreticular cells possess:

• Intercellular junctions

• Intermediate filaments

Types of Epithelioreticular Cells

✔ Six types exist

• Three types in cortex

• Three types in medulla

Cortex Epithelioreticular Cells

Type I Epithelioreticular Cells

Location

• Boundary of the cortex and connective tissue capsule

• Between cortical parenchyma and trabeculae

• Surround adventitia of cortical blood vessels

Function

• Separate thymic parenchyma from connective tissue of the organ

Structural Feature

• Occluding junctions between cells

Result

• Form a barrier isolating developing T cells from:

  • Capsule

  • Trabeculae

  • Perivascular connective tissue

Type II Epithelioreticular Cells

Location

• Within the cortex

Ultrastructure

• Desmosomes connect cytoplasmic processes of adjacent cells.

• Cytoplasmic processes contain abundant intermediate filaments.

Morphology

• Stellate shape

• Large pale nucleus that stains lightly in H&E due to abundant chromatin.

Function

• Compartmentalize the cortex into isolated areas for developing T cells.

Immunologic Role

• Express:

  • MHC I

  • MHC II

✔ Participate in thymic education of T cells.

Type III Epithelioreticular Cells

Location

• Boundary between cortex and medulla

Structure

• Occluding junctions between cytoplasmic processes

Function

• Form a functional barrier between cortex and medulla

Immunologic Molecules

• Express:

  • MHC I

  • MHC II

Macrophages in the Thymic Cortex

Function

• Phagocytose T cells that do not fulfill thymic education requirements.

Apoptosis of T Cells

• T cells are programmed to die before leaving the cortex.

✔ Approximately 98% of T cells undergo apoptosis.

Identification

• Cortical macrophages are difficult to see in H&E preparations.

PAS Reaction

• Their large lysosomes stain with PAS.

✔ Therefore they are called PAS cells.

Interaction Between Cells (Cross-Talk)

• Epithelioreticular cells play an important role in the development of immunocompetent T cells.

• Developing T cells control the microarchitecture of thymic epithelioreticular cells.

✔ This mutual influence is called cross-talk.

Thymus (Medulla) —

Distinguishing Feature of the Thymic Medulla

• Thymic (Hassall’s) corpuscles

• Derived from Type VI epithelioreticular cells

• Characteristic feature of the thymic medulla

Thymic Medulla

Definition

• The thymic medulla is the inner portion of the thymic parenchyma.

Cellular Composition

Contains:

• Large numbers of epithelioreticular cells

• Loosely packed T cells

Staining Characteristics

• Stains less intensely than the cortex.

Reason

• Contains mostly large lymphocytes

• These lymphocytes have:

  • Pale-staining nuclei

  • More cytoplasm than small lymphocytes

Epithelioreticular Cells in the Medulla

Like the cortex, the medulla contains three types of epithelioreticular cells:

• Type IV

• Type V

• Type VI

Type IV Epithelioreticular Cells

Location

• Located between the cortex and the medulla

• Close to type III cells

Structure

• Have sheet-like processes

• Possess occluding junctions:

  • Between adjacent cells

  • Between type IV and type III cells

Function

• Together with type III cells, they create the barrier at the corticomedullary junction.

Type V Epithelioreticular Cells

Location

• Found throughout the medulla

Structure

• Cytoplasmic processes of adjacent cells are joined by desmosomes

Function

• Provide the cellular framework of the medulla

• Compartmentalize groups of lymphocytes

Nuclei

• Nuclei contrast markedly with densely staining lymphocyte nuclei

Type VI Epithelioreticular Cells

Function

• Form thymic (Hassall’s) corpuscles

Thymic (Hassall’s) Corpuscles

Structure

• Isolated masses of closely packed type VI epithelioreticular cells

• Cells arranged concentrically

• Cells have flattened nuclei

Ultrastructural Features (TEM)

Cells contain:

• Keratohyalin granules

• Bundles of cytoplasmic intermediate filaments

• Lipid droplets

Cell Connections

• Cells are joined by desmosomes

Central Changes

• The center may show keratinization

Characteristics of Thymic Corpuscles

• Unique structures of the thymic medulla

• Antigenically distinct

• Functionally active multicellular components

Function (Proposed)

• Thought to produce interleukins:

  • IL-4

  • IL-7

These cytokines function in:

• Thymic differentiation

• Education of T lymphocytes

Blood Supply of the Thymus

Entry of Blood Vessels

• Blood vessels pass from trabeculae into the thymic parenchyma

Typical Pathway

• Blood vessels enter the medulla from deeper parts of the trabeculae

Perivascular Connective Tissue Sheath

• Blood vessels carry a sheath of connective tissue

Thickness

• Thicker around large vessels

• Gradually thinner around smaller vessels

Composition of the Perivascular Connective Tissue

When Thick

Contains:

• Reticular fibers

• Fibroblasts

• Macrophages

• Plasma cells

• Other loose connective tissue cells

When Thin

Contains:

• Reticular fibers

• Occasional fibroblasts

Blood–Thymus Barrier & T-Cell Educatation

Blood–Thymus Barrier

Function

• The blood–thymus barrier protects developing lymphocytes in the thymus from exposure to antigens.

• Lymphocytes reaching the thymic cortex are prevented from contacting antigens by a physical barrier called the blood–thymus barrier.

Components of the Blood–Thymus Barrier

(From the lumen of cortical blood vessels outward)

1. Endothelium of Capillaries

• Capillary endothelium is continuous type with occluding junctions.

• Highly impermeable to macromolecules.

• Major structural component of the barrier in the cortical parenchyma.

Associated Structures

• Basal lamina of endothelial cells

• Occasional pericytes

These structures are also part of the capillary wall.

2. Macrophages

• Located in the surrounding perivascular connective tissue.

• Function:

  • Phagocytose antigenic molecules that escape from the capillary lumen into the cortical parenchyma.

3. Type I Epithelioreticular Cells

• Have occluding junctions.

• Provide additional protection to developing T cells.

Arrangement

• Surround the capillary wall in the cortex.

Structural Role

• Their basal lamina forms another major structural component of the blood–thymus barrier.

T-Cell Education

Site

• The thymus is the site of T-cell education.

Origin of Cells

During fetal life:

• The thymus becomes populated by multipotential lymphoid stem cells.

• These originate from the bone marrow.

These cells will develop into immunocompetent T cells.

Thymic Cell Education

Definition

• Stem cell maturation and differentiation into immunocompetent T cells.

Mechanism

• Characterized by expression and deletion of specific surface CD molecules.

Stages of T-Cell Differentiation

1. Early Stage (Double-Negative Stage)

Markers

• Expression of:

  • CD2

  • CD7

Meaning of “Double-Negative”

• Absence of both CD4 and CD8 molecules.

2. Middle Stage

Marker

• Expression of CD1 molecule

Indicates the middle stage of T-cell differentiation.

3. Double-Positive Stage

As maturation progresses, T cells express:

• TCRs

• CD3

• CD4

• CD8

This stage is called the double-positive stage of T-cell differentiation.

Positive Selection

• T cells are presented with self and foreign antigens by:

  • Type II epithelioreticular cells

  • Type III epithelioreticular cells

Outcome

• If the lymphocyte recognizes self-MHC molecules and antigen → survives.

This survival process is called positive selection.

If recognition does not occur

• The cell dies.

Movement After Positive Selection

• Cells that pass positive selection:

  • Leave the cortex

  • Enter the medulla

Negative Selection

• Occurs in the medulla.

Process

• Cells that recognize self-antigen displayed by self-MHC are eliminated.

This process is called negative selection.

Final Differentiation (Single-Positive Stage)

Cells surviving negative selection differentiate into:

1. Cytotoxic T Lymphocytes

• CD8⁺ T cells

• Lose CD4

• Retain CD8

2. Helper T Lymphocytes

• CD4⁺ T cells

• Lose CD8

• Retain CD4

This stage is called the single-positive stage of T-cell differentiation.

Exit from the Thymus

• Mature T cells leave the thymus:

  • From the medulla

  • Into the blood circulation

Factors Promoting Thymic Cell Education

Substances secreted by epithelioreticular cells promote the process:

• Interleukin-4 (IL-4)

• Interleukin-7 (IL-7)

• Colony-stimulating factors

• Interferon-γ

Spleen

1. Basic Overview

• The spleen is the largest lymphatic organ.

• Size: Approximately the size of a clenched fist.

• Location:

  • Upper left quadrant of the abdominal cavity.

• It has a rich blood supply.

Key Function

• Filters blood.

• Reacts immunologically to blood-borne antigens.

Filtering Functions

The spleen has two types of filtering functions:

1. Morphologic filtering

2. Immunologic filtering

Components that allow immune monitoring of blood

The spleen contains:

• Large numbers of lymphocytes

• Specialized vascular spaces or channels

• Meshwork of reticular cells

• Reticular fibers

• Macrophages

• Dendritic cells

These components allow the spleen to monitor blood immunologically, similar to how:

• Macrophages and dendritic cells in lymph nodes monitor lymph.

2. Capsule and Trabeculae

Capsule

• The spleen is enclosed by a dense connective tissue capsule.

Trabeculae

• Trabeculae extend from the capsule into the parenchyma of the organ.

Contents of Capsule and Trabeculae

They contain:

• Myofibroblasts

  • Contractile cells

  • Produce extracellular connective tissue fibers

Functional Significance

In many mammals:

• The spleen stores large volumes of red blood cells.

When capsule and trabeculae contract:

• Stored RBCs are discharged into systemic circulation.

Human spleen

• Normally retains relatively little blood.

• However, it can contract due to contractile cells in capsule and trabeculae.

3. Hilum of the Spleen

Location

• The hilum is located on the medial surface of the spleen.

Structures Passing Through the Hilum

• Splenic artery

• Splenic vein

• Nerves

• Lymphatic vessels

Lymphatic Vessels

• Originate in the white pulp near the trabeculae.

• Provide a route for lymphocytes leaving the spleen.

4. Splenic Pulp

Most of the spleen consists of splenic pulp.

It is divided into two regions based on the color of fresh sections:

1. White pulp

2. Red pulp

Appearance

• White pulp: Circular or elongated whitish-gray areas

• Surrounded by red pulp

5. White Pulp

Definition

White pulp consists of lymphatic tissue, mainly lymphocytes.

Key Structural Concept

White pulp is a thick accumulation of lymphocytes surrounding an artery.

Histological Appearance (H&E)

• Appears basophilic.

Reason

• Due to dense heterochromatin in nuclei of numerous lymphocytes.

6. Arterial Supply of White Pulp

Path of the Splenic Artery

1. Branches of the splenic artery pass through:

   • Capsule

   • Trabeculae

2. They then enter the white pulp.

Central Artery

Inside white pulp:

• The arterial branch is called the central artery.

7. Periarterial Lymphatic Sheath (PALS)

Definition

• Lymphocytes aggregating around the central artery form the PALS.

Full name:
Periarterial Lymphatic Sheath

Shape

• Has a roughly cylindrical configuration.

• Conforms to the course of the central artery.

Appearance in Cross Section

• Appears circular.

• May resemble a lymphatic nodule.

Distinguishing Feature

• Presence of the central artery distinguishes it from typical lymphatic nodules elsewhere.

8. Splenic Nodules

Formation

• Nodules are localized expansions of the PALS.

Effect on Central Artery

• The central artery becomes eccentrically placed rather than central.

Cellular Composition

• B lymphocytes occupy the nodules.

Cells in PALS

• Mainly T lymphocytes.

Functional Classification

• The PALS is a thymus-dependent zone.

Comparable Structure

• Similar to the deep cortex of a lymph node.

9. Germinal Centers

Location

• Usually present in splenic nodules.

Development

• Form after antigen exposure when B cells proliferate.

Timing

• In humans, germinal centers develop within 24 hours after antigen exposure.

Size

• Can become extremely large and visible with the naked eye.

10. Splenic Nodules (Malpighian Corpuscles)

Definition

• Enlarged nodules with germinal centers.

Other Name

• Malpighian corpuscles

Important Note

• Not to be confused with renal corpuscles, which have the same name.

Spleen – Red Pulp

Main Function of Red Pulp

• Red pulp contains large numbers of red blood cells that it filters and degrades.

Appearance

• Red appearance in:

  • fresh state

  • histologic sections

Reason:
Contains large numbers of red blood cells.

Structure of Red Pulp

Red pulp consists of:

1. Splenic sinuses

2. Splenic cords (cords of Billroth)

Splenic Cords (Cords of Billroth)

Structure

• Loose meshwork of reticular cells

• Reticular fibers

Collagen Types

Reticular fibers contain:

• Type III collagen

• Type V collagen

Cells Present in Splenic Cords

The reticular meshwork contains:

• Erythrocytes

• Macrophages

• Lymphocytes

• Dendritic cells

• Plasma cells

• Granulocytes

Function of Macrophages in Splenic Cords

• Phagocytose damaged red blood cells

• Begin hemoglobin breakdown

• Reclaim iron

Fate of Iron

• Used in formation of new red blood cells

Megakaryocytes in Red Pulp

• Present in some species:

  • rodents

  • cat

• Not present in humans

  • except during fetal life

Splenic (Venous) Sinuses

Definition

• Special sinusoidal vessels

Lining

• Lined by rod-shaped endothelial cells

Endothelial Cells of Sinuses

Characteristics:

• Extremely long cells

• Longitudinal axis runs parallel to vessel direction

• Few contact points between adjacent cells

Result

• Prominent intercellular spaces

Function of These Spaces

Allow blood cells to pass easily:

• into sinuses

• out of sinuses

Macrophage Processes

• Macrophage processes extend:

  • between endothelial cells

  • into sinus lumen

Function

• Monitor passing blood for foreign antigens

Basal Lamina of Splenic Sinuses

Key Feature

Sinuses do NOT have a continuous basal lamina.

Instead:

• Strands of basal lamina loop around the outside of the sinus.

Appearance

• Similar to hoops around a barrel

Orientation

• At right angles to the long axis of endothelial cells

Staining

This material stains with:

• Silver-containing reagents

• PAS reaction

Cells NOT Present in Sinus Walls

The walls lack:

• Smooth muscle

• Pericytes

Additional Structural Feature

• Reticular cell processes may extend to the basal side of endothelial cells.

• Associated with reticular fibers merging with:

  • perisinusoidal loops of basal lamina

Histology Section Appearance

• Blood fills:

  • sinuses

  • splenic cords

This may obscure underlying structures, making it difficult to distinguish sinuses from cords in sections.

Blood Circulation in the Red Pulp

Arterial Pathway

1. Branches of splenic artery enter white pulp from trabeculae

2. Central artery gives branches to:

   • white pulp

   • sinuses at white pulp perimeter

Marginal Sinuses

Located at perimeter of white pulp.

Penicillar Arterioles

• Central artery continues into red pulp

• Branches into straight arterioles called penicillar arterioles

Capillaries

Penicillar arterioles continue as arterial capillaries.

Sheathed Capillaries

Some capillaries are surrounded by aggregations of macrophages.

These are called:

Sheathed capillaries

Open Circulation

Mechanism

Sheathed capillaries empty:

• directly into the reticular meshwork of splenic cords

NOT directly into sinuses.

Blood then:

1. Percolates through splenic cords

2. Is exposed to macrophages

3. Reenters circulation by squeezing through sinus walls

Importance

• Only route of venous return in humans

Closed Circulation

In some species (rat, dog):

• Blood from sheathed capillaries enters splenic sinuses directly

This is called:

Closed circulation

Venous Drainage ( open )

1. Blood enters splenic sinuses

2. Drains into tributaries of trabecular veins

3. Trabecular veins merge into larger veins

4. Blood leaves spleen via splenic vein

5. Splenic vein joins intestinal drainage in hepatic portal vein

Functional Significance of Open Circulation

Open circulation:

• Exposes blood efficiently to macrophages of red pulp

• Allows macrophages to screen antigens

Functions of the Spleen

The spleen performs both:

1. Immune functions

2. Hemopoietic functions

Reason:
It filters blood, just as lymph nodes filter lymph.

Immune System Functions of the Spleen

Include:

1. Antigen presentation

   • by APCs

   • mainly dendritic cells and macrophages

2. Initiation of immune response

3. Activation and proliferation of

   • B lymphocytes

   • T lymphocytes

4. Production of antibodies

   • against antigens in circulating blood

5. Removal of macromolecular antigens from blood

White Pulp Immune Activity

Occurs in white pulp, including:

• Activation of T cells

• Differentiation of B cells

• Formation of plasma cells

• Antibody secretion

White pulp functions like other lymphatic organs.

Hemopoietic Functions of the Spleen

Include:

1. Removal and destruction of

   • senescent erythrocytes

   • damaged erythrocytes

   • abnormal erythrocytes

   • platelets

2. Retrieval of iron from erythrocyte hemoglobin

3. Formation of erythrocytes during early fetal life

4. Storage of blood

   • especially RBCs

   • in some species

Blood Filtration in Red Pulp

Primary role:

Blood filtration

Removes:

• particulate material

• macromolecular antigens

• aged blood cells

• abnormal blood cells

• damaged blood cells

• platelets

Role of Macrophages in RBC Breakdown

Macrophages in red pulp:

• break down senescent RBCs

Iron Fate

Iron from hemoglobin is stored as:

• Ferritin

• Hemosiderin

Heme Breakdown

Heme → bilirubin

Bilirubin transported to:

Liver via portal system

In liver:

• conjugated with glucuronic acid

Conjugated bilirubin:

• secreted into bile

• gives bile characteristic color

Recognition of Senescent RBCs by Macrophages

Macrophages detect aged RBCs through:

1. Nonspecific Mechanisms

Due to morphologic and biochemical changes in aging erythrocytes.

Effects:

• RBCs become more rigid

• More easily trapped in red pulp mesh

2. Specific Mechanisms

Involve:

Opsonization of RBC membrane

By:

anti-band 3 IgG antibodies

This triggers:

Fc receptor–dependent phagocytosis

Additional Recognition Mechanism

Changes in glycosylation of glycophorins in aging erythrocytes:

• act as recognition signals

• trigger elimination of senescent erythrocytes by macrophages