The lymphatic system and the immune system

Introduction

The lymphatic system plays two essential roles in the human body:

1.
Absorbs fluid from interstitial space and returns fluid to intra-vascular space.
- a.
  Transports lymph filtration fluid that enters the interstitial space from the capillaries.
2.
Functional connection of blood and endothelium to the immune system.
- a.
  Transport of immune cells and products.

Lymphatic system structure

The lymphatic system plays an essential role in fluid transport:

Capillary endothelium provides a semipermeable barrier between intravascular and extravascular interstitial space.
Fluid crosses into the interstitial space as arterial blood passes through capillaries.
Most fluid is reabsorbed at the venous end of the capillary, but a small fraction remains.
This excess, acellular fluid containing solutes and proteins collects as lymph.
The lymphatic system then returns lymph to systemic circulation.

The extracellular fluid

Total body water, or TBW, is composed of approximately two-thirds intracellular fluid (ICF) and one-third extracellular fluid (ECF) ( Fig. 8.1 ). ECF occupies two compartments:

25% of the ECF is within blood vessels as intravascular fluid (plasma).
75% is within tissues as extravascular interstitial fluid.

Fig. 8.1, Division of total body water ( TBW ) into extracellular and intracellular fluid compartments ( ECF and ICF ). The volumes listed are calculated for a 70-kg person. The ECF is further subdivided into interstitial fluid bathing body cells outside the vascular space and plasma, the ECF volume in the vascular space.

These two ECF compartments are dynamic, with water molecules, ions, and macromolecules moving between them according to physical forces.

The interstitial space

The interstitial compartment surrounds tissue cells and forms their immediate environment. It is composed of:

Collagenous framework filled with a gel-like solution containing negatively charged glycosaminoglycans (GAGs) and proteoglycans.
- GAGS are long unbranched polysaccharides consisting of a repeating disaccharide unit.
  - Examples: Heparin, chondroitin, dermatan, keratan, and hyaluronic acid.
- Proteoglycan consist of “core proteins” attached to one or more GAGs.
Salts
Water
Plasma-derived proteins (e.g., albumin)

The particular composition varies greatly among different tissues. The skin, for example, has denser or “tighter” interstitial spaces with relatively high concentrations of collagen, hyaluronic acid, and albumin, whereas lung tissue has a “looser” matrix.

Lymphatic system components

To efficiently return fluid from the interstitial space to systemic circulation, the lymphatic system extends small vessels into almost all tissues. This network of vessels is interrupted by lymph nodes, where the immune surveillance is carried out.

Lymphatic system gross anatomy

The lymphatic system consists of:

Lymphatic vessels (lymphatics), a network of tubules connecting the entire system ( Fig. 8.2 ).
- The largest lymph vessel is the thoracic duct, which feeds into the left subclavian vein to reconnect lymph and systemic circulation.
- Most lymphatics feed into the cisterna chyli, a large lymph sac feeding into the thoracic duct.
- Certain lymph vessels drain instead into the right lymphatic duct → right subclavian vein (the right upper extremity, half of thorax, half of head)
Lymph, fluid contained within the lymphatics.
Lymph nodes, small swellings linked by lymphatics, are sites of immune cell trafficking.
- Distributed unevenly throughout the body, particularly numerous in the neck, axillae, and inguinal areas.

Other important organs of the lymphatic system, such as the spleen, thymus, tonsils, and Peyer’s patches, are discussed in the context of the immune system (see Clinical Correlation Box 8.1 ).

Clinical Correlation Box 8.1

Virchow’s node, or the “signal node,” is a lymph node that sits above the left clavicle and drains the lymph vessels from the abdominal cavity. Swelling of this node is strongly associated with cancer in the abdomen, especially gastric cancer.

Lymphatic system tissues and cells

Lacteals are lymphatic capillaries embedded within the interstitial space ( Fig. 8.3 ):

Thin, blind-ended channels lined by a single layer of endothelial cells.
- In contrast with vascular capillary endothelium (see Ch. 9 and the appendix on endothelial function), lacteal endothelium has no fenestrations, no tight junctions, and virtually no basal lamina.
Contain bileaflet valves to prevent backflow of lymph.

Fig. 8.3, Lymphatics vessel components. Small lymphatic capillaries called lacteals are embedded in tissues. Lymph enters the sealed end and travels out of the tissue ( arrow ). Also shown is a nearby arteriole, blood capillary, and venule, with the flow of progressively deoxygenated blood indicated.

Lymph contains very few cells normally:

Red blood cells do not ordinarily leave the vasculature and thus are not found in normal lymph.
White blood cells, on the other hand, can exit (or extravasate) from the postcapillary venules by the process of diapedesis and enter tissues.

Lymph nodes are kidney bean shaped collections of tissue cells and leukocytes, such as macrophages and lymphocytes ( Figs. 8.4 and 8.5 ):

On the outer (convex) surface, one or more afferent lymphatic vessels “plug into” the node, penetrating the capsule.
The deeper node is divided into an outer cortex and an inner medulla.
- Outer cortex
  - Subdivided by connective tissue trabeculae, contains dynamic collections of immune cells called follicles.
- The arrangement of these resident immune cells into follicles and zones expedites their communication (described later).
- Inner medulla
The node’s hilum is the area on the inner (concave) surface where efferent lymphatic vessels exit and where a feeding artery and a draining vein “plug into” the node.

Fig. 8.4, Microscopic view of a lymphatic vessel. Note the thin wall of endothelium and the bileaflet valve, which ensures that lymph flows unidirectionally ( arrows ).

Lymphatic system function

The starling forces

The process of fluid moving from the vascular space of the capillary into the interstitial tissue is known as transudation.

The three main determinants of filtration of fluid across a capillary membrane into the interstitial space are:

1.
The net hydrostatic pressure
2.
The net oncotic pressure
3.
Capillary filtration

These three variables determine the direction and magnitude of fluid flux between the vascular space of a capillary and the interstitial space.

The hydrostatic and oncotic pressures are called Starling forces and are related to the capillary wall permeability and fluid flux by the Starling equation, described later.

Hydrostatic pressures

There are two hydrostatic pressures:

1.
Capillary hydrostatic pressure (Pc) is the force per unit area of the capillary endothelium that pushes fluid out of the capillary and into the interstitial space.
- a.
  Determined by systemic blood pressure and the specific resistances of the local arterioles and venules.
  - i.
    Systemic blood pressure is a function of total intravascular salt and water volume, pumping forces generated by the heart, and total vascular resistance (see Part IV).
- b.
  Pc is approximately 32 mm Hg at the arteriolar end but decreases along the length of the capillary, reaching approximately 15 mm Hg at the venous end of a typical capillary.
2.
Interstitial hydrostatic pressure (Pi) opposes Pc.
- a.
  Thought to be determined by:
  - i.
    Imbalance of opposing mechanical forces exerted by hyaluronan and collagen.
  - ii.
    Affinity of hyaluronan for water
- b.
  Pi is slightly negative, approximately –3 to 0 mm Hg.
  - i.
    This causes it to “suck” fluid from the capillary into the interstitial space – in the same direction as Pc.

The difference between these pressures represents the net driving hydrostatic pressure for filtration. Note that because Pi is negative, the net driving hydrostatic pressure exceeds Pc.

Arteriolar end: Pc – Pi = 32 mm Hg – (–3 mm Hg) = 35 mm Hg
Venous end: Pc – Pi = 15 mm Hg – (–3 mm Hg) = 18 mm Hg

Oncotic pressures

Similarly, there are two opposing oncotic pressures. Because there are no large differences in salt concentrations between the interstitium and the plasma, the oncotic pressures are determined entirely by the differences in protein concentrations of the two compartments.

1.
Capillary oncotic pressure (IIc) is defined as the colloid osmotic pressure, the component of the total osmotic pressure that is contributed by plasma proteins.
- a.
  The capillary endothelium allows essentially free diffusion of small solutes, but severely restricts filtration of protein into the interstitial space.
- b.
  High relative protein content.
- c.
  IIc is approximately 25 mm Hg.
2.
Interstitial oncotic pressure (IIi) is the colloid osmotic pressure exerted by the osmotically active proteins in the interstitium.
- a.
  Low relative protein content as discussed.
- b.
  IIi is approximately 0 to –5 mm Hg.

Thus the difference between these pressures represents the net driving oncotic pressure for filtration. In normal conditions, it is positive and thus favors fluid reabsorption.

Fig. 8.6 shows the direction of the vectors for the two hydrostatic and two oncotic pressures.

At the arteriolar end of the capillary, the hydrostatic forces for filtration exceed the oncotic forces for resorption, and the net effect is fluid filtration.
At the venous side of the capillary (because of hydrostatic pressure reduction), the oncotic forces exceed hydrostatic forces and the net effect is fluid reabsorption.

Fig. 8.6, Forces determining fluid flux across a capillary endothelium. As blood flows from the arteriolar end of the capillary toward the venous end, the capillary hydrostatic pressure, Pc, decreases. The interstitial hydrostatic pressure (Pi), the capillary oncotic pressure (Πc), and the interstitial oncotic pressure (Πi) are also shown. At a critical point, the balance of forces shifts from favoring the efflux of fluid from the capillary lumen into the interstitium (transudation) to favoring the resorption of fluid from the interstitium back into the capillary (resorption). Filtration exceeds resorption, but the lymphatics maintain fluid homeostasis in the interstitium by absorbing the excess fluid.

In most tissues, the volume of fluid that leaves the capillary and enters the interstitial space exceeds the volume of fluid that is resorbed from the interstitial space back into the capillary. Thus there is a net loss of fluid from the vascular space into the extravascular tissue space. If this fluid is not resorbed and returned to the circulatory compartment by the lymphatic system, it accumulates in tissues and causes swelling called "edema." The compliance of the extracellular space is relatively high, so it takes a considerable volume of fluid to start increasing tissue pressure. This increased interstitial hydrostatic pressure opposed capillary hydrostatic pressure and limits further accumulation of fluid, and it promotes fluid flow into the lymphatic system, both of which are mechanisms of escape from edema.

The capillary filtration coefficient

The third factor important in fluid flow across the capillary is capillary filtration, or the volume of fluid filtered from the intravascular to interstitial spaces. It is directly proportional to:

Capillary wall permeability: the intrinsic hydraulic permeability of the endothelium and the other structural components of the capillary wall.
Total surface area of the capillaries supplying a local area of tissue.

The capillary filtration coefficient (K _f ) is a quantitative measure of these two parameters.

Units: milliliters of fluid transported per minute per 1 mm Hg pressure per 100 g of tissue.
Independent of hydrostatic and oncotic pressures and depends on the microscopic structure of the vessels and tight junctions between the endothelial cells (see Clinical Correlation Box 8.2 )

Clinical Correlation Box 8.2

If the capillary wall is damaged by toxins or inflammatory stimuli, then it becomes much more permeable and K _f increases. Thus, more plasma enters the interstitial space (transudation). Likewise, if the smooth muscle of small arterioles relaxes, opening (or recruiting) previously closed capillaries in a tissue bed, the total capillary surface area rises. This also leads K _f (and thus transudation) to increase.

The starling equation

The relationship among hydrostatic pressures, oncotic pressures, and the K _f can be expressed in a compact form known as the Starling equation:

Q = (K_{f}) × [(Pc - Pi) − σ (IIc − IIi)]

$Q = (K_{f}) × [(Pc - Pi) − σ (IIc − IIi)]$

The Starling equation states that the overall flow of fluid, Q, expressed in units of volume per time in a given mass of tissue (mL of fluid transported per minute per 100 g tissue) is equal to K _f multiplied by the differences between the hydrostatic and oncotic forces between the capillary lumen and interstitial space.

The reflection coefficient, σ, a correction factor that varies from 0 to 1 to simulate the decreased contribution of the oncotic pressure gradient to the net driving force. This correction is sometimes necessary to simulate small protein leakage in many body capillaries.

A positive value for Q indicates fluid filtration from the vasculature into the tissues (transudation), whereas a negative value for Q indicates fluid resorption.

The magnitude of Q indicates the quantity of fluid flow.

The flow of lymph

The production of lymph takes place in almost all major organs. Lymph does not flow via a pump (such as with the cardiovascular system), but rather by a combination of extrinsic and intrinsic forces. Overall, the net force favors drainage of fluid from the interstitium to the terminal lymphatics.

Extrinsic forces lead to the generation of tissue compressive or suction forces.
- Active striated muscle contractions, particularly limb movements during periods of standing and walking.
- Rhythmic changes of intraabdominal and intrathoracic pressure because of respiration, peristalsis, and arterial pulsation.
Intrinsic forces occur because of intrinsic contractility of the lymphatic vessels.
- Individual segments between valves accumulate fluid, which leads to distension and then contraction.
- This propels fluid upstream in a peristaltic fashion.

Lymphatic system pathophysiology

Any processes in lymph physiology, including filtration, resorption, or lymph flow, can become dysfunctional and result in disease. The aberrant accumulation of fluid in the interstitial space leads to edema.

Edema occurs most commonly by one of four possible mechanisms:

1.
Increased intravascular hydrostatic pressure
2.
Decreased intravascular oncotic pressure
3.
Increased capillary permeability
4.
Lymphatic obstruction

Increased intravascular hydrostatic pressure

Increased intravascular hydrostatic pressure (Pc) occurs in:

States of generalized increased intravascular plasma volume, such as total fluid overload.
Localized obstruction (increased pressure occurs proximal to the obstruction).

In congestive heart failure (CHF), impaired pumping function of the heart’s left ventricle leads to increased pressure in the pulmonary venous circulation as blood backs up, leading to dangerous fluid accumulation in the lungs called pulmonary edema.

In cirrhotic liver disease, obstruction to flow in the portal venous system owing to the destruction of liver parenchyma leads to portal hypertension (elevated Pc) and fluid accumulation in the abdominal cavity called ascites.

Decreased intravascular oncotic pressure

Decreased intravascular oncotic pressure (P _c ) occurs in states of hypoproteinemia, usually measured as hypoalbuminemia, a low concentration of albumin in the blood. This condition occurs in cases of:

Reduced protein intake, as in cases of malnutrition.
Reduced ingested dietary protein absorption, as in gastro-intestinal (GI) malabsorption.
Reduced albumin production, as in liver failure.
Increased albumin urinary losses, as in nephrotic syndrome.

Whatever the cause, decreased oncotic pressure impairs the ability of the venous end of the capillary to resorb fluid. Initially, the excess interstitial fluid is returned to the systemic circulation by the lymphatics, but once the volume of fluid exceeds the capacity of the lymphatics, edema results.

Increased capillary filtration coefficient

Increased capillary permeability, expressed quantitatively as an increased capillary filtration coefficient (CFC), occurs when the capillary endothelium is damaged. Examples include:

Burns, in which connective tissue is destroyed.
Local inflammation, in which inflammatory stimuli loosen the tight junctions between endothelial cells.
Toxic damage, in which endothelial cell dysfunction occurs, as in sepsis, pancreatitis, and inhalation injuries (e.g., damage from inhaling smoke).

Lymphatic obstruction

Lymphatic obstruction occurs in any disease in which lymphatic vessels or nodes are blocked.

Invasion of neoplastic cells in cancer may invade and disrupt lymphatic channels.
Surgical removal of lymph nodes.
Certain parasitic infections, such as filariasis, where small worms penetrate the system and obstruct lymph flow.

In all cases, the resultant edema is localized to the area drained by the affected nodal group.

Introduction

The many diverse structures and functions of the immune system can be imagined as a great war carried out by the cells of the immune system in defense of the body.

Immune system cells are the soldiers.
Immune system molecules are their tools and weapons.
Immune system responses are the tactical moves.

The immune system primarily exists to protect the body from infection (the invasion of the body by pathogenic microbes).

Immune system cells sample the matter contacting the body’s borders, looking for invaders.
If detected, the immune system activates and responds to destroy or drive out the enemy.

Note this chapter will focus on broad principles; there is an enormous amount of subtlety in the immunology, as well as frequent, exciting new research insights.

Innate versus adaptive immunity

The body’s immune defense has two distinct but highly interrelated subsystems.

The first, the innate immune system, is a nonspecific, immediate immune response. It is multitiered:

Anatomic barriers
- Mechanical: skin, mucus, sweat, coughing/sneezing.
- Chemical: saliva (lysozyme, phospholipase A2), gastric acid, defensins, vaginal secretions.
- Microbial: commensal flora (“good bacteria”).
Inflammation
- Definition
  - Influx of immune cells, fluid, and blood proteins into an area of the body that has been injured and/or infected.
  - Prevents infection spread and promotes healing.
- Acutely inflamed tissue typically shows:
  - Rubor (redness)
  - Dolor (pain)
  - Calor (heat)
  - Tumor (swelling)
  - Functio laesa (loss of function)
Cellular response
- Certain white blood cells (i.e., macrophages, neutrophils, and eosinophils).
- Detect microbes by means of cell-surface receptors called pattern recognition receptors (PRRs)
  - PRRs are generally glycoproteins that bind to specific structures (called pathogen-associated molecular patterns [PAMPs]).
    - Found in microbes, but not humans.
- PRRs binding → innate immune cell activation → inflammatory response.
Plasma protein systems
- Complement cascade (discussed later)

The innate immune system is rapid and somewhat specific because of the dependence on PAMPs, but PRRs are encoded by invariant genes and cannot adapt. It is also involved in tissue repair following trauma and help contain injurious agents, such as foreign bodies.

If the innate immune system cannot eradicate an invader, then the adaptive immune response is invoked. It differs importantly from innate immunity in several ways ( Table 8.1 )

TABLE 8.1

Essential Differences Between Innate and Adaptive Immune System

	Time	Specificity	Plasticity	Memory
Innate	Minutes to hours	Relatively nonspecific	None	None
Adaptive	Days	Highly specific	Yes	Yes

The major cells of adaptive immunity are lymphocytes: T cells and B cells.

The cell-surface receptors of T and B cells recognize particular structures of microbes, produced by a dramatic reshuffling of genes (plasticity).
Adaptive immune memory cells persist in the circulation (memory).
- Primary response: The first interaction particular microbe and a human host will produce disease as the host’s adaptive immune system responds.
- Secondary response: On reexposure to the same pathogen, the adaptive immune response is almost instantaneous.
- If the pathogen is eliminated so quickly as to avoid disease symptoms, this is called immunity.
  - Differentiates “self” (the human host, in this case) from “nonself.”
- Protects the body by triggering a powerful response to neutralize and destroy pathogens, proteins, or cells that are nonself.

The lines of defense are highly intertwined and interdependent. Innate immune cells detect invaders and signal adaptive immune cells about a threat. When in turn the adaptive immune system marshals its forces, it conscripts innate immune cells to do much of the fighting.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here

Introduction

Lymphatic system structure

The extracellular fluid

The interstitial space

Lymphatic system components

Lymphatic system gross anatomy

Lymphatic system tissues and cells

Lymphatic system function

The starling forces

Hydrostatic pressures

Oncotic pressures

The capillary filtration coefficient

The starling equation

The flow of lymph

Lymphatic system pathophysiology

Increased intravascular hydrostatic pressure

Decreased intravascular oncotic pressure

Increased capillary filtration coefficient

Lymphatic obstruction

Introduction

Innate versus adaptive immunity

You're Reading a Preview

Related Posts

Appendix 5

Appendix 4

Appendix 3

Appendix 2