The Lymphatic and Immune Systems: Fluid Return and Defence

1Overview

The body is under constant attack. Bacteria on the skin, viruses in the air and abnormal cells arising from within all threaten the internal environment, yet most are neutralized without the person ever noticing. Two linked systems manage this. The lymphatic system drains and filters the fluid that leaks from capillaries and houses the cells of defence. The immune system, built from these cells and their chemicals, recognizes and destroys threats and remembers them. A related article describes the immune system in general; this lesson adds the structure, mechanisms and links to homeostasis.

2Structure of the lymphatic system

The lymphatic system has three roles: returning tissue fluid to the blood, absorbing dietary fat from the intestine, and providing a base for immune cells.

• Lymph and capillaries. Interstitial fluid that enters the lymphatic system is called lymph. Lymphatic capillaries are blind-ended tubes made of overlapping endothelial cells that act as one-way flaps: fluid enters, but cannot flow back. They are absent from the central nervous system, bone marrow, bones, teeth and the cornea.
• Vessels and ducts. Larger vessels resemble veins and have valves. Lymph is not pumped by the heart; it moves through skeletal muscle contraction, body movement and breathing, with valves keeping it flowing toward the heart. The right lymphatic duct drains the upper right body into the right subclavian vein, and the thoracic duct drains the rest into the left subclavian vein.
• Lacteals. In the small intestine lymph capillaries called lacteals absorb dietary fats and fat-soluble vitamins as a milky fluid called chyle (Lesson 11).
• Lymph nodes. There are roughly 500 to 600 nodes, clustered in the neck, armpits, chest, abdomen and groin. Lymph enters through afferent vessels, is filtered through channels lined with macrophages and dendritic cells that trap and destroy pathogens, and leaves through an efferent vessel. Lymphocytes in the cortex (B cell follicles) and medulla multiply when an infection is present, which is why nodes swell.
• Spleen. About 12 cm long, it filters blood, removes microbes and dying red blood cells in its red pulp, and its white pulp is a site of adaptive immune responses.
• Thymus. A bilobed organ behind the sternum, the site where T cells mature. It shrinks after puberty, which is linked to age-related decline in immunity.
• Tonsils and MALT. Tonsils trap pathogens in crypts. Mucosa-associated lymphoid tissue, including the Peyer's patches of the small intestine and the bronchus-associated tissue of the lungs, guards the surfaces most exposed to the outside.

3Innate immunity: the first and second lines of defence

Innate immunity is present at birth, acts the same way against every threat and responds in minutes to hours.

Barriers

Cells and proteins

• Phagocytes engulf particles. The vesicle (phagosome) fuses with a lysosome that digests the contents (Lesson 3). Neutrophils move quickly from the blood to infection sites by chemotaxis and are the main pathogen-killers in inflammation. Macrophages are long-lived tissue cells (Kupffer cells in the liver, alveolar macrophages in the lungs). Monocytes are blood precursors that become macrophages or dendritic cells.
• Natural killer (NK) cells are lymphocytes that induce apoptosis in virus-infected and some cancer cells. They release perforin, which forms pores in the target membrane, and granzymes, enzymes that enter through the pores and trigger programmed cell death.
• Pattern recognition receptors on innate cells detect molecular patterns common to pathogens and molecules released by damaged cells. There are only a limited number of them, in contrast to the huge variety of receptors in adaptive immunity.
• Complement is a cascade of plasma proteins made mainly in the liver. Fragments coat pathogens for phagocytosis (opsonization) and attract phagocytes, and the final proteins form a membrane-attack complex that makes pores in bacteria.
• Interferons are released by virus-infected cells; neighbouring cells respond by making antiviral proteins, protecting nearby tissue.

Inflammation

Inflammation is the local response that brings defence to a damaged area. Injury causes mast cells to release histamine and other chemicals; capillaries dilate (heat and redness) and become more permeable so plasma leaks out (swelling); and chemical signals draw neutrophils and then macrophages. Chronic inflammation, which persists, can destroy tissue and cause scarring.

A fever, a regulated rise in the hypothalamic set point for body temperature, often accompanies infection; the related article explains it in more detail.

4Adaptive immunity: specific and with memory

Adaptive immunity is slower on first exposure (days) but is highly specific and remembers. It depends on lymphocytes, of which the body contains about a trillion.

Antigens, MHC and antigen presentation

An antigen is any molecule recognized by lymphocyte receptors; the small region bound is the epitope. T cells recognize antigen only when it is displayed on an MHC molecule by an antigen-presenting cell. MHC class I is on nearly all cells and displays fragments of proteins made inside the cell (for example viral proteins); MHC class II is found on professional antigen-presenting cells (macrophages, dendritic cells and B cells) and displays material taken in from outside. Dendritic cells carry antigen to nearby lymph nodes, where most T cell responses begin.

T cells (cell-mediated immunity)

T cells mature in the thymus. Selection there is strict: cells that cannot recognize self-MHC die, and cells that react strongly to self-antigens die, establishing tolerance. Only about 2% of the cells entering the thymus leave as mature T cells.

B cells and antibodies (humoral immunity)

B cells develop in the bone marrow. When a B cell binds its antigen and receives help from a helper T cell, it multiplies and becomes plasma cells, which secrete large amounts of antibody, or memory B cells. An antibody has two identical heavy chains and two identical light chains with two identical antigen-binding sites. Antibodies agglutinate (clump) pathogens, label them for phagocytosis, and activate complement.

Clonal selection and memory

Each lymphocyte carries receptors of a single specificity, and an antigen activates only the clones whose receptors fit it. Those cells proliferate (clonal expansion) to produce identical effector cells and long-lived memory cells.

On a second exposure, memory cells respond with no delay and at a much higher level, so the pathogen is often eliminated before symptoms appear. That is the basis of immunity after infection and of vaccination.

A timeline of one infection

The layers of defence act in sequence when bacteria enter a cut. Within minutes, resident macrophages and mast cells detect the invaders and damaged tissue; complement proteins coat the bacteria and inflammation recruits neutrophils, which engulf them. Over the next hours, dendritic cells that have picked up bacterial antigen travel through lymphatic vessels to the nearest lymph node. In the node, a helper T cell with a matching receptor and a B cell that binds the antigen are selected and multiply. After several days, plasma cells release antibodies into the blood, which help phagocytes clear the remaining bacteria and neutralize toxins. When the infection is over, most effector cells die by apoptosis, but memory cells remain for years.

5Types of immunity and vaccination

A vaccine imitates an infection to engage the body's natural defences. Its active ingredient is an antigen, which may be a weakened or killed organism, a piece of its surface or genetic material, or a bacterial toxin made harmless. Live-attenuated vaccines (such as MMR) give long-lasting protection but can cause serious infection in people with weak immune systems; non-live vaccines are safer for those people but protection fades, so boosters are needed. Seasonal flu vaccines are reformulated each year. Protection takes weeks to develop, and vaccinated people are much less likely to become seriously ill. A related article explains vaccines in more depth.

6When the immune system fails or misfires

• Allergy: an exaggerated response to a harmless antigen, involving IgE bound to mast cells and release of histamine; severe cases cause anaphylaxis.
• Autoimmune disease: tolerance breaks down and the immune system attacks the body's own cells. Type 1 diabetes, in which beta cells are destroyed (Lesson 7), is one example.
• Immunodeficiency: HIV infects and destroys immune cells, and without treatment can lead to AIDS, defined partly by a CD4 cell count below 200 cells per millilitre or certain opportunistic infections. Antiretroviral therapy lowers the virus in the blood, allows long healthy lives and, when it keeps the virus undetectable, prevents sexual transmission. HIV spreads through blood, semen, pre-seminal fluid and rectal and vaginal fluids; condoms, never sharing injection equipment, PrEP and PEP help prevent infection, and testing is the only way to know.
• Transplant rejection: the recipient's immune system recognizes the donor's MHC and cell-surface carbohydrates (Lesson 3) as foreign.

7Interdependence and homeostasis

The lymphatic and immune systems are tightly bound to others. They return fluid to the cardiovascular system and depend on blood to transport their cells; the digestive system supplies lacteals and a large mass of lymphoid tissue; the respiratory system relies on mucus, cilia and alveolar macrophages; the integumentary system provides a physical barrier; the endocrine system modulates immunity (cortisol suppresses inflammation, and the thymus shrinks as sex hormones rise); and the nervous system links stress with immune function.

The immune response is itself a set of feedback loops. Positive feedback amplifies it (activated T cells release cytokines that activate more cells, and inflammation recruits more phagocytes), and negative feedback limits it (regulatory T cells suppress responses and the loop ends when the antigen is cleared). Failure of this balance is the origin of autoimmune disease, chronic inflammation and immunodeficiency, a theme continued in Lesson 14.

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