Innate Immunity: Barriers and the Inflammatory Response

Innate immunity is the body’s first, non-specific line of defense against pathogens, made up of physical and chemical barriers, white blood cells that engulf invaders (phagocytes) and the inflammatory response. In brief: skin and mucous membranes block most microbes from entering. If a pathogen gets through, phagocytes such as neutrophils and macrophages engulf it, and inflammation brings more defenders to the area. Innate defenses respond within minutes to hours, work against many types of pathogen and do not form a specific memory.

The innate system is present from birth, and it is the reason that most of the microbes we meet every day never make us ill. This guide explains the barriers, the cells involved, the steps of inflammation and the roles of fever and other defenses, compares innate and adaptive immunity, works through a cut in the skin and corrects common mistakes.

What are the physical and chemical barriers?

The best defense is to keep pathogens out of the body. Barriers act on any microbe, which is why they belong to non-specific immunity.

• Skin: a tough outer layer of dead cells filled with keratin, which is difficult for most microbes to penetrate. The skin is dry and slightly acidic (pH about 5.5), and sebum and sweat contain substances that inhibit microbes. Harmless bacteria that live on the skin compete with harmful ones.
• Mucous membranes: the linings of the nose, throat, airways, gut and urinary tract make sticky mucus that traps microbes. In the airways, cilia move the mucus upward to the throat, where it is swallowed, a process called the mucociliary escalator.
• Enzymes and secretions: lysozyme in tears, saliva and mucus breaks down bacterial cell walls. Stomach acid (pH 1.5 to 2) kills most microbes that are swallowed. Vaginal secretions are acidic.
• Reflexes: coughing, sneezing, vomiting and diarrhea remove pathogens.
• Normal microbiota: the harmless bacteria on the skin and in the gut occupy space and use nutrients, so pathogens find it hard to establish themselves.

Which white blood cells are involved?

When pathogens pass the barriers, white blood cells (leukocytes) take over. The innate system includes:

• Neutrophils: the most numerous white blood cells (about 60 percent). They arrive first at a site of infection, engulf bacteria and live for only a few days. Pus consists largely of dead neutrophils.
• Macrophages: large cells that develop from monocytes. They engulf and digest pathogens, dead cells and debris, release chemical signals and show pieces of pathogens to the adaptive immune system.
• Dendritic cells: catch antigens and carry them to lymph nodes to alert the adaptive system.
• Natural killer (NK) cells: destroy virus-infected cells and some tumor cells.
• Mast cells: release histamine in damaged tissue.
• Eosinophils: attack parasitic worms.

These cells recognize general patterns found on many microbes, such as components of bacterial cell walls, using receptors. They do not recognize individual species.

How does phagocytosis work?

1. The phagocyte is attracted to the pathogen by chemical signals (chemotaxis).
2. It attaches to the pathogen’s surface. Antibodies or complement proteins on the pathogen can help (they act as “tags”, a process called opsonization).
3. The membrane of the phagocyte surrounds the pathogen and takes it into a vesicle called a phagosome.
4. A lysosome fuses with the phagosome, and its enzymes and reactive chemicals digest the pathogen.
5. Remains of the pathogen are released, or parts of it are displayed on the cell surface as antigens.

What is the inflammatory response?

Inflammation is a rapid, local response to tissue damage or infection. The four classic signs are redness, heat, swelling and pain.

1. Damage or infection: injured cells and mast cells release chemicals, including histamine and prostaglandins.
2. Vasodilation: blood vessels near the site widen and become more permeable. More blood flows to the area, which causes redness and heat.
3. Fluid leaks out: plasma leaks into the tissue, which causes swelling. The fluid carries antibodies, clotting proteins and complement.
4. Phagocytes arrive: they squeeze through the walls of capillaries (diapedesis) and move to the site, following chemical signals. They engulf the invaders.
5. Pain and clotting: chemicals stimulate pain receptors, which warns of damage. Clotting forms a barrier to limit spread.
6. Resolution and repair: after the pathogens are cleared, the swelling falls and the tissue is repaired.

Inflammation is helpful in short bursts. Chronic inflammation is harmful, and it is associated with diseases such as arthritis, heart disease and some cancers. Anti-inflammatory drugs such as ibuprofen and aspirin reduce prostaglandin production.

What other innate defenses are there?

• Fever: a rise in body temperature, controlled by the hypothalamus in response to chemicals called pyrogens. It slows the growth of some microbes and speeds up immune reactions. Moderate fever is generally beneficial.
• Complement system: about 30 proteins in the blood that, when activated, mark pathogens for phagocytosis, attract phagocytes and can punch holes in bacterial membranes.
• Interferons: proteins released by virus-infected cells that warn neighboring cells and make them resistant to the virus.

Innate defenses at a glance

Worked example: a splinter in the finger

A wooden splinter breaks the skin and carries bacteria from the soil into the finger. Follow the immune response.

1. Barrier breached: the splinter bypasses the skin, so the first defense is passed.
2. Recognition: resident macrophages and mast cells in the tissue detect bacterial molecules and damage. They release histamine and other signals.
3. Inflammation: within minutes, the finger becomes red, warm, swollen and painful because of vasodilation and leakage of fluid.
4. Neutrophils arrive within a few hours and engulf bacteria. Macrophages continue to clear debris.
5. Result: if the bacteria are eliminated, the swelling goes down within days. Pus may form, containing dead neutrophils and bacteria. If bacteria spread, the adaptive immune system is activated by dendritic cells that carry antigens to nearby lymph nodes, which may become swollen.

The question of which signs show a more serious infection is practical. Spreading redness, increasing pain, fever or red streaks from the wound show that the infection is spreading, and a doctor should be seen. Cleaning the wound and, if necessary, a tetanus vaccination, help to prevent complications.

How was innate immunity discovered?

Élie Metchnikoff observed phagocytosis in starfish larvae in 1882, when he saw mobile cells surround a thorn, and proposed that white blood cells defend the body. He shared the 1908 Nobel Prize in Physiology or Medicine with Paul Ehrlich. Alexander Fleming discovered lysozyme in 1921, before his discovery of penicillin. Jules Hoffmann and Bruce Beutler found the receptors, called Toll-like receptors, that detect microbial patterns in the 1990s, and they shared the 2011 Nobel Prize with Ralph Steinman for dendritic cells.

Which mistakes are common?

Mistake 1: Saying that innate immunity targets specific pathogens

It is non-specific. It responds to general patterns found on many microbes.

Mistake 2: Thinking that inflammation is a sign that something has gone wrong with the immune system

It is a normal and useful response. Problems arise when it is excessive or chronic.

Mistake 3: Calling the skin an organ with no role in immunity

The skin is the first and most important barrier.

Mistake 4: Assuming that fever should always be reduced

A moderate fever is part of the defense, though very high fever is dangerous and should be treated.