White blood cell

• 1. Introduction

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  White blood cells stand at the front line of the body's defense against disease, yet they make up only about 1% of the total volume of human blood. That tiny fraction is remarkable. The red blood cells that give blood its color account for 40% to 45% of blood volume. The white cells, so outnumbered, carry the weight of immunity.

  The name itself comes from the laboratory. When a blood sample is spun in a centrifuge, the cells separate by density. Red blood cells sink to the bottom. Above them appears a thin, typically white layer called the buffy coat. That pale band is where the white blood cells collect, visible and distinct. Doctors noticed it and named the cells accordingly.

  The scientific name, leukocyte, reaches back to ancient Greek. "Leuk" means white; "cyt" means cell. Simple, descriptive, exact. Yet the biology those two syllables point to is anything but simple. There are not one but three broad types of white blood cell, each with subtypes, each playing a different role in a system that must recognize friends from enemies, remember past invaders, and respond within hours to threats the body has never seen before.

  The count of white blood cells in a drop of blood is one of the first things a doctor checks when something is wrong. Between 4,000 and 11,000 cells per microliter is considered normal in the United States. Stray too far above that range, and the body is likely fighting an infection. Stray below, and the immune system is weakened. The number alone tells a story. What follows is the fuller story of what these cells are, how they work, and what happens when they fail.

• 2. A Cell With a Nucleus

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  Every white blood cell carries a nucleus. That single feature sets them apart from the other cellular passengers in blood. Red blood cells lack nuclei entirely; so do platelets. White blood cells have them, and the shape of those nuclei is one of the primary ways scientists tell one type of white cell from another.

  All white blood cells originate in the bone marrow, derived from a class of cells called hematopoietic stem cells. These stem cells are described as multipotent, meaning they can develop along different paths to produce any of the white blood cell types the body needs. Once produced, the cells do not stay in one place. They circulate through the blood and through the lymphatic system, moving throughout the body.

  The broadest division in the family of white blood cells runs along two lines. One distinction is structural: some cells carry visible granules in their cytoplasm, the gel-like substance that fills the cell, while others do not. The granule-bearing cells are granulocytes; the others are agranulocytes. The second distinction is by lineage: some white blood cells develop along the myeloid path, while others develop along the lymphoid path. Myeloid cells include neutrophils, monocytes, eosinophils, and basophils. Lymphoid cells are the lymphocytes.

  A practical mnemonic has existed for remembering the approximate proportions of the five main white blood cell types: Never Let Monkeys Eat Bananas, standing for neutrophils, lymphocytes, monocytes, eosinophils, and basophils. Neutrophils are by far the most numerous, making up 60% to 70% of all circulating white blood cells.

• 3. Neutrophils and the First Response

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  Neutrophils are the body's most plentiful white blood cell, constituting 60% to 70% of the circulating leukocyte pool. They are built for speed and short service. Their lifespan in an inactive state in the bloodstream has been measured in a range from as little as 5 hours to as long as 135 hours, depending on the methods used to assess it.

  Their target is primarily bacteria and fungi. When microbial infection begins, neutrophils are typically the first white blood cells on the scene, a quality that makes them the early-stage face of acute inflammation. They destroy pathogens through a process called phagocytosis, essentially engulfing and digesting the invader. The pus that forms in a wound is largely the accumulated bodies of dead neutrophils that have done exactly this work.

  Neutrophils carry fine granules in their cytoplasm that appear pale lilac under certain stains. Their nucleus is divided into three to five lobes connected by slender strands, an unusual multi-part structure that gives them their alternative name: polymorphonuclear leukocytes, or PMNs. The lobed shape allows them to squeeze through capillary walls and into tissue at an infection site.

  There is a cost to their efficiency. Neutrophils cannot replenish their lysosomes, the internal structures that do the digesting. After phagocytosing a relatively small number of pathogens, a neutrophil's capacity is exhausted and the cell dies. The buffy coat from a blood sample can reveal an important clue about what is happening inside the body: when the sample contains large numbers of neutrophils, the normally white layer can turn green, a result of the heme-containing enzyme myeloperoxidase that neutrophils produce.

• 4. Eosinophils, Basophils, and the Allergic Response

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  Eosinophils make up only about 2% to 4% of white blood cells in circulating blood. Their count is not constant. It rises and falls throughout the day, shifts with the seasons, and fluctuates during menstruation. It climbs in response to allergies, parasitic infections, collagen diseases, and disease of the spleen and central nervous system.

  Their particular talent is dealing with large parasites. Hookworms and tapeworms are too large for a single white blood cell to swallow through phagocytosis. Eosinophils handle them differently: they secrete chemicals that destroy the parasite from outside. Eosinophils are also the main inflammatory cell in allergic reactions, and conditions such as asthma, hay fever, and hives rank among the most significant triggers of elevated eosinophil counts. In the lymphatic tissue of the respiratory, digestive, and urinary tracts, eosinophils are far more numerous than they are in the blood itself. Their characteristic appearance under a microscope is defined by granules that stain a vivid pink-orange with a dye called eosin.

  Basophils are the rarest of all white blood cells, accounting for less than 0.5% of the total count. Their rarity and their shared properties with other blood cells make them difficult to study. They are identifiable by their coarse, dark violet granules, which give the cell a blue appearance and often obscure the bi- or tri-lobed nucleus beneath.

  Despite their scarcity, basophils carry two chemicals central to immune defense. Histamine widens blood vessels and increases blood flow to injured tissue, and it makes vessel walls more permeable so that neutrophils and clotting proteins can move into the surrounding connective tissue. Heparin, an anticoagulant, inhibits clotting and promotes the movement of white blood cells toward an infection. Basophils can also release signals that recruit both eosinophils and neutrophils to a site of infection.

• 5. Lymphocytes and Adaptive Immunity

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  Lymphocytes are more numerous in the lymphatic system than in the blood. Visually, they are defined by a deeply staining nucleus that may sit off-center within the cell, surrounded by a relatively small amount of cytoplasm. They come in three main varieties: B cells, T cells, and natural killer cells, each with a distinct role in the immune response.

  B cells produce antibodies, proteins that bind to pathogens, block their invasion, activate a cascade called the complement system, and mark pathogens for destruction. T cells split into several subtypes. CD4+ T helper cells carry a surface molecule called CD4 and bind to antigenic peptides presented on a structure called MHC class II on antigen-presenting cells. They make cytokines and coordinate the immune response. In HIV infection, CD4+ T cells serve as the primary indicator of how intact the immune system remains.

  CD8+ cytotoxic T cells carry the CD8 co-receptor and are designed to kill. They bind antigens displayed on MHC class I molecules, which appear on nearly all nucleated cells in the body, and they target virus-infected or cancerous cells for destruction. A third type, gamma delta T cells, carries a different form of T-cell receptor and occupies a bridging role, sharing properties with helper T cells, cytotoxic T cells, and natural killer cells.

  Natural killer cells patrol for cells that have lost their normal MHC class I surface markers, a condition that can arise when a cell is infected by a virus or turns cancerous. They also respond to stress markers such as MHC class I polypeptide-related sequence A. Memory lymphocytes, the cells that retain the record of past infections, can survive for years, allowing the immune system to mount a faster response to a pathogen it has encountered before.

• 6. Monocytes and Fixed Defenders

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  Monocytes are the largest white blood cells in circulation, ranging from 15 to 30 micrometers in diameter. They are described as sharing the phagocytic function of neutrophils, but with a crucial difference: monocytes are much longer lived and carry an additional responsibility that neutrophils cannot perform.

  After consuming a pathogen, a monocyte can present fragments of it to T cells. This presentation allows the immune system to recognize the pathogen again in the future and build an antibody response. Monocytes can also replace their lysosomal contents, allowing them to continue phagocytizing after neutrophils would have died. They carry a kidney-shaped nucleus and lack the visible granules of the granulocytes, though they possess abundant cytoplasm.

  Most monocytes eventually leave the bloodstream entirely. They migrate into tissues and transform into macrophages, cells whose job includes clearing dead cell debris and attacking microorganisms that neutrophils cannot handle effectively. In the liver, tissue-resident macrophages take on the specific name Kupffer cells.

  Some white blood cells take this settlement process even further and take up permanent residence in specific tissues without ever returning to the blood. These fixed leucocytes include histiocytes, dendritic cells, mast cells, and microglia. Dendritic cells are notable for their tendency to migrate to local lymph nodes after they have taken in antigens, carrying information about the threat to the lymph nodes where T and B cells are concentrated. Mast cells and microglia, by contrast, remain stationed in their home tissues, part of a distributed immune network embedded throughout the body.

• 7. When White Cells Go Wrong

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  White blood cell disorders divide into two broad groups: those in which there are too many cells and those in which there are too few. A count above 11 billion cells per liter is defined as leukocytosis; below the lower bound of the normal range is leukopenia.

  Leukocytosis has four main mechanical causes: increased production in the bone marrow, increased release from bone marrow storage, reduced attachment of cells to vessel walls, or reduced uptake by tissues. The most common cause is inflammation. Among the causes of elevated neutrophil counts specifically, cigarette smoking stands out as a secondary trigger; it occurs in 25% to 50% of chronic smokers and the elevated count can persist for up to five years after quitting.

  Neutropenia, a drop in neutrophil numbers, is the most common form of leukopenia. Drug-induced neutropenia is the most frequent acquired form, and a person experiencing it may show symptoms of medication overdose or toxicity. The list of implicated drugs is long: chemotherapy agents, sulfa antibiotics, phenothiazines, benzodiazepines, antithyroid medications, anticonvulsants, quinine, quinidine, indometacin, procainamide, and thiazides all appear on it, alongside alcohol and benzene as toxic exposures.

  Lymphocytopenia is defined as a total lymphocyte count below 1.0 billion per liter. The cells most commonly affected are CD4+ T cells. The causes span infectious diseases including HIV, tuberculosis, and measles; autoimmune conditions such as systemic lupus erythematosus and Sjögren syndrome; nutritional factors including alcohol use disorder and zinc deficiency; and physical causes including major surgery and severe burns.

  Cancers of white blood cells fall broadly into leukemias and lymphomas. These categories overlap considerably and are often grouped together. Disorders in which the cell count is normal but the cells fail to function correctly represent a third, qualitative category of white blood cell disease.