Inclusions are small, nonliving structures found inside cells that store or accumulate substances like fats, pigments, proteins, and carbohydrates. Unlike organelles such as mitochondria or the Golgi apparatus, inclusions don’t have their own membranes and aren’t considered active, functioning “mini-organs.” They’re more like deposits, collections of material that the cell has produced, absorbed, or failed to break down. Inclusions show up across nearly every area of medicine, from routine blood work to the diagnosis of Parkinson’s disease.
How Inclusions Differ From Organelles
Cells contain two broad categories of internal structures: organelles and inclusions. Organelles are membrane-bound compartments with dedicated jobs. Mitochondria generate energy. The Golgi apparatus packages and ships proteins. Each one is essential for the cell to survive.
Inclusions, by contrast, are passive. They sit in the cytoplasm (or sometimes the nucleus) as stored nutrients, waste products, or clumps of protein. Glycogen granules, for example, are inclusion bodies that store sugar for energy. Melanin granules are pigment inclusions that give skin its color. Secretory granules hold enzymes or hormones waiting to be released. None of these have their own membrane or carry out an independent metabolic process the way an organelle does.
Common Types of Cytoplasmic Inclusions
Most inclusions fall into a few broad categories based on what they’re made of:
- Lipid droplets: Stored fat that cells can break down for energy when needed. These are especially common in fat tissue and liver cells.
- Glycogen granules: Stored sugar, concentrated in liver and muscle cells. The body taps into these reserves between meals or during exercise.
- Pigment granules: Melanin in skin cells, lipofuscin (a yellowish “wear and tear” pigment) in aging neurons and heart muscle cells, and hemosiderin, an iron-storage pigment found in tissue after bleeding or iron overload.
- Secretory granules: Packets of hormones, enzymes, or other signaling molecules that the cell releases in response to a stimulus.
These are all normal parts of cell biology. They appear in healthy tissue and reflect routine storage, signaling, or metabolism.
Inclusions in Red Blood Cells
When a lab technician examines a blood smear under a microscope, certain inclusions inside red blood cells can point toward specific disorders. Three of the most clinically recognized types are Howell-Jolly bodies, Heinz bodies, and Pappenheimer bodies.
Howell-Jolly bodies are small, dark, round remnants of nuclear DNA left behind in a mature red blood cell. Normally the spleen filters these out, so their presence on a blood smear often signals that the spleen has been removed or isn’t functioning properly. They stain purple with standard blood-smear dyes and are easy to spot.
Heinz bodies are clumps of damaged, denatured hemoglobin stuck to the inner membrane of a red blood cell. They measure 1 to 3 micrometers and can sometimes be seen moving inside the cell on a wet preparation. Heinz bodies show up in conditions where hemoglobin is unstable or under oxidative stress, including G6PD deficiency (a common inherited enzyme disorder), certain drug toxicities, and chemical poisoning. They’re also seen after splenectomy.
Pappenheimer bodies are iron-containing granules. They tend to appear in sideroblastic anemia, lead poisoning, thalassemias, and iron overload conditions. Spotting them on a blood smear helps narrow down what’s causing abnormal blood counts.
Viral Inclusion Bodies
Some of the most well-known inclusions in diagnostic medicine are caused by viral infections. When certain viruses replicate inside a cell, they leave behind visible clumps of viral protein or altered cellular material in either the nucleus or the cytoplasm. These clumps, called viral inclusion bodies, can be seen under a microscope using standard staining and often help identify which virus is responsible for an infection.
Herpes simplex virus and cytomegalovirus, for instance, produce characteristic intranuclear inclusions. Rabies virus creates Negri bodies in the cytoplasm of brain cells. The appearance, location (nuclear vs. cytoplasmic), and staining pattern of these inclusions give pathologists important diagnostic clues, sometimes before other test results are available.
Inclusions in Neurodegenerative Disease
In neurology, protein inclusions are central to understanding diseases like Parkinson’s and dementia with Lewy bodies. Lewy bodies are intracellular inclusions made primarily of misfolded clumps of a protein called alpha-synuclein. They form inside the cell bodies of neurons, while related deposits called Lewy neurites form in the branching extensions of those neurons.
Lewy bodies aren’t simple. Beyond alpha-synuclein, they contain fragments of lysosomes (the cell’s waste-disposal system), mitochondria, pieces of the cell’s internal skeleton, lipids, and dozens of other proteins involved in cellular cleanup and degradation. The current understanding is that Lewy bodies represent a failure of the cell’s protein-disposal machinery: misfolded proteins accumulate faster than the cell can clear them, and the resulting deposits interfere with normal function.
A rarer condition called neuronal intranuclear inclusion disease (NIID) involves eosinophilic inclusions, which are abnormal protein masses, forming inside the nuclei of neurons and their supporting glial cells. Recently, researchers linked NIID to a genetic change in the NOTCH2NLC gene. The disease causes a wide range of neurological symptoms, and diagnosis often depends on detecting these characteristic nuclear inclusions in tissue samples.
Crystal Inclusions in Joint Fluid
Inclusions aren’t limited to what’s inside cells. In rheumatology, the term also applies to crystalline deposits found in joint fluid. When a joint is swollen and painful, doctors may draw a small sample of fluid and examine it under polarized light microscopy to look for crystals.
Monosodium urate crystals are the hallmark of gout. They appear as bright, needle-shaped structures with strong birefringence (they glow distinctly under polarized light). Calcium pyrophosphate dihydrate crystals cause a condition sometimes called pseudogout. These crystals vary more in size and shape and are less consistently birefringent, which can make them trickier to identify. Distinguishing between these two crystal types determines the diagnosis and guides treatment.
How Inclusions Are Detected
Most inclusions are identified using staining techniques and microscopy. The workhorse method in pathology is hematoxylin and eosin (H&E) staining, which reveals a wide range of structures including many types of inclusion bodies. Giemsa staining is particularly useful for identifying protozoan parasites and certain viral inclusions. PAS (periodic acid-Schiff) staining highlights carbohydrate-rich structures, making it effective for detecting fungi like Candida, Aspergillus, and Histoplasma, as well as certain parasitic cysts.
For red blood cell inclusions, Romanowsky-type dyes (the family that includes Wright-Giemsa and similar stains) work well for Howell-Jolly bodies but poorly for Heinz bodies, which require a supravital stain like crystal violet or brilliant cresyl blue. The choice of stain depends entirely on what the pathologist suspects they’re looking for.
In joint fluid analysis, no chemical stain is needed. Polarized light microscopy alone reveals the crystal type based on shape, size, and optical behavior. This makes crystal identification in synovial fluid one of the faster and more straightforward diagnostic techniques in medicine.