15-6 Bone marrow is the origin of all immune cells

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• Stem cells in the bone marrow are the progenitors of all immune cells.
• Cytokines are small signaling proteins that guide the development of immune cells.
• The types of immune cells are polymorphonuclear cells, mast cells, monocytes, macrophages, and lymphocytes.

The bone marrow is the source of many immune and blood cells in the healthy adult animal. If the bone is split lengthwise, a marked difference in tissue is noticed. Part of the tissue is red, which is the source of red and white blood cells. The other portion is yellow adipose tissue that is inactive. During an infection, the yellow marrow can be reactivated to become red marrow to help in the production of larger numbers of immune cells.

In the adult animal, all immune cells originate from hematopoietic stem cells located in the bone marrow. Stems cells constantly divide and differentiate into various types of immune cells under the influence of cytokines. Figure 15-3 shows the origin of the cells of the immune system. Cytokines are small signaling proteins that help to regulate the behavior of the cells of the body. The bone marrow is ultimately responsible for the synthesis of eight types of cells: red blood cells, platelets, neutrophils, basophils, eosinophils, mast cells, monocytes/macrophages, T lymphocytes and B lymphocytes. Some of these cell types mature in the bone marrow itself, while others migrate through the circulatory system and undergo final maturation in other tissues. At this point, we will take a short stop and look briefly at some of the features of the cells created in the bone marrow as an introduction to their function. You will learn more details about each immune cell type later when we cover specific immune responses.

Stem cell research

Stem cells are of great interest to physicians, researchers and the public due to their potential benefit in a number of important human diseases. There is great confusion as to what a stem cell is, where they come from and their function. So before we go on, lets try to clear up some of that confusion. Embryonic stem cells are completely undifferentiated cells that are found in the developing embryo and can potentially mature into any kind of tissue. These types of cells are most often associated with a developing fetus and are not found in adults. Adults stem cells, of which hematopoietic stem cells are one class, are undifferentiated cells found among differentiated cells in a tissue or organ. They can renew themselves and develop into the specialized cell types of that organ. Adult stem cells have been found in many tissues, including the bone marrow, the brain, the digestive tract, and the skin.

James Thompson of the University of Wisconsin-Madison was the first to obtain embryonic stem cells by taking them from a growing embryo. These cells are the progenitors of all the cells in the body and are unique in a number of ways.

1. Embryonic stem cells can proliferate indefinitely. Typical mammalian cells are capable of a limited number of divisions. After about 20-50 cell cycles, they are incapable of dividing further. This occurs because at each division a small portion of the ends of the chromosomes, called telomeres, is lost. Initially, this is acceptable because the telomere does not contain vital DNA. However, as subsequent divisions proceed, the cells lose more and more of the telomeres and eventually the chromosomes fail to function. Embryonic stem cells get around this difficulty by activating an enzyme called telomerase. Telomerase adds extra DNA onto the ends of chromosomes during division so that they do not shorten.
2. Because of the role of embryonic stem cells in normal development, they have the capability of differentiating into any cell type. In contrast, mature differentiated cells have their function dictated by a fixed pattern of gene expression. We currently do not know how to revert differentiated cells to a more neutral state. As a consequence stem cells offer the best hope for generating useful cell types for various treatments.

Research on embryonic stem cells may result in a number of promising developments. Having these cells available for research will give us new insight into how humans and other mammals develop. It seems clear that embryonic stem cells develop into other cells types and tissues under the influence of cytokines. By studying the process we will learn what these signals are and how they work. Being able to create an unlimited supply of different cell types may eventually allow the development of new tissues and organs for use in transplants. Presently, there is a great need for organs and tissues for ailing patients. Scientists have already been able to create lungs, bladders and kidneys in animal experiments. These cells may also lead to the creation of cures for brain disorders such as Alzheimer's and Parkinson's diseases.

Embryonic stem cells are also controversial because to obtain them, it has been necessary to destroy a developing embryo. A fertilized egg is allowed to divide for a period of time and then the cells are extracted. Some consider this equivalent to killing a human being, but the key to the controversy is when we decide a human life begins. Does it begin the minute that a mass of cells has the potential to develop into a human? Does it begin when that groups of cells can survive on its own? Medicine is getting better at saving babies born prematurely. What if a time comes when an embryo can be raised completely out of the uterus? Scientists cannot and should not make these decisions by themselves. Human society must decide what is acceptable and the key to making good decisions is educating ourselves about the issues.

Research in the years since Dr. Thompson's first efforts has begun to demonstrate that adult stem cells may be able to replace embryonic stem cells for some purposes. But at the present time, undifferentiated, embryonic stem cells are still necessary for many important experiments.

Cells made in the bone marrow

The major cell type made by the bone marrow is red blood cells. Platelets also form in the bone marrow and assist in formation of blood clots following any kind of injury. Neither of these cell types plays a role in the immune response, but we mention them here because they also originate from bone marrow stem cells and are essential components of the blood.

Polymorphonuclear granulocytes is the general term given to neutrophils, eosinophils and basophils. The first half of the name describes the appearance of the nucleus that seems to be split into a number of different lobes. In reality, the nucleus is contiguous, but contains many infoldings, which give it a polynuclear appearance. The rest of the name comes from the appearance of the cytoplasm, which looks speckled. The cytoplasm is full of granules that contain compounds and enzymes important in fulfilling the function of each cell type. Polymorphonuclear granulocytes make up 50-70% of the white blood cells found in blood. They last only about three days and have to be replaced at a rate of 80 million cells per minute.

Neutrophils are the most common type of polymorphonuclear cells, making up 90% of granulocytes in the blood. These cells function as phagocytes in attacking and destroying infectious agents. We will cover their roles in more detail when we discuss phagocytes.

Eosinophils make up 2-5% of granulocytes in the blood, but this number can rise considerably in people with parasitic diseases as well as asthma, eczema or other diseases associated with allergies. They are primarily found in the blood, but also near epithelia that have high bacterial populations (e.g., intestines, vagina, nasal passages). The granules in these cells bind the red dye eosin, giving the cells their name. Eosinophil granules contain a number of different enzymes including, acid phosphatase, glucuronidase, cathepsins, RNase, and arylsulfatase and peroxidase. They also produce toxic basic proteins. They respond to the chemical signals put out by other immune cells and can then participate in an immune response. The major reactions take three forms.

1. They can down-regulate an immune response by destroying histamine secreted by mast cells using the enzyme histinase. Eosinophils also liberate arylsulphatase that breaks down the slow reactive substance of anaphylaxis (a dangerous form of allergic response) that is released by mast cells.
2. Eosinophils combat antigenic challenges too big to be attacked by phagocytes. Examples of such challenges are parasitic worms or helminths. In battling these infections, the body first covers the worm with antibody. This then activates eosinophils, which bind to the parasite and release the contents of their granules, thus causing external digestion of the worm.
3. As is the case with neutrophils, eosinophils can phagocytize microorganisms, but this is a secondary role.

Basophils are small cells that make up less than 1% of all white blood cells. The granules of these cells contain heparin, histamine, decarboxylase, histidine, dehydrogenase and diaphorase. Heparin is an important anti-clotting compound, and histamine finds its use modulating the immune response. Histidine is converted to histamine by decarboxylase. The role of basophils in the immune response is not yet clear, but they seem to play a role in the defense against parasitic worms and in severe allergic reactions. They have a very high affinity for IgE antibodies and they are usually found coated with IgE in tissues. Binding of IgE may set in motion a series of events that causes other immune cells to respond to the high concentrations of IgE. Basophils may be cellular alarms that notify the rest of the immune system and help to concentrate the point of attack.

Mast cells are closely related to basophils but are distinct in their reactions to antigens. They are found throughout the body in lymph nodes, spleen, bone marrow, around blood vessels, nerves, glands and in the skin. Mast cells have granules that, like basophils, contain heparin and histamine. They have a high affinity for IgE as well and their activation by antigen triggers histamine release. Until recently, they were mostly thought to trigger unwanted allergic reactions, but it is now becoming clear they participate in immune responses to gram-negative bacteria. Their wide distribution indicates that they are important in many immune responses.

Monocytes and macrophages are long-lived specialized phagocytic cells. Monocytes are migrating phagocytic cells found in the bloodstream and when they enter other tissues, they differentiate into macrophages. Macrophages are found in the brain, lungs, liver, spleen, lymph nodes, joints and peritoneum. The key functions of monocytes and macrophages are to remove our own dead cells when they reach the end of their useful life and also to remove pathogens. For example macrophages in the liver, called Kupffer cells, phagocytize old erythrocytes from the blood and remove them. Another one of their functions is the creation of important immune proteins and peptides. They are responsible for synthesizing transferrin (an iron-binding protein), complement proteins and various cytokines necessary for immune function.

B lymphocytes or B cells are antibody-producing cells. They are very important in fighting many different types of infections, especially, bacterial infections. T lymphocytes are involved in regulating the immune system and destroying host cells that are out of control, either due to a breakdown in cell division regulation (cancer) or infection by a virus or even an intracellular parasite. We will discuss the functions of these cells in more detail when we cover the adaptive host response.

The thymus is a fist-sized organ located above the heart that is involved in the maturation of T lymphocytes (we will call them T cells from now on). T cells produced by the bone marrow are immature and journey to the thymus through the bloodstream. The blood vessels that supply the thymus with oxygen and other nutrients also contain a blood-thymus barrier that only allows immature T cells in and mature T cells out. The thymus is also connected to the lymphatic system through lymph vessels. We will talk more about thymus function when examining T cell maturation later in the chapter.

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