Table of Contents
What is Bone Marrow?
- Bone marrow is an essential component of the human body, functioning as the primary site for hematopoiesis, the production of new blood cells. It is a delicate, highly vascularized, and flexible connective tissue that is present within the cavities of certain bones. Bone marrow is predominantly located in the ribs, vertebrae, sternum, and pelvic bones of adult humans.
- From a common type of stem cell known as hematopoietic stem cells (HSCs), the bone marrow generates a variety of immune-system-related cell types. These HSCs are present in the fetal liver, embryonic spleen, and the bone marrow of both neonates and adults. They generate pluripotent stem cells, which generate all blood cell types, including lymphocytes.
- Bone marrow is an essential organ for the maturation of B cells, a form of lymphocyte, as it plays a crucial role in the development of B cells. In addition, precursor cells for thymic lymphocytes are produced. T and B cells must mature in the thymus and bone marrow before migrating to secondary lymphoid tissues such as the spleen, lymph nodes, and mucosal-associated lymphoid tissues (MALT).
- In the final months of fetal development, bone marrow becomes the primary site for the formation of blood cells in mammals. The vast majority of immune cells in mammals are derived from precursors in the bone marrow.
- Bone marrow is the spongy, blood-forming tissue that fills bone cavities. It contains fat and embryonic blood cells and is responsible for the production of mature blood cells, including white blood cells that aid in the fight against disease and the development of immunity, red blood cells, and platelets. Any disease or drug that affects the bone marrow can impair the production of these cells, resulting in potentially fatal conditions.
- The composition of bone marrow includes spongy or trabecular bone, blood vessels, and various varieties of blood-forming cells. There are two primary varieties of bone marrow: red bone marrow and yellow bone marrow. Red bone marrow, also known as myeloid tissue, contains a higher concentration of blood-forming cells and is responsible for hematopoiesis. Yellow bone marrow is predominantly composed of adipose cells and has a low concentration of blood-forming cells.
- Bone marrow is responsible for producing and releasing various forms of blood cells into the circulatory system. It generates oxygen-carrying red blood cells (erythrocytes), infection-fighting white blood cells (leukocytes), and blood-clotting platelets (thrombocytes).
- Despite the fact that bone marrow is essential for sustaining the body’s blood cell population, certain diseases can impair its function. Diseases of the bone marrow, including leukemia, lymphoma, and myeloma, are characterized by abnormal growth and development of blood cells. These conditions can disrupt normal blood cell production, resulting in deficiencies, excesses, or abnormalities. Chemotherapy, radiation therapy, immunotherapy, and stem cell transplantation are potential treatments for bone marrow disorders.
- In conclusion, bone marrow is a porous, sponge-like tissue found in the cavities of specific bones. It is essential to the immune system and is responsible for the production of new blood cells. Understanding the structure, types, function, and potential disorders associated with bone marrow aids in appreciating its importance for maintaining overall health.
Definition of Bone Marrow
Bone marrow is the soft tissue found within the cavities of bones that produces various types of blood cells, including red blood cells, white blood cells, and platelets.
Location of Bone Marrow
The location of bone marrow within the human body is widely distributed, but it undergoes changes as a person grows and develops. At birth, bone marrow can be found in all bone cavities. However, as individuals reach their teen years, the distribution of bone marrow becomes more concentrated in specific areas known as axial bones. These axial bones include the chest bones, ribs, spinal bones, collar bone, shoulder blades, skull, pelvic bones, as well as parts of the femur and humerus bones in the legs. These regions serve as the primary locations for bone marrow in the adult human body.
Types of Bone Marrow
- Red Bone Marrow:
- Location: Red bone marrow is predominantly located in the medullary cavity, which is located near the bone’s outer surface.
- Hematopoietic Tissue: It contains hematopoietic tissue, which is composed of stem cells responsible for the production of blood cells.
- Types of Stem Cells: The hematopoietic stem cells in the red bone marrow give rise to myeloid stem cells and lymphoid stem cells, which then differentiate into red blood cells, white blood cells, and platelets.
- Supporting Components: Red bone marrow contains stroma, reticulum (phagocytes and undifferentiated progenitor cells), dispersed fat cells, and an abundant vascular supply.
- Distribution: Red marrow is primarily located in the bones of the skull, pelvis, spine, ribs, sternum, and shoulder blades, as well as near the attachment points of the long bones in the limbs and legs.
- Functions: In addition to producing blood cells, red marrow also aids in the removal of aging cells from circulation. In addition, organs such as the spleen and liver filter out damaged and aged blood cells from the circulation.
- Yellow Bone Marrow:
- Location: Yellow bone marrow can be found in the medullary cavity within the shaft of long bones, and it is frequently bordered by a coating of red bone marrow.
- Composition: Yellow marrow has the same ingredients as red marrow, however fat cells make up the majority of its makeup (about 80% vs. 40% in red marrow).
- Vascular Supply: Yellow marrow has a limited vascular supply as compared to red marrow.
- Inactive Hematopoiesis: The hematopoietic tissue in the yellow marrow has ceased to function.
- Distribution: Yellow marrow is present in spongy bones and the shafts of long bones.
- Conversion to Red Marrow: To promote enhanced hematopoiesis, yellow marrow can be changed to red marrow under instances of extremely low blood supply or high need for blood cell formation.
These distinct types of bone marrow, red and yellow, have different locations, compositions, and functions, reflecting their roles in the production and regulation of blood cells within the body.
Difference Between Red Bone Marrow and Yellow Bone Marrow
Red Bone Marrow:
- Composition: Red bone marrow consists of a mesh of networks that contain blood cells, including red blood cells, white blood cells, and megakaryocytes in various stages of development.
- Appearance: It is named “red” due to its color, which is caused by the presence of hemoglobin in red blood cells.
- Development: Red bone marrow is more prominent during childhood and gradually replaced by yellow bone marrow. In adults, red bone marrow is relatively less abundant.
- Functions: Red bone marrow produces and forms three essential types of blood cells: red blood cells, white blood cells, and platelets.
- Location: It surrounds the outer surface of the bone and is found at the ends of long bones, skull, shoulder blades, ribs, and spine.
- Active Division: Red bone marrow cells actively divide to continuously produce new blood cells.
- Name: Red bone marrow is also known as medulla ossium rubra.
- Rich Blood Supply: It has a rich vascular supply to support the production of blood cells.
Yellow Bone Marrow:
- Composition: Yellow bone marrow appears yellow due to a high concentration of fat cells.
- Development: Yellow bone marrow dominates during the adolescence stage, and in adulthood, it is more prominent in many bones.
- Functions: It primarily functions in the storage of fats in adipocytes (fat cells), as well as in the production of blood cells when needed.
- Location: Yellow bone marrow is present in the marrow cavity of long bones and occupies the hollow region in the diaphysis.
- Blood Supply: It has relatively less blood supply compared to red bone marrow.
- Appearance: The yellow color of yellow bone marrow is attributed to the presence of fat droplets containing carotenoids.
- Name: Yellow bone marrow is also referred to as medulla ossium flava.
- Production: It produces fat cells, cartilage, and bone in addition to its role in blood cell production.
Overall, red bone marrow is responsible for active hematopoiesis and the production of red and white blood cells and platelets, while yellow bone marrow serves as a site for fat storage and can also produce blood cells when necessary.
|Red Bone Marrow
|Yellow Bone Marrow
|– Contains red blood cells, white blood cells, and megakaryocytes in various developmental stages.
|– Appears yellow due to a high concentration of fat cells.
|– More prominent during childhood and gradually replaced by yellow bone marrow in adults.
|– Dominates during adolescence and remains prominent in adulthood.
|– Also known as medulla ossium rubra.
|– Also referred to as medulla ossium flava.
|– Produces red blood cells, white blood cells, and platelets necessary for survival.
|– Primarily involved in fat cell production, cartilage formation, and bone support.
|– Located within the inner cavities of bones, such as long bones, skull, shoulder blades, ribs, and spine.
|– Found in the medullary cavity of long bones and the hollow region within the diaphysis.
|– Appears red in color due to the presence of hemoglobin in red blood cells.
|– Appears yellow due to the presence of fat droplets containing carotenoids.
|– Actively divides to generate new blood cells.
|– Functions as a storage site for fat (adipocytes) and can produce blood cells when needed.
|– Well-supplied with blood vessels.
|– Has a relatively lower blood supply compared to red bone marrow.
Structure of Bone Marrow
- The structure of bone marrow is distinguished by the presence of hematopoietic tissue islands and adipose cells, which are surrounded by vascular sinuses that are distributed within a trabecular bone matrix. Bone marrow, which is located within the bones, is a soft and flexible connective tissue that plays a vital function as the primary site of blood cell production.
- Bone marrow consists of both cellular and non-cellular components and is responsible for performing its functions. The bone marrow is structurally divided into vascular and non-vascular regions.
- Non-vascular bone marrow contains numerous varieties and stages of hematopoietic cells densely packed between fat cells, trabeculae (thin bands of bone tissue), collagen fibers, fibroblasts, and dendritic cells. This non-vascular region is the site of hematopoiesis, the process of blood cell formation. This region contains hemopoietic cells of various lineages and stages of maturation.
- In contrast, the vascular region of the bone marrow contains blood vessels that transport blood stem cells and mature blood cells into the bloodstream. Studies of ultrastructure have revealed that hemopoietic cells congregate around vascular sinuses, where they mature before being released into the circulation.
- In terms of cell distribution, lymphocytes, a form of white blood cell, are frequently found in the bone marrow surrounding the small radial arteries. In contrast, the most underdeveloped myeloid precursors, which are part of the lineage of white blood cells, are typically located deep within the bone marrow parenchyma.
- Bone marrow is a specialized tissue involved in the production and maturation of blood cells, with distinct vascular and non-vascular regions that support the different phases of hematopoiesis.
The structure of bone marrow can be divided into two main sections: the non-vascular section and the vascular section. Here are key points about each section:
Non-Vascular Section of Bone Marrow:
- Hematopoiesis, the production of all the cellular components of the blood and plasma, occurs in this section.
- It consists of hemopoietic cells of diverse lineages and maturities.
- Myeloblasts, myelocytes, metamyelocytes, band cells, and erythropoietic cells are interspersed with adipose cells, collagen fibers, dendritic cells, and fibroblasts in the bone.
- This section is responsible for blood cell maturation and differentiation.
- It is essential for maintaining the balance and production of distinct types of blood cells.
Vascular Section of Bone Marrow:
- The vascular section contains the blood vessels that deliver nutrients to the bone.
- It functions as a transport system for blood stem cells and mature blood cells, transporting them into circulation.
- In this section, vascular sinuses promote the clustering of hemopoietic cells prior to their release into the circulation.
- The network of blood vessels supports the bone marrow’s overall function and nutrition.
- It facilitates the exchange of substances and blood cell distribution throughout the body.
These two sections work together to ensure the continuous production, maturation, and circulation of blood cells, contributing to the proper functioning of the hematopoietic system.
Hematopoietic components refer to the cellular constituents of the bone marrow responsible for the production and maturation of blood and lymphoid cells. Here are key points about hematopoietic components:
- Progenitor Cells: The main functional component of bone marrow includes progenitor cells that have the potential to mature into different types of blood and lymphoid cells.
- Hematopoietic Stem Cells: Marrow contains hematopoietic stem cells that give rise to three classes of blood cells found in circulation: white blood cells (leukocytes), red blood cells (erythrocytes), and platelets (thrombocytes).
- Production Rate: Human marrow produces approximately 500 billion blood cells per day, highlighting the continuous and high-rate production of these cells.
- Cellular Composition: The cellular constitution of red bone marrow parenchyma includes various cell types involved in hematopoiesis.
- Myelopoietic Cells: This group includes myeloblasts, promyelocytes, neutrophilic myelocytes, eosinophilic myelocytes, neutrophilic metamyelocytes, eosinophilic metamyelocytes, neutrophilic band cells, eosinophilic band cells, segmented neutrophils, segmented eosinophils, and segmented basophils and mast cells.
- Erythropoietic Cells: This group comprises pronormoblasts, basophilic normoblasts, polychromatic normoblasts, and orthochromatic normoblasts, which are involved in the production of red blood cells (erythrocytes).
- Other Cell Types: Other cell types present in the bone marrow parenchyma include megakaryocytes, plasma cells, reticular cells, lymphocytes, and monocytes.
- Cellular Fractions: The average fractions or percentages of these cell types within the red bone marrow parenchyma can vary within certain reference ranges, indicating the dynamic nature of hematopoiesis.
These hematopoietic components play a vital role in maintaining the balance and production of different types of blood cells, contributing to the proper functioning of the hematopoietic system.
The stroma is an essential component of bone marrow that encompasses all the tissues not directly involved in the primary function of hematopoiesis, which is the production of blood cells. Here is some information about the stroma:
- Indirect Role in Hematopoiesis: Stromal cells within the bone marrow play an indirect role in hematopoiesis by creating a microenvironment that influences the function and differentiation of hematopoietic cells. They provide crucial support and regulatory signals for the hematopoietic process.
- Colony Stimulating Factors: Stromal cells generate colony stimulating factors, which are signaling molecules that have a significant effect on hematopoiesis. These factors stimulate the growth and differentiation of specific types of blood cells.
- Cell Types in the Bone Marrow Stroma: The stroma is composed of various cell types, including:
- Fibroblasts: Fibroblasts are responsible for producing reticular connective tissue, which forms the structural framework of the stroma.
- Macrophages: Macrophages have a special contribution to red blood cell production. They deliver iron, an essential component for hemoglobin production, to developing red blood cells.
- Adipocytes: Adipocytes, or fat cells, are present in the bone marrow stroma and contribute to the overall composition of the tissue.
- Osteoblasts: Osteoblasts are involved in bone formation (synthesize bone) and help maintain the integrity of the bone structure within the marrow.
- Osteoclasts: Osteoclasts are responsible for bone resorption, which is the process of breaking down and remodeling bone tissue.
- Endothelial Cells: Endothelial cells form sinusoids, specialized blood vessels within the bone marrow. These cells derive from endothelial stem cells, which are also present in the bone marrow.
Collectively, these stromal cell types create a supportive environment for hematopoiesis, regulate the development and function of hematopoietic cells, and contribute to the overall structure and function of the bone marrow.
Bone Marrow Transplant
- A bone marrow transplant, also known as a hematopoietic stem cell transplant, is a medical procedure performed when the body is severely affected due to damage in the bone marrow. It is a treatment option recommended by experts or professionals in cases where it is deemed necessary. However, it is important to note that a bone marrow transplant carries risks for both the donor and the recipient, and it should only be undertaken after careful consideration.
- The complications associated with a bone marrow transplant can vary depending on factors such as the recipient’s age, overall health, the specific disease being treated, and the type of transplant being performed. In milder cases, the symptoms experienced after the transplant may be acute and short-lived. These can include a drop in blood pressure, headache, nausea, pain, shortness of breath, chills, and fever.
- However, in more severe cases, complications can arise that have a significant impact on the patient’s well-being. These complications may include damage to vital organs, early menopause, persistent nausea, diarrhea, and internal bleeding in the lungs, brain, or other parts of the body. In some instances, transplanted cells may not begin producing new cells as planned, leading to graft failure. Another potential complication is graft-versus-host disease (GVHD), where the donor’s immune cells recognize the recipient’s body as foreign and attack it. GVHD can be a life-threatening condition.
- It is crucial to emphasize that the degree of risk associated with a bone marrow transplant can be managed with the guidance and expertise of a doctor. The medical team will assess the individual circumstances of the donor and recipient, closely monitor the transplant process, and provide appropriate care to mitigate potential complications. The decision to undergo a bone marrow transplant should always be made in consultation with healthcare professionals who can assess the risks and benefits based on the specific situation.
Types of Bone Marrow Transplant
There are different types of bone marrow transplants, each with its own characteristics and considerations. Here are the main types of bone marrow transplant:
- Autologous Bone Marrow Transplant: In an autologous transplant, a person’s own stem cells are used. Before undergoing radiation treatment or high-dose chemotherapy for cancer, the individual’s stem cells are collected from their body and preserved (often by freezing). These stem cells are then reintroduced into the body after the treatment to help restore the proper function of blood cell formation. This procedure is sometimes referred to as a “rescue transplant” since it allows the individual to receive intensive treatment without completely depleting their bone marrow.
- Allogeneic Bone Marrow Transplant: In an allogeneic transplant, stem cells are obtained from another person, who serves as the donor. It is crucial for the donor’s genes to at least partially match the recipient’s genes. Extensive testing is performed to determine if the donor is a suitable match. Often, family members, particularly siblings, are the best matches due to genetic similarities. However, a good match can also be found among other relatives, such as parents and children. In an allogeneic transplant, the donor’s stem cells replace the recipient’s damaged or diseased marrow and establish new, healthy blood cell production.
- Umbilical Cord Blood Transplant: This type of transplant is a form of allogeneic transplant. It involves using stem cells derived from the umbilical cord blood of a newborn baby. Immediately after birth, the stem cells are collected from the umbilical cord and placenta, and then stored for future use. Since the stem cells from umbilical cord blood are not as mature as those from adult donors, it takes time for them to start producing new blood cells at the required pace. Therefore, the stored cord blood is used for transplantation when needed. This type of transplant offers the advantage of a wider range of potential donors, as cord blood units can be obtained from public cord blood banks.
It is important to note that the specific type of bone marrow transplant recommended for an individual depends on various factors, including the underlying condition being treated, the availability of a suitable donor, and the overall health of the patient. The medical team will assess the individual case and determine the most appropriate type of transplant for the patient’s specific needs.
Bone Marrow Disorders and Related Bone Marrow Diseases
Bone marrow disorders and related bone marrow diseases encompass a range of conditions that affect the production and functioning of bone marrow, resulting in widespread effects throughout the body. Here are some of the problems that can arise within the bone marrow:
- Leukemia: Leukemia is a type of cancer that affects the blood and bone marrow. In this condition, the bone marrow produces abnormal white blood cells, which can interfere with the normal functioning of the immune system.
- Aplastic anemia: Aplastic anemia is a disorder where the bone marrow fails to produce enough red blood cells. This can lead to symptoms such as fatigue, weakness, and an increased risk of infections and bleeding.
- Myeloproliferative disorders: Myeloproliferative disorders are a group of conditions that include chronic myelogenous leukemia (CML), polycythemia vera, primary myelofibrosis, essential thrombocytopenia, chronic neutrophilic leukemia, and chronic eosinophilic leukemia. These disorders affect the production of various blood cells, including white blood cells, red blood cells, and platelets.
- Lymphoma: Lymphoma is a cancer that originates in the immune cells, specifically the lymphocytes. It can affect the bone marrow, leading to disruptions in the production of healthy blood cells.
When bone marrow becomes damaged or diseased, it can result in low production of blood cells, compromising the immune system and depriving organs and tissues of vital oxygen and nutrients.
Bone marrow and blood cancers, such as leukemia, can give rise to bone marrow diseases. Risk factors for these conditions include exposure to radiation, certain infections, as well as specific diseases like aplastic anemia and myelofibrosis.
Treatment for blood and marrow diseases may involve a bone marrow transplant. This procedure aims to replace cancerous, faulty, or destroyed stem cells with healthy ones. The bone marrow, which contains hematopoietic stem cells responsible for developing into red blood cells, white blood cells, and platelets, is typically obtained from the donor’s blood or bone marrow. In some cases, stem cells from umbilical cord blood can also be used for transplantation. The extraction of bone marrow usually takes place in areas such as the hip or sternum.
Bone Marrow Biopsy
A bone marrow biopsy is a medical procedure commonly performed alongside bone marrow aspiration. During this procedure, two needles may be used, or the same needle may be repositioned, to collect samples of bone marrow for testing purposes. In addition to the aspiration of bone marrow, a biopsy involves the removal of a small piece of bone containing marrow for further examination.
When a bone marrow aspiration and/or biopsy is conducted, the collected marrow can be utilized for various tests to gain valuable insights into a patient’s condition. Here are some of the tests that can be performed using the collected bone marrow samples:
- Florescence in situ hybridization (FISH): This test examines the chromosome composition of the bone marrow. It is particularly useful in identifying abnormal cells and evaluating the efficacy of treatments for bone marrow diseases. FISH can provide valuable information about the genetic makeup of the cells within the bone marrow sample.
- Flow cytometry: This test involves the analysis of bone marrow cells to identify specific antibody features. By examining the characteristics of these cells, flow cytometry can provide insights into the types and properties of the cells present in the bone marrow. It is a valuable tool for diagnosing and monitoring various blood-related disorders.
- Immunophenotyping: This test helps identify different types of blood cells within a bone marrow sample. By examining the antigen markers present on the surface of these cells, immunophenotyping can aid in the classification and characterization of various cell types. It is commonly used in the diagnosis and classification of leukemia and lymphoma.
- Karyotype tests: This test is focused on identifying the order, number, and appearance of chromosomes within a bone marrow sample. By analyzing the chromosomal abnormalities, karyotype tests can help diagnose genetic disorders, such as Down syndrome, and identify certain types of cancer.
- Polymerase chain reaction (PCR): PCR is a highly sensitive test that examines biomarkers present in blood or bone marrow cells. It is particularly useful in detecting the presence of cancer cells, especially when other diagnostic tests have failed. PCR amplifies specific DNA sequences to identify genetic abnormalities or mutations associated with certain types of cancer, providing valuable information for diagnosis and treatment planning.
These tests play a crucial role in diagnosing various bone marrow disorders, such as leukemia, lymphoma, myeloma, and other hematological malignancies. By analyzing the bone marrow samples, healthcare providers can gain a deeper understanding of the patient’s condition, which aids in developing an accurate diagnosis and formulating an appropriate treatment plan.
Functions of Bone Marrow
- Production and migration of T cells and B cells: The bone marrow is responsible for producing and releasing T cells and B cells, which are important components of the immune system.
- T cell production: The bone marrow produces all of the lymphoid cells that migrate to the thymus, where they mature into T cells. T cells are critical for adaptive immune responses and play a role in identifying and eliminating specific pathogens or abnormal cells.
- B cell maturation: B cells also undergo maturation within the bone marrow. They are primarily responsible for the production of antibodies, known as immunoglobulins (Ig). The bone marrow serves as the site where B cells mature and undergo selection for non-self before moving to peripheral lymphoid tissues.
- Hemopoietic cell production: The bone marrow consists of hemopoietic cells derived from multipotential stem cells. These cells give rise to all of the lymphoid cells found in lymphoid tissue, as well as all the cells found in the blood, including red blood cells, white blood cells, and platelets.
- Platelet production: Red bone marrow cells are involved in the production of platelets, which are crucial for the blood clotting process. Platelets help prevent excessive bleeding by forming clots at the site of cuts or injuries.
- Yellow bone marrow’s role in lipid storage: Yellow marrow, found in certain bones, is actively involved in lipid storage. It serves as a source of energy and can be used when needed.
What is bone marrow?
Bone marrow is a soft, spongy tissue found within the hollow centers of certain bones in the body.
What are the types of bone marrow?
There are two types of bone marrow: red bone marrow (also known as myeloid tissue) and yellow bone marrow.
What is the function of red bone marrow?
Red bone marrow is responsible for the production of blood cells, including red blood cells, white blood cells, and platelets.
What is the function of yellow bone marrow?
Yellow bone marrow consists mainly of fat cells and serves as a storage site for energy reserves.
How does bone marrow contribute to the immune system?
Bone marrow produces and releases lymphoid cells, including T cells and B cells, which play essential roles in immune responses.
How are T cells and B cells produced in the bone marrow?
Bone marrow produces all of the lymphoid cells that migrate to the thymus, where they mature into T cells. B cells also undergo maturation in the bone marrow.
What is the significance of T cells in the immune system?
T cells are important for adaptive immune responses and help in recognizing and eliminating specific pathogens or abnormal cells in the body.
What is the role of B cells in the immune system?
B cells are primarily responsible for producing antibodies (immunoglobulins) that bind to specific antigens and facilitate immune responses against foreign substances.
Are platelets produced in the bone marrow?
Yes, platelets, which are crucial for the blood clotting process, are produced in the bone marrow along with other blood cells.
Can bone marrow serve as a source of energy?
Yes, the yellow bone marrow, which consists of stored fat, can be utilized as an energy source by the body when needed.
- Lucas D. Structural organization of the bone marrow and its role in hematopoiesis. Curr Opin Hematol. 2021 Jan;28(1):36-42. doi: 10.1097/MOH.0000000000000621. PMID: 33177411; PMCID: PMC7769132.
- Lydyard, P.M., Whelan,A.,& Fanger,M.W. (2005).Immunology (2 ed.).London: BIOS Scientific Publishers.
- Bailey, Regina. (2017, October 16). Bone Marrow and Blood Cell Development. Retrieved from https://www.thoughtco.com/bone-marrow-anatomy-373236
- Playfair, J., & Chain, B. (2001). Immunology at a Glance. London: Blackwell Publishing.
- Owen, J. A., Punt, J., & Stranford, S. A. (2013). Kuby Immunology (7 ed.). New York: W.H. Freeman and Company.