Introduction


Any course on stem cells must include a section on the hematopoietic system, as it was the first organ system to provide stem cells for therapeutic medicine. Even in 2011-2012, bone marrow transplants provide a rich source of stem cells used to treat a variety of cancers, anemias, AIDS, and sickle cell disease.

In order to appreciate the current and potential utility of hematopoietic stem cells (hSC) in clinical medicine, one must first understand fundamental principles of immunology. This module provides a brief review of immunology.

Readers first learning about immunology must always keep in mind one of its most basic tenets: the immune system is designed to “destroy the pathogen/tumor and protect the host.” Most of the information contained in this chapter is based on an excellent textbook called Janeway's Immunobiology: 8th Edition.

How does the hematopoietic system preserve or protect the host?


The hematopoietic system is vital organ that is provides several functions by:
  • Generating specific immune cells that have the capacity to destroy pathogens and tumors and protect the body against toxins;
  • Disseminating essential nutrients, such as oxygen, to all tissues of the body. Red blood cells serve as essential cells that transport oxygen from the lungs to all the tissues of the body;
  • Repairing tissues and maintaining organ system function. Many organs undergo constant repair and maintenance. In the blood, for example, neutrophils are short lived and must be cleared each day by various macrophages located in vital organs in the body;
  • Enabling clotting, a process in which platelets rapidly form a barrier to prevent blood loss and protect the host from infection.

Before we go into the details of the various functions of immune cells, it is important to define the term ‘immunity’. Historically, immunity was once exclusively used to connote ‘exemption from taxes’. It also has a political definition, as in ‘diplomatic immunity’ from legal action. Use of the word immunity in biology represents a collective process by which the organism fights pathogens and diseases.

Return to Top

What makes our immune system so effective?


  • Rapid Response - a rapid response system designed to attack a pathogen or prevent a specific disease such as cancer from killing the host.
  • Diversity - similar to the design of airport security where there are different layers of protection. The immune system also has various layers of protection. The skin, for example, is the first defense against a bacterial infection, restricting its entry from entering the host and causing damage. If the skin barrier is compromised and bacteria enter the host, then neutrophils are rapidly recruited to the infected site to kill the bacteria. A few days after a bacterial infection, monocytes enter the site of infection and clean up any viable bacteria that the neutrophils left behind.
  • Specificity - The immune system is able to distinguish between foreign cells (pathogen or cancer) and self.
  • Memory - The immune system has mechanisms to insure that the host does not become infected with the same bacteria or pathogen a second time.
  • Demobilization - A critical property of the immune system is its capacity to downregulate itself after a pathogen has been eradicated. When the immune response does not deactivate itself it can lead to autoimmune diseases such as multiple sclerosis or lupus.

Return to Top

Origins of immunology


  • 429 BC: Thucydides notices that smallpox survivors do not get re-infected.
  • 900 AD: The Chinese were the first to discover and use a primitive form of vaccination called variolation. By inhaling dried powders derived from the crusts of smallpox lesions or by placing these samples under the skin, people could become “immunized” and not become infected with smallpox.
  • 1774: Benjamin Jesty, a farmer who inoculated his wife with the vaccinia virus obtained from “farmer Elford of Chittenhall, near Yetminster”. First record of anyone using vaccinia virus to "protect" against smallpox.
  • 1796: British physician Dr. Edward Jenner discovered vaccination in its modern form and proved to the scientific community that it worked. Jenner received a cash prize of 30,000 pounds and election to nearly all of the learned societies throughout Europe.

Was Dr. Jenner really a physician? Did he really prove his theory? How many people did he kill before he got it right?
Source: Silverstein AM (2009). A History of Immunology. 2nd Edition Publisher: Elsevier Science


Cellular origins of hematopoietic cells


In the fetus and embryo, hematopoietic cells are formed and produced by the liver and bone marrow. Once an infant is born, bone marrow takes over as the primary organ responsible for producing all the cells that comprise the immune system (Notta, 2011).

The following diagram outlines how all hematopoietic cells emerge from a single hematopoietic stem cell. Within the bone marrow is a specialized, anatomically defined, regulatory environment referred to as the ‘stem cell niche’, where all hematopoietic stem cells reside and differentiate.Hematopoietic stem cell differentiation occurs in are two primary areas of stem cell development. One is an area that contains small blood vessels, called sinusoids, made up of endothelial cells together with a variety of immune cell and the axonal processes of peripheral neurons. The second area in the bone marrow is closer to the actual bone mass and is composed of mesenchymal cells.
The proliferatrion and differentiation of HSC within these areas are regulated by neighboring cells that comprise the stem-cell niche.

CellsOfImmunesystem.png
Cells of the Immune System (Source: NIH.gov)

Return to Top

Innate and Adaptive Immunity


In general, cells of the immune system can be divided into two categories: those involved in innate immunity and those involved in adaptive immunity.

Innate immunity, was first characterized by Elie Metchnikoff, involves cells derived from a myeloid progenitor cell and differentiate into natural killer (NK) cells, mast cells, dendritic cells, neutrophils, and phagocytes. All these cells exhibit a rapid non-specific response to either foreign cells or to tumor cells. In addition to the white blood cells involved in innate immunity, various secretions, in saliva, tears, gut, and mucus, as well as cells comprising the skin, gastrointestinal tract, and pulmonary system create a protective barrier to prevent entry or survival of pathogens such as viruses and bacteria. The innate system represents the first line of defense against an intruding pathogen.

Adaptive immunity, first described by Paul Ehrlich, involves cells derived from the lymphoid progenitor cell and differentiate into various types of lymphocytes that display a high degree of memory and specificity. While the innate system represents the first line of defense to an intruding pathogen, the adaptive system exhibits slower temporal dynamics. Additionally, the cells of the acquired immune system possess a high degree of specificity and evokes a more potent response on secondary exposure to a pathogen. In 1908 Drs. Metchnikoff and Ehrlich shared the Nobel Prize for their pioneering work in immunology.

In addition, both types of immunity can be divided into two humoral and cellular components:
  • a humoral component consists of the complement system composed of about 30 proteins that can become activated (by cleaving the proteins into various fragments). These activated biological substances can trigger inflammatory response and assist neutrophils, monocytes, and macrophages with their task as cellular assassins;
  • a cellular component that involves the various types of myeloid cells described above.
  • a humoral or B-cell-mediated immune response that leads to production and release of immunoglobulins (IgM, IgG, IgA, IgE, IgD);
  • a cellular or T-cell-mediated immune response that results in production of effector T cells that have the capacity to target and kill either virally infected cells or cancer cells. T-cells can also be generally divided into two types of cells, helper cells (CD 4) whose role is to regulate the immune response or cytotoxic CD 8 cells that kill specific target cells.

Clinical or genetic defects in cells involved in either innate or acquired immunity may lead to immunodeficiencies, and may result in autoimmune diseases, allergies, and tumors.
Return to Top

FunctionsOfDifferentImmuneCells.png
Functions of different types of immune cells (Source: Garland Science 2005)

How does one classify a specific cell type?


There are many cells that comprise the immune system. Several methods are used to classify a specific cell type and type of immune cell. Historically, morphological (i.e., histological) and functional properties were used to classify the types of immune cells, to distinguish between a monocyte, red blood cell, platelet, mast cell, eosinophil, lymphocyte, basophil, and neutrophil.

Other ways to classify a specific cell type


Genomic approach: identifying the mRNAs or transcription factors that a cell expresses are other effective methods to identify and specify a cell type.

Expression of surface proteins: Many cell types express unique cell surface proteins. These proteins are called CD ("cluster of differentiation") surface receptors that characterize the specific cells of origin, their differentiation state and their activation state. As of 2011, about 110 different CD proteins have been identified. For example, the integrin family of Beta 2 proteins are a unique family of CD cell surface markers of immune cells.
Often, identification of several CD cell surface markers in one cell helps to identify the cell type. A common way to identify a CD cell surface marker is to use specific antibodies directed against that CD protein. By using fluorescent labeled antibody, fluorescence-activated cell sorting (FACS) can characterize the type of immune cell by the nature of cell surface receptors it expressed. Immunohistochemistry is another microscopic method that researchers can use to visualize cells by the kinds of antibodies that attach to the cells.

  • CellTable.png
    Table: Identifying type of immune cell by its CD surface receptors


Return to Top

Immune recognition of foreign vs. self


One of the key functional capacities and roles of immune cells is distinguishing what is foreign -- i.e., whether cells, viruses, bacteria, or proteins -- and what is “self” or native. In general, cells are recognized as being foreign, or native, by a series of surface CD markers, as encoded by the genes of the major histocompatibility complex (MHC).

The capacity of the immune system to recognize a protein or cell as foreign has tremendous implication for infections, cancerous tumors, and organ transplantation. Infectious pathogens are often easy to recognize as foreign. The problem for the host is to try to generate an antibody or cellular response to clear the pathogen. In the case of tumors, the situation is slightly more complex since tumor cells arise from normal cells and will generally express the same MHC cell surface markers as all other cells of the body. Tumor cells, however, often express unique tumor-specific proteins on their cell surfaces that can at times generate an immune response. Some tumors, however, produce tumor-specific proteins that are weak antigens and do not generate a strong immunological response. As most readers know, many cancers and virus-caused diseases such as HIV/AIDS can “fool” our immune system in various ways to avoid detection and elimination (as an evolutionary survival mechanism).

Major histocompatibility complex

Class I MHC
  • This gene complex contains three major loci, A, B, and C – encodes for an alpha chain that is polymorphic (has many alleles) and associates with another protein called beta-2 microglobulin. Beta-2 microglobulin is encoded by a gene outside the MHC complex
  • MHC-class I proteins are expressed on all nucleated cells and platelets.

Class II MHC
  • This gene complex contains at least three loci, DP, DQ and DR; encoding for one alpha- and one beta-chain polypeptide,
  • These genes are polymorphic,
  • These proteins are expressed on B lymphocytes, a proportion of macrophages and monocytes, skin associated (Langerhans) cells, and dendritic cells.

As mentioned in several other Modules and Supplements, a major advantage of using patients’ own stem cells in either tissue repair or organ regeneration is that the patient’s immune system will not reject his own cells. In organ transplantation to date, physicians try to match the MHC between the organ donor and recipient. It is often hard to find an exact match (unless they pair are identical twins). In the absence of an exact match, anti- rejection drugs must be given to prevent serious side effect from occurring after organ donation, i.e., to prevent the patient from immunologically rejecting the transplanted organ or cells. These powerful drugs may have to be taken for years or even for life. Anti-rejection drugs have powerful, unwanted, debilitating side-effects.
Return to Top

Human Hematopoietic Stem Cells (hSC)


As stated above, all mature blood cell lineages are derived from distinct progenitor cells that arise from self-renewing hematopoietic stem cells (hSCs). There is a lot of information about the murine (mouse or rat) hSC system but the biology of the human HSC remains poorly understood. This is because only a small percent of the bone marrow cells are stem cells, and the lack of methods to segregate HSCs from multipotent progenitors (MPPs) to obtain pure populations for biological and molecular analysis.

Conclusion


The hematopoietic system is an important source for stem cells. Learning how to manipulate these cells can yield new methods to create a large variety of differentiated cells. These cells could then be applied clinically to treat diverse illnesses and conditions. In breast cancer, high dose chemotherapy presents an opportunity to eradicate the tumor but is associated with impairing the immune system. Autologous bone marrow transplantation in which all the stem cells have been purified and separated from cancer cells that lodge in the marrow may offer new opportunities to treat this deadly disease. HIV primarily infects and destroys immune cells. We have already seen that eradicating an AIDS patient’s immune system, and replenishing it with bone marrow cells derived from hematopoietic stem cells of an HIV-resistant individual, has been used to cure a patient of HIV infection. Imagine if this experimental therapy could be scaled up for wide-spread clinical use. Bone marrow transplantation has historically been a viable model for stem cell replacement therapy and will continue to serve as a clinically useful model to treat disease using stem cells.



Click here to Test Your Knowledge


Return to Top

References


  • Garver-Apgar CE, Gangestad SW, Thornhill R, Miller RD, Olp JJ (2006) Major histocompatibility complex alleles, sexual responsivity, and unfaithfulness in romantic couples. Psychol Sci. Oct;17(10):830-5.
  • Murphy KM, P Travers, M Walport (Eds.) (2010) Janeway's Immunobiology. 8th Edition. New York:Taylor & Francis, Inc.
  • Notta F, Doulatov S, Laurenti E, Poeppl A, Jurisica I, Dick JE (2011). Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science Jul 8;333(6039):218-21.
  • Silverstein AM (2009). A History of Immunology. 2nd Edition. New York: Elsevier Science.


StemCellBioethLogo.jpgnystem_NoImage.jpgccnmtl.gif