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  • Yuzo Endo, M.D., Ph.D.
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Multiple Myeloma 2

Clonality of lymphocytes

Immunocytes, such as lymphocytes and monocytes in the blood or macrophages in the tissue, belong to some groups of leukocytes. Those cells are called as mononuclear cells from the morphological point of view. Therefore, lymphocytes and monocytes are with simple outward appearances when seen through microscope. On the other hand, the standard group of leukocytes are called lobocytes or granulocytes, such as neutrophiles, eosinophiles and basophiles. In addition, mononuclear cells include plasma cells, which are more mature type of one of the two big groups of lymphocytes. As mentioned later, each of mononuclear cells has individual difference called single clonal (mono-clonal) nature with regards to its own function in terms of monoclonality in immune reaction. Human body always maintains more than 1 billion of mononuclear cells as diverse clonality in the blood vessels and tissues, which keep on moving and functioning all over the body.

Lymphocytes are called by this name because they were found in the lymph vessels. Mononuclear cells go patrol while circulating in any area of blood vessels or any extravascular tissue under normal condition. They cells go out of blood capillary into the interstitial spaces, and then go into lymph vessels, and finally come back into veins at the neck again.

Moreover, lymphocytes, plasma cells and monocytes are distributed under the layer of mucosal epithelia throughout the gastrointestinal and respiratory tracts. They are, of course, distributed along with blood vessels in the bone marrow, spleen, thymus, lymph nodes. They can be also found in tonsils, appendix, and Peyer’s patches. They are going outside these lymphatic apparatus and getting into the blood vessels, moving so actively. The total number of mononuclear cells with nature of monoclonality are very flexible in accordance with any antigenic stimuli from the outside or inside of the body. This nature of flexible number and of diverse monoclonality of individual lymphocyte is unique and fundamental in immune response under physiological and pathological condition.

Clonality of T lymphocyte

Lymphocytes originated from the bone marrow are circulated in the thymus, in which they are able to be educated and graduated. They are called Thymus-dependent lymphocytes, abbreviated term as T lymphocyte. Another counterpart of lymphocytes are called B lymphocytes, derived from the organ called Bursa-Fabricius of the bird species.

Since specific selection of lymphocytes in the thymus occurs just after birth, T lymphocytes do not react to self-materials as antigens making up own body, but to “non-self” materials coming from outside. If some T lymphocyte could react to “self”-materials from inside, they may cause autoimmune diseases. Such a condition may occur in complicatedly abnormal balance of immune systems.

T lymphocytes work to control functions of B lymphocytes and they are divided into  helper T cells which help B lymphocyte clones producing antibodies, and suppressor T cells which suppress function of B lymphocytes to produce antibodies. On the other hand, T lymphocytes play major roles in cellular immunity, which is closely related to “cancer immune therapy”. Suppressor T cells include “killer T lymphocytes” and cytotoxic T lymphocytes. They are different from NK cells. All of them work to maintain our natural healing power.

T lymphocytes are also involved in protective reactions against tuberculosis or in tuberculin reactions for detection of anamnestic cellular reaction of invasion of tubercle bacilli. More than 70% of lymphocytes in the peripheral blood consists of T lymphocytes and remaining around than 20% are B lymphocytes as another counterpart.

Clonality of B lymphocytes

Lymphocytes which are inappropriate for thymus “school” are called B lymphocytes, as mentioned above. B lymphocytes and mature type of B lymphocytes, called plasma cells  produce unique protein family, Y-shaped immunoglobulins. According to researches on genetic sites regarding immunoglobulin molecules, there are five kinds of immunoglobulin for human beings, which are IgG, IgA, IgM, IgE, and IgD.

B lymphocytes produce IgM type, and plasma cells produce IgG, IgA, or IgE.

IgG and IgM show antibody function for protection against microorganism, such as bacteria and virus. Immunoglobulin E (IgE) is called reagin, which works as hypersensitivity to cause allergy. IgA plays an important role as antibody function along mucosal membrane of digestive, respiratory and urogenital tracts. IgD is a special antibody function working on the surface of immature B lymphocyte while B lymphocyte are maturing. Therefore this type of immunoglobulin D is hardly detected as a secretory type of immunoglobulin molecule in the blood.

The most important point in immunology is clonality of each B lymphocyte producing monoclonal immunoglobulin molecule and of each T lymphocyte bearing T cell receptor. The number of clonality of B and T lymphocytes is dependent upon diverse antigenic stimulation.

Diverse clonality of antibodies (immunoglobulins)

I mentioned that immunoglobulin molecule is Y-shaped. It consists of two-pairs of two kinds of polypeptide chains, and is composed of two chains of heavy chain and two chains of light chain. Both upper parts of the two heavy chains are entangled with two light chains. Immunoglobulin consists of two heavy chains and two light chains. As for light chains, there are only two kinds, kappa and lambda. As for heavy chains, there are five kinds, mentioned above. In total, we assume, there are only 10 types of immunoglobulin molecules. However, our body can produce almost innumerable clones of antibody protein, which enables us to fight against myriad of foreign objects such as bacteria or virus. 

Here I would like to talk about clonal diversity of antibody protein. Upper two parts of the Y-shape of antibody is bound with specific foreign materials. This part has a hollow just like a pocket (antigen-binding site). The binding shape of this site differs according to each type of immunoglobulin, which is determined to have infinite diversity.

This diversity is determined by various amino-acid sequences shaping this hollow, which is dependent upon mutation of somatic gene. This is called “somatic mutation” and is a revolutionary system of human body, which is a characteristic of clonality of B as well as T lymphocyte. In general, cancer is developed by somatic mutation related with cell growth genes of a single cell under pathological conditions. However, lymphocyte has somatic mutation of immunoglobulin genes in itself under physiological condition. It is amazingly surprised. Dr. Susumu Tonegawa received Nobel Prize with his research on it.

T lymphocytes also have limitless diversity in T cell receptor. Those lymphocytes of huge diversity are communicating with each other to keep the balance and maintaining the whole body in a consolidated manner.

Taken together, it is a sophisticated nature of immune balance. This system creating diversity enables us to fight against a wide variety of foreign materials in terms of infinite diversity of antibody formation including IgE system in allergy.

Cancer growth of B lymphocytes

When each clone of matured B lymphocyte or each clone of plasma cell gets malignant, it may cause primary macroglobulinemia producing monoclonal IgM molecules called Waldenstrom macroglobulinemia as the former or multiple myeloma producing monoclonal immunoglobulin other than IgM as the latter. Cancer of other lymphocytes is called malignant lymphoma.

When lymphocyte is moving in blood capillary in the skin of face, arms, or legs, they are stimulated by ultraviolet rays. In the blood there are a few bone marrow stem cells. They are also exposed to ultraviolet rays which might destroy its DNA. Lymph system at the tonsil and digestive tract, lymphocytes of appendix, and stem cell in bone marrow are stimulated by various foreign objects contained in food. Viruses in those subjects may cause infections on cells. Those various stimulations may injure DNA of lymphocyte. If this process is repeated and finally important part of gene is injured, it may cause malignant alternation of cells and result in autonomic growth of lymphocyte. In some worse cases, plasma cells get malignant, developing into multiple myeloma.


Monocyte plays a main role in promoting of lymphocytic functions. This cell type called monocyte is patrolling in the blood. When monocytes go out of blood, they grow in size and get activated. Activated monocyte is called macrophage. The most important function of this cell is to eat and digest foreign materials, and present the antigenic fragment (epitope)on its cellular membrane (antigen presentation). If T cell receptor on the surface of T lymphocyte and antigenic binding site of B lymphocyte are specifically matched with this antigenic fragment (epitope) presented on the surface of macrophage, then a set of these three cells is called mono-clonal relationship. As a result of this relationship, this antigenic fragment (epitope) must induce to secret specific antibody against this antigenic fragment (epitope).

This is the reason why monocyte=macrophage is called a conductor of immune system. Macrophage is patrolling and staying in the local area Moreover, those cells are conveyed in blood throughout the body. Macrophage is also called “dendritic cell”, namely cellular projection like many branches. This cell type in the skin surface is called Langerhans cell. Resident macrophage in the liver is called Kupffer cell. Like this, Macrophage is distributed everywhere of the whole body. Strengthening of dendritic cells is required to improve natural healing power in terms of enhancement of immune harmony.

In the next essay, it is time to talk about multiple myeloma producing monoclonal immunoglobulin in detail on the basis of the recent two chapters.


Yuzo Endo, M.D., Ph.D.

Yuzo Endo, M.D., Ph.D.
Hamamatsu University School of Medicine

1969.9: Graduated from Medical School, University of Tokyo Consultant pathologist in Hamamatsu University, Medical School, and Fujimoto General Hospital. Medical Consultant in conventional and integrative medicine.

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