Bd

BLOOD

Description

Understanding changes in basic blood counts is important in monitoring and managing MCL. There are three major types of blood cells: red blood cells (erythrocytes), white blood cells (leukocytes), and platelets (thrombocytes).

The various types of cells found in the peripheral blood are all derived from a common stem-cell, and develop through a process of maturation and proliferation called 'haemopoiesis'. Cells are broadly classified as either myeloid or lymphoid. Myeloid elements include erythrocytes (red-cells), granulocytes and platelets, and normally undergo all stages of maturation in the bone marrow. Monocytes are part of the macrophage lineage, and may develop within the bone marrow, or in other extra-medullary sites. Lymphocytes, both B-cells and T-cells, begin development in the marrow, and then move to lymphoid organs such as spleen, lymph nodes and thymus to complete their development.

Although the normal bone marrow contains cells at all stages of development, from the earliest precursor stem-cells to terminally Fdifferentiated and functionally mature lymphoid and myeloid cells, the peripheral blood normally only contains mature lymphocytes, granulocytes, red-cells, monocyte/macrophages and platelets.

Red blood cells (RBC's) are the major component of blood. They carry oxygen and carbon dioxide throughout the body. The percentage of red blood cells in the blood is called the hematocrit. The part of the red blood cells that carries oxygen in a protein is called hemoglobin.

White blood cells (WBC's) are the main component of the immune system, the body's defense mechanism that fights and destroys such foreign substances as bacteria and viruses. There are several types of white blood cells, each with its own function in protecting the body from germs. Three major types of white blood cells are granulocytes (neutrophils, eosinophils, and basophils), monocytes, and lymphocytes.

Platelets prevent excessive bleeding by helping blood clot at the site of an injury. An abnormally low platelet count (thrombocytopenia) may result in small vessel bleeding (petechia) or in excessive bleeding from wounds in mucous membranes, skin, or other tissues (hematomas).

Normal blood counts are difficult to state as they vary with the age and sex of the patient as well as where they live. Higher values are usually seen in people who live at higher elevations. The reference ranges for each test will be printed on the laboratory report form and will be specific to your locale.

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Bc

BLOOD COUNTS

On the whole, adult values are typically:

Red blood cells: per microlitre of blood

Male: 4.32 - 5.66 x 1012/l

Female: 3.88 - 4.99 x 1012/l

Leukocytes (White blood cells):

Male: 3.7 - 9.5 x 109/l

Female: 3.9 - 11.1 x 109/l

  Granulocytes: 1.8 - 8.9 x 109/l

      Neutrophils: 1.5 - 7.4 x 109/l

       Eosinophils: 0.02 - 0.67 x 109/l  (0% to 3% of total white blood cells)

       Basophils: 0 - 0.13 x 109/l  (0% to 2% of total white blood cells)

Lymphocytes: 1.1 - 3.5 x 109/l  (25% to 35% of total white blood cells)

   B-cells: 0.06 - 0.66 x 109/l

   T-cells: 0.77 - 2.68 x 109/l

   CD4+: 0.53 - 1.76 x 109/l

   CD8+: 0.30 - 1.03 x 109/l

   NK cells: 0.20 - 0.40 x 109/l

Monocytes: 0.21 - 0.92 x 109/l  (3% to 10% of total white blood cells)

Platelets:

140 - 440 x 109/l

Hemoglobin:

In males, 14 to 18 grams per 100 milllitres of blood or 14-18g/dL. (In some countries, these values are given in litres, so they read 140-180 g/L.)

In females, 12 to 15 grams per 100 milllitres of blood or 12-15g/dL.

Hematocrit:

The percentage of red blood cells per microlitre of blood:

In males 40% to 54%. In females 35% to 47%

When speaking about these values, many practitioners use a shortened  language by omitting adjectives such as grams. For example, suppose the white cell count is 10.5x109L. Since all white cell counts end in 109L, the number spoken is just the 10.5. A hemoglobin value would be 14 instead of 14 grams per decilitre.

One calculation that is very important is the absolute cell count. This is achieved by multiplying the total white cell count by the percent of a specific cell reported. Based on these figures, the normal lymphocyte count is in the range of 1,000 to 3,850 per microlitre of blood or 1.0-3.8x109L. Often the first symptom of MCL is an above normal lymphocyte count, which is discovered in a routine blood test.

Copyright© 1999 David M. Thomas. who kindly gave me permission to reproduce this document. (plus material which was derived from a number of sources added by Ron Edwards)

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B-L

Normal Function of B-Lymphocytes

B-lymphocytes form that fraction of the healthy immune system which produce antibodies in response to antigens, which are proteins displayed by invading  organisms, toxins, and allergens. When an antigen is encountered, a specifically designed  antibody, also a protein, chemically binds to the antigen and marks that cell or molecule for destruction by other cells in the immune system. While there are over 1 million known antigens, the entire human genome contains, at the most generous estimate, only about 100,000 genes. This number is far too few to code for each antigen separately. B-cells solve this dilemma by shuffling genetic material within chromosomes 2, 14, and 22. recombination system creates a nearly infinite variety of protein products, each of which  can react with a different antigen. Of particular importance to this paper is the  immunoglobulin heavy chain located on chromosome 14.

Antibodies, in their simplest form, consist of hundreds of amino acids arranged in a Y-shape. Each "arm" of the Y contains a light and a heavy immunoglobulin chain intertwined with each other. The light and heavy chains are so named because of their respective molecular weight. Both chains consist of a variable and a constant region. The "base" of the Y is formed from the longer constant portion of the heavy chains. The arms are identical to each other. At the extreme end of each arm is a hypervariable region which acts as the antigen binding site. It is this region of the antibody which makes each type of antibody unique.

A complete heavy-chain is encoded by a single gene on chromosome 14, which is the combination of several gene segments which recombine during differentiation. This process involves a somatic rearrangement, an actual physical shifting of the DNA segments.

When it is over, chromosome 14 contains, from the 5' end, a set of variable genes and a set of constant genes. The antibody structure consists of a variable region at the 5' end which is responsible for the difference between antibodies. The variable gene section contains, again form the 5' end, a variable region, a diversity region which is specifically responsible for variations in heavy chains, and a joining segment, which links the variable portion to the constant gene. This entire unit remains intact throughout the life of the cell line and is transcribed as a whole.

In addition to rearrangement of entire gene sequences, the variable (V) sequences exhibit a singularly high rate of mutation, called hypermutation, which occurs during the expansion and differentiation of activated B-cells. The mechanism of this phenomenon is not yet fully understood, but is can increase B-cell diversity by two to three orders of magnitude.

Offspring of activated differentiated B-cells differentiate once again: They can become either plasma cells, which actively produce antibodies, or they can develop into memory cells, which "remember" the antigen and help to mount an enhanced response when the antigen is encountered again. In MCL, one of these clonal cells (a clone of a differentiated cell) has mutated and begun to proliferate rapidly and beyond the realm of normal cellular control

CELL CYCLE IN NORMAL CELLS

All cancers are genetic malfunctions in cells. Usually the malfunction arises in a single cell, allowing it to proliferate uncontrollably. Often these malfunctions manifest themselves as one or many phenotypic flaws which allow cells to grow without regard to the usual inhibitions that normally regulate cell expansion. Cancer is often thought of in terms of  tumors formed by cells proliferating in this manner. However, MCL can just as easily be defined as a population of defective lymphocytes that cannot function normally and yet are not able to die.

Proliferation

A cell's lifecycle can be considered to resemble an old patent drawing for some crazy contraption, such as a better mousetrap. In these drawings, the new "product" is invariably a complicated system of pulleys, weights, and ropes, which form a delicate balance system. In order for this proposed apparatus to work, some outside event (for example, the presence of a mouse) sets off a complex system of chain reactions, which ultimately leads to the desired conclusion (the capture of said mouse).

In cells, it appears that two overlapping cycles occur at the same time. One B-cells can divide either before or after differentiation. Those which divide afterward produce more like themselves which in turn are equipped to produce the same antibody as the parent cell.

Clone cells (memory cells) from the original differentiated parent cell lie in wait for the next visit from the antigen they were created to attack. When that visit transpires, the memory cells begin to proliferate and differentiate into cytotoxic T-cells or into more plasma cells. The plasma cells are capable of secreting about 2000 antibodies per second per cell. Researchers have established a model with which one can follow a normal B-lymphocyte from the moment it receives the external cue to divide until it completes mitosis, although many of the details remain fuzzy.

 All normal cells require external stimuli in the form of mitogens to begin their shift from the resting stage (G0 phase) into the stage for DNA replication (S-phase). In the case of B-cells, mitogens are a family of cytokines, or small protein hormones called interleukins. Interlukin-1 (IL-1), Interleukin -2 (IL-2), Interleukin-4 (IL-4) and Interleukin-5 (IL-5) are all co-stimulators for B-cells. IL-4 and IL-5 also stimulate production of antibodies in plasma cells. These growth factors can cross the cell membrane by means of specialized receptors. Receptors are protein portals which extend across the plasma membrane and have a specific configuration to accept only one kind of stimulus. Once inside the cell, the growth factors set off a chemical chain reaction, which consists of the phosphorylation of various molecules by specific protein kinases. The exact molecular mechanism of phosphorylation has not yet been established.

Following this chemical chain reaction is a series of steps in which genes are transcribed and then translated into proteins. These proteins in turn stimulate or inhibit the transcription of still more genes, including the myc family of growth promoters and the proto-oncogenes fos and jun, all of which appear to bind to DNA and stimulate or inhibit the expression of other genes later in the process as well as bcl-2 which prevents cell suicide (apoptosis), and the nuclear proteins pRB and p53, which act as brakes on the cell cycle. At the end of this chain reaction, is the production of the DNA synthesizing enzymes.

One of these is cyclin D1, which is encoded from the genetic information contained in the bcl-1 gene. Cyclin D1 and its associated kinase D4 help push the cell into S-phase. They migrate from the cytoplasm into the nucleus where they phosphorylate the protein pRB. This action changes pRB's nature and repudiates its tumor-suppressor function. This transaction then releases transcription factors which trigger DNA replication and in the process, cyclin D1 is also destroyed. As the last step in the G1 phase, DNA replication enzymes begin to synthesize DNA. At the same time, histones, the proteins that physically hold the chromosomes together, are synthesized. Once the replication of chromosomes is complete, a separate chain of events leads the cell through the G2 phase and mitosis.Upon completion of mitosis, the daughter cells return to G0 phase and wait for the next influx of interleukins.

APOPTOSIS IN NORMAL CELLS

Cells normally die by systematic apoptosis when they contain a genetic or other defect. Since cancer cells are able to avoid apoptosis, a definition of cancer might include their ability not to die. Withdrawal of growth factors, the cell's loss of a firm base on which to grow, conflicting messages regarding mitosis, and genetic defects can trigger this natural, self-policing form of "cell suicide"

Moreover, in B-lymphocytes, heavy-chain immunoglobulin M (IgM) serves as a surface receptor, and crosslinking of these molecules engenders apoptosis in defective B-cells. In every organism studied, apoptosis is brought on by "ICE-like" proteases, the "ICE" standing for "interleukin-converting enzyme."

These enzymes degrade the interleukens and prevent them from pushing the defective cell into another cycle. In addition, defective or damaged DNA triggers production of p53, which throws the brakes on cell division and induces apoptosis. The newest research suggests that much of the apoptic process is regulated by the equilibrium between the apoptosis inhibitor and related  molecules, like Bad, Bax, and Bcl-xL. Bcl-xL is an especially potent an apoptosiss-blocker. It was found to rescue mouse lymphocytes from apoptosis induced by withdrawal of growth factors, radiation, chemotherapy, oxidation, and anti-IgM-triggered apoptosis . Bcl-2 is also known to block oxidant-related cell death, but is neither as potent nor as versatile as Bcl-xL. Beyond this, however, the exact mechanism of cellular suicide remains mysterious.

One thing we do know, memory B-cells can live for decades. This accounts for the phenomenon of lifelong immunological memory. Memory cells' longevity is due in part to the presence of large amounts of bcl-2 and bcl-xL. Lymphocytes deficient in this substance experience severely shortened lifespans.

Source  http://mclresource.com/MCLAid/#Bl  2001