A consideration of the origin and maturation sequence of white blood cells (WBCs) is helpful in understanding the classification and behavior of the leukemias and their close relatives, the malignant lymphomas. Most authorities agree that the basic cell of origin is the fixed tissue reticulum cell. Fig. 7-1 shows the normal WBC development sequence. In the area of hematologic malignancy, those of lymphocytic origin predominate since they produce nearly all of the malignant lymphomas as well as over half of the leukemias.

Normal WBC maturation sequence (some intermediate stages omitted)
Fig. 7-1 Normal WBC maturation sequence (some intermediate stages omitted).

It is now possible to differentiate most malignant lymphoid tumors from benign tumorlike proliferations and to evaluate the degree of lymphoid cell maturation (which in lymphoid malignancies may have prognostic or therapeutic importance) by means of immunologic tests that demonstrate cell antigens or structural arrangements found during different stages of lymphocyte maturation. Before discussing this subject it might be useful to briefly review the role of the lymphocyte in the immune response to “foreign” or harmful antigens. Considerably simplified, most lymphocytes originate from early precursors in the bone marrow; some mature in the bone marrow (B-lymphocytes, although later maturation can take place in the spleen or lymph nodes) and others mature in the thymus (T-lymphocytes). The T-lymphocytes first develop an antigen marker for T-cell family called CD-2 (the CD system will be discussed later), then a marker for T-cell function (CD-4, helper/inducer; or CD-8, cytotoxic/suppressor) and a surface marker for specific antigen recognition (CD-3). All nucleated body cells have elements of the Major Histocompatibility Antigen Complex (MHC; also called Human Leukocyte Antigen system, or HLA) on the cell surface membrane; this consists of MHC class I antigen (HLA-A, B, or C antigen) for all cells except brain glial cells. Some cells (including macrophages and B-lymphocytes but not CD-8 cytotoxic or suppressor T-lymphocytes) also have surface MHC class II antigen (HLA-D or DR).

In the primary (first contact) immune response, certain cells known as antigen-presenting cells (usually macrophages) ingest the harmful or foreign antigen, partially digest (“process”) the antigen, and attach certain antigenic portions (epitopes) of it to an area on the macrophage surface membrane that contains the MHC Class II complex. The antigen-presenting cell (APC) then must meet a T-lymphocyte of the CD-4 helper category that has a surface receptor specific for the foreign/harmful antigen held by the APC. The two cells link together at the MHC-II complex area of both cells. The APC then releases a hormonelike substance known as a cytokine; more specifically, a category of the cytokines called interleukins; and specifically, a subgroup of the interleukins called interleukin-1 (IL-1). This substance (factor) stimulates the helper T-lymphocyte into activity. The activated T-cell secretes another interleukin called interleukin-2 (IL-2) that causes the helper T-cell to replicate itself with the same specific antigen receptor as the parent cell.

The newly formed helper T-cells in turn can affect CD-8 cytotoxic/suppressor T-lymphocytes and B-lymphocytes. CD-8 cytotoxic lymphocytes recognize the original unaltered foreign or harmful antigen in the body by means of specific receptor and MHC Class I surface antigen complex, after which the cytotoxic T-lymphocyte attaches to the foreign antigen, develops IL-2 receptors, and tries to destroy the antigen by producing toxic chemicals. If helper T-cell IL-2 reaches the activated cytotoxic T-cell, the cytotoxic T-cell is stimulated to replicate itself to generate more cytotoxic cells that can find and destroy more of the same antigen. The helper T-cell IL-2 is also thought to activate other CD-8 T-lymphocytes that have a suppressor function to keep the antiantigen process from going too far and possibly harming normal body cells.

B-lymphocytes are also affected by activated helper T-cells. B-lymphocytes have surface antibody (immunoglobulin) rather than CD-3 antigen-recognition receptor, but the surface immunoglobulin (Ig) recognizes a single specific antigen in similar manner to the CD-3 receptor. B-lymphocytes can recognize and bind cell-free antigen as well as antigen bound to the surface of other cells, whereas T-cells require cell-bound antigen. A B-lymphocyte with the appropriate antigen-recognition Ig attaches to APC macrophages with foreign/harmful antigen at a MHC antigen-binding complex site. If an activated helper T-cell is also bound to the macrophage, the B-lymphocyte attaches simultaneously to it also. IL-2 from the activated helper T-cell stimulated the B-cell to replicate (clone) itself exactly. In addition to IL-2, the helper T-cell can secrete a B-cell differentiation factor that causes some of the newly cloned B-lymphocytes to differentiate into plasma cells (either through an intermediate immunoblast stage or more directly) and some become memory cells, able to reactivate when encountering the same antigen months or years later. Plasma cells secrete specific immunoglobulin antibodies that can attack the specific antigen originally recognized by the parent B-lymphocyte. The first antibodies are IgM; later, production usually changes to another Ig type such as IgG, A, or E, at least partially under the influence of certain interleukins produced by the helper T-cell. Activated B-lymphocytes may on occasion become APC, processing and presenting antigen to T-lymphocytes similar to the activity of macrophages.

Finally, there is a group of lymphocyte-like cells known as natural killer cells (NKC) that does not have either T-lymphocyte marker antigens or B-lymphocyte surface Ig. These cells can chemically attack foreign or cancer cells directly without prior sensitization or the limitation (restriction) of needing the MHC receptor. Of peripheral blood lymphocytes, 75%-80% (range, 60%-95%) are T-cells; 10%-15% (range, 4%-25%) are B-cells; and 5%-10% are NKCs. Of the T-cells, about 60%-75% are CD-4 helper/inducer type and about 25%-30% are CD-8 cytotoxic/suppressor type.