White Blood Cells
The principal function of phagocytes is to defend against invading microorganisms by ingesting and destroying them, thus contributing to cellular inflammatory responses. There are two types of phagocytes: mononuclear phagocytes and granulocytes. Mononuclear phagocytes arise primarily from the marrow and are released into the blood as monocytes. They may circulate for hours to a few days before entering the tissues and differentiating to become macrophages. Granulocytes have a segmented nucleus and are classified according to their staining characteristics as neutrophils, eosinophils, or basophils. Neutrophils circulate for only a few hours before travelling to the tissues.
Five distinct stages in the process of phagocytosis have been identified: 1) attraction of phagocytes (chemotaxis) to microorganisms, antigen-antibody complexes, and other mediators of inflammation; 2) attachment to the organism; 3) ingestion; 4) fusion of cell lysosomes with ingested microorganisms and bacterial killing; and 5) digestion. In addition, many phagocytes have other specialized functions. Monocytes form a link to the specific immune system by processing antigen for presentation to lymphocytes and by producing substances such as interleukin-1, which initiates fever and lymphocyte activation and stimulates early hematopoietic progenitors.
Eosinophils, while having a role as phagocytes, also have more specific functions that include providing a defense against metazoan parasites and modulating the inflammatory process. They respond chemotactically to histamine, immune complexes, and eosinophil chemotactic factor of anaphylaxis, a substance released by degranulating mast cells. Basophils are not true phagocytes but contain large amounts of histamine and other mediators of inflammation. Eosinophilia and basophilia may be seen in response to systemic allergic reactions and invasion of tissues by parasites.
As with the RBCs, the production and circulating numbers of phagocytes are tightly regulated and controlled by various humoral factors, including colony-stimulating factors and interleukins. Unlike the RBCs, which remain circulating in the blood, the phagocytes use this compartment as a pathway to the tissues. Consequently, the number of phagocytes in the blood reflects circumstances in the tissues (eg, inflammation) as well as the proliferative function of the bone marrow. The sensitivity with which phagocytes reflect these conditions varies from species to species. Abnormal response, such as neutropenia from marrow failure, infections, drugs, or toxins, is likely to result in secondary bacterial infections. Some cases of “idiopathic” neutropenia in dogs may have an immune-mediated cause. Finally, phagocyte precursors may undergo malignant transformation, which results in acute or chronic myelogenous leukemia.
Lymphocytes are responsible for both humoral and cellular immunity. Cells of the two branches of the immune system cannot be differentiated morphologically, but they differ in their dynamics of production and circulation. Lymphocyte production in mammals originates in the bone marrow. Some of the lymphocytes destined to be involved in cellular immunity migrate to the thymus and differentiate further under the influence of thymic hormones. These become T cells and are responsible for a variety of helper or cytotoxic immunologic functions. Most circulating lymphocytes are T cells, but T cells are also present in the spleen and lymph nodes. The B cells migrate directly to organs without undergoing modification in the thymus and are responsible for humoral immunity (antibody production).
Thus, lymphoid organs have populations of both B and T lymphocytes. In the lymph nodes, follicular centers are primarily B cells, and parafollicular zones are primarily T cells. In the spleen, most of the lymphocytes of the red pulp are B cells, whereas those of the periarteriolar lymphoid sheaths are T cells. Close association of T cells and B cells within lymphoid organs is essential to immune function.
Lymphocyte function in the cellular immune system features both afferent (receptor) and efferent (effector) components. Long-lived T cells of the peripheral blood are the receptors. In response to antigens to which they have been previously sensitized, they leave the circulation and undergo blast transformation to form activated T cells, which in turn cause other T cells to undergo blast transformation, both locally and systemically. Stimulated T cells produce lymphokines with a wide range of activities, such as attraction and activation of neutrophils, macrophages, and lymphocytes.
The humoral immune system is composed of B cells that produce antibodies of several classes. When sensitized B cells encounter antigen, they divide and differentiate into plasma cells that produce antibody. Therefore, each initially stimulated B cell produces a clone of plasma cells, all producing the same specific antibody.
Antibody molecules (immunoglobulins) fall into several classes, each with its own functional characteristics. For example, IgA is the principal antibody of respiratory and intestinal secretions, IgM is the first antibody produced in response to a newly recognized antigen, IgG is the principal antibody of the circulating blood, and IgE is the principal antibody involved in allergic reactions.
Antibodies perform their function by combining with the specific antigens that stimulated their production. Antigen-antibody complexes may be chemotactic for phagocytes, or they may activate complement, a process that produces both cell lysis and substances chemotactic for neutrophils and macrophages. In this manner, the humoral immune system is related to, and interacts with, the nonspecific immune system.
The humoral immune system also is related to both the nonspecific immune system and the cellular immune system in other ways. Both “helper” (CD4) and “cytotoxic” (CD8) T-cell classes have been described. Helper T cells recognize processed antigen and activate the humoral immune response. Cytotoxic T cells, after sensitization by antigen, are effector cells, which are especially important in antiviral immunity. Natural killer cells, which are a class of lymphocyte distinct from T cells and B cells, destroy foreign cells (eg, neoplastic cells) even without prior sensitization. Antigen processing by macrophages precedes recognition of an antigen by lymphocytes. These complex processes are involved in routine surveillance against neoplastic cells and recognition of “self.”
Lymphocyte response in disease may be appropriate (activation of the immune system) or inappropriate (immune-mediated disease and lymphoproliferative malignancies). (Also see The Biology of the Immune System.) Immune-mediated disease results from failure of the immune system to recognize host tissues as self. For example, in immune-mediated hemolytic anemia, antibodies are produced against the host’s own RBCs. Another inappropriate response of the immune system is allergy. In allergic individuals, IgE antibodies to allergens are bound to the surface of basophils and mast cells. When exposure to the allergen occurs, antigen-antibody complexes are formed, and degranulation of the mast cells and basophils releases vasoactive amines. Reaction to this may be mild (as in urticaria or atopy) or life-threatening (as in anaphylaxis).
Lymphocytosis occurs in some species, especially the cat, as a response to epinephrine secretion. Atypical lymphocytes may be seen in the blood in response to antigenic stimulation (eg, vaccination). Persistent lymphocytosis in cattle infected with bovine leukemia virus is a benign polyclonal increase in lymphocyte numbers. Lymphoproliferative malignancies include lymphomas and acute lymphoblastic and chronic lymphocytic leukemias. Lymphopenia may occur most commonly as a response to glucocorticoid secretion.