By Levi Clancy for Student Reader on
After understanding Clonal Expansion Theory, it is important to become familiar with the origin and nature of cells involved in the immune systems.
Granulocytes and monocytes travel only in the blood. Lymphocytes circulate through both blood and lymph; lymphocytes can exit a lymph node via its efferent vessel, travel through the lymph and then enter the bloodstream via the neck.
Cells go back and forth between blood vessels, lymph vessels and tissue via extravasation. Leukocytes (aka white blood cells) are just any cell in the blood other than red blood cells, meaning all the cells below can be white blood cells depending on their location.
All blood cells arise via hematopoiesis.
After hematopoiesis in the bone marrow, granulocyte-monocyte progenitor cells differentiate into promonocytes. These promonocytes enter the bloodstream, where they mature further into monocytes; monocytes enlarge five- to ten-fold and become phagocytic while circulating for about up to three days in the blood. Next, these monocytes extravasate into tissues, where they become either fixed (tissue-specific) or free (wandering about the body) macrophages.
Monocytes move quickly to sites of infection in the tissues, and are one of the five major types of white blood cell. Monocytosis is the state of excess monocytes in the blood, and is indicative of disease. Monocytes can perform phagocytosis using intermediary (opsonising) proteins such as antibodies or complement that coat the pathogen, as well as by binding to the microbe directly via pattern-recognition receptors. Splenocytes are monocytes found in the spleen; macrophages are monocytes which have migrated from blood circulation to other tissues.
Granulocytes are a type of white blood cell containing granules. Granulocytes are aka polymorphonuclear neutrophilic leukocytes (PMNs/PMLs) or polys, although PMN can refer specifically to neutrophils since neutrophils are the most common granulocyte. The granules inside granulocytes are secretory vesicle containing a molecule (for example, basophil granules contain histamine). The granules are dormant in the cytoplasm until a cell signal instructs the granules to release their components. This signal is typically shock or distress. Degranulation is when granules release their contents from the cell.
|Neutrophils||Neutrophils are granulated, intensely phagocytic and constitute 50-60% of white blood cells. Neutrophils arrive quickly at infection sites to phagocytize pathogens. Neutrophils have an Fc Receptor (FcR) which detects antibodies cross-linked to antigens on the surface of pathogens. The process of detecting antibody-antigen complexes is called opsonization. After opsonization, the neutrophil absorbs the infectious microbe and degrades it.|
|Basophils||Basophils contain granules filled with histamine and serotonin. An antibody (typically IgE) sits in the basophil FcR. When the antibody cross-links to its antigen, the basophil degranulates and releases histamine and serotonin. This leads to an allergic reaction constituting difficulty breathing (bronchiole constriction), capillary permeability and mucous secretion. Basophils resides mostly in connective tissue and rarely circulate; they are very granular and have a condensed nucleus.|
|Eosinophils||Eosinophil populations grow during parasitic infections and allergies but are not well understood. Eosinophils are highly granulated cells that degranulate when their antibody-FcR complex cross-links with an antigen (similar to basophils).|
Neutrophils are commonly referred to as polymorphonuclear neutrophilic leukocytes (PMNs/PMLs) or polys, even though technically any granulocyte is a PMN. Neutrophils are intensely phagocytic and arrive quickly at infection sites (unhealthy tissues) to phagocytize pathogens. Neutrophils have an F(c) receptor (FCR) which detects antibodies bound to antigens on the surface of pathogens. The process of detecting antibody-antigen complexes is called opsonization. After opsonization, the neutrophil absorbs the infectious microbe and degrades it.
Neutrophils have a lobulated nucleus, meaning it is condensed and dead -- hence the term polymorphonuclear. Their cytoplasm is filled with granules containing degradative enzymes such as lysozyme, collagenase, elastase and others. During phagocytosis, these granules combine with phagosomes to break down pathogens.
Neutrophils are abundant in blood, constituting 50-60% of circulating white blood cells. However, neutrophils are absent from healthy (uninfected) tissues and only live about six hours. After performing phagocytosis several times, the neutrophil dies and degranulates (thus releasing its degradative enzymes). These enzymes damage and inflame local tissues -- making neutrophils important in inflammation -- but these corrosive enzymes also initiate healing.
Lymphocytes bind to specific antigens and generate from stem cells in primary lymphoid tissue via hematopoiesis. Mφs, dendritic cells and B cells originate in bone marrow; and T cells originate in the thymus. After maturing, lymphocytes migrate to secondary lymphoid tissues (lymph nodes, blood and other tissues) to fulfill their role.
|B Cells||B cells (aka B lymphocytes) produce antibody when exposed to their complementary antigen. These antibodies can cause engulfment of infectious bacteria, neutralization of virions and induction of the complement cascade.|
|T Cells||There are two measures to make sure that T cells (aka T lymphocytes) do not react with self: their maturation process in the thymus; and T cells only react to antigens that are presented by an MHC protein. There are kinds of T cells: CD4+ cells and CD8+ cells. CD4+ cells are helper cells that react with cytokines to improve immune responses. CD8+ cells are cytotoxic cells which kill self cells that are infected and presenting foreign proteins on their cell surface.|
|Dendritic Cells||Dendritic cells have long processes with surfaces that can trap antigens. Dendritic cells are found throughout the entire body -- including primary and secondary lymph tissues -- intercalated among other cells. Also, dendritic cells can migrate from skin and other tissues to lymph nodes. Dendritic cells may be very important in keeping antigens present so that B cell memory can be maintained in germinal centers.|
Mast cells are a distinct lineage, but still very similar to basophils. Mast cells are packed with histamine-filled granules, and their cell-surface bears an IgE-FcR complex. This IgE-FcR complex binds to an antigen, initiating degranulation that results in inflammation and allergy.
Inflammatory cells are involved in inflammation, a very primitive but valuable feature of the immune system. Inflammatory cells are not antigen-specific. They interact with antigen via secondary receptors such as F(c) receptors, lack any specificity or memory, and die after activation.
Antigen-presenting cells include dendritic cells, macrophages and B cells.
Only antigen presenting cells (APCs) are able to present antigens in the context of a Class II MHC molecule, and deliver the costimulatory signal needed for T cell activation, proliferation and differentiation. The principal costimulatory molecules on antigen presenting cells are the glycoproteins CD80 and CD86. B cells and dendritic cells constitutively express Class II MHC molecules, while only activated macrophages can be induced to express Class II MHC molecules.
Only dendritic cells and activated B cells can activate naive T cells; dendritic cells, activated B cells and activated Mφs can activate effector and memory T cells.
Macrophages (aka mononuclear phagocytes or Mφs) have two main functions: phagocytosis and antigen presentation.
In phagocytosis, the macrophage or monocyte cell-surface F(c) Receptor (FcR) binds to the antibody-antigen complex (an antibody bound to an antigen on the cell-surface of a pathogen). The pathogen, antigen and antibody are engulfed and degradative granules and enzymes break it down in the lysosome. Digested antigen fragments are bound to MHC molecules and presented on the macrophage or monocyte cell-surface so that effector cells (B and T cells) can recognize the antigen. Because macrophages present antigens on their cell surface, they are antigen presenting cells (APCs). These antigens are then recognized by effector cells (B cells and T cells). Macrophages also activate cytokines, which stimulate differentiation and reproduction of lymphoid cells. Macrophages play a tremendous role in clearing tagged antigens and releasing degradative enzymes to damage tissues and initiate healing.
The precursor to a macrophage is a monocyte. Macrophages are continuously maturing from circulating monocytes. Macrophages: trap, engulf and destroy pathogens (phagocytosis); present antigens for the adaptive immune response (antigen presentation); produce cytokines (including IL-12); and induce co-stimulatory molecules. Also, macrophages also bear CD14 (and LPS receptor), CD11b/CD18 complex (binds C3b and C4b, complement byproducts), scavenger receptor (binds sialic acid), TLR and F(c)R (described above).