Cells of the Immune System

1.            Leukocytes: Immune cells

a.         The primary cells of the immune system are the white blood cells, or leukocytes.

b.         About 7,000 white blood cells are found in a microliter of whole blood.

c.         They are divided into granulocytes and mononuclear leucocytes:

d.            Granulocytes:

i.          they are so named for their prominent cytoplasmic secretory granules.

ii.          each of the three different types of granulocytes has type specific granules, the names neutrophil, eosinophil and basophil being derived from the staining characteristics of these specific granules.

iii.            neutrophil granules do not stain and considered ‘neutral’, basophil granules stain dark blue with basic dye and eosinophil granules stain dark pink with the dye eosin.

iv.         the granulocytes have a single multilobed nucleus and are named polymorphonuclear leukocyte or polymorph.

e.            Lymphocytes and monocytes have relatively non-lobulated nuclei and were named mononuclear leukocytes.

f.            Phagocytes are white blood cells that engulf and ingest their targets by phagocytosis: neutrophils, macrophages, monocytes and eosinophils.

g.            Cytotoxic cells kill the cells they are attacking: eosinophils and some types of lymphocytes.

h.            Antigen-presenting cells display fragments of foreign proteins on their cell surface: lymphocytes, dendritic cells and macrophages.

2.         Role in Immune system

a.            Leukocytes constitute an important part of the body’s defenses against foreign invaders.

b.            Neutrophils and monocytes are highly phagocytic and engulf microorganisms, cell debris and particulate matter in a non-specific manner.

c.            Lymphocytes play the key role in all immune responses and their activity is always directed against specific foreign agents.

d.         In general, all the leukocytes perform their functions in the tissues and use the blood as a vehicle for transit between sites of formation, storage and activity.

e.         All leukocytes exhibit amoeboid movement which provides the means for migration in and out of the circulatory system and through the tissues.

3.            Neutrophils

a.            Neutrophils are the most common type of leukocyte in blood and constitute 40-75% of circulating leukocytes.

b.         They are characterized by their highly lobulated nucleus.

c.         Being highly mobile and phagocytic, their principal function is in the acute inflammatory response to tissue injury where they ingest and destroy damaged tissue and invading microorganisms, particularly bacteria.

d.         In addition, they release a variety of chemicals, fever-causing pyrogens and chemical mediators of the inflammatory response.

e.            Migration of Neutrophils:

i.            neutrophils in the circulation are attracted by the presence of organisms, particularly bacteria.

ii.          this process is mediated by chemotactic factors (chemotaxins) released from damaged tissue and generated by the interaction of antibodies with antigens on the surface of the microorganisms.

iii.         the coating of organisms with antibodies and complement greatly enhances neutrophilic phagocytic activity – opsonization.

iv.            organisms which do not generate chemotaxins or become opsonized are thus relatively resistant to neutrophil phagocytosis and are thus highly pathogenic.

f.            Phagocytosis:

i.            organism is surrounded by pseudopodia which then fuse to completely enclose it in an endocytotic vesicle called a phagosome.

ii.          this then fuses with the cytoplasmic granules which discharge their contents exposing the organism to lysosomal enzymes.

iii.         killing is greatly enhanced by the generation of hydrogen peroxide and superoxide by enzymatic reduction of oxygen.

g.            Neutrophil stimulation:

i.            important precursor to granule discharge.

ii.          involves the binding of complement fraction C5a to a significant proportion of receptors on the neutrophil plasma membrane.

iii.         C5a is the most potent neutrophil chemotaxin and induces chemotaxis, a degranulation and generation of hydrogen peroxide and superoxide.

4.            Eosinophils

a.            Eosinophils account for 1-6% of leukocytes in circulating blood.

b.         They remain in the bone marrow for several days after production, then circulate for about three to eight hours; the majority then enter the skin, pulmonary or gastrointestinal mucosae from which they may migrate into local secretions.

c.            Increased numbers of circulating eosinophils are found in many types of parasitic disease and defense against parasites.

d.            Ultrastructure:

i.          large, ovoid, specific granules.

ii.          specific granules are membrane-bound and contains hydrolytic enzymes including histaminase.

iii.         small granules contain aryl sulfatase and acid phosphatase.

e.            Immunologic capabilities:

i.            eosinophils are phagocytic cells with a similar metabolism to neutrophils but with a greater oxidative capacity via the hexose monophosphate shunt.

ii.          they have a greater phagocytic affinity for antigen-antibody complexes.

iii.         all eosinophils have receptors for IgE which is important in the destruction of parasites; this is not present on neutrophils.

iv.            eosinophils undergo chemotaxis in response to bacterial products and complement components, substances released from basophils and mast cells, notably histamine, eosinophil chemotactic factor of anaphylaxis (ECF-A) and activated lymphocytes.

v.            phagocytosis occurs in the usual manner but if the object is too large to be engulfed, the eosinophil release its granule contents to the external environment.

f.            Eosinophils may play a role in ameliorating some aspects of hypersensitivity reactions as they neutralize histamine and produce a factor called eosinophil-derived inhibitor which inhibit mast cell degranulation.

5.            Basophils

a.            Basophils are the least common of leukocyte and constitute less than 1% of leukocytes in circulating blood.

b.            Cytoplasmic granules contain:

i.            proteoglycans and heparin

ii.            histamine, slow reacting substance of anaphylaxis and ECF-A.

c.         The principal function of basophils and mast cells is in immunological responses to certain parasites.

d.         They are found concentrated in the connective tissue of skin, lungs and the GI tract where they are ideally located to intercept pathogens.

e.            Basophils and mast cells have membrane receptors highly specific for the Fc segment of IgE which is produced by plasma cells in response to a variety of environmental antigens (allergens).

f.            Exposure to allergen, results in the antigen forming bridges between adjacent IgE molecules which triggers degranulation.

g.         The release of histamine and other vasoactive mediators in responsible for the immediate hypersensitivity reaction characteristic of allergic rhinitis, some forms of asthma and anaphylactic shock.

6.            Lymphocytes

a.         The lymphocytes and plasma cells are the key cells that mediate the acquired immune response of the body.

b.         Only 5% of all lymphocytes are found in the circulation, where they constitute 20-35% of all white blood cells.

c.         Most lymphocytes are found in the lymphoid tissues such as lymph nodes, the spleen, bone marrow, and the submucosal glands of the GI tract.

d.         They are characterized by a round, densely stained nucleus and a relatively small amount of pale, basophilic, non-granular cytoplasm.

7.         The Lymphoid organs

a.         The lymphoid organs are organized tissues where lymphocytes interact with non-lymphoid cells, which are important either to their maturation or to the initiation of adaptive immune responses.

b.         They can be divided into primary or central lymphoid organs, where lymphocytes are generated, and secondary or peripheral lymphoid organs, where adaptive immune responses are initiated.

c.         Central lymphoid organs:

i.          these are the bone marrow and thymus.

ii.          both B and T lymphocytes originate in the bone marrow but only B lymphocytes mature there.

iii.         T lymphocytes migrate to the thymus to undergo maturation.

iv.         once they have completed their maturation, both types of lymphocytes enter the bloodstream, from which they migrate to the peripheral lymphoid organs.

d.            Pathogens can enter the body by many routes and set up infections anywhere but antigen and lymphocytes will eventually encounter each other in the peripheral lymphoid organs – lymph nodes, spleen and mucosal lymphoid tissues.

e.         Lymph nodes:

i.          they are highly organized lymphoid structures that are the sites of convergence of an extensive system of vessels that collect the extracellular fluid from tissues and return it to the blood.

ii.          the fluid is called lymph and the vessels that carry it lymphatic vessels.

iii.         the afferent lymphatic vessels which drain fluid from the tissues, also carry cells bearing antigens from sites of infections in most parts of the body, to the lymph nodes, where they are trapped.

iv.         B lymphocytes are localized in follicles, with T cells more diffusely distributed in surrounding paracortical areas.

f.          Spleen:

i.          it collects antigen from the blood and also collects and disposes of senescent red blood cells.

ii.          the bulk of the spleen is composed of red pulp, which is the site of red blood cell disposal.

iii.         the lymphocytes surround the arterioles entering the organ, forming areas of white pulp.

g.         Gut-associated lymphoid tissues (GALT):

i.          these are the tonsils, adenoids, appendix and Peyer’s patches in the small intestine which collect antigen from epithelial surfaces of the gastrointestinal tract.

ii.          in Peyer’s patches, the antigen is collected by specialized epithelial cells called M cells.

iii.         more diffusely organized aggregates of lymphocytes protect the respiratory epithelium, where they are known as bronchial-associated lymphoid tissue (BALT) and other mucosa as mucosal-associated lymphoid tissue (MALT).

h.            Circulation of Lymphocytes:

i.          small T and B lymphocytes that have matured in the bone marrow and thymus, but have not yet encountered antigen are referred to as naive lymphocytes.

ii.          these cells circulate continually from the blood into the peripheral lymphoid tissues, which they enter by means of specialized adhesive interactions with the capillaries supplying these tissues.

iii.         they are returned to the blood via the lymphatic vessels.

iv.         in the presence of an infection, lymphocytes that recognize the infectious agent are arrested in the lymphoid tissue where they proliferate and differentiate into effector cells capable of combating the infection.

v.         when an infection occurs in the periphery, large amounts of antigen are taken up by phagocytes which then travel from the site of the infection through the afferent lymphatic vessels into the lymph nodes.

vi.         in the lymph nodes, these cells display the antigen to recirculating lymphocytes, which they also help to activate.

vii.        once these specific lymphocytes have undergone a period of proliferation and differentiation, they leave the lymph nodes as effector cells through the efferent lymphatic vessel.

I.          All the lymphoid tissues operate on the same principle, trapping cells arriving from sites of infection that present antigen to migratory small lymphocytes to stimulate adaptive immune responses.

8.            Monocytes and Macrophages

a.            Monocytes are the largest of the white cells and constitute 2-10% of leukocytes in peripheral blood.

b.         They are highly motile and phagocytic cells and are the precursors of macrophages, large phagocytic cells of various types found in peripheral tissues and lymphoid organs.

c.            Ultrastructure:

i.            characterized by a large, eccentrically placed nucleus that stain less intensely than other leukocytes.

ii.            cytoplasmic granules are electron-dense, homogenous and membrane-bound.

iii.         primary lysosomes contain acid phosphatase, aryl sulfatase and peroxidase.

iv.         capable of lysosomal activity and regeneration.

d.            Monocyte-macrophage system:

i.          migrate to peripheral tissues where they assume the role of macrophages.

ii.          consist of circulating monocytes, their bone marrow precursors and tissue macrophages.

iii.         Kupffer cells of liver, microglia of CNS, Langerhans cells of the skin and osteoclasts of bone.

iv.            multinucleate giant cells may form by fusion of macrophages or nuclear reduplication.

9.            Macrophage functions

a.            Phagocytosis:

i.          ingest bacteria, viruses, and other foreign particles.

ii.          have Fc receptors that interact with the Fc portion of immunoglobulins, thereby enhancing the uptake of opsonized organisms.

b.         Antigen presentation:

i.          foreign material is ingested and degraded, and fragments of antigen are presented on the macrophage cell surface in conjunction with

ii.          class II MHC molecules for interaction with the T cell receptor.

iii.            degradation of the foreign protein stops when the fragment associates with the class II MHC protein in the cytoplasm.

iv.         the complex is then transported to the cell surface by specialized ‘transporter’ proteins.

c.            Cytokine production:

i.            macrophages produce interleukin-1 and tumor necrosis factor.

ii.          IL-1 plays an essential role in the activation of T helper cells.

iii.         TNF is an important inflammatory mediator.

d.            Macrophages migrate to the site of inflammation, attracted by certain mediators, especially C5a, an anaphylatoxin released in the complement cascade.