Ординатура / Офтальмология / Английские материалы / Ocular Pathology_6th edition_Yanoff, Sassani_2009

Fig. 1.2 Summary of the actions of complement and its role in the acute inflammatory reaction. Note how the elements of the reaction are induced: increased vascular permeability (1) due to the action of C3a and C5a on smooth muscle (2) and mast cells (3) allows exudation of plasma protein. C3 facilitates both the localization of complexes in germinal centers (4) and the opsonization and phagocytosis of bacteria

(5). Neutrophils, which are attracted to the area of inflammation by chemotaxis (6), phagocytose the opsonized micro-organisms. The membrane attack complex, C5–9, is responsible for the lysis of bacteria

(7) and other cells recognized as foreign (8). (Adapted with permission from Roitt IM, Brostoff J, Male DK: Immunology, 2nd edn. London, Gower Medical. Copyright Elsevier 1989.)

1)HLA-B 27 is positive in a high percentage of young women who have acute anterior uveitis and in young men who have ankylosing spondylitis or Reiter’s disease.

2)HLA-B 5 is positive in a high percentage of patients who have Behçet’s disease.

3)Factors (mainly unknown) other than HLA play an important role in the pathogenesis of ocular inflammation.

7.Nonspecific soluble mediators of the immune system include cytokines, such as interleukins, which are mediators that act between leukocytes, interferons

(IFNs), colony-stimulating factors (CSFs), tumor

necrosis factor (TNF), transforming growth factor- β, and lymphokines (produced by lymphocytes).

a.The TNF ligand family encompasses a large

group of secreted and cell surface proteins (e.g., TNF and lymphotoxin-α and -β) that may a ect the regulation of inflammatory and immune responses.

Both are homotrimers and are soluble products of activated lymphocytes (e.g., CD4+ type 1 T-helper cells,

CD8+ lymphocytes, and certain B lymphoblastoid and monocytoid cell lines.

b.The actions of the TNF ligand family are somewhat of a mixed blessing in that they can protect against infection, but they can also induce shock and inflammatory disease.

C.Immediately after an injury, the arterioles briefly contract (for approximately 5 minutes), and then gradually relax and dilate because of the chemical mediators discussed earlier and from antidromic axon reflexes.

After the transient arteriolar constriction terminates, blood flow increases above the normal rate for a variable time (up to a few hours), but then diminishes to below normal (or ceases) even though the vessels are still dilated. Part of the decrease in flow is caused by increased viscosity from fluid loss through the capillary and venular wall. The release of heparin by mast cells during this period probably helps to prevent widespread coagulation in the hyperviscous intravascular blood.

D.During the early period after injury, the leukocytes

(predominantly the PMNs) stick to the vessel walls, at

first momentarily, but then for a more prolonged time; this is an active process called margination (see Fig

1.1C).

1.Ameboid activity then moves the PMNs through the vessel wall (intercellular passage) and through the endothelial cell junctions (usually taking 2 to

12 minutes); this is an active process called emigration.

2.PMNs, small lymphocytes, macrophages, and immature erythrocytes may also pass actively across

endothelium through an intracellular passage in a process called emperipolesis.

3.Mature erythrocytes escape into the surrounding tissue, pushed out of the blood vessels through

openings between the endothelial cells in a passive process called diapedesis.

E.Chemotaxis, a positive unidirectional response to a chemical gradient by inflammatory cells, may be initiated by lysosomal enzymes released by the complement system, thrombin, or the kinins.

1. A family of low-molecular-weight proteins, the chemokines, may help control leukocyte chemotaxis.

2.MIP-1α, a member of the β chemokine subfamily, induces chemotaxis of monocytes, CD8+ T cells, CD4+ T cells, and B cells in vitro, and is an important mediator of virus-induced inflammation in vivo.

3.RANTES (“regulated on activation, normal T cell expressed and secreted”) is a potent chemoattractant chemokine (cytokine) for monocytes and T cells of the memory phenotype.

4.Mature erythrocytes escape into the surrounding tissue, pushed out of the blood vessels through

openings between the endothelial cells in a passive process called diapedesis.

F.PMNs (neutrophils; Fig. 1.3) are the main inflammatory cells in the acute phase of inflammation.

All blood cells originate from a small, common pool of multipotential hematopoietic stem cells. Regulation of the hematopoiesis requires locally specialized bone marrow stromal cells and a co-ordinated activity of a group of regulatory mole- cules—growth factors consisting of four distinct regulators known collectively as CSFs.

1.PMNs are born in the bone marrow and are considered “the first line of cellular defense.”

2.CSFs (glycoproteins that have a variable content of carbohydrate and a molecular mass of 18 to 90 kD) control the production, maturation, and function of

PMNs, macrophages, and eosinophils mainly, but also of megakaryocytes and dendritic cells.

Interleukin-8 (IL-8) induces PMN shape change, chemotaxis, granule release, and respiratory burst by binding to receptors of the seven transmembrane segment class. The oxidative bursts of human PMNs, which are critical to the inflammatory response, are mediated by a multicomponent nicotinamide-adenine dinucleotide phosphate hydrogenase (NADPH) oxidase regulated by the small guanosine triphosphatase (GTPase) Rac2.

3.PMNs are the most numerous of the circulating leukocytes, making up 50% to 70% of the total.

4.PMNs function at an alkaline pH and are drawn to a particular area by chemotaxis (e.g., by neutrophilic chemotactic factor produced by human endothelial cells).

5.The PMNs remove noxious material and bacteria by phagocytosis and lysosomal digestion (e.g., by

lysozyme, superoxide anion, N-chloramines, alkaline phosphatase, collagenase, and acyloxyacyl hydrolysis).

PMNs produce highly reactive metabolites, including hydrogen peroxide, which is metabolized to hypochlorous acid and then to chlorine, chloramines, and hydroxyl radicals, all important in killing microbes. Lysosomes are saclike cytoplasmic structures containing digestive enzymes and other polypeptides. Lysosomal dysfunction or lack of function has been associated with numerous heritable storage diseases: Pompe’s disease (glycogen storage disease type 2) has been traced to a lack of the enzymes α-1,4-glucosidase in liver lysosomes (see p. 454 in Chapter 11); Gaucher’s disease is caused by a deficiency of the lysosomal enzyme β-glucosidase (see p. 454, Table 11.5, in Chapter 11). Metachromatic leukodystrophy is caused by a deficiency of the lysosomal enzyme arylsulfa- tase-A (see p. 454, Table 11.5, in Chapter 11). Most of the common acid mucopolysaccharide, lipid, or polysaccharide storage diseases are caused by a deficiency of a lysosomal enzyme specific for the disease (see under appropriate diseases in Chapters 8 and 11). Chédiak– Higashi syndrome may be considered a general disorder of organelle formation (see section on congenital anomalies in Chapter 11) with abnormally large and fragile leukocyte lysosomes.

6.PMNs are end cells; they die after a few days and liberate proteolytic enzymes, which produce tissue necrosis.

G.Eosinophils and mast cells (basophils) may be involved in the acute phase of inflammation.

1.Eosinophils (Fig. 1.4) originate in bone marrow, constitute 1% to 2% of circulating leukocytes, increase in number in parasitic infestations and

A

C

allergic reactions, and decrease in number after steroid administration or stress.They elaborate toxic lysosomal components (e.g., eosinophil peroxidase) and generate reactive oxygen metabolites.

2.Mast cells (basophils; Fig. 1.5) elaborate heparin, serotonin, and histamine, and are imperative for the initiation of the acute inflammatory reaction.

Except for location, mast cells appear identical to basophils; mast cells are fixed-tissue cells, whereas basophils constitute approximately 1% of circulating leukocytes. Basophils are usually recognized by the presence of a segmented nucleus, whereas the nucleus of a mast cell is large and nonsegmented.

H.The acute phase is an exudative* phase (i.e., an outpouring of cells and fluid from the circulation) in which the nature of the exudate often determines and characterizes an acute inflammatory reaction.

1.Serous exudate is primarily composed of protein (e.g., seen clinically in the aqueous “flare” in the

*Exudation implies the passage of protein-containing fluid (and cells) through the opened endothelial vascular junctions into the surrounding tissue (inflammatory exudate). Transudation implies the passage of fluid through an intact vessel wall into the surrounding tissue so that its protein content is low or nil

(aqueous fluid).

B

Fig. 1.4 A, Eosinophils are commonly seen in allergic conditions like this case of vernal catarrh. B, Eosinophils are characterized by bilobed nucleus and granular, pink cytoplasm. C, Electron micrograph shows segmentation of nucleus and dense cytoplasmic crystalloids in many cytoplasmic storage granules. Some granules appear degraded.

anterior chamber or under the neural retina in a rhegmatogenous neural retinal detachment).

2.Fibrinous exudate (Fig. 1.6) has high fibrin content

(e.g., as seen clinically in a “plastic” aqueous).

3.Purulent exudate (see Figs 1.1 and 1.3) is composed primarily of PMNs and necrotic products (e.g., as seen in a hypopyon).

The term “pus” as commonly used is synonymous with a purulent exudate.

4.Sanguineous exudate is composed primarily of erythrocytes (e.g., as in a hyphema).

II.Subacute (intermediate or reactive countershock and adaptive) phase.†

A.The subacute phase varies greatly and is concerned with healing and restoration of normal homeostasis (formation of granulation tissue and healing) or with the exhaustion of local defenses, resulting in necrosis, recurrence, or chronicity.

†Although the immune reaction is described separately in this chapter, it is intimately related to inflammation, especially to this phase. Many of the processes described under the section on inflammation are a direct result of the immune process.

B.PMNs at the site of injury release lysosomal enzymes into the area.

1.The enzymes directly increase capillary permeability and cause tissue destruction.

2.Indirectly, they increase inflammation by stimulating mast cells to release histamine, by activating the kinin-generating system, and by inducing the chemotaxis of mononuclear (MN) phagocytes.

C.MN cells (Fig. 1.7) include lymphocytes and circulating monocytes.

1.Monocytes constitute 3% to 7% of circulating leukocytes, are bone marrow-derived, and are the progenitor of a family of cells (monocyte–histio- cyte–macrophage family) that have the same fundamental characteristics, including cell surface receptors for complement and the Fc portion of immunoglobulin, intracellular lysosomes, and specific enzymes; production of monokines; and phagocytic capacity.

2.Circulating monocytes may subsequently become tissue residents and change into tissue histiocytes, macrophages, epithelioid histiocytes, and inflammatory giant cells.

3.CSFs (glycoproteins that have a variable content of carbohydrate and a molecular mass of 18 to 90 kD) control the production, maturation, and function of

MN cells.

4.These cells are the “second line of cellular defense,” arrive after the PMN, and depend on release of chemotactic factors by the PMN for their arrival.

a.Once present, MN cells can live for weeks, and in some cases even months.

b.MN cells cause much less tissue damage than do

PMNs, are more e cient phagocytes, and produce IL-1, formerly called lymphocyteactivating factor.

5.Monocytes have an enormous phagocytic capacity and are usually named for the phagocytosed material [e.g., blood-filled macrophages (erythrophagocytosis), lipid-laden macrophages (Fig. 1.8), lens-filled macrophages (as in phacolytic glaucoma), and so forth].

D.Lysosmal enzymes, including collagenase, are released by PMNs, MN cells, and other cells (e.g., epithelial cells and keratocytes in corneal ulcers) and result in considerable tissue destruction.

In chronic inflammation, the major degradation of collagen may be caused by collagenase produced by lymphokine-acti- vated macrophages.

E.If the area of injury is tiny, PMNs and MN cells alone can handle and “clean up” the area with resultant healing.

F.In larger injuries, granulation tissue is produced.

1.Granulation tissue (Fig. 1.9) is composed of leukocytes, proliferating blood vessels, and fibroblasts.

2.MN cells arrive after PMNs, followed by an ingrowth of capillaries that proliferate from the endothelium of pre-existing blood vessels.

The new blood vessels tend to leak fluid and leukocytes, especially PMNs.

3.Fibroblasts (see Fig. 1.9), which arise from fibrocytes and possibly from other cells (monocytes),

proliferate, lay down collagen (Table 1.1), and elaborate ground substance.

4.With time, the blood vessels involute and disappear, the leukocytes disappear, and the fibroblasts return to their resting state (fibrocytes). This involutionary process results in shrinkage of the collagenous scar and a reorientation of the remaining cells into a parallel arrangement along the long axis of the scar.

5.If the noxious agent persists, the condition may not heal as described previously,but instead may become chronic.

6.If the noxious agent that caused the inflammation is immunogenic, a similar agent introduced at a future date can start the cycle anew (recurrence).

III.Chronic phase

A.The chronic phase results from a breakdown in the preceding two phases, or it may start initially as a chronic inflammation (e.g., when the resistance of the body and the inroads of an infecting agent, such as

the organisms of tuberculosis or syphilis, nearly balance; or in conditions of unknown cause such as sarcoidosis).

B.Chronic nongranulomatous inflammation is a proliferative inflammation characterized by a cellular infiltrate of lymphocytes and plasma cells (and sometimes PMNs or eosinophils).

1.The lymphocyte (Fig. 1.10) constitutes 15% to 30% of circulating leukocytes and represents the competent immunocyte.

a.All lymphocytes probably have a common stem cell origin (perhaps in the bone marrow) from which they populate the lymphoid organs: the thymus, spleen, and lymph nodes.

b.Two principal types of lymphocytes are recognized: (1) the bone marrow-dependent (or bursal equivalent) B lymphocyte is active in humoral immunity, is the source of immunoglobulin production (Fig. 1.11), and is identified by the presence of immunoglobulin on its surface; (2) the

thymus-dependent T lymphocyte participates in cellular immunity, produces a variety of lymphokines, and is identified by various surface antigens (e.g., the antigen common to T cells, T3, and well as T4, T8, and particularly the antigen representing the erythrocyte-rosette receptor, T11).

1)Helper-inducer T lymphocytes (T4-positive) initiate the immune response in conjunction with macrophages and interact with (helper) B lymphocytes.

T-helper 1 (TH1) and T-helper 2 (TH2) cells secrete a distinctive suite of cytokines: TH1 produces predominantly cell-mediated immunity (e.g., cytotoxic T-cell response); TH2 produces particular classes of immunoglobulin antibodies. For CD4 T cells to be activated, they need to receive signals from mature dendritic cells in peripherals lymphoid organize. TH1 immunity protects against intracellular

Fig. 1.11 The basic immunoglobulin structure. The unit consists of two identical light polypeptide chains linked together by disulfide bonds (black). The amino-terminal end (N) of each chain is characterized by sequence variability (VL, VH), whereas the remainder of the molecule has a relatively constant structure (CL, CH1–CH3). The antigen-binding sites are located at the N-terminal end. (Adapted with permission from Roitt IM, Brostoff J, Male DK: Immunology, 2nd edn. London, Gower Medical. Copyright Elsevier 1989.)

parasites (e.g., Leishmania), and TH2 immunity protects against extracellular parasites (e.g., nemotodes).

2)Suppressor-cytotoxic T lymphocytes (T8positive) suppress the immune response and are capable of killing target cells (e.g., cancer cells) through cell-mediated cytotoxicity.

2.The plasma cell (Fig. 1.12) is produced by the bone marrow-derived B lymphocyte, elaborates immunoglobulins (antibodies), and occurs in certain modified forms in tissue sections.

After germinal center B cells undergo somatic mutation and antigen selection, they become either memory B cells or plasma cells. CD40 ligand directs the differentiation of germinal center B cells toward memory B cells rather than toward plasma cells.

a.Plasmacytoid cell (Fig. 1.13A and B): this has a single eccentric nucleus and slightly eosinophilic granular cytoplasm (instead of the normal basophilic cytoplasm of the plasma cell).

b.Russell body (see Fig. 1.13C and D): this is an inclusion in a plasma cell whose cytoplasm is filled and enlarged with either eosinophilic grapelike clusters (morular form), with single eosinophilic globular structures, or with eosinophilic crystalline structures; usually the nucleus appears as an eccentric rim or has disappeared.

The eosinophilic material in plasmacytoid cells and in Russell bodies appears to be immunoglobulin that has become inspissated, as if the plasmacytoid cells can no longer release the material because of defective transport by the cells (“constipated” plasmacytoid cells). In addition, as has been shown in Russell bodies in B-cell lymphoma cells, other glycoprotein accumulations may be found (e.g., CD5, CD19, CD22, CD25, and Leu 8).

C.Chronic granulomatous inflammation is a proliferative inflammation characterized by a cellular infiltrate of lymphocytes and plasma cells (and sometimes PMNs or eosinophils).

1.Epithelioid cells (epithelioid histiocytes, Fig. 1.14) are bone marrow-derived cells in the monocyte– histiocyte–macrophage family (Fig. 1.15)

a.In particular, epithelioid cells are tissue monocytes that have abundant eosinophilic cytoplasm, somewhat resembling epithelial cells.

b.They are often found oriented around necrosis as large polygonal cells that contain pale nuclei

and abundant eosinophilic cytoplasm whose borders blend imperceptibly with those of their neighbors in a pseudosyncytium (“palisading” histiocytes in a granuloma).

c.All cells of this family interact with T lymphocytes, are capable of phagocytosis, and are identified by the presence of surface receptors for complement and the Fc portion of immunoglobulin.

Fig. 1.14 Epithelioid cells in conjunctival, sarcoidal granuloma, here forming three nodules, which are identified by eosinophilic color resembling epithelium. Giant cells, simulating Langhans’ giant cells, are seen in nodules.