I. Noninfectious causes

A. Exogenous causes: originate outside the eye and body, and include local ocular physical injury (e.g., perforating trauma), chemical injuries (e.g., alkali), or allergic reactions to external antigens (e.g., conjunctivitis secondary to pollen).

B. Endogenous causes: sources originating in the eye and body, such as inflammation secondary to cellular immunity [phacoanaphylactic endophthalmitis (phacoantigenic uveitis)]; spread from continuous structures (e.g., the sinuses); hematogenous spread (e.g., foreign particles); and conditions of unknown cause (e.g., sarcoidosis).

II. Infectious causes include viral, rickettsial, bacterial, fungal, and parasitic agents.

I. Acute (immediate or shock) phase (Fig. 1.1)

A. Five cardinal signs: (1) redness (rubor) and (2) heat (calor)—both caused by increased rate and volume of blood flow; (3) mass (tumor)—caused by exudation of fluid (edema) and cells; (4) pain (dolor) and (5) loss of function (functio laesa)—both caused by outpouring of fluid and irritating chemicals. Table 1.2 lists the roles of various mediators in the inflammatory reaction.

B. The acute phase is related to histamine release from mast cells and factors released from plasma (kinin, complement, and clotting systems).

1. Histamine is found in the granules of mast cells, where it is bound to a heparin–protein complex. Serotonin (5-hydroxytryptamine), found in platelets and some neuroendocrine cells, has a similar effect to histamine.

2. The kinins are peptides formed by the enzymatic action of kallikrein on the α₂-globulin kininogen. Kallikrein is activated by factor XIIa, which is the active form of the coagulation factor XII (Hageman factor). Factor XIIa converts plasma prekallikrein into kallikrein. Plasmin also can activate Hageman factor.

3. Plasmin, the proteolytic enzyme responsible for fibrinolysis, has the capacity to liberate kinins from their precursors and to activate kallikrein, which brings about the formation of plasmin from plasminogen. Plasmin also cleaves C3 complement protein, resulting in the formation of C3 fragments. It also breaks down fibrin to form fibrin split products.

4. The complement system consists of 35–40 proteins present in blood plasma or on cell surfaces. More than 45 genes encode proteins of complement components or related receptors, etc. Complement achieves its effect through a cascade of the separate components working in special sequences (Fig. 1.2).

a. Major roles in immune defense against microorganisms and in clearing damaged host components.

b. Complement proteins opsonize or lyse cells so they may injure healthy tissue, particularly when there is a defect in complement regulation.

1) Important in such diseases as macular degeneration, rheumatoid arthritis, multiple sclerosis, Alzheimer’s disease, schizophrenia, and angioedema.

2) C3 has a major role in complement activation and generation of immune responses.

c. System, components and their genetic deficiency.

1) Deficiency of early components of the classical pathway (C1q, C1r/s, C2, C4, and C3) is associated with autoimmune diseases resulting from failure of clearance of immune complexes and apoptotic materials and impairment of humoral response.

2) Deficiencies of mannan-binding lectin and the early components of the alternative (factor D and properdin) and terminal pathways (from C3 onward components C5, C6, C7, C8, and C9) increase susceptibility to infections and to their recurrence.

5. Prostaglandins (prostanoids), which have both inflammatory and anti-inflammatory effects, are 20-carbon, cyclical, unsaturated fatty acids with a 5-carbon ring and two aliphatic side chains.

a. They are produced by mast cells, macrophages, endothelial cells, and others.

b. With leukotrienes, they are designated eicosanoids. Leukotrienes are metabolized through the lipoxygenase pathway and prostaglandins through the cyclooxygenase pathway.

c. Active in vascular and systemic reactions of inflammation, oxidative stress, and physiologic functions.

d. Cyclooxygenase helps catalyze the biosynthesis of prostaglandins from arachidonic acid.

e. Prostaglandins, cytokines, and leukotrienes function to dilate lymphatics at a site of injury.

f. Prostaglandins play an important role in nociception and pain.

6. Major histocompatibility complex (MHC), called the human leukocyte antigen (HLA) complex in humans, is critical to the immune response.

a. HLAs are present on all nucleated cells of the body and platelets.

b. The three genetic loci belonging to HLA class I are designated by the letters HLA-A, HLA-B, and HLA-C. Class II MHC molecules are encoded at the locus HLA-D with three subregions HLA-DP, HLA-DQ   , and HLA-DR.

1) Class I MHC molecules display proteins derived from foreign antigens, which are recognized by CD8⁺ T lymphocytes.

2) Class II MHC molecules present antigens that are contained in intracellular vesicles and derived from foreign organisms and soluble proteins.

c. A tentatively identified specificity carries the additional letter “W” (workshop) and is inserted between the locus letter and the allele number—for example, HLA-BW 15.

d. The HLA system is the main human leukocyte isoantigen system and the major human histocompatibility system.

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.

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 affect the regulation of inflammatory and immune responses.

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 five minutes) and then gradually relax and dilate because of the chemical mediators discussed previously and from antidromic axon reflexes.

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 2–12 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.

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

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 18–90 kDa) control the production, maturation, and function of PMNs, macrophages, and eosinophils mainly, but also of megakaryocytes and dendritic cells.

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

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 or 2% of circulating leukocytes, increase in number in parasitic infestations and 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 they are imperative for the initiation of the acute inflammatory reaction.

H. The acute phase is an exudative² 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 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).

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

II. Subacute (intermediate or reactive countershock and adaptive) phase³

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.

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

1. Monocytes constitute 3–7% of circulating leukocytes, are bone marrow-derived, and are the progenitor of a family of cells (monocyte–histiocyte–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 18–90 kDa) 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, and they are more efficient phagocytes.

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

6. Monocytes replace neutrophils as the predominate cell 24–48 hours after the onset of inflammation.

D. Lysosomal 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.

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.

3. Fibroblasts (see Fig. 1.9), which arise from fibrocytes and possibly from other cells (monocytes), proliferate, lay down collagen (Table 1.3), 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 15–30% 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.

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

2) Suppressor-cytotoxic T lymphocytes (T8-positive) suppress the immune response and are capable of killing target cells (e.g., cancer cells) through cell-mediated cytotoxicity.

3) MHC molecules present antigenic peptides to CD8⁺ T cells, thereby providing the foundation for immune recognition.

2. The plasma cell (Fig. 1.13) is produced by the bone marrow-derived B lymphocyte, elaborates immunoglobulins (antibodies), and occurs in certain modified forms in tissue sections.

a. Plasmacytoid cell (Fig. 1.14A 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. 1.14C and D): This is an inclusion in a plasma cell whose cytoplasm is filled and enlarged with 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.

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 (Fig. 1.15) are bone marrow-derived cells in the monocyte–histiocyte–macrophage family (Fig. 1.16).

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.

2. Inflammatory giant cells, probably formed by fusion of macrophages rather than by amitotic division, predominate in three forms:

a. Langhans’ giant cell (Fig. 1.17; see Fig. 1.15): This is typically found in tuberculosis, but it is also seen in many other granulomatous processes. When sectioned through its center, it shows a perfectly homogeneous, eosinophilic, central cytoplasm with a peripheral rim of nuclei.

b. Foreign-body giant cell (Fig. 1.18): This has its nuclei randomly distributed in its eosinophilic cytoplasm and contains foreign material.

c. Touton giant cell (Fig. 1.19), frequently associated with lipid disorders such as juvenile xanthogranuloma, appears much like a Langhans’ giant cell with the addition of a rim of foamy (fat-positive) cytoplasm peripheral to the rim of nuclei.

3. Three patterns of inflammatory reaction may be found in granulomatous inflammations:

a. Diffuse type (Fig. 1.20A): This typically occurs in sympathetic uveitis, disseminated histoplasmosis and other fungal infections, lepromatous leprosy, juvenile xanthogranuloma, Vogt–Koyanagi–Harada syndrome, cytomegalic inclusion disease, and toxoplasmosis. The epithelioid cells (sometimes with macrophages or inflammatory giant cells or both) are distributed randomly against a background of lymphocytes and plasma cells.

b. Discrete type (sarcoidal or tuberculocidal; see Fig. 1.20B): This typically occurs in sarcoidosis, tuberculoid leprosy, and miliary tuberculosis. An accumulation of epithelioid cells (sometimes with inflammatory giant cells) forms nodules (tubercles) surrounded by a narrow rim of lymphocytes (and perhaps plasma cells).

c. Zonal type (see Fig 1.20C): This occurs in caseation tuberculosis, some fungal infections, rheumatoid scleritis, chalazion, phacoanaphylactic (phacoantigenic) endophthalmitis, toxocara endophthalmitis, and cysticercosis.

1) A central nidus (e.g., necrosis, lens, and foreign body) is surrounded by palisaded epithelioid cells (sometimes with PMNs, inflammatory giant cells, and macrophages) that in turn are surrounded by lymphocytes and plasma cells.

2) Granulation tissue often envelops the entire inflammatory reaction.