White blood cells, or leukocytes, include several kinds of nucleated cells that can be distinguished by the shape of their nuclei and the presence or absence of cytoplasmic granules, as well as by their uptake of various histologic stains. They can be broadly divided into 2 subsets:
myeloid (neutrophils, eosinophils, basophils and mast cells, monocytes and macrophages, and dendritic cells and Langerhans cells)
lymphoid (T lymphocytes, B lymphocytes, and natural killer cells)
Neutrophils possess a multilobed nucleus of varying shapes; hence, they are also called polymorphonuclear leukocytes (PMNs). Neutrophils also feature cytoplasmic granules and lysosomes and are the most abundant granulocytes in the blood. They are efficient phagocytes that readily clear tissues, degrade ingested material, and act as important effector cells through the release of granule products and cytokines.
During the beginning or acute phases of inflammation, neutrophils are one of the first inflammatory cells to migrate from the bloodstream toward the site of inflammation. This process is called chemotaxis. Neutrophils dominate the inflammatory infiltrate in experimental models and clinical examples of active bacterial infections of the conjunctiva (conjunctivitis), sclera (scleritis), cornea (keratitis), and vitreous (endophthalmitis). They are also dominant in many types of active viral infections of the cornea (eg, herpes simplex virus keratitis) and retina (eg, herpes simplex virus retinitis). Neutrophils constitute the principal cell type in ocular inflammation induced by lipopolysaccharides (discussed later) or by direct injection of most cytokines into ocular tissues.
Eosinophils are characterized by the presence of abundant lysosomes and cytoplasmic granules that consist of more basic protein than other polymorphonuclear leukocytes, (thus acidic dyes, such as eosin, will bind to these proteins.) Eosinophils have receptors for, and become activated by, many mediators; interleukin-5 (IL-5) is especially important. Eosinophilic granule products, such as major basic protein and ribonucleases, destroy parasites efficiently; thus, these cells accumulate at sites of parasitic infection. Eosinophils are also important in allergic immune reactions.
Eosinophils are abundant in the conjunctiva and tears in many forms of allergic conjunctivitis, especially atopic and vernal conjunctivitis. They are not considered major effectors for intraocular inflammation, with the notable exception of helminthic infections of the eye, especially toxocariasis.
Basophils and mast cells
Basophils are the blood-borne equivalent of the tissue-bound mast cell. Mast cells exist in 2 major subtypes, connective tissue and mucosal, both of which can release preformed granules and synthesize certain mediators de novo that differ from those of neutrophils and eosinophils. Connective tissue mast cells contain abundant granules with histamine and heparin, and they synthesize prostaglandin D2 upon stimulation. In contrast, mucosal mast cells normally contain low levels of histamine and require T-cell–derived growth-promoting cytokines for stimulation. Stimulated mucosal mast cells primarily synthesize leukotrienes, mainly leukotriene C4. Tissue location can alter the granule type and functional activity, but regulation of these differences is not well understood.
Mast cells act as major effector cells in immunoglobulin E (IgE)–mediated, immunetriggered inflammatory reactions, especially of the allergic or immediate hypersensitivity type. They perform this function through their expression of high-affinity Fc receptors for IgE. Fc (from “fragment, crystallizable”) refers to the constant region of immunoglobulin that binds cell surface receptors (see Chapter 2). Mast cells may also participate in the induction of cell-mediated immunity, wound healing, and other functions not directly related to IgE-mediated degranulation. Other stimuli, such as complement or certain cytokines, may also trigger degranulation.
The healthy human conjunctiva contains numerous mast cells localized in the substantia propria. In certain atopic and allergic disease states, such as vernal conjunctivitis, the number of mast cells increases in the substantia propria, and the epithelium—usually devoid of mast cells—becomes densely infiltrated. The uveal tract also contains numerous connective tissue–type mast cells, whereas the cornea has none.
Monocytes and macrophages
Monocytes, the circulating cells, and macrophages, the tissue-infiltrating equivalents, are important effectors in innate and adaptive immunity. They are often detectable in acute ocular infections, even if other cell types, such as neutrophils, are more numerous. Monocytes are relatively large cells (12–20 μm in suspension and up to 40 μm in tissues) that normally travel throughout the body. Most tissues have at least 2 identifiable macrophage populations: tissue resident and blood derived. Although exceptions exist, tissue-resident macrophages are monocytes that migrated into tissue during embryologic development and later acquired tissue-specific properties and cellular markers. Various resident macrophages have tissue-specific names (ie, Kupffer cells in the liver, alveolar macrophages in the lung, and microglia in the brain and retina). Blood-derived macrophages are monocytes that have recently migrated from the blood into a fully developed tissue site.
Macrophages may serve in 3 capacities:
sentinels that recognize danger signals from pathogens and/or tissue damage
effectors that induce inflammation and fight pathogens directly
regulatory/repair cells that conduct tissue repair, regulate the adaptive immune system, and serve as checkpoints during immune cell migration
Various signals can prime resting monocytes into efficient antigen-presenting cells (APCs) and, upon additional signals, activate them into effector cells. Effective activation stimuli include exposure to bacterial products, such as lipopolysaccharide (LPS); phagocytosis of antibody-coated or complement-coated pathogens; or exposure to mediators released during inflammation, such as interleukin-1 (IL-1) or interferon gamma (IFN-γ).
Only after full activation do macrophages become most efficient at the synthesis and release of inflammatory mediators and the killing and degradation of phagocytosed pathogens. Macrophages may undergo activation into epithelioid cells, with larger nuclei, abundant cytoplasm, and indistinct cell borders, resembling squamous epithelium. These epithelioid histiocytes are characteristic of granulomatous inflammation, either in infectious uveitis (ie, tuberculosis, syphilis, herpesviruses, fungi, parasitic uveitis) or noninfectious uveitis (ie, sarcoidosis, rheumatoid arthritis, granulomatosis with polyangiitis). Macrophages may also be activated to fuse into multinucleated giant cells, which may accompany granulomatous inflammation or occur in the tissue reaction to foreign material.
Dendritic cells and Langerhans cells
Dendritic cells (DCs) are terminally differentiated, bone marrow–derived, mononuclear cells that are distinct from macrophages and monocytes. These specialized cells bridge the innate and adaptive immune systems, but do not directly participate in effector activities. DCs use pattern recognition receptors, such as Toll-like receptors (TLRs), to recognize pathogens. Activated DCs upregulate costimulatory molecules and produce cytokines to drive T-cell priming and effector differentiation as well as activate various types of immune cells. Interestingly, antigen presentation by nonactivated, steady-state DCs might lead to T-cell unresponsiveness, promoting tolerance. All human DCs express high levels of major histocompatibility (MHC) class II (HLA-DR) molecules and may be classified by lineage markers as myeloid/classical or plasmacytoid. Dendritic cells can also be classified functionally and anatomically, as their function is linked to their location:
Blood DCs are precursors of tissue and lymphoid organ DCs.
Migratory or tissue DCs reside in most epithelial tissues, where they acquire antigen and migrate via afferent lymphatics to lymph nodes. In tissue sites, DCs are enlarged (15–30 μm), with cytoplasmic veils that form extensions 2–3 times the diameter of the cell and resemble the dendritic structure of neurons.
Resident or lymphoid DCs arise in lymph nodes directly from blood.
Inflammatory DCs are in tissues and lymphoid organs during inflammation. Precursors include classical monocytes.
Langerhans cells (LCs) are myeloid cells with dendritic cell function that reside in the epidermis and stratified epithelia of the conjunctival, corneal, buccal, gingival, and genital mucosae. LCs are identified by their many dendrites, electron-dense cytoplasm, and Birbeck granules. Interestingly, they originate from primitive hematopoiesis in the yolk sac and form a stable, self-renewing network that does not require bone marrow–derived precursors in the absence of inflammation. At rest, they are not active APCs, but activity develops after in vitro culture with specific cytokines. On activation, LCs lose their granules and transform to resemble blood and lymphoid DCs. Evidence suggests that LCs migrate along the afferent lymph vessels to the draining lymphoid organs. LCs are important components of the immune system and play roles in antigen presentation, control of lymphoid cell traffic, differentiation of T lymphocytes, and induction of delayed hypersensitivity. Elimination of LCs from skin before an antigen challenge inhibits induction of the contact hypersensitivity response. In the conjunctiva and limbus, LCs are the only cells that constitutively express MHC class II molecules. LCs are present in the peripheral cornea, and any stimulation to the central cornea results in central migration of the peripheral LCs.
Lymphocytes are small (10–20 μm) cells with large, round, and dense nuclei. They are also derived from stem cell precursors within the bone marrow; however, unlike other leukocytes, lymphocytes require subsequent maturation in peripheral lymphoid organs. The expression of specific cell-surface proteins (ie, surface markers) can subdivide lymphocytes. These markers are in turn related to the functional and molecular activity of individual subsets. Three broad categories of lymphocytes are T lymphocytes; B lymphocytes; and non-T, non-B lymphocytes. Two types of lymphocytes participate in the innate immune response, serving as a bridge between innate and adaptive responses: (1) gammadelta (γδ) T cells or sentinel T cells, also known as intraepithelial lymphocytes, and (2) natural killer (NK) cells, a subset of non-T, non-B lymphocytes. Chapter 2 discusses the roles of lymphocytes in adaptive immunity.
Excerpted from BCSC 2020-2021 series: Section 9 - Uveitis and Ocular Inflammation. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.