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

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

a.Langhans’ giant cell (Fig. 1.16; see Fig. 1.14): this is typically found in tuberculosis, but 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.

It is important to note that the central cytoplasm is perfectly homogeneous. If it is not, foreign material such as fungi may be present: the cell is then not a Langhans’ giant cell but a foreign-body giant cell. When a Langhans’ giant cell is sectioned through its periphery, it simulates a foreign-body giant cell.

b.Foreign-body giant cell (Fig. 1.17): this has its nuclei randomly distributed in its eosinophilic cytoplasm and contains foreign material.

Fig. 1.16 Langhans’ giant cells have homogeneous central cytoplasm surrounded by rim of nuclei.

c.Touton giant cell (Fig. 1.18): this is frequently associated with lipid disorders such as juvenile xanthogranuloma; it 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.Di use type (Fig. 1.19A): this typically occurs in sympathetic uveitis, disseminated histoplasmosis and other fungal infections, lepromatous leprosy, juvenile xanthogranuloma, Vogt–Koy- anagi–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. 1.19B): 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 1.19C): this occurs in caseation tuberculosis, some fungal infections, rheumatoid scleritis, chalazion, phacoanaphylactic (phacoimmune) endophthalmitis, toxocara endophthalmitis, and cysticercosis.

1)A central nidus (e.g., necrosis, lens, 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.

Staining Patterns of Inflammation

I.Patterns of inflammation are best observed microscopically under the lowest (scanning) power.

II.With the hematoxylin and eosin (H&E) stain, an infiltrate of deep blue (basophilia) usually represents a chronic non-

granulomatous inflammation. The basophilia is produced by lymphocytes that have blue nuclei with practically no cytoplasm, and by plasma cells that have blue nuclei and blue cytoplasm.

III.A deep blue infiltrate with scattered gray (pale pink) areas (“pepper and salt”) usually represents a chronic

granulomatous inflammation, with the blue areas lymphocytes and plasma cells, and the gray areas islands of epithelioid cells.

IV. A “dirty” gray infiltrate usually represents a purulent reaction with PMNs and necrotic material.

A.If the infiltrate is di use [Fig. 1.20; e.g., filling the vitreous (vitreous abscess)], the cause is probably bacterial.

B.If the infiltrate is localized into two or more small areas (Fig. 1.21; i.e., multiple abscesses or microabscesses), the cause is probably fungal.

IMMUNOBIOLOGY

Background

I.Many reactions in cellular immunity are mediated by lym- phocyte-derived soluble factors known collectively as lym-

phokines, which exert profound e ects on inflammatory cells such as monocytes, neutrophils, and lymphocytes themselves. Such action falls into three main categories:

(1) e ects on cell motility (migration inhibition, chemotaxis, and chemokinesis); (2) e ects on cell proliferation or cellular viability; and (3) e ects on cellular activation for specific specialized functions.

The immune system provides the body with a mechanism to distinguish “self” from “nonself.” The distinction, made after a complex, elaborate process, ultimately relies on receptors on the only immunologically specific cells of the immune system, the B and T lymphocytes.

II.All lymphocytes in mammalian lymph nodes and spleen have a remote origin in the bone marrow: those that have undergone an intermediate cycle of proliferation in the thymus (thymus-dependent, or T lymphocytes) mediate cellular immunity, whereas those that seed directly into lymphoid tissue (thymus-independent, or B lymphocytes)

provide the precursors of cells that produce circulating antibodies.

The Janus family tyrosine kinase, Jak3, is essential for lymphoid development. B and T lymphocytes are quiescent until called on by a specific, unique antigen to proliferate into a clonal population. Once the antigen is eliminated, excess B and T cells are removed by apoptosis (programmed cell death), thereby keeping the total number of B and T cells in correct balance.

A.Thus, mediators of immune responses can be either specifically reactive lymphocytes (cell-mediated immunity) or freely di usible antibody molecules (humoral immunity).

B.Antibody-producing B cells or killer T-type cells are only activated when turned on by a specific antigen.

When an antigen (immunogen) penetrates the body, it binds to an antibodylike receptor on the surface of its corresponding lymphocyte that proliferates and generates a clone of differentiated cells. Some of the cells (large B lymphocytes and plasma cells) secrete antibodies, T cells secrete lymphokines, and other lymphocytes circulate through blood, lymph, and tissues as an expanded reservoir of antigen-sensitive (memory) cells. When the immunogen encounters the memory cells months or years later, it evokes a more rapid and copious secondary anamnes-

tic response. Other immune cells (e.g., NK) are less specific and eliminate a variety of infected or cancerous cells.

III.T lymphocytes derive from lymphoid stem cells in the bone marrow and mature under the influence of the thymus.

Interactions between immature thymocytes and thymic stromal cells expressing CD81 appear to be required for T-cell development.

A.T lymphocytes are identified by surface antigens (T3,

T4, T8, T11).

1.T lymphocytes are divided into two major subsets that express either CD4 or CD8 protein on their surface.

2.ZAP-70, a 70-kD cytosolic T-cell tyrosine kinase, is essential for human T-cell function, and CD4+ and CD8+ T cells depend on di erent signaling pathways to support their development and survival.

B.T lymphocytes are the predominant lymphocytes in the peripheral blood and reside in well-defined interfollicular areas in lymph nodes and spleen.

C.The T-lymphocyte system is responsible for the recognition of antigens on cell surfaces and, thus, monitors self from nonself on live cells (Fig. 1.22).

D.The MHC (HLA) allows T cells to recognize foreign antigen in cells and then, aided by macrophages, mobilizes helper T cells to make killer T cells to destroy the antigen-containing cells.

The chemokine RANTES can act as an antigen-independent activator of T cells in vitro.

E.T lymphocytes, therefore, initiate cellular immunity (delayed hypersensitivity), are responsible for graft-

versus-host reactions, and initiate the reactions of the body against foreign grafts such as skin and kidneys

(host-versus-graft reactions).

F.When activated (by an antigen), they liberate lymphokines such as macrophage inhibition factor (MIF),

macrophage activation factor (MAF), IFN, and interleukins IL-2 (previously called T-cell growth factor), IL-3, and IL15 (Fig. 1.23).

1.Activation of peripheral T cells by an antigenpresenting cell is the result of the engagement of both the T-cell receptor and CD4 or CD8 coreceptors, and of receptor–ligand pairs, such as LFA-1–

intracellular adhesion molecule, CD2–CD48, and

CD28–CD80.

Cytokine Eta-1 (also called osteopontin), a gene product, may play an important role in the early development of cell-mediated (type 1) immunity.

2.When both the CD3 T-cell receptor and the CD28 receptor are occupied by their appropriate ligands,

T cells are stimulated to proliferate and produce Il-2, whereas occupation of the T-cell receptor alone favors T-cell anergy or apoptosis.

The proliferation and differentiation of T lymphocytes are regulated by cytokines that act in combination with signals induced by the engagement of the T-cell antigen receptor. A principal cytokine is IL-2, itself a product of activated T cells. IL-2 also stimulates B cells, monocytes, lymphokine-activated killer cells, and glioma cells. Another growth factor that stimulates the proliferation of T lymphocytes, the cytokine IL-15, competes for binding with IL-2 and uses components of the IL-2 receptor. T lymphocytes will not go “into action” against an “enemy” unless they are triggered by several signals at once. When one of the signals needed is lacking, the T cell becomes “paralyzed” (anergy). The cause for the anergy may lie in a block early in the Ras signal pathway. For CD4 T cells to be acti-

vated, they need to receive signals from mature dendritic cells in peripheral lymphoid organs.

G.T lymphocytes also regulate B-cell responses to antigens by direct contact and by the release of di usible factors that act as short-range stimulators of nearby B cells.

IV. The B lymphocyte also arises from lymphoid stem cells in the bone marrow, but is not influenced by the thymus.

A.It resides in follicular areas in lymphoid organs distinct from the sites of the T lymphocyte.

B.The B-lymphocyte system is characterized by an enormous variety of immunoglobulins having virtually all conceivable antigenic specificities that are capable of being recognized by at least a few B-lymphocyte clones.

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.

C.The system is well designed to deal with unpredictable and unforeseen microbial and toxic agents.

D.The B lymphocyte can be stimulated by antigen to enlarge, divide, and di erentiate to form antibodysecreting plasma cells (Fig. 1.24).

Under most circumstances, T lymphocytes collaborate with B lymphocytes during the induction of antibody-forming cells by the latter (see section on humoral immunoglobulin, later).

V.Null lymphocytes, which constitute approximately 5% of lymphocytes in peripheral blood, lack the surface markers used to identify T and B lymphocytes.

A.Most mull cells carry a surface receptor for the Fc portion of the immunoglobulins, can function as killer

cells in antibody-dependent cell-mediated cytotoxicity, and are called NK cells.

B.NK cells are probably a separate lineage of cells.

VI. Initially, the sheep red blood cell resetting test (especially with fixed, embedded tissue) and the immunofluorescence or immunoperoxidase techniques that demonstrate surface immunoglobulins were the principal techniques for identification of T or B lymphocytes, respectively.

A.Now, monoclonal antibodies (especially with fresh tissue) are used for the localization of lymphocyte subsets in tissue sections, and their use has revolutionized research in immunology, cell biology, molecular genetics, diagnosis of infectious diseases, tumor diagnosis, drug and hormone assays, and tumor therapy.

B.A myriad of di erent types of monoclonal antibodies now exist, and new ones are continuously being created.

C.Monoclonal antibodies can be obtained against B and

T lymphocytes, monocytes, Langerhans’ cells, keratins, type IV collagen, retinal proteins (e.g., human s-100), and tumor antigens (e.g., factor VIII, intermediate

filaments—cytokeratins, vimentin, desmin, neurofilaments, and glial filaments—neuron-specific enolase, and glial fibrillary acidic protein; all may be found in tumors).

Cellular Immunity (Delayed Hypersensitivity)*

I.Two distinct cell types participate in cellular immunity: the

T lymphocyte and the macrophage (histiocyte).

A.Phagocytic cells of the monocytic line (monocytes, reticuloendothelial cells, macrophages, Langerhans’ dendritic cells, epithelioid cells, and inflammatory giant cells—all are di erent forms of the same cell) are devoid of antibody and immunologic specificity.

1.Macrophages, however, have the ability to process proteins (antigens) and activate the helper T cells.

2.Macrophages also secrete proteases, complement proteins, growth-regulating factors (e.g., IL-1), and arachidonate derivatives.

B.All lymphocytes seem to be precommitted to make only one type of antibody, which is cell-bound.

II.The delayed hypersensitivity reaction begins with perivenous accumulation of sensitized lymphocytes and other MN cells (i.e., monocytes, which constitute 80% to 90% of the cells mobilized to the lesion). The infiltrative lesions enlarge and multiply (e.g., in tuberculosis, where the lesions

*The terms cellular immunity and hypersensitivity are synonymous.

take a granulomatous form), and cellular invasion and destruction of tissue occur.

III.Delayed hypersensitivity is involved in transplantation immunity, in the pathogenesis of various autoimmune diseases (e.g., sympathetic uveitis), and in defense against most viral, fungal, protozoal, and some bacterial diseases

(e.g., tuberculosis and leprosy). Perhaps the most important role is to act as a natural defense against cancer, i.e., the immunologic rejection of vascularized tumors and immunologic surveillance of neoplastic cells.

Humoral Immunoglobulin (Antibody)

I.Four distinct cell types participate in humoral immunoglobulin (antibody) formation: the T lymphocyte, the B lymphocyte, the monocyte (macrophage), and the plasma cell.

A.Macrophages process antigen in the early stage of the formation of cellular immunity and secrete IL-1.

B.Specifically precommitted cells of both the T and B lymphocytes attach to di erent determinants of the antigen; T cells then secrete a B-cell growth factor

(BCGF).

C.BCGF and IL-1 evoke division of triggered B cells, which then di erentiate and proliferate into plasma cells that elaborate specific immunoglobulins. All humoral immunoglobulins (antibodies) are made up of multiple polypeptide chains and are the predominant mediators of immunity in certain types of infection, such as acute bacterial infection (caused by streptococci

and pneumococci) and viral diseases (hepatitis).

II.The B lymphocyte, once a specific antigen causes it to become committed (sensitized) to produce an immunoglobulin, makes that immunoglobulin and none other, as does its progeny. It, or its progeny, may produce immunoglobulin or become a resting memory cell to be reactivated at an accelerated rate (anamnestic response) if confronted again by the same antigen.

Immunohistochemistry

I.As stated previously, monoclonal antibodies can be obtained against B and T lymphocytes, monocytes, Langerhans’ cells, keratins, type IV collagen, retinal proteins, and so forth (Figs 1.25 and 1.26).

A.Keratin and epithelial membrane antigen are markers for epithelia.

B.Factor VIII and Ulex europaeus-1 are markers for vascular endothelia.

C.Intermediate filaments: vimentin is a marker for mesen-

chymal cells, including smooth muscle, Schwann cells, histiocytes, and fibrocytes; desmin is a marker for smooth and striated muscles; cytokeratin is a marker for

epithelia; neurofilament is a marker for neurons; and glial fibrillary acidic protein is a marker for astrocytes and

Schwann cells.

D. Neuron-specific enolase is a marker for Schwann cells, neurons, smooth muscle, and neuroendocrine cells.

E.S-100 and antimelanoma antigen are markers for melanin-containing and neural tissue.

F.Muscle actin is a marker for smooth and striated muscles; smooth-muscle actin for smooth muscles.

G.Ubiquitin is a marker for lymphocyte-homing receptor.

H.Many antibodies are available for immunophenotyping of lymphomas and leukemias, both on fresh and para n-embedded tissue—the following are a few examples:

1.In non-Hodgkin’s lymphoma, markers are available to diagnose both B-cell and T-cell lymphomas.

In B-cell lymphoma, the determination of surface immunoglobulin light-chain restriction by either immunofluorescence microscopy or flow cytometry is most useful in distinguishing malignant lymphoma from reactive follicular hyperplasia.

Normally, κ light-chain expression is more prevalent and has a normal ratio of 3 to 4 : 1 over λ light chains. Any marked alteration from the normal ratio is strongly suggestive of malignancy.

2.In Hodgkin’s lymphoma, CD15 is relatively specific in identifying Reed–Sternberg cells. CD30 and peanut agglutinin are also helpful.

3.In histiocytic proliferations, S-100 stain and peanut agglutinin are useful in identifying histiocytes (e.g., in Langerhans’ histiocytosis).

4.In the acute leukemias, CD34 is helpful in the diagnosis. A polyclonal antibody for myeloperoxidase is now available to help diagnose acute myeloblastic leukemia.

5.In the plasma cell disorders κ and λ light-chain markers are most useful in making the diagnosis.

I.Many other markers are available, and new markers seem to appear almost weekly!

1.Useful websites for further information regarding immunohistochemical stains and techniques include

the following:

a.http://www.chemicon.com/resource/ANT101/

a2D.asp

b.http://www.ipox.org/login.cfm?IQMessage=1&

RequestTimeout=200

2.Throughout this textbook, appropriate key immunohistochemical markers will be cited where appropriate for each histopathologic diagnosis.

3.Similarly, although genetics is not the focus of this textbook, critical genetic abnormalities will be highlighted as appropriate.

Immunodeficiency Diseases

I.More than 50 genetically determined immunodeficiency diseases occur; only a few that are of major ocular importance are discussed.

II. Wiskott–Aldrich syndrome (see p. 176 in Chapter 6).

III. Ataxia–telangiectasia (see p. 36 in Chapter 2).

IV. Chédiak–Higashi syndrome (see p. 396 in Chapter 11).

V.Severe combined immunodeficiencies (SCIDs)—hetero- geneous group of inherited disorders characterized by profound deficiency of both T-cell and B-cell immunity.

Males who have X-linked SCID have defects in the common cytokine receipt γ chain (γc) gene that encodes a shared essential component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. The lack of Jak3 plays a role in the development of SCID and is essential for lymphoid development.

VI. Chronic granulomatous disease of childhood (see p. 98 in Chapter 4).

VII. Acquired immunodeficiency syndrome (AIDS).

A.From an ocular point of view, this is the most important immunodeficiency disease.

B.AIDS, first recognized in the 1980s, is caused by the highly lethal retrovirus, the human immunodeficiency virus (HIV).

1.HIV type 1 (HIV-1) causes almost all cases in the

United States and HIV-2 in West Africa.

2.HIV-1 and HIV-2 have an a nity for the CD4 antigen on T lymphocytes, macrophages, and other cells (see Fig. 1.25).

HIV-1 consists of an electron-dense core surrounding a single-stranded RNA genome, both enveloped by a cell membrane. Retroviruses contain DNA polymerase (reverse transcriptase) complexed to the RNA in the viral core. Reverse transcriptase catalyzes the transcription of the RNA genome into DNA form (the provirus). The provirus migrates from the host cell’s cytoplasm to the nucleus, assumes a double-stranded circular form, integrates into the host cell DNA, and may remain throughout the life of the host cell.

C.Patients are prone to life-threatening opportunistic infections, wasting, central nervous system dysfunction, generalized lymphadenopathy, and Kaposi’s sarcoma.

Kawasaki’s syndrome has been reported in association with HIV infection. Also, multifocal leukoencephalopathy may occur as a result of AIDS.

D.Cytomegalovirus is the most common opportunistic agent. The other agents include most of the viral, bacterial, fungal, and parasitic agents customarily associated

with cellular immunodeficiency, with herpes simplex virus, Mycobacterium tuberculosis and Myobacterium avium-intracellulare, cat-scratch bacillus (Bartonella henselae), Candida albicans, Cryptococcus neoformans, Pneumocystis carinii, and Toxoplasma gondii heading the list.

E.The location and character of the retinal vascular changes in AIDs indicate an ischemic pathogenesis, most profound in cytomegalovirus retinitis.

F.The histologic appearance depends on the site of involvement and the causative agent (see under appropriate sections of this book).

Transplantation Terminology

I.Autograft: transplantation of tissue excised from one place and grafted to another in the same individual.

II.Syngraft (isograft): transplantation of tissue excised from one individual and grafted to another who is identical genetically.

III.Allograft (homograft): transplantation of tissue excised from one individual and grafted to another of the same species.

IV. Xenograft (heterograft): transplantation of tissue excised from one individual and grafted to another of a di erent species.

V.Orthotopic graft: transplantation to an anatomically correct position in the recipient.

VI. Heterotopic graft: transplantation to an unnatural position.

CELLULAR AND TISSUE REACTIONS

Hypertrophy

Hypertrophy is an increase in size of individual cells, fibers, or tissues without an increase in the number of individual elements

[e.g., retinal pigment epithelium (RPE) in RPE hypertrophy].

Hyperplasia

Hyperplasia is an increase in the number of individual cells in a tissue; their size may or may not increase. Hyperplasia, therefore, is cellular proliferation in excess of normal, but the growth eventually reaches an equilibrium and is never indefinitely progressive

(e.g., RPE hyperplasia secondary to trauma; see section on neoplasia, later).

Dysplasia

Dysplasia is an abnormal growth of tissue during embryonic life

(e.g., retinal dysplasia).

Neoplasia

I.Neoplasia is a continuous increase in number of cells in a tissue, caused by unregulated proliferation and, in some cases, failure of mechanisms (e.g., apoptosis) that lead to cell death.

A.The neoplastic proliferation is probably caused by either excessive or inappropriate activation of oncogenes or reduced activity of genes that downregulate growth (antioncogenes).

B.It di ers from hyperplasia in that its growth never attains equilibrium.

C.The neoplasm* may be benign or malignant.

II.A malignant neoplasm di ers from a benign one in being invasive (it infiltrates and actively destroys surrounding tissue), in having the ability to metastasize (develop second-

ary centers of neoplastic growth at a distance from the primary focus), and in showing anaplasia [histologically, the features of a malignancy that include variation from the normal structure (Fig. 1.27) or behavior in the sense of a loss of specialized or “adult” characteristics of the cell or tissue, e.g., loss of cellular or tissue polarity, or inability to form photoreceptors].

Mutations in the p53 tumor suppressor gene, located on the short arm of chromosome 17 at position 17p13.1, represent the most frequent genetic alteration detected in human solid malignancies. In approximately half of all cancer cases, p53 is inactivated by mutations and other genomic alterations, and in many of the remaining cases the binding of the cellular MDM2 oncoprotein, a

Aplasia

Aplasia is the lack of development of a tissue during embryonic life (e.g., aplasia of the optic nerve).

Hypoplasia

Hypoplasia is the arrested development of a tissue during embryonic life [e.g., hypoplasia of the iris (aniridia)].

Metaplasia

Metaplasia is the transformation of one type of adult tissue into another type [e.g., fibrous metaplasia of lens epithelium (in anterior subcapsular cataract)].

Atrophy

Fig. 1.27 Abnormal tripolar mitotic figure in a sebaceous gland carcinoma.

Atrophy is a diminution of size, a shrinking of cells, fibers, or tissues that had previously reached their full development (e.g., retinal vascular atrophy in retinitis pigmentosa).

*A neoplasm is a tumor, but not all tumors are neoplasms. Tumor simply means “mass” and may be secondary to neoplasia, inflammation, or edema.