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(B) Restrided eel surface dislrJxition

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Focal adhesion conüicts

Leading (trailing) edge

Focal adhesion conüicts

Leading (trailing) edge

(C) Cell surface ehuft of cryptic antigens

Precurecr (Qalgl only)

Prtcureor on cell surfHCC

Prtcureor on cell surfHCC

Malignant I nans formation

Figure 1 Differential localization of cell surface antigens. Examples of antigen expression on lymphoid, epithelial and fibroblastic cells are illustrated as follows. (A) Uniform antigen distribution on the surface membrane, as seen for MHC class I molecules. (B) Spatially restricted cell surface distribution on polarized cells growing on extracellular matrix (ECM). In epithelial cells, apical, basolat-eral and cell junctional patterns are distinguished. For fibroblastic cells, antigen localization to focal adhesion contacts and the leading (or trailing) edge of migrating cells are indicated. (C) Cryptic antigens may be present in intracellular compartments of some cells but become exposed on the surface of other cells. The example shown here represents a mAb-defined carbohydrate structure, lacto-A/-tetraose (type I blood group precursor), carried by glycolipids and glycoconjugates, that is detectable in the Golgi apparatus of normal adult cells, but becomes further glycosylated and 'cryptic' before reaching the cell surface. By contrast, in fetal endoderm and teratocarcinomas, the glycosylation of lacto-A/-tetraose moieties is deficient and large numbers of the precursor structure reach the cell surface.

Antigen

Antigen

Figure 2 Dynamic view of cell surface antigen expression on the plasma membrane. Using immunocytochemical staining methods with permeabilized cells, some antigens are detected as biosynthetic precursors in the cytoplasm and Golgi complex, prior to their appearance on the cell surface. Similarly, antigens that are internalized through clathrin-coated vesicles, macropinosomes, or caveo-lae can be followed by these methods until they are either degraded (e.g. lysosomal pathway) or recycled in intact form to the cell surface. Alternative splicing of antigen-coding mRNAs with removal of membrane-anchoring transmembrane domains or cleavage of membrane-bound antigens by specific proteases may result in secreted or shed variants of the antigen.

Figure 2 Dynamic view of cell surface antigen expression on the plasma membrane. Using immunocytochemical staining methods with permeabilized cells, some antigens are detected as biosynthetic precursors in the cytoplasm and Golgi complex, prior to their appearance on the cell surface. Similarly, antigens that are internalized through clathrin-coated vesicles, macropinosomes, or caveo-lae can be followed by these methods until they are either degraded (e.g. lysosomal pathway) or recycled in intact form to the cell surface. Alternative splicing of antigen-coding mRNAs with removal of membrane-anchoring transmembrane domains or cleavage of membrane-bound antigens by specific proteases may result in secreted or shed variants of the antigen.

most cancer antigens when the analysis of normal adult tissues has been sufficiently detailed. Antigens that fit an 'oncofetal' pattern in one system are invariably found in other systems with a different mode of expression and control. Similar departures from the presumed modes of expression have been found for other categories of 'transformation-related' or 'proliferation-related' antigens of cancer cells. (Much of the current interest in tumor-specific antigens focuses on clonogenetic determinants on cell surface differentiation antigens detected by the host immune system, as described above.) Even for those antigens for which a biochemical function has been identified, such as various cell surface receptors, membrane-bound enzymes and adhesion molecules, the unpredictable cross-lineage patterns are observed.

Understanding the genetic and biochemical control of the complexity in cell surface antigen display will require decoding the signals that initiate, regulate and maintain the differentiated state. Understanding the physiologic role of a cell surface antigen in the organism, even if it has been assigned an in vitro biochemical function and its mode of genetic control is known, may require highly specialized test systems. A search for genetic diseases caused by abnormalities in a single cell surface antigen locus may facilitate the study of physiologic function for some molecules, as illustrated by the analysis of patients with leukocyte adhesion deficiency due to defects in the CD 18 gene. However, it is tempting to speculate that many common biological functions of the cell surface are not assigned to individual proteins. They are the responsibility of integrated circuits comprising multiple components, both in the plasma membrane and inside and outside of the cell, in which individual proteins serve as structural and functional modules. The same module may be used over and over in different cell types and different circuits to serve different functions, and similar functions may be mediated, in parallel or alternatively, by separate molecular mechanisms. Such a concept is consistent with the experience that targeted inactivation of genes in knockout mice is commonly associated with unexpectedly subtle phenotypes.

What lessons can be drawn at this stage of the analysis?

1. From the large pool of genes coding for cell surface antigens, distinct but widely overlapping sets are activated during differentiation in disparate lineages.

2. The distinctive surface phenotype of differentiated cells is achieved not by the display of unique lineage-restricted antigens but rather through unique combinations of antigens that are drawn from a common pool.

3. Although the surface phenotype of differentiated cells is quite stable, there is considerable flexibility in reprogramming individual antigens. Surface antigens are not irreversibly silenced or expressed during differentiation but can be induced or suppressed by specific extrinsic/ intrinsic signals.

4. Individual surface antigens can be viewed as modular elements that together generate complex and unique surface patterns. This concept of modularity in the construction of cell surfaces could explain unique functions achievable with common elements, as the same module in different cell types would come under different regulatory control and could impart different information.

See also: ABO blood group system; Alloantigens; B-

lymphocyte differentiation; Carbohydrate antigens;

CD antigens; Flow cytometry; Immunocytochemistry and enzyme markers; Monoclonal antibodies (mAbs);

T lymphocyte differentiation; Thy-1; Tumor antigens.

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