Ganong's Review of Medical Physiology, 23rd Edition

74 SECTION ICellular & Molecular Basis for Medical Physiology

Diversity is brought about in part by the fact that in immune
globulin molecules there are two kinds of light chains and eight
kinds of heavy chains. As noted previously, there are areas of
great variability (hypervariable regions) in each chain. The vari-
able portion of the heavy chains consists of the V, D, and J seg-
ments. In the gene family responsible for this region, there are
several hundred different coding regions for the V segment,
about 20 for the D segment, and 4 for the J segment. During B cell
development, one V coding region, one D coding region, and one
J coding region are selected at random and recombined to form
the gene that produces that particular variable portion. A similar
variable recombination takes place in the coding regions respon-
sible for the two variable segments (V and J) in the light chain. In
addition, the J segments are variable because the gene segments
join in an imprecise and variable fashion (junctional site diversi-
ty) and nucleotides are sometimes added (junctional insertion di-
versity). It has been calculated that these mechanisms permit the
production of about 10^15 different immunoglobulin molecules.
Additional variability is added by somatic mutation.
Similar gene rearrangement and joining mechanisms oper-
ate to produce the diversity in T cell receptors. In humans, the
α subunit has a V region encoded by 1 of about 50 different
genes and a J region encoded by 1 of another 50 different
genes. The β subunits have a V region encoded by 1 of about
50 genes, a D region encoded by 1 of 2 genes, and a J region
encoded by 1 of 13 genes. These variable regions permit the
generation of up to an estimated 10^15 different T cell receptors
(Clinical Box 3–2 and Clinical Box 3–3).
A variety of immunodeficiency states can arise from defects
in these various stages of B and T lymphocyte maturation.
These are summarized in Figure 3–12.

PLATELETS

Platelets are circulating cells that are important mediators of
hemostasis. While not immune cells, per se, they often partic-
ipate in the response to tissue injury in cooperation with in-

flammatory cell types (see below). They have a ring of

microtubules around their periphery and an extensively in-

vaginated membrane with an intricate canalicular system in

contact with the ECF. Their membranes contain receptors for

collagen, ADP, vessel wall von Willebrand factor (see below),

and fibrinogen. Their cytoplasm contains actin, myosin, gly-

cogen, lysosomes, and two types of granules: (1) dense gran-

ules, which contain the nonprotein substances that are

secreted in response to platelet activation, including seroto-

nin, ADP, and other adenine nucleotides; and (2) α-granules,

which contain secreted proteins other than the hydrolases in ly-

sosomes. These proteins include clotting factors and platelet-

derived growth factor (PDGF). PDGF is also produced by

macrophages and endothelial cells. It is a dimer made up of A

and B subunit polypeptides. Homodimers (AA and BB), as

well as the heterodimer (AB), are produced. PDGF stimulates

wound healing and is a potent mitogen for vascular smooth

muscle. Blood vessel walls as well as platelets contain von

Willebrand factor, which, in addition to its role in adhesion,

regulates circulating levels of factor VIII (see below).

When a blood vessel wall is injured, platelets adhere to the

exposed collagen and von Willebrand factor in the wall via

receptors on the platelet membrane. Von Willebrand factor is

a very large circulating molecule that is produced by endothe-

lial cells. Binding produces platelet activations which release

the contents of their granules. The released ADP acts on the

ADP receptors in the platelet membranes to produce further

accumulation of more platelets (platelet aggregation).

Humans have at least three different types of platelet ADP

receptors: P2Y 1 , P2Y 2 , and P2X 1. These are obviously attrac-

tive targets for drug development, and several new inhibitors

have shown promise in the prevention of heart attacks and

strokes. Aggregation is also fostered by platelet-activating

factor (PAF), a cytokine secreted by neutrophils and mono-

cytes as well as platelets. This compound also has inflamma-

tory activity. It is an ether phospholipid, 1-alkyl-2-

acetylglyceryl-3-phosphorylcholine, which is produced from

membrane lipids. It acts via a G protein-coupled receptor to

TABLE 3–3 Human immunoglobulins.a

Immunoglobulin Function

Heavy

Chain

Additional

Chain Structure

Plasma Concentration

(mg/dL)

IgG Complement activation γ 1 , γ 2 , γ 3 , γ 4 Monomer 1000

IgA Localized protection in external

secretions (tears, intestinal secre-

tions, etc)

α 1 , α 2 J, SC Monomer; dimer with J or SC

chain; trimer with J chain

200

IgM Complement activation μ J Pentamer with J chain 120

IgD Antigen recognition by B cells δ Monomer 3

IgE Reagin activity; releases histamine

from basophils and mast cells

ε Monomer 0.05

aIn all instances, the light chains are k or γ.