Following blood of the recipient. Thus, it was

Following a similar procedure, studies were made concerning various plasma protein
components. However, in the early days of research, quite a number of experiments were
carried out in regard to such electrophoretically-separated fractions as a-globulin, fJglobulin,
and others. Consequently, however, reliable results have become available
through the progress of the procedures in purifying plasma proteins.
The methods for demonstrating the sites of plasma protein synthesis are classified roughly
into in vitro and in vivo procedures.
In vitro procedures: There are four in vitro procedures, 1) the incubation and perfusion
of organs which have been removed from the body; 2) the use of fresh tissues or organ
sections for the same purpose; 3) the use of cell or tissue cultures; and 4) the use of microsomal
fractions of cells.
The problem in the use of these procedures is that the protein components which are
already present in cells before the experiment may be freed and be mistaken as newly synthesized
protein. There is also a possibility of some proteins to form a complex with the
protein to be studied. Therefore, it is necessary for sure to prove that a radioactive isotope
has been incorporated into the polypeptide chain,l22)
In vivo procedures: The most direct procedure for determining the site of protein synthesis
is the one reported by GRABAR et al.52) It involves two species of animals having plasma
proteins of different antigenicity. In this method, the organs of one animal are first
transplanted to the other whose immunity has been depressed by strong irradiation, and
then the plasma proteins of the latter animal are studied immunochemically.
In men, this procedure was adapted coincidentally on liver transplantation between
two indivduals having haptoglobins of different hereditary types. The haptoglobin type
of the donor was subsequently detected in the blood of the recipient. Thus, it was verified
in vivo that haptoglobins are synthesized in the liver.91) The sites of synthesis may be
T. Kawai, Clinical Aspects of THE PLASMA PROTEINS
© Springer-Verlag Berlin Heidelberg 1973
104 METABOLISM OF THE PLASMA PROTEINS
indirectly demonstrated from the fact that plasma proteins decrease after a particular
organ is experimentally or surgically removed. Also, the sites of protein synthesis may be
assumed by a significant decrease of the particular proteins followed by diffuse necrosis
or injury of a certain organ. By clinical observations such as these, it had been supposed
that many plasma proteins other than immunoglobulins were synthesized in the liver cells
but in vitro procedures have served to confirm this assumption.
In addition to these procedures, fluorescent antibody techniques may be mentioned
though they are not direct ways of demonstrating the sites of plasma protein synthesis.
That is, the localization of particular plasma proteins may be determined by direct or
indirect methods of fluoresent antibody techniques.55,99) Even if particular plasma
proteins are demonstrated to be present with this method, it does not necessarily indicate
the site of synthesis. When a particular organ is known through other analytical methods
to be the site of synthesis, fluorescent antibody techniques are useful to confirm the result
at the cell level.
2. Synthetic Organs
It has long been thought that the liver plays an important role in plasma protein synthesis,
and it has been cofirmed gradually by the above mentioned procedures, especially in
in vitro experiments. In Table 17, the results on various plasma proteins are summarized.l33)
It may be thus concluded that the liver and reticuloendothelial system has
a major role in plasma protein synthesis but the nerves, the heart, the muscles, the renal
parenchyma and the endocrine organs are not involved. As shown in Table 17, the liver
mainly synthesizes the following proteins: albumin, a1-acid glycoprotein, a1-antitrypsin,
haptoglobin, a2-macroglobulin, Gc-globulin, transferrin, various lipoproteins, chylomicron,
fibrinogen, prothrombin, factor VII, and C-reactive protein. Moreover, ceruloplasmin
and hemopexin are also thought to be synthesized in the liver. Complement components
and immunoglobulins are not synthesized at least in the healthy liver. 66,133) Therefore,
when the greater part of the liver cells are removed or destroyed as in hepatectomy or liver
cirrhosis, there is a marked decrease of albumin, fibrinogen and lipoproteins in plasma.
In severe liver damage, a further decrease of a- and ,8-globulins may result.
The second major site of plasma protein synthesis is the reticuloendothelial system.
The reticuloendothelial cells are widely distributed throughout the system and involved
chiefly in the synthesis of immunoglobulins. Not all immunoglobulins are produced from
reticuloendothelial cells. Rather, a variety of cells are involved in their production. For
instance, IgG-immunoglobulin is synthesized mainly in mature plasma cells.29,89) It is
also synthesized in the cells which are present in germinal centers of the lymph node.
Moreover, most investigators believe that one plasma cell synthesizes the immunoglobulin
of either the K or the L type, one or the other, while there are reports saying that the
light chain of both the K and the L type is contained in one cell.l09) There are some discrepancy
among investigators with regard to the cells that synthesize IgM-immunoglobulin.
Though it is produced in plasma cells, they may not be exactly the same as IgG-producing
mature plasma cells.l60) In fact, in WALDENSTROM’s macroglobulinemia, the cells with
atypical morphology, known as lymphocytoid plasma cells or plasmacytoid lymphocytes
produce IgM-immunoglobulin.37,138) IgA-immunoglobulin is synthesized mainly in
mature plasma cells.21,89) Plasma cells and similar immunoglobulin-producing cells are
distributed widely in nearly all the tissues and organs. However, the following organs are
particularly rich in plasma cell: the spleen, the lymph nodes, the bone marrow, the lungs,
the intestinal mucosa, the appendix, the tonsils, the interstitial tissues of various exocrine
glands, and the hepatic sinusoids. In normal conditions, immunoglobulins are produced
chiefly in these organs.