Immunology and Cell Biology- (1997) 75.

65-68

Review

A brief history ofthe discovery ofthe

immunoglobulins and the origin ofthe modern
immunoglobulin nomenclature
C ALLEN BLACK

Discipline of Patholog}'. University of Newcastle. Newcastle. New South Wales. Australia

Suinmar>' On the 30th anniversary of the discovery of IgE, the last immunoglobulin identified, the discover)
and subsequent naming ofthe immunoglobulins is recounted. The first immunoglobulin-like protein to be
discovered was the Bence Jones protein or light chain in 1845. Over 100 years later, the final isotype. IgE. was
discovered. During this century, there have been various names for what we now know as IgA, igD. IgE, IgG
and IgM. There was also confusion over what constituted a 'new" immunoglobulin and how u should be
named. As a result the current nomenclature seems arbitrary; however, it reflects both a historical tradition of
preserving the original name ofthe protein as well as a rational system designed in the early 1960s to codify
the basic proteins of the humoral response.

Keywords: histor>', immunoglobuiin, nomenclature.

In the early 20th century. Immunology was emerging as a
viable scientific discipline. Immune sera and humoral
immunity have been studied ever since Nuttall observed
that animal sera could kill bacteria.' Novel techniques
still in use today, e.g. centrifugation, electrophoresis and
immunoadsorption. had recently been discovered, allow-
ing the unprecedented dissection ofthe chemistr>' of hu-
man blood proteins which of course included complement
and antibodies. As researchers began to unravel the chem-
ical nature of these proteins, it was necessary to name
them in a consistent manner. Some, like Tiselius. at-
tempted to follow the Victorian ideal that new scientific
objects should be designated by Greek words or letters to
preserve the scientific nomenclature and separate it from
trivial everyday language.- Similar naming conventions
were already in place in physics (e.g. alpha particle, beta
particle, gamma rays) and ehemistr\' (e.g. hydrogen, oxy-
gen, helium). Unfortunately, this tradition has ultimately
led to an almost arbitrary naming system for the immuno-
globulins since the proteins were rarely pure when they
were first discovered. In 1964. the World Health Organi-
zation (WHO) defined a consistent system for 'correctly'
naming each ofthe isotypes.^ The original names given to
most of the proteins by the discoverers were preserved,
albeit somewhat modified, to give us the modern names of
IgG. IgM, IgA, IgD, IgE and the kappa and lambda light
chains. Today, 150 years after the discovery of the first
Correspondence: C Allen Black, 3rd level DMB, Discipline of
Pathology. University ofNeweastle. Newcastle. NSW 2290, Aus-
tralia.
Reeeived 20 Mareh 1996; accepted I July 1996.
immunoglobulin, the derivation of these names has be-
come obscured.
Electrophoresis and ultracentrifugation gave the first
indications of the biochemical properties oi' individual
isotypes. In 1930, Tiselius mvented the procedure
whereby protein was electrophoresed in a buffer."* This
was itself based on an earlier eleetrophoretic technique
invented by Landsteiner.^ When human plasma was elec-
trophoresed. certain protein groups, measured with
Schlieren optics, were then ascribed the Greek letters a. p
and Y to designate where the protein fell in order of
mobility {Fig. 1). Since denaturing gels had not yet been
invented, the protein's mobility did not have any direct
relationship to molecular weight. Therefore, many dif-
ferent proteins were actually present within each region.
Ultracentrifugation, invented by Svedburg. allowed the
calculation of molecular weights.
In 1939, Tiselius and Kabat^ showed that the gamma
fraction of electrophoresed serum eontained the largest
amount of immunoglobulin. They immunized animals
with ovalbumm, then absorbed the serum with ovalbu-
min, resulting in a decrease in the amount of protein in
the gamma region. This was the first isotype of antibody
to be discovered and was called y-globulin since it was in
the y region of mobility. However, as investigators began
to use more specific techniques, it was found that immu-
noreactive fractions also migrated in the alpha and beta
regions.
Another impact of electrophoresis on immunology was
in the study of multiple myeloma (B cell lymphoma)
patients. In these patients, certain proteins were highly
elevated and seemed to correspond to certain serum glob-
ulin fractions. These proteins represented mono or oligo-
66
4-7 +6 +5 +4 + 3 -^2 +1 0 -1 -2 -3 -4 -5
Figure 1 A = densitomctnc curve ofa normal human serum and
of a preparation of levan (LE). B = zones of eleetrophoretic mi-
gration. C = photograph of simple electrophoresis in agar o f a
normal human serum. 1964. reprinted with permission of
publisher.-'
clonal production of antibody of different isotypes. In
1944, immunoelectrophoresis and ultracentrifugation al-
lowed Waldenstrom and Pedersen. and independently
Kunkel. to characterize the second immunoglobulin,
IgM.''*^ Sera from these patients contained a 1x10^ mo-
lecular weight protein which migrated next to the
(3-globulin. It sedimented at 19 Svedburgs unlike the 7S
protein know at the time as gamma-globulin (IgG). The
form of multiple myeloma that Waldenstrom discovered
was named macroglobulinemia and the protein macroglo-
bulin. Later in the 1960s, when nomenclature was finally
decided upon, the historical reference was preserved by
designating this antibody as IgM, the 'M' standing for
macroglobulin. IgG was similarly termed although the
Greek gamma was discarded for the Roman capital 'G' to
preserved consistency among the names ofthe isotypes.-^
IgA was the next isotype characterized. Subsets of both
IgG and IgM had been identified in the gamma and beta
regions (p2macroglobulin and a2globulin). But yet an-
other immunoreactive region in both the beta and gamma
fractions was found. It did not absorb out with anti-
gamma or anti-macroglobulin sera and had different sed-
imentation coefficients to the then known immunoglobu-
lins. These new fractions were termed p2\ ^"d y,^.
Finally in 1959 they were identified as a new immunoglo-
buiin by Heremans el al.'' In their seminal paper they
described the confusion over the designations used to
characterize the beta proteins:
Recently our knowledge of the nature of these p.-{ory|-)
proteins has increased by some precise information. Thus
GRABAR et al. using the immuno-electrophoretic tech-
nique, has established beyond doubt that the gamma-
globuhns really consist of a whole family of eomponents
with identical antigenie specificity. The most rapid mem-
CA Black
bers reach the slower alpha2 region, and the slowest mole-
cules extend to the eathodic end ofthe graph. From this it
follows that the so-called P^ (or M, or gamma 1 or Q region
at least contains some "gamma-globulin' (using the word in
Lt.
its immunological meaning).
Next, KUNKEL's group succeeded in preparing a high-
molecular weight component, whose mobility slightly ex-
eeeds that corresponding to the classical gamma-peak. Al-
though the final proof has not yet been given, it may be
assumed with reasonable certainty that KUNKEL's heavy
gamma 1-globulin at least partially coincides with an anti-
genie eonsituent. which BURTIN and eo-workers called
•beta2M'. The latter protein appears to be appreciably in-
creased in cirrhotic sera, as is KUNKEL's heavy gammal-
globulin, and it has been show n to be specifically involved in
macroglobulinaemia Waldenstrom.
Finally, a third globulin with eharaeteristic p, mobility
-6 -7
has been know sinee the ven first immuno-electrophoretie
investigations of human sera, performed b> GRABAR and
WILLIAMS in 1953. It was merely called 'p^-globulin" by
them, until the disco\er>' ofthe "P^-macroglobulin" preeipi-
tation line prompted them to change the name to ^^2\'
globulin", in order to avoid eonfusion."
Later [3^.,.-globulin was truncated to a-immunoglobulin or
IgA which fulfils the requirements ofthe recently codified
nomenclature and preserves to some extent the historical
name. However, the 'A" of IgA does not stand for its
mobility in the alpha fraction in immuno-eiectrophoresis.
No immunoglobulin fraction was ever found in the alpha
region.
The next immunoglobulin discovered was IgD by
Rowe and Fahey."^ This protein migrated in the yl re-
gion. It was elevated in a multiple myeloma patient and
was unreactive with antisera to the then known isotypes —
IgG, IgM and IgA- (These terms are actually used in their
paper showing the adoption of the recommended WHO
nomenclature which had been decided upon that same
year.) They could also show that the protein had other
immunogiobulin characteristics — it was unobserved in
newbom or agammaglobulinaemia patients and con-
tained immunoglobulin light chains. Interestingly, the
letter 'D' in IgD was arrived upon rather by a process of
elimination (pers. comm., 1996). IgA had already been
designated. Their first choice was IgB or p-globulin but. at
the time, it was expected that the murine immunoglobu-
lins would be called P-globulin. even though this never
eventuated. The Roman letter ' C has no Greek equiva-
lent. The 'E" reactive antibody (later termed IgE) had
traditionally been associated with allergy. Thus. Fahey
and Rowe were left with little choice but to name the new
immunoglobulin IgD.
Later in 1964, Fahey along with Wunderlich and
Mishell also characterized the murine immunoglobulin
subclasses." •' - Using immuno-eiectrophoresis they
found a ditference in the ISy (IgG) protein which they
classed as 7S.^, and IS.^^- They were further able to distin-
guish a difference in the 7S.^2 protein, and thus it was
subdivided into the 7Sy2a 3"^ 7S.^2h proteins. The names
have only been changed by the truncation of the '7S',
leaving IgGl, IgG2a and IgG2b which are used today.
The World Health Organization did not recommend a
system for naming the subclasses ofthe murine immuno-
 The discovery and naming ofthe immunoglohulins
globulins, so the designation has remained essentially the
same since the discovery ofthe subclasses.
The last immunoglobulin isotype to be deseribed was
IgE. Although the 'reaginie antibody" had long been
known, Ishizaka. Ishizaka and Hombrook, and Johansson
and Bennich working independently were the first to de-
scribe it as a novel immunoglobulin in 1966.'^"'^ In
1890. it was shown that immune sera from sensitized
animals could transfer allergy.'" Also, allergy could be
induced by injecting ragweed pollen. Upon the advent of
biochemical separation techniques a defined fraction of
the pollen proteins was shown to be the most potent in
inducing an erythema-wheal response after subcutaneous
injection. This extract was termed fraction or antigen E,
the 'E" denoting er>'thema.'^ Using similar techniques as
Fahey and Rowe which included ion-exchange and size
exclusion chromatography. immunoelectrophoresis.
Ouchterlony precipitin reactions and immunoadsorption.
they concluded that the antibody reacting with antigen E
was a new immunoglobulin. Even though the protein mi-
grated in the yA, fraction of electrophoresed sera, the
nomenclature used was straightforward — IgE denoting a
novel immunoglobulin isotype and preserving the original
historical observation of ervthema in allergy.
The discovery of the light chains of the immunoglobu-
lins actually predates that of the immunoglobulins them-
selves. In 1845, Henr\ Bence Jones discovered a protein
in urine of multiple myeloma patients.'^ He described it
chemically as 'hydrated deutoxide of albumen' and it was
the first attempt at a structural study of immuno-
globulins.'" It wasn't until the iy50s that much more
progress was made on this protein. It was during this time
that Korngold and Lipari separated the Bence Jones pro-
teins into two types which are now know as kappa and
lambda.-" The Greek letters taken from the first letter of
their last names.'"
The nomenclature for the immunoglobulin isotypes
and subclasses was finally cemented when the WHO for-
malized the naming conventions at their 1964 meeting in
Prague.^ In their statements they proposed the names
which we now use for ihe immunoglobulins and proposed
a system to name immunoglobulins discovered in the
future. Interestingly, they do not force any particular
name for subsequent discoveries beyond the Ig followed
by Roman letter convention, thus preserving the right of
the discoverers to name their discovery. At the time. IgD
and IgE were not known, so the table of names of the
immunoglobulins was incomplete.
In summary: y, 7Sy, 6.6Sy, y2, yss became yG or IgG:
p2A> 7IA became yA or IgA; ylM. p2M. l9Sy, y-macro-
globulin became yM or IgM. The names for light chains
were consolidated, as well: type I, 1. B became type K:
type II, 2, A became type L.
The gamma designation before the name of the immu-
noglobulin was a convention designed to allow speech of
the immunoglobulin names, since the now common "eye-
gee' pronunciation for the notation Ig was not used or
predicted at the time. Additional rules were formulated
for naming the subclasses although these apparently were
never generally adopted. They proposed that each sub-
class have a Roman letter subscript to designate it; for
67
example IgAa. instead of what would now be termed IgA,.
Letters were recommended instead of numerals since they
might imply electrophoretic mobility as had been the case
in the past. The polypeptide chains themselves were to be
noted with Greek letters corresponding to the Roman
letter designation. Even the peptide fragments from diges-
tions were codified. For papain digests: A. C. S became
Fab-fragment (antigen-binding); B. F became Fc-fragment
(crvstallizable). For pepsin digests: Fab' for univalcnt
fragments and F{ab}'2 for divalent fragments.
The final result is. with little modification, what we now
use for eveo'day discourse on the immunoglobulins. al-
though the derivation of these names has become arcane.
In I960 Pierre Burtin commented on the confusion over
immunoglobulins at the time. "It is really difficult to be
rigorous about classification. The nomenclature itself is
sometimes imperfect or arbitrar\\ But. at the moment, it
is difficult to do better, as knowledge ofthe biochemistr\
of serum proteins increases, specific nomenclature based
on structure or function will replace the arbitrary
nomenclature.-' With hindsight we can say thai Burtin
was overly optimistic. Despite solved cr\stal structures
for the immunoglobulins. the naming conventions h;tvc
remained csscntiall> arbitrar>.
Acknowledgements
I am grateful to Drs John Fahey. Howard Goodman and
David Rowe for their critical appraisal and helpful com-
ments on the historical accuracy of this paper.
References
1 Nuttall G. Experimentc ubcr die bacterienrcindlichcn Ein-
(lussc des thcirischcn Korpcrs. Z IIy,u'. 1888: 4: 35.^-^? (in
Gorman).
2 Tiselius A. Electrophoresis of scrum globulin HuKhcnx .1
1937:31: 313-17.
3 Ceppclhni R. Dray S. Edclmen G ct al. Nomenclature lor
Human Immunoglobulins. BJ///. World Health Or}". 1964:30;
447-50.
4 Tiselius A. The mo\ing bound;ir\ [iicthod oi stud\ing (he
elcclrophoresis of proteins. (Inaugural Dissertation; Univer-
sity of Uppsala. Sweden: 1^30.
? Landsteincr K. Pauli W Eleklri.sclic Wanderung der Immu-
nostorte. Wrhandi J. A.VC Kon}^. j. innac Med. 1908: 25:
571-4.
6 Tiselius A. Kabat EA. An eleetrophoretic study of immune
sera and punhed antibody preparations. / h.\p. .\lcd. 1939;
69: 119-31.
7 Waldenstrom J. Incipient myleomatosis or 'essential' hypcr-
globulincmia with fibrinogenopcnia — a new syndrome?.li/a
.\h'd. Stand. 1944; 67: 216-47.
8 Wallenius G. Trautman R. Kunkel HG. Franklin EC. Ultra-
centrifugal studies of major non-lipidc electrophoretic com-
ponents of normal human serum.,/ Biol. Chem. 1957" 22S
253-7.
9 Heremans JF. Heremans M-Th. Sehultz HE. Isolation and
description ofa few properties ofthe p,^-globulin of human
serum. CItn. Chim. .Aeta 1959; 4: 96-102.
68
10 Rowe DS, Fahey JL. A new class of human immunoglobulin.
II normal serum IgD. / Exp. Med. 1965; 121: 171-84.
11 Fahey JL. Wunderlich J. Mishel! R. The immunoglobulins of
mice: 1. Four major classes of immunoglobulin. / Exp. Med.
1964; 120:223-42.
12 Fahey JL. Wunderlich J. Mishell R. The immunoglobulins of
mice: II. Two subclasses of mouse 7S.^2-Globulins: y23 and
y2^ globulins. / Exp. Med 1964; 120: 243-51.
13 Ishizaka K. Ishizaka T. Hombrook M. Physicochemical
properties of reaginie antibody. V. Correlation of reaginie
activity and yE-globulin antibody. ./. Immunol. 1966: 97;
840-53.
14 Ishizaka K, Ishizaka T, Hornbrook M. Physicochemical
properties of reaginie antibody. IV. presence of a unique
immunoglobulin as a carrier of reaginie activity. J. Immunol.
1966:97: 75-85.
15 Johansson SG, Bennich H. Immunological studies of an
atypical myeloma immunoglobulin. Itntnunology 1967; 13:
381-94.
CA Black
16 Prausnitz C. Kustner H. Studien uber die Ueberempfind-
lichkeit. Ceniralhl. f. Bakleriol. 1921; 86; 160-76 {in
German).
17 Silverstein AM. A History of Immunology. San Diego: Aca-
demic Press, 1989.
18 Jones HB. Papers on chemical pathology; prefaced by the
Gulstonian lectures read at the Royal College of Physicians.
1846. Lecture 3. Lancet 1846; 2: 88-92.
19 Putnam FW. From the first to the last ofthe immunoglobu-
lins: Perspectives and prospects. Clin. Physiol. Biochem.
1983: 1:63-91.
20 Komgold L, Lipari R. Multiple myeloma proteins. HI. The
antigenie relationship of Bence-Jones proteins to normal
gamma-globulin and multiple myeloma serum proteins.
Cancer 1956:9: 262-72.
21 Burtin P. The proteins of normal human plasma. In: Grabar
P. Burtin P. eds. Immuno-Eleetrophoretic Analysis. Amster-
dam: Elsevier Publishmg Co., I 964; 94-5.