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FISHERIES AND MARINE SERVICE

Translation Seiles No. 2995

Immune globulins

by Thomas TaIlberg

Original title: Immunoglobuliner

From: Finska Laekare Saellskapets liandlingar (The Finnish Medical Society Reports), 111(1) : 52-68, 1967

Translated by the Translation Bureau(LT/PNB) Multilingual Services Division

Department of the Secretary of State of Canada

Department of the Environment Fisheries and Marine Service

Halifax Laboratory Halifax, N.S.

1974

18 pages typescript

SECRÉTARIAT D'ÉTAT

BUREAU DES TRADUCTIONS

DEPARTMENT OF THE SECRETARY OF STATE

TRANSLATION BUREAU

DIVISION DES SERVICES MULTILINGUAL SERVICES CANADA

TRANSLATED FROM — TRADUCTION DE INTO — EN

Swedish English

PUBLIeHER — ÉDITEUR PAGE NUMBERS IN ORIGINAL

NUMÉROS DES PAGES DANS

L'ORIGINAL

DATE OF PUBLICATION DATE DE PUBLICATION The Serobacteriological

Institute of Helsinki Y 52 -68 ISSUE NO.

NUMÉRO VOLUME

Universit YEAR

ANNÉE PLACE OF PUBLICATION

LIEU DE PUBLICATION

NUMBER OF TYPED PAGES

NOMBRE DE PAGES

DACTYLOGRAPHIÉES 111 1967 1 Helsinki, Finland

18

DIVISION MULTILINGUES

AUTHOR — AUTEUR

Thomas Tallberg

TITLE IN ENGLISH — TITRE ANGLAIS

Immune globulins

TITLE IN FOREIGN LANGUAGE (TRANSLITERATE FOREIGN CHARACTERS) TITRE EN LANGUE ÉTRANGÈRE (TRANSCRIRE EN CARACTkRES ROMAINS)

Immunglobuliner

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nzre:RENcE IN ENGLISH — RErinr.:NcE EN ANGLAIS

The Finnish Medical Society Reports

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7030-21-029.8333

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MUD For infonr.:-:::k•7;

TRA DU C- N N

Informa:ion

evi •

• ' DEPARTMENT OF THE SECRETARY OF STATE

TRANSLATION BUREAU

SECRÉTARIAT D'ÉTAT

BUREAU DES TRADUCTIONS

MULTILINGUAL SERVICES

DIVISION

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MULTILINGUES

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784484 Swedish LT 7P1-11.- APR 2 - 1t:1 74

IMMUNE GLOBULINS

by

Thomas Tallberg

The Serobacteriological Institute of Helsinki University

It is rather peculiar that within a research field as

extensive and diverse as immunology, the most important research

tool, - immune globulins, - at the same time constitutes its

perhaps most interesting object of study. The unbelievably rapid

development in this field makes it difficult even for professionals

to follow and coordinate all the new sprouts of knowledge. Ex -

tensive surveys with reference lists and detailed descriptions

are published every year. In this respect I refer to articles by

Fudenberg (5), Gitlin (6), and Fleischman (3).

It is difficult to present this group of problems in a

readily understandable form without reverting to a mere outline.

uNlupnD /

1111011T.Z. ■ i011 smuiaracnt SOS-200-10-31

7530-21-02g-5332

To be able to offer something to both -the -pxafessi.onal man and the

uninitiated, I have chosen a-type of presentation that is 1argeTy

based on tables. I believe that the-mass of details In this way-wi11

be easiertn digest.

Any strict classification of research areas within im

munology is bound to be deficient because of the striking inter-

action of the areas. However, an orientational outline (table 1)

serves a useful purpose. The interplay of the properties and effects

of immune globulins is symbolised by the two-headed arrow con -

necting the main branches of immunology : irimunochemistry, immuno-

genetics, transplantation and tumour immunology, and immunobiology.

TABLE 1

IIDiUNOLOGY

(immunopathology )(immunophysiology)

Immunochemistry mmunogenetics Transplantationand tumour

mmunobiology I1

1immunoloq:

Primary and ter- Blood group Allergy

tiary structure, serology, glob- Anaphylaxis

kinetic and phys-: ulin classiFi^ Atopy

iochemical pro- cation, serum Cell-bound

1perties ofglobulin

protein,enzyme, reaetions

etc.

Classification and structure

Autoimmunity

Antihormone

Antienzyme

Transport

protein

A complicatod pê^^_er-ij of n:Rti^od.ies h.4,% vecn, developed

(53)

since the timeg when t-jie pi©nenr-s of th,q field nzkâe tha-ir great

Ter,

Human serum in starting point

• '

• •

igA •4, IgG •

(53- 54 )

3

inventions. Tiselius and Waldenstrom, the former by means of

electrophoresis and the latter by ultracentrifugation, established

that antibodies (antibody activity) are found in the gamma globulin

fraction mainly as :7S gamma globulin, today called immune globulin

G (IgG), and in a macroglobulin fraction as 195, now called IgM.

This system was developed further by Grabarts immunoelectrophoresis

(fig. 1 A).

Cathode Anode- Antihuman gamma globulin serum

A)

B)

Figure 1. Immunoelectrophoresis with specifigama_globulin serum.

TABLE II

Immune globulin .ol ejide chains and inolecular structure

Light chains; Ig type Heavy chains Ig class (24) Structural formula

'X (kappa) Mlambda)

:y K l '(gamma) IgG or y G L !,,k(mu) IgM or 11.1

1(X(alpha) IgA or ? A & (delta) IgD or ?D 1 1

.)(2 2x2 in or V'-2112)n n=5

- 6 or (0e2/12) n n=1,2,3 ,or

62X2 °r e2/12

.

IgM IgG , or

Y Y

or X

Disulphide linkages

IgA or )■ or.

a a

or 4

i , i • Mol. % of Amount in Re- :T2* Carbon w. . total:mg/100 ml•newal days hydrate '

Ig serum g/day . in % ' . /molecule

Synonym :Sed-- I Amen- ;

I tation;

h; A/2-2SY2 , 3S V1

2%

lo%

?

Class

7S I 160000

7-163 160000- 900000

19S 1000000

78 . 160000 160000?

28, .39 ca. 15000'

.ca. 2 gr

0,2-0,7

?

IgG

IgA

Ig1■1

xeo ien Low molecular imm.globulins

yG, 78y, y Ya

•>PA, yAl, bsA

ylM, 199? • POI •

J Reagitt, allergin

70-80

8-15

• 8-15

>1

600-1600 mg

90-390 mg

70L.90 mg

0,3-40 Mg

1,0 mg

go—so

4

TABLE III

Physical properties of immune globulins

*) T2 = half-life

Research on this heterogeneity is still going on and is based on the

fact that the basic structure of the four main classes of immune

globulin, IgG, IgM, IgA, and IgD (and IgE ?)i consists of four poly-

peptide chains. A complete immune globulin molecule is composed of

two identical H (heavy) chains with a molecular weight of about

55,000, and two L (light) chains (mol.w. about 20,000) bound to-

gether with disulphide links. The chains determine which main

class of immune globulins is in question. The L chains among which

two polypeptide structures, (kappa) and (lambda), can be dis-

tinguished, are common to all main groups of antibodies, - how-

a ever, in such/way that each complete molecule contains two identical

ulight" polypeptide chains (2Xor 2)i.), as shown by table II. Tables

=and IV summarize some of the general properties of human immune

5

globulin as well as some of its most typical physical parameters.

TABLE IV

General nroperties of immune globulins

General properties

Complement fixationAgglutinationPrecipitationCrossing of placental barrierAnaphylaxis and passive cutaneous

anaphylaxis

IgG IgA Ighi IgE IgD

Genetic variants

(56)

The main classes of immune globulin show some genetically,

conditioned diffe.rences. Two different types of antigenicity can

be distinguished. One of them is relatively easy to observe, as the

antigen variants create specific antibodies in other animal.groups

if these are immunized with heterologous material. The second type

is based on much smaller variation in the antigenic structure,

probably on small differences in the amino acid sequence or in the

tertiary structure. The last mentioned variants are called allo-

types or isoantigens and can in general only be discovered within

one and the same animal group. In humans, these are called Gm

determinants and are situated mainly in the so-called Fc fragment

of the heavy chain of an IgG molecule, but certain determinants

are probably created by the combined effect of H and L chains.

Corresponding allotypes in the^/-chains of the light chain group

are named Inv determinants. It has not been possible up to now

Mew!

Jleavy I • •

1 ----=r7=-7771

•ca • • : e •

1

kO8% . "20% ''..3.%.:f4% i813 % : •-Y-qa G1 let lee :Ma** !Pie** ?

ftWe) (N.e) WI) (Gé) • . :n • • • • •

' . c :5

ig

•

Genetic Inv allotypes Curt

Isoantigenic

1

- 11

. 34%

Light 1

f • 66 %

Chains

Groups

Antigenic (A4+. A4—)* (Z1+, Z1—) subgroups

a

to group )1/4-polypeptide chains accor_cling o.thjs sy_stem

(table V).

TABLE - V

Genetically conditioned -variants of immune .globulins

Immune g1ob3.11.in vG, yD,

(57- *) (18) (15)

**) (22) -***) (10)

t) WHO has recently published e :nomenclature :listing ;the ,:about :20 allotypes.

Production and function

It seems to be necessary to :different-late ..between -the 5steges

In antibody formation lea.ding e ey.nthesis :of -.immune g b.ulin And

the fo-rmation of specificity :and ;the tertiary .strueture -of ;anti_bo.di-es.

For the time% being, the •eve.lopment -is ...being remaained 33y :-rins ;of

:58)

f

s • [sl ' ==S:=7«.f_ZZi_ 2e

• L s n . . C terminal

7

Burnett's clone selection theory according to which the antigen

stimulates a predetermined cell clone which becomes responsible

for production of a specific immune globulin with a limited varia-

bility (about 10,000). Another group of researchers havapresented a

so-called instructive theory according to which the structure and

physicochemical nature of the antigen actively affects the formation

of specificity. And finally, Grabar is of the opinion that immune

globulin constitutes a physiologicely adaptive transport mechanism.

All main theories contain both acceptable and unacceptable axioms )

a combination of which possibly lies nearest to the truth.

The classical portrait of immune globulin is a spherical

elongated molecule with a length of about 240 A and cross sections

of 19 and 57 A. The four basic chains are intertwined and held to-

gether by a number of disulphide links within a chain and between

the different chains. The molecule is bivalent which means that two

antigen molecules can be attached to it. The combining sites are

situated so that both ends of an IgG molecule are able to attract an

antigen molecule. On the other hand, the five constituents of an IgM

molecule are, for some reason, monovalent when tested individually

after fission (figs. 2, 3).

IgG

240 A

about 107 amino acids variable constant

L chain qa 'tviimteloommero c N' terminal cg;fEsizME=3

-5-5

H chain

Fc . FraweilL •

Figure 2. Heavy and light chain structure for IgG molecules, modified after Ovary_ (16). Combining site regions are marked with (X), disulphide links within chains are shown as (). The number of the latter has not yet been finally determined. The com-

8

plementary variables and constant parts of L and H chain poly - peptides are marked in different ways because they are not completely identical. Areas affected by papain and pepsin are shown. The molecule is split into main fractions (Fab)2 and Fc (see fig. 4).

101:41{,.[71 r ftroui

X X

J%----tx • (.7% ‘\..e e •

Figure 3 A. The structure of an IgM molecule is probably regulated by disulphide links which connect the five basic molecules (see fig. 2) at one of the combining regions (the variable part of an.Lor chain) of every basic unit. Thus several alternative molecules could be created. Two examples are illustrated above. Changes in the con - figuration depend on an active binding of antigens. A tightly closed palisade formation can be seen at the end of agglutination (fig. B).

. - , . • . •

...t. -

• • as : ■1/4

•

,

•

• jel --«," • .

tee' im • •,• ;t

• rs:.;r.e.:;• , • • •;;27.„1 •s: • •• .• • 1;:r."

B. Latex particles enlarged 60,000 times by electron microscopy. Immune globulin molecules have fastened in different places on the surface of the latex particle, and different agglutination phases occur: The=otein antigen conjugated with the latex particle is invisible in this enlargement. (Unpublished results, Tallberg & Weckstrem).

Light .chain (L)

Heavy chain (H) ' ' IgG-molekyl

)■

cOon COOH

Figure 4. Snlittini . of immune globulin (earlier often called Porter's Fragment).

9

Fragment Fragment ' . Fragment *. ' .. : ' Fragment Pc _ — . • (Fab). . . l'ab • ' ' • . Pd

• . papain

PePsbl . kedjor

COOÙ NH • : I' H

•

* •

II .

. . • 14 . .

. t - . .

. . • .. t . . ' . .

Gm, . .

• . •

.

. .

. . .

determinants + Splitting of disulphide links determinants ** Combining sites

Disulphide links COOH= C-terminal N112= N-terminal

The combining sites are able to bind molecules with about 9

amino acids (Kabat (14), Singer & Doolittle (20) )) mhich corresponds

to a molecular weight of 500 - 1,000. An interaction of H and L

chains is required to create a fully combining region. The binding

force is not a covalent chemical bond but is created as a consequence

of a joint effect of several weaker forces such as the van der Waals

dipole moment, hydrogen bonds, and Coulomb forces (see Abraham (1) ).

The sum of these forces seems to be relatedto the character of complem.

mentary tertiary structures in such a way that the better the com-

bining site of the immune globulin coincides with the antigen, the

firmer the bond becomes. This force, i.e., the avidity of immune

globulin, usually increases in relation to immunization time. It is

1 0

also probable that if the reaction time becomes extended, the antigen-

antibody complex undergoes an active conformational change which re-

sults in a firmer aggregate with a decreased reversibility.

One half of a light chain molecule (about 107 amino acids)

is variable, while the other half, i.e., the C-terminal part, is more

or less constant. A corresponding part of a heavy chain polypeptide

is variable as well, and this variable part constitutes the combining

region together with the corresponding part of the L chain (fig. 2) 1

(Singer (20) ).

Only five different positions of these variable polypeptide

chains display variations of the amino acid sequence (Kabat, personal

communication). As only 2 - 3 different amino acids have been dis-

covered in these variable points, the specificity of the combining

region is hardly regulated by changes in the amino acid sequence

alone. An active conformation of the volume structure of immune glob-

ulin is probably important for the specificity and action of the anti-

body.

The C-terminal part of the H chain is, like that of the L

chain, constant, with the exception of certain amino acidic differences

which form a basis for the antigenic and isoantigenic variation that

has been discovered in immune globulin classes (Ovary, 16).

This presentation of the infrastructure of immune globulins

is the joint result of efforts by several research teams. An important

part of these efforts has consisted of enzymatic decomposition and

fission of disulphide 11,nks- . The term Porter's fractionsis used here

after its inventor Porter. These fragments of the gamma globulin mole-

cule are called Fab, Fc, and Fd (fig. 4), - terms that often occur

in modern theoretical immunology. It has been discovered that

(59)

the (Fab)2 fragment alone is able to bind two antigen molecules^

while the Fc fragment (He:nneY & Stanworth (11) ) has no combining

sites. However, it binds complement (out of which about 8 components

are known today), fixes immune globulin in cells and determines

whether immune globulin can cross the placental barrier, etc.

(Table IV').

Wing, to the very effective transplacental transfer of mainly

IgG during the final stage of pregnancy, active production of immune

globulin during the fetal life is very low. However, it has been

possible to prove that a potential ability to produce immune globulin

actively exists already during the embryonic life, since the thymus,

which has an important function in regulating the defense mechanism,

is e:cistent. As for the questions of immunological specificity,

hypersensitivity, and immunotolerance, we refer to Good & Gabriels%n

(7).

The cellular phases of immune globulin production constitute (60)

a complicated chapter. We do not know enough of what actually happens

after phagocytosis with the consequent antigenic coding, the transmit-

tance of this coding (via RNA or 1ZiT:1+ the antigenic determinant ?

(Braun & Cohen (2) ), the creation of cell-mediated hypersensitivity

reactions - immunological memory carried by some lymphocytes

while the rest of them develop into complete plasma cells producing

immune globulin, - formation of the tertiary structure and specificity,

- formation of natural antibodies, etc. A plasma cell is finally

clearly able to produce one or several specific immune globulins,

although always of one type only (Igili, IgA or IgG).

12

Anew-born baby starts actively producing immune globulin,

primarily IgM (against new antigens) at the age of 4-5 weeks, and at

the age of 3 years, the child reaches a relative composition of IgM,

IgG and IgA similar to that of adults (table III), occurring in the

mentioned order. Lfter this stage has been reached, half of the body's

gamma globulin reserves usually lie in the circulating plasma while

the rest of it is found in the extravascular part of the extracellular

body fluid. However, different organs show varying concentrations.

Antigen, which constitutes the actual stimulus for the

specific immune globulin synthesis, often gives rise to both a primary

and a secondary immunareaction. In the primary phase, when the immuno-

logical memory and the "delayed hypersensitivity" are created, an

irmune globulin synthesis results mainly in IgM. This is derived from

plasmacytoid PAS-positive cells. IgA is formed as well in the tran-

sitional phase) while a noticeable IgG production takes place in the

seconctryphase (Janeway, 13). It is often characterised by a high

antibody titre. A reinfection or an immunizing "booster" (or re-

vaccination) therefore most often result in a rapid IgG titre increase.

Additionally, certain forms of antibodies occur in urine,

saliva, and colostrum, which are not fully identical wlth the four main

groups of gamma globulin present in plasma (Gitlin, 6). It muetbe re-

membered as well that all immune globulin types are not even known.

One of the problems is that a great part of human globulin consists of

immune globulins such as "natural antibodies" (like properdin),

"isoantibodies", opsonin, etc, the specificities of which have not been

determined yet.

13

Immune .ffl.obulin - deficienoy and malformation

In normal cases such a physiological balance is created

as to reF,ulateautomaticallythe amounts of immune globulin. How-

ever, this mechanism with anabolism, catabolism, and consequent half-

lives naturally displays both physiological and pathological varia-

tions.

Different forms of overproduction can be discerned,such as poly-

alonal and monoclonal gammopathies,as well as deficiencies like

common hypo- or agammaglobulinemias. The specific lack of a certain

type of immune globulin is called dysproteinemia. A lack of one or

several immune globulins is often diagnosed in connection with basic

medical examination of patients suffering from recurrent common in-

fections. Recently, both Hobbs (12) and Janeway (13) have produced

excellent and detailed descriptions of these complex antibody defi-

ciencies. In children younger than 12 months a value remaining under

100 mg/100 ml is defined as indicating hypogammaglobulinemia. In

older children this limit value is 200 mg/100 ml.

As many cases already can be clinically treated with human

gamma globulin, I have summarized in table vr the different forms

of gamma globulin deficiencies. It might be of special interest to

point out that the most difficult form of deficiency, "thymus

alymphoplasia", along with the lack of "delayed hypersensithrity",

(e.g. tuberculin reaction), is often characterized by a complete

agammaglobulinemia. The other cases are mostly only relative deficien-

cies and must therefore be defined as hypogammaglobulinemias.

Dysproteinemdas with consequent "immune paresis" display a total

14

lack of either a certain immune globulin or two classes of it.

An abnormal variation in the relative physiological combination

of the four main classes is often created in this connection.

Efforts have been made to design a numerical nomenclature for

dysproteinemia types, but unfortunately the usefulness of such a

nomenclature is impaired by extensive variability and the fact that

it does not directly reveal which type of dysproteinemia is con-

cerned.

The syndrome of immune globulin deficiencies certainly has a

very complicated etiological background. However, certain simple

theories can be conjured astp how the deficiencies are created.

A) The light chain synthesis is lacking, resulting in a shortage of all

immune globulins. B) Certain heavy chain types (p,ft.,CX, 8 ) are not

produced, which results in selective dysproteinemias. C) The amino

acid sequence of the tertiary structure of a combining site develop

defectively and decrease the effectivity of immune globulins. D)

The immune globulin molecule does not emerge from the producing cell

in an undisturbed state or is affected by humoral depressor

mechanisms, etc.

.As mentioned earlier, a group such as dysproteinemias at

least gives rise to some optimism because a great number of patients

have been saved by supporting therapies with human gamma globulin,

antibiotics, and what is perhaps most important, by effective pre-

ventive hygienic care. However, the genetic variations of immune glob-

ulins do create a difficulty mhich can cause unexpected complications.

TALLE VI

Antibody deficiency syndrome *)

A. Thymus alymphoplasia

B. Congenital a(hypo)gamma.globulinemia

C. Acquired hypoganunaglobulinemia1. Primary (idiopathic)2. Secondary

a. Radiation

b. In reticuloendothelial diseasesc. Chemical, cytotoxic (pharma-

cological) suppressiond. General protein deficiency

D. Dysganma,s ,̂lobulinemia

1. Transient

a. Neonatal dysganunaglobulinemiab. Transient hypo;amnaglobulinemiac. Transient hypoganLnagloUulinemia

2. Congenital dysgamma^lobulinersia

3. Acquired dysgammaglobulinemia

E. In connection with apparently normalimmune g,_lobulins

Farailial, fatal results before the age of 2,usually male children, "delayed hypersensitivitysr-reactions lacking.Sex-influenced recessive, most often male children,

starts at the age of 6 months-3 years, relatïvely

conma.zdeficiency syndrome, "delayed hypersensitivi-

ty" present.

At any age.Familial predisposition ?

Malabsorption, malnutrition, renal causes.

Prematurity and a so-called brief physiological. (65)In children, delayed development.In adults, complicated and diverse etiology.

Total lack of one or several immune globulintypes, IgG, IgA, Igii, IgD. In connection with e.g.

ataxia telangiectasia, the Wiscott-Aldrich syn-

drome, etc.In certain autoiimuune and infectious conditions.

*) Modified after Janeway (13a).

16

Polyclonal gammopathy, an overproduction of gamma globulin,

can be physiological and occurs in the form of a generally broad

increase in all immune globulin types. It occurs often it' bbnnettron

with cirrhosis, chronic infections, LED, hyperglobulinemic purpura,

chronic sialoadenitis and certain collagenoses, sarcoidesis, rheuma-

toid arthritis, and autoimmune conditions. As a whole., it could be

stated that even if the clinical condition is often •iIptoved by

cortisone treatment, we do not understand the etiology of it.

I shall not dwell on problems related to the "théunatoid

factor syndrome" because these have recently been dealt With by both

Squire (21) and Gothoni (8).

The actual paraproteinemias are almost exclusiVely related

to the so-called monoclonal gammopathies. Myelona can very rarely

be regarded as a result of a simultaneous aberration of several ful=

ly separate cell clones.

Following Waldenstromts discovery of nacroglobulinenlas,

cases of nyelomatosis have been found within all •itune grobulin

classes. The small monoclonal bands making their appéaYabce during

electrophoresis were named M-bands by Riva (19), and •they can be

seen in immune electrophoresis even more clearly as nodules on the

precipitation lines of respective immune globulins (fig. 1 B).

The most common form is the IgG-type of nyeloma (about 65 %

of all cases) while IgA constitutes about 25 % and IgM 1 %.

There have been a few cases of IgD myeloma as well. 1 % of the Caseà

have not been classified yet. Certain gamma globulin aberrations

make their presence known in overproduction of light chain poly-

peptide components alone. This is the cause of the Bence-Jones

17

protein in which as much as 50 g/day of certain light chain

type components are found in the urine in monomeric or dimeric

form. Consequently, one would expect to come upon cases with an ab-

normally increased heavy chain production without a corresponding

increase in light chain production. Franklin (4) has been the first

to describe such cases.

The clinical course of paraproteinemias can be rapidly pro-

gressing and extremely malign, but a surprisingly great number of

cases represent a benign or only slowly progressing disease (Hobbs

(121) ). Excluding asymptomatic cases, the ii-band is present in

1 % of normal population and 3 % of persons over 70. These essential

monoclonal gammopathies do not make our problems easier to solve.

Often the disease is revealed by classical bone lesions,

different forms of anemia, immunoparesis,(primarily in connection with

IgG myeloma), renal complications, amyloid formation, pyelonephritis.

and hypercalcemia (often in IgA myelonm), cryoglobulinemia,

and last of all IgTI myeloma with the so-called viscosity syndrome.

This means mainly a feeling of thorough fatigue, distension of

the retinal veins, frequently with bleedings in the bottom of the eye,

an SR exceeding 100, and purpura.

However, these symptoms are not limited to one parricular form of

myeloma, and Waldenstrom has discovered e.g. that because of different

polymerization phenomena, certain forms of IgG myeloma and the Bence-

Jones protein lead to results strongly resembling the symptoms of an

IgM myeloma.

(67)

19. Riva,

• 18

The data concerning immune globulinsaxe accumulating mith such

a speed that we shall probably soon find ourselves in a situation

where we do no longer control the problem. We are conscious

of the fact that immune globulins are living proteins with all the

relevant details that are so fascinatingly difficult to understand.

The usability and the advanced specificity by mhich gamma globulins

are characterized make us grateful for the Privilege of being allowed

to study them.

1. Amun.tra, E. P.: I •Ge_neral Path .°logy III. Ed.» editor Florey, Lloyd-! Luke LTD. (London). 1962. - 2. BRAUN, W. & CORES, E. P.: On the Role of ! . -nucleic Acids in Antibody Formation. Information Exchange Group No. 5, •

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