Humoral and celtular immunity in asthma

D. I. Grove, T. 0. Burston, M. 1. Wellby, R. Munro Ford, and

1. J. Forbes Adelaide, Australia

Parameters of humor-al and cellular immunity have been measured in 91 asthmatic

patients. Yenn s~rnrn levels of IgG and IgE were raised. IgG levels were higher k~
those with a family history of asthma. IgE levels were higher in those with a past
history of atopic eczema, but intrinsic and extrinvic asthma could not be differ-
entiated on the basis of IgE levels. Thirteen of 74 patients failed to respond to
tetanus immunization, while only 1 failed to respond to Salmonella typhi H antigen.
Tetanus nonresponders had a raised mean serum IgA level, I-e&cod spontaneous
lymphocyte tritiated thy&dine uptake, and reduced thymidine uptake in fetal
calf serum. Eight of 87 patients failed to mount delayed&hypersensitivity reactions
to a battery of five intradermal antigens. The tritiated thymidine uptalce of lympho-
cytes stimulated with phytohemaggktinin was normal in antologows sernm, but
reduced in fetal calf serum. The data support the hypothesis that asthma may 6e
associated with immnnodeficiency states.

Leskowitz, Salvaggio, and Schwartz1 listed four hypotheses to account

for the development of the, atopie state: (1) a predisposition of atopic persons
to produce skin-sensitizing antibody on a hereditary basis, (2) a defect allowing
prolonged retention of antigen with consequent heightened reaginie antibody
production, (3) an enhanced reactivity to released pharmacologic intermediates,
and (4) a defect in the defense barrier aeross mucosal surfaces with more e&
cient contact between antigen and immunologically competent hells. There have
also been suggestions that there may be an association between immunodefidency
and atopy. Kaufman and Hobbs* have suggested that atopy develops in indi-
viduals whose immunologic memory is “backward” and demonstrated immuno-
globulin deficiencies in an atopic population. A high prevalence of atopy has
been noted in immunoglobulin deficiency syndromes.3 It has been suggested that
transient IgA deficiency in infancy may be associated with the subsequent de-
velopment of atopy.4 This study has been undertaken to measure various param-
eters of humoral and cellular immunity in asthma. The data support the hypoth-
esis that asthma may be associated with a variety of immunodeficieney states,
PATENTS AND CoN?lKtL SlbEIlECTS
Forty-two male and 49 female asthmatic patients were studied. Their ages
ranged from 9 to 63 years, with a mean age of 31 years. There was one patient
in the first decade, and there were 18, 22, 29, 13, 6, and 2 patients in each suc-

Prom the Department of Medicine, University of Adelaide, Department of Clinical Chemistry,

Queen Elizabeth Hospital, and Royal Adelaide Hospital.
Supported by the National Health and Medical Research Council of Australia.
Received for publication Dec. 5, 1973.
Reprint requests to: Dr. D. 1. Grove, Department of Medicine, Queen Elizabeth Hospital,
Woodville, South Australia 5011.
Vol. 55, No. 3, pp. 156-163
VOLUME 55 Humorol and cellular immunity in asthma 153
NUMBER 3

ceetling decade. There were unselected patients who consulted an allergist and
agreed to take part in the study.
Patients were considered to be asthmatic if they gave a history of intermittent
wheezing and shortness of breath which resolved either spontaneously or on
treatment with bronchotlilators.” Many patients had additional objective evidence
of reversible airway obstruction on spirometry before and after inhalation of
orciprenaline. It was dif?icult to demarcate clearly all patients as either intrinsic
or extrinsic asthmatics; each patient was therefore classified into one of the
following five groups on the basis of the clinical features and results of skin
testing for immediate hypersensitivity and without knowledge of the other im-
munological findings. (I) Extrinsic: caused only by demonstrable allergens.
,Symptoms usually worse in spring and summer. All had positive skin tests.
(2) dlosfly extrimic: as in (1) plus some wheezing aft.er colds or for no apparent
reason. (3) ~xtri?lsic-iwtri~lsic: ev nly balanced (1) and (5). (4) J1ostZy i?l-
/e
trinsic: as in (5) plus some incrimination of extrinsic factors. (5) Intrinsic: n0
demonstrable extrinsic cause, but wheezing frequently associated with respiratory
infections, weather changes, emotion, exercise, often with a tendency for symp-
toms to be worse in winter. All had negative skin tests.
Most patients were receiving some form of drug therapy both prior to and
during the study. Fifty-one patients were receiving bronchodilators, either orally
or by inhalation. Twenty-seven were taking antihistamines; 18, disodium cromo-
glycate, 20 to HOmg. daily; 12, antibiotics, mostly benzathine penicillin; 3, brom-
hexine; 1, amitriptyline; 1, diazepam. Thirty-one patients had been on a course
of hyposensitizing injections, twice a week or more, for at least one month, with
graded antigen preparations (Commonwealth Serum Laboratories, CSL) .
The control values were established on normal people, together with a few
patients suffering from vascular or neurologic diseases. Control patients were
not receiving drug therapy. Xot all parameters were measured for each control
subject.
The mean age of the control population was 33.1 years, with age range and
distribution similar to those of the asthmatic group.
METHODS
Patients were skin-tested for immediate hypersensitivity responses to a wide range of
allergens and respiratory function assessed by spirometry.

lmmunoglobulin levels
Serum levels of immunoglobulins (Ig) G, A, M, and D were measured with Behringwerke
immunodiffusion plates. Standard solutions were obtained from Behringwerke.
Serum levels of IgE were measured both by the radioactive single radial diffusion method
described by Rowe6 and with the commercially available solid-phase radioimmunoassay
“Phadebas IgE Test” (Pharmacia, Uppsala). A high correlation was obtained between the two
methods (r = 0.9765, p < 0.001). lgE standard was from a batch of pooled human sera,
69/204, supplied by WHO.

Antibody responses
Patients were immunized with tetanus toxoid (CSL), 0.5 ml. subcutaneously, and typhoid
vaccine (CSL), 0.1 ml. subcutaneously, and blood was collected, usually at 2 weeks, but up to
154 Grove et al. J. ALLERGY CLIN. IMMUNOL.
MARCH 1975

TABLE I. Serum immunoglobulin levels

kl* I No. / Mean / S.D. ( Pi-obabliiy t

TgG asthmatic patients 91 1,462 394 < 0.001
Control subjects 88 1,190 311
Igll asthmatic patients 91 203 90 N.S.$
Control Puhjects $7 197 77
IgM asthmatic patients 91 149s 56 N.S.
Control subjects x9 14X$ 70
IgI) asthmatic subjects 91 11.9$ 47 S.S.
Control subjects 74 16.9$ 62
IgI+; asthmatic patients 91 2259 480 < 0.001
Control sulljeets 100 w 110
“IgG, IgR, and IgM in milligrams per 100 ml. IgD and IgE in units per milliliter.
t Probability by Student’s t test.
:s.s. : not significant.
QGeomctric mean and standard deviation.

,4 weeks in a small number, after immunization. Hemagglutinating antibodies to tetanus anti-

gen and precipitating antibodies to S. typhi H antigen were measured.7 Patients were con-
sidered to fail to respond t,o immunization when no antibodies were detectable.
Nosi South Australians have previously been exposed to tetanus toxoid, but have not
usually l)een immunized with typhoid vaccine. Slercaptoethanol treatment of sera from normal
subjects and patients with chronic infections, patients with dystrophia myotonica, and a
sample of asthmatic patients in this series confirmed that response to tetanus toxoid was usually
of the IgQ type, while 8. typki II antigen usually produced an IgM response.

Delayed hypersensitivity reactions

Delayed hypersensitivity (DHS) reactions to intradermal injections of 0.1 ml. of Asper-
gi/.Z~s fumigntks (CSL), Candidn a&cans (Rencard), mumps skin test antigen (Eli Lilly),
old tuberculin (CR,), and streptokinase-streptodornase (Varidase, Lederle) were measured at
48 hours. Patients were considered to have a negative response if they failed to react to at
least one antigen.

Lymphocyte tritiated thymidine uptake

l)ose-response curves to phytohemagglutinin (PHA) were established. The tritiated (“II)
thymidine uptake at varying periods of incubation with the PHA dose producing maximum
responsiveness was measured. On the basis of these results, the most appropriate PHA dosage
and period of incubation were used for l~oth xutologous and fetal calf serum as described
klorv.
PHA-induced uptake of :{H thymidine by lymphocytes was measured in whole blood oul-
tures. Cultures contained 0.2 ml. of whole blood, 3.4 ml. of Hepes-buffered medium 198 (CSL),
0.02 ml. of PHA (Burroughs Welleome Co. reagent grade), and 0.4 ml. of fetal calf serum
(CSL) or autologous serum. Triplicate cultures were incubated for 4 days at 37” C. At 92
hours, 2.5 &i of aH thymidine (specific activity: 500 mCi per millimole) were added and
incubated for another 4 hours. Cultures were then kept at 4” C. for half an hour, centrifuged
at 250 g for 10 minutes, washed with 3 per cent acetic acid, 0.9 per cent saline, and 5 per cent
trichloroaeetia acid in 0.45 per cent saline in suecession, then centrifuged at 1,990 g for 29
minutes with 5 per cent trichloroacetic acid and twice with methanol. After drying, the residue
was dissolved in 0.5 ml. of Soluene (Packard) for liquid scintillation counting.
The spontaneous uptake of sII thymidine by cultures, i.e., in the absence of PHA, was
measured by incubating 0.2 ml. of whole blood in 3.8 ml. of medium with 2,.5 &i of sH thy-
midino at 37” C. for 4 hours and then treating as above.
Total white blood cell counts were measured with a Coulter counter and differential
VOLUME 55 Humoral and cellular immunity in asthma 155
NUMBER 3

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NORMAL I>E I-E E*l EXTRINSIC

CONTROLS AwnMA TYPR
FIG. 1. Serum IgE values (units per milliliter) plotted on a logarithmic scale for normal
control subjects and patients in each asthma class.

counts were performed. Results were calculated as disintegrations per culture tube per minute
and as disintegrations per million lymphocytes per minute. The results obtained from both
methods mere similar. Results reported here are expressed only as disintegrations per culture
per minute.

Statistical methods
Two-by-two table comparisons were made wit.h Fisher’s Exact Test.8 The significance of
differences in the means of two populations was calculated with Student’s t test.9 The values
for IgM, IgD, IgE, and spontaneous lymphocyte sII uptake followed a log-normal distribution.
For these parameters, t calculations were made with the use of logarithmically transformed
values but, for ease of interpretation, the tables show the geometric mean and standard
deviation calculated as follows :
Geometric mean = antilog of logarithmic mean
Standard deviation =
antilog (log mean + 1.96 log S.D.) - antilog (log mean - 1.96 log S.D.)
3.92
156 Grove et al. J. ALLERGY CLIN. IMMUNOL.
MARCH 1975

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HG. 2. Titers of antibody to tetanus toxoid before and after immunization. Each soLid
line represents 2 patients and each broken line 1 patient, with the dot on tha left being
the preimmunization titer and that on the right representing the postimmunimtion tRer.
Titer is log, of reciprocal of highest dilution at whii herrtaggtutination w& ~krved.

Mean serum levels of IgG and IgE were raised (Table I). Levels of IgA,
IgM, and IgD were normal.
Pamily history of atop%. Patienta who had a family history of a&ma, bay
fever, or atopic eczema had significantly higher (p < 0.05) serum IgG levels
VOLUME 55 Humoral and cellular immunity in asthma 157
NUMBER 3

TABLE II. Delayed hypersensitivity reactions

I Reactors Nonreactors Probability*

Asthmatic patients 79 8 < 0.02
Control subiects
Y
86 1
*Fisher’s Exact Test.

TABLE III. Serum IgE* and DHS skin responses

I NO. I Geometric mean I S.D. 1 Probabilitd

hspergillus
+ 13 152 395 x.8.:
- 74 210 560
Candida
+ 48 143 290 < 0.01
39 299 870
Mumps
f 67 171 410 N.S.
20 277 490
Old tuberculin
+ 194 530 N.S.
- i,” 19R 500
Varidase
+ 61 157 540 N.S.
26 234 470
“IgE expressed as units per milliliter.
tI’robahility by Student’s t test.
tN.8. : not significant.

(68 subjects, mean 1,499 + 315 mg. per 100 ml.) compared with those without
such a family history (22 subjects, mean 1,350 ? 229 mg. per 100 ml.). Patients
without such a history did not have significantly elevated levels when compared
with normal control subjects. The mean serum levels of the other immunoglobu-
lins were not related to such a history.
Past history of eczema. Only 3 patients were currently suffering from atopic
dermatitis, but serum IgE levels were significantly elevated (p < 0.02) in the
group with a positive past history (1’7 subjects, geometric mean 412 Ii. per milli-
liter, SD. 1,560 U. per milliliter) when compared with those without such a
history (73 subjects, geometric mean 199 U. per milliliter, SD. 320 TJ. per milli-
liter). Other immunoglobulin classes were not affected,
Asthma classification. When the mean serum levels of immunoglobulins G,
A, &I, and D were compared in the five classes of the asthma classification, no
significant differences were seen. Similarly, no significant differences were found
when the mean IgE levels were compared (Fig. 1) . Nine patients were classified
as intrinsic (geometric mean IgE 202 U. per milliliter, SD. 950 U. per milliliter),
17 as mostly intrinsic (239, 590), 14 as intrinsic-extrinsic (176, 305), 31 as
mostly extrinsic (222, 370), and 20 as extrinsic (270, 495).

Antibody responses
Antibody titers were measured before and after immunization in 74 asth-
matic patients. No hemagglutinating antibodies to tetanus toxoid were detectablr
in 13 of the patients (18 per cent) (Fig. 2). This result is highly significant
(p < 0.001, Fisher’s Exact Test) when compared with only one failure to make
158 Grove et al. J. ALLERGY CLIN. IMMUNOL.
MARCH 1975

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CONTROLS ASTHMATICS
FIG. 3. individual values for 3H thymidine uptake (disintegrations per minute per culture)
in fetal calf serum of asthmatic patients and control subiects.

antibody in 74 age- and sex-matched control subject.s. Xesponse to tetanus im-

munization was not related to past. history of eczema or family history of atopy.
When tetanus respondew were compared with nonresponders, no dS%rences were
found in the mean serum levels of immunoglobulins (1, M, D, and E. There was,
however, a significantly higher (p < 0.005) serum IgA level in nonresponders
(13 subjects, mean 258, standard deviation 86 mg. per 100 ml.) than in t.hose
who responded normally (61 subjects, 191. .t_ 77 mg. per HI0 ml.). Failure of
tetanus response could not be related to drug therapy or clinical status.
Precipitating antibodies to 8. typhi II antigen were not detectable in one of
the 74 asthmatic patients. No failure to respond occurred in control subjects.
This result was not statistically significant.

Delayed hypersensitivity reactions

IJIIS reactions were measured in 87 patients, Eight (9 per cent) failed to
rcact to any of the five antigens compared with only 1 such failure in 87 control
subjects (Table II ) .
There were no significant differences in the immuoglobulin levels of any of
the five major immunoglobulin elasses between skin teat reactors and nonreactors.
In the case of IgE, the mean value for the 8 nonreactors was 261 U. per milli&er
with a range of 15 to 1,600; for the 79 reactors the mean was 227 with a range
of 35 to 1,530 IT. per milliliter. The mean serum IgE levels in reactors and non-
reactors to individual skin tests is shown in Table III. There was a significantly
higher serum IgE level in those patients who failed to mount a rea@&u to Can-
dida antigen. A similar, though in the individual cases, not siig;ll&oant, trend,
VOLUME 55 Humoral and cellular immunity in asthma 159
NUMBER 3

TABLE, IV. 3H thymidine uptake*

No. 1 Moan 1 S.D. 1 Probability t

PHA sH uptake-autologous serum
Control suhieets 74 76.000 39.400 N.8.t
Asthmatic patients 90 78;300 37;700
PHA nH uptake-FCS§
Control subjects 84 71,500 32,300 < 0.001
Asthmatic patients 90 52,500 27,600
Spontaneous sH uptake
Control subjects 90 400; 208 N.S.
Asthmatic patiants 80 3921 299
*Disintegrations per culture per minute.
tProbahility by Student’s t test.
:s.s. : not significant.
SF&al calf serum.
/IGeometric mean and standard deviation.

TABLE V. 3H thymidine uptake* and DHS skin reaction

I RMlCtOir I Nonmacton
PEA, autologous
No. 77 8
Mean 73,500 64,600
8.D. 37,100 37;400
PITA, FCS
NO. 77 8
Mean 52,700 44,200
S.1). 27,700 23,100
*I)isintegrations per culture per minute.

was seen with the other four antigens. No patient failed to respond to both DHS
skin testing and tetanus immunization.
lymphocyte tritiated thymidine uptake

The uptake of 3H thymidine by lymphocytes is shown in Table IV. The up-

take of “II thymidine by lymphocytes stimulated by PHA in the presence of
autologous serum was normal, whereas there was a depressed uptake in the pres-
ence of fetal calf serum (Fig. 3). The spontaneous uptake of 3H thymidine by
lymphocytes fell within the normal range.
When the mean 311 thymidine uptake was compared among the five classes
of asthmatic patients, no differences were found in any of the three parameters.
Similarly, 3H thymidine uptake was not related to family history of atopy or
past history of eczema.The 3H thymidine uptake was less in the DHS skin test-
negative patients in both autologous and fetal calf serum (Table V), but not
at a statistically significant level. PHA-stimulated uptake of 3H thymidine was
normal in the presence of autologous serum, but even further reduced in fetal
calf serum, in those patients who failed to make an antibody response to tetanus
toxoid (Table VI). The spontaneous 3H thymidine uptake was also reduced in
this latter group.
There were no differences for any of the parameters in patients undergoing
160 Grove et al. J. ALLERGY cw. IMMUNOL.
MARCH 1975

TABLE VI. 3H thymidine uptake* and tetanus response

Tetaws responders Tdpnur nonnsporr&rr 1 Probub~lily t

PHA, autologous
WO. 60 13 S.S.$
Mean 68,100 62,400
SD. 37,100 37,400
I’HA, FCS
NO. 57 13 < 0.05
Mean 54,500 36,400
R.D. 28,800 14,500
9L.pontaneous
SO. 54 I1 < 0.01
Geometric meau 400 238
SD. 225 240
*Disintegrations per culture per minute.
tProbability by Student’s t test.
#;Y.S. : not siguificant.

hyposensitization therapy. Analysis of data revealed no differences in patients

receiving either disodium cromoglycate or antibotics.
DISCUSSI0N
These results provide evidence of impairment of antibody production 01
cellular immune processes in some patients with asthma. It is proposed bhat
diminished function may be related to the pathogenesis of asthma.
Impaired cellular immunity was demonstrated by absent DHS skin reactions
in some patients. The mean serum IgE level of the nonreaetors to each antigen
was higher than that of the reactors, although this difference was significant
only for Candida antigen. This may be evidence of increased reaginic stimulation
secondary to impairment. of the cell-mediated immune system.
It is generally recognized t,hat lymphocyte responsiveness to PHA is an index
of cellular immunity.lO The 3H thymidine uptake was within normal limits when
the lymphocytes were cultured in autologous serum but depressed when cultured
in fetal calf serum. If drugs were to affect lymphocyte activity significantly, more
profound depression of transformation would be expected in lymphoeytes that
were cultured in autologous rather than fetal calf serum. The significance of the
finding is obscure. It is possible that the depressed uptake may simply represent
an altered kinetic or dose response to PHA rather than an inherent defeet of
lymphocytes. Alternatively, the reduced uptake in fetal calf serum may be a
result of intrinsic hyporeaetivity of lymphocytes of asthmatic patients, with
the normal uptake in autologous serum due to less of a postulated inhibitor of
lymphocyte aetivity’l in the serum of asthmatic patients.
Eighteen per cent of astmatic patients failed to make antibodies after im-
munization with tetanus toxoid, this usually being an IgG secondary response.
This represents not merely failure to increase the titer but also failure to pro-
duce any detectable antibodies. There is, however, not a complete block in anti-
body production, for 10 nonresponders produced antibody after reimmuniz&ion.
This phenomenon has been observed previously in people au&ring fIvlrn &r&e
VOLUME 55 Humoral and cellular immunity in asthma 161
NUMBER 3

infcctions.7 It is probable that this test is a relatively sensitive indicator of

humoral immunologic competence.
Other workers have assessed the humoral immune response in asthma. Kuhns
and PappenheimeF described an asthmatic boy who produced reaginic but not
precipitating antibodies to diphtheria toxoid and 3 nonatopic subjects who failed
to produce precipitating antibodies despite high titers of reaginic antitoxin.
Leskowitz and I,ovell13 did not demonstrate any differences in the capacity of
atopic and nonatopic subjects to produce precipitating antibodies on immuniza-
tion with dextran and pneumococcal polysaccharide administered parenterally.
Tho failure of response to tetanus toxoid in our series may reflect a different
population of asthmatic patients, difference in the antigen, or production of
antibody with reduced affinity for tetanus toxoid. Alternatively, these findings
may be analogous to those in mice in which the secondary response to tetanus
toxoid is thymus-dependcnt,l” whereas antibody responses to Salmonella flagellar
antigen arc less thymus dependent and to pneumococcal polysaccharide, thymus-
indcpendent.l”
Ot.her abnormalities in the group of tetanus nonresponders were a raised mean
serum IgR level, reduced spontaneous lymphocyte % thymidine uptake, and an
even more depressed PHA-stimulated uptake in the presence of fetal calf serum.
These data suggest that tetanus nonresponse is not simply an isolated defect in
these patients.
&Iost workers have found little difference between mean levels of IgG, IgA,
and IgM in control and allergic populations.lO-“o In contrast., our patients with
a positive family history of atopy had a raised mean IgG level. Normal levels of
IgR and IgN were seen in this study. Kaufman and HobbsZ1 demonstrated that
7 per cent OS atopic subjects had immunoglobulin levels at least two standard
deviations below the mean, this finding being most marked with IgA. In our
series, no patients had an IgG or IgM reading less than two standard deviations
below the normal range, and serum IgA was not detectable in one patient.
Only 27 per cent of patients had IgE levels above the normal range. This
proportion is less than that found by some workers, but is similar to the findings
of Kumar, Newcomb, and Hornbrookz2 in working with children. It is possible
that the levels were low because the study was carried out in winter, when aller-
genic stimulation may have been less. Many attempts have been made to classify
asthma.2J Many reports dealing with serum IgE levels in asthma have differenti-
ated between extrinsic and intrinsic groups.16v 22s24,Z5We were not able to make
such a sharp distinction in many cases, and considered it preferable to grade
patients into one of five classes, passing from most intrinsic to most extrinsic.
No differences were apparent among any of the five classes. This finding is in
agreement with the observation of Henderson and associates,26 who found that
21 per cent of patients with intrinsic asthma had raised IgE levels. It is con-
sistent with the conclusion of Rackemann that clinical evidence “gives strong
support to the idea that these diseases are all the same.“23
The data presented support the hypothesis that atopy results from deficiencies
in the immunologic defense mechanisms, humoral or cellular, leading to increased
162 Grove et al. J. ALLERGY CLIN. IMMUNOL.
MARCH 1975

stimulation of the rcaginic system. This system may have evolved for other
reasons--perhaps, for example, defense against helminth infestation.“” Iteaginic
antibodies can bc induced in almost every individual under the appropriate cir-
(2U**sta~*(ys,l:i. Zb-‘+O
The factors that determine these circumstances may be higher
intrinsic activit>T of the reaginic system or relative inefficiency of the other hu-
moral or cellular immune mechanisms. These two systems may each he subject
to gcnctie influences. The great range ill sevt4t.y of clinical asthma may similarly
rctlect the interaction of these factors. There may be many varieties of immuno-
logic deficiency that have, as their common response, a clinical presentation as
one of the atopic diseases.
\vc wish to thank Mr. M. O’Halloran for statistical advice.

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2 Kaufman, H. S., and Hobbs, J. R.: Immunoglobulin deficiencies in an atopic population,
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3 Hobbs, .J. K.: ‘Primary immune paresis, in Adinolfl, M.: Bmnunolog~ and development,
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(:ittions, chap. 5, p. 114.
4 Taylor, H., Norman, A. P., Ogel, II. A., Stokes, C. B., Turner, M. W., and Soothill, J. F.:
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IgA and 1gM in children with intractable asthma, Ann. Allergy 25: 177, 1967.
VOLUME 55 Humoral and cellular immunity in asthma 163
NUMBER 3

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Select the ONE best answer for the following question from the Allergy
Foundation of America Self-Assessment Program:

Question 1. Pulmonary emphysema is associated with each of the following

EXCEPT

(A) increased airway resistance due to hyperinflation of the lung

(6) increased airway resistance that is irregularly distributed
(C) airway resistance that is especially increased during expira-
tion
(D) increased lung volume
(E) irregular distribution of the pulmonary blood flow

The correct answer and bibliographic reference will be found on page 194 of
this Journal.