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OCR for page 317
The Medical Implications of Nuclear War, Institute of
Medicine. ~ 1986 by the National Academy of Sciences.
National Academy Press, Washington, D.C.
The Immunological Impact of
Nuclear Warfare
DAVID S. GOFER, M.D., md LA~NCE S. MEN
Brown University Program in Medicine,
Providlence, Rhode Islandt
Medical interest in nuclear warfare initially was focused on the im-
mediate effects in human populations of blast, heat, and radiation and the
futility of civil defense measures. Recently, the concept of nuclear winter
has called attention to intermediate and long-term outcomes. The biolog-
ical impact of a major exchange of nuclear weapons has been addressed
in general terms, but little attention has been given to the specific elements
of potential biological injury. With this paper, we hope to carry biomedical
interest in nuclear warfare to another level of detail and specificity by
postulating, from a review of relevant literature, that there would be major
immunological damage to surviving human populations. We also speculate
on the likelihood of additive or synergistic deleterious effects that would
arise from exposure to multiple toxic agents.
BACKGROUND
Human lymphocytes are classified on the basis of differing develop-
mental pathways as B lymphocytes and T lymphocytes, which display
different immunological functions. B lymphocytes are precursors of an-
tibody-secreting cells. T lymphocytes control cellular immune responses
and are the effecters of cell-mediated immune reactions; they protect
against certain bacterial infections and many veal and fungal infections,
and they provide resistance to malignant tumors.
There are several distinct functional T lymphocyte subpopulations (Ta-
ble 11. Effector T lymphocytes respond specifically to target antigens in
317
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318
HEALTH CONSEQUENCES OF NUCLEAR WAR
TABLE 1 Functional Subpopulations of Lymphocytes
I. T lymphocytes
A. Regulatory T lymphocytes
1. Helper lymphocytes
2. Suppressor lymphocytes
B. Effector T lymphocytes
1. Delayed-type hypersensitivity (DTH)
2. Mixed lymphocyte reactivity
3. Cytotoxic T lymphocyte (CTL or killer cells)
II. B lymphocytes
A. Precursors of antibody-forming cells
B. Memory cells
C. Regulatory B lymphocytes
cell-mediated immune responses, such as the rejection of foreign tumors
and the elimination of virus-infected cells. Helper T lymphocytes stimulate
the differentiation of B lymphocytes into mature antibody-secreting plasma
cells and regulate the activation of effecter T lymphocytes. Suppressor T
lymphocytes actively suppress the initiation of specific immune responses
by preventing the activation of helper T lymphocytes, hindering helper T
lymphocyte interactions with B lymphocytes and directly inhibiting B
lymphocyte differentiation.
IONIZING RADIATION
Numerous studies in animals have demonstrated that ionizing radiation
produces significant impairment of the immune system. Whole-body x
irradiation with 400 reds in albino rabbits completely eliminates antibody
response to an antigen presented 48 hours after exposure. ~ Mice exposed
to 450 reds of total body x irradiation exhibit suppressed intracellular
digestion of foreign erythrocytes.2 Sublethal x irradiation in mice results
in an increased incidence of neoplastic diseases.3
There is much clinical evidence of immunosuppression by x irradiation
in humans. Patients receiving extensive radiotherapy for Hodgkin's disease
experience an increased incidence of viral infections (herpes zoster and
varicella-zoster virus).4 The antibody response to pneumococcal vaccine
is profoundly impaired in patients receiving total lymphatic irradiation.
The ability of these patients to respond to immunization may not return
to normal for as long as four years following therapy.5 Impaired T lym-
phocyte-mediated immunity has been noted in Japanese atom bomb sur-
vivors 30 years after exposure.6
Studies of human radiation injuries resulting from laboratory accidents,
the Pacific Testing Ground accidents, and medical whole-body radiation
therapy and in Hiroshima and Nagaski victims reveal an almost 100 percent
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THE IMMUNOLOGICAL IMPACT OF NUCLEAR WAR
319
fatality rate in individuals exposed to 500-600 reds or more of whole-
body irradiation.7 At the other extreme, recovery and survival is virtually
certain in whole-body exposures of less than 100 reds in healthy humans.
Infections are prominent among individuals exposed to 200-450 reds.
Although there may be some increase in infections 2 to 4 weeks after
human exposure in the 100-200 red range, there are usually no serious
long-term clinical consequences.7 However, hematopoietic suppression is
observed in the 150-200 red range.8 Various studies suggest, therefore,
that the vulnerability of the human immune system begins at levels of
about 150-200 reds of x irradiation. Rotblat's studies9 suggest that under
wartime conditions these levels of vulnerability may be lowered by other
deleterious factors, e.g., malnutrition, stress, and exposure.
Much of our knowledge of radioimmunology in humans comes from
clinical experience with total lymphoid irradiation (TLI) therapy, in which
suppression of undesirable immune reactions is attempted by delivering
ionizing radiation in multiple doses to lymphoid tissue over a period of
weeks. it TLI produces marked and prolonged humoral and cell-mediated
immunosuppressive effects in humans. TLI in patients with Hodgkin's
disease results in a decrease of helper T lymphocytes for up to 12 months,
while the fraction of suppressor T lymphocytes remains constant. Similar
effects have been observed in rheumatoid arthritis patients treated with
TLI.~2 TLI induces potent nonspecific suppressor lymphocytes which in-
hibit the cytotoxic T lymphocyte response.~° In a variety of clinical sit-
uations, TLI produces lasting reductions in the ratio of helper to suppressor
T lymphocytes.
The mechanism of immune suppression by x irradiation appears to be
a reduction in T lymphocyte function associated with a reduced ratio of
helper to suppressor T lymphocytes. The calculations of Harwell,~3 Ehrlich
et al.,~4 Daugherty,is and others indicate that millions of people in the
Northern Hemisphere would be exposed to sublethal x irradiation in this
range in a 5,000-10,000 megaton (Mt) nuclear exchange. They would be
susceptible, therefore, to a wide range of immunodeficiency diseases.
ULTRAVIOLET RADIATION
Studies in animals have confirmed that ultraviolet-B (UV-B) exposure
results in a state of T lymphocyte-mediated immune suppression attrib-
utable to a predominance of suppressor T lymphocyte. In mice, for
example, UV-B irradiation results in an impairment of antigen-presenting
cell functional and a relative excess of suppressor T lymphocytes.
The suppressor T lymphocytes generated following exposure to UV-B
inhibit the antitumor response. UV-irradiated mice are unable to reject
UV-B-induced tumors.'9 This inability to reject tumors is mediated by
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320
HEALTH CONSEQUENCES OF NUCLEAR WAR
suppressor cell activity, which persists in UV-B-exposed animals long
after termination of UV-B exposure.20 2~ UV-irradiated mice are more
susceptible to leukemias and lymphomas22 and to tumors induced by
chemical carcinogens.23 UV-induced suppressor lymphocytes appear to
be the agents that predispose the host to the premature development of
cancer.
In studies of the effect of UV irradiation on humans, it has been noted
that helper T lymphocytes are more sensitive to UV than are B lympho-
cytes.24 Normal human subjects exposed to UV irradiation, both In com-
mercial solar and in natural sunlight, exhibit increases in suppressor T
lymphocyte activity sufficient to impair defense against tumors.25~26 The
pathophysiologic mechanism appears to differ for UV-A and UV-B ex-
posure, but relative predominance of suppressor T lymphocytes results in
both instances.27
Clinical data on the effect of UV irradiation on humans also are available
from studies of long-term psoralen plus UV-A (PUVA) radiation therapy
for psoriasis. PUVA photochemotherapy causes a reduction in helper T
lymphocytes and a reduction in the lymphocytic response to the mitogen
phytohemagglutinin.28 The abnormally low response to mitogens is as-
sociated with a decrease in the percentage of helper lymphocytes.29
If the predominant nuclear winter scenarios prove accurate, the in-
creased UV-B exposure of human populations can be expected to impair
immune function in a manner similar to the effects of ionizing radiation;
i.e., it would result in a reduction of the helper-to-suppressor T lymphocyte
ratios in many survivors. Crutzen and Birks30 estimate a 37-70 percent
average ozone reduction in a nuclear exchange ranging from 5,000 to
10,000 Mt and predict that a 10,000-Mt nuclear war would result in
increases in UV-B radiation by a factor greater than 5 throughout most
of the Northern Hemisphere. Turco et al.3~ and Ehrlich et alto estimate
UV-B doses of roughly twice the normal level in the Northern Hemisphere
after a 5,000-Mt exchange and an increase by a factor of 4 following a
10, 000-Mt exchange. Such increases in UV radiation exposure would be
in the range expected to affect T lymphocyte populations in the survivors.
Based on the assumption that skin cancer incidence is proportional to
lifetime UV radiation dose, a National Academy of Sciences committee
has estimated that a 50 percent reduction in global ozone would cause an
increase in skin cancer of approximately 10 percent that would be main-
tained for 40 years.32
BURNS AND TRAUMA
Severe immunosuppression occurs after major burns and traumatic in-
juries. Burn patients often show altered cellular immune responses, such
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THE IMMUNOLOGICAL IMPACT OF NUCr:FAR WAR
321
as impaired skin test reactivity to antigens and delayed graft rejection.
Burns and wounds in the skin also serve as portals of entry for infection.
The resultant increase in the incidence and severity of infection in trauma
and burn patients is well known. Gram-negative bacilli are the most com-
mon wound pathogens, and sepsis is the most common cause of death in
survivors of the shock phase of thermal injury.33 34
Several recent studies support the concept that reduced T lymphocyte
activity is largely responsible for burn-induced immunosuppression.35 36
Clinical evidence suggests that depressed T lymphocyte function is caused
by a shift in the balance of suppressor and helper T lymphocyte subpop-
ulations following thermal injuries. Sepsis is most likely to occur when
suppressor cell populations are at a maximum, 7 to 14 days after the
injury.37 A high suppressor-to-helper T lymphocyte ratio has been noted
in patients soon after burn injuries of greater than 30 percent of body
surface area, and high levels of postburn suppressor T lymphocyte activity
accurately predict the incidence of mortality from sepsis.38 T lymphocyte
function is significantly depressed in burn injuries covering more than 25
percent of the body surface area,36 accompanied by a reduction in helper
and an increase in suppressor T lymphocytes.39 Reduced helper-to-sup-
pressor ratios are a predictor of mortality from sepsis.
Thus, blast and burn injuries in nuclear war survivors can be expected
to reduce immune competence in a manner similar to the effect of ionizing
and ultraviolet radiation. The T lymphocytes would primarily be affected,
and, specifically, a decrease in the ratio of helper-to-suppressor T lym-
phocytes would be anticipated.
PSYCHOLOGICAL FACTORS: STRESS, DEPRESSION,
AND BEREAVEMENT
Chazov and Vartanian40 have estimated that at least one-third of the
population surviving a nuclear war would suffer from severe emotional
and behavioral disturbances. Stress, depression, and bereavement have
all been reported to alter the immune system and increase the risk of
infection.
Studies in animals under stress have shown an increased susceptibility
to infection by coxsackie B. polio, herpes, and vesicular stomatitis vi-
ruses.4~ Rats given a graded series of stressors manifest progressive
suppression of lymphocyte function.42
Clinical studies suggest that psychological variables influence suscep-
tibility to infection and delay recovery from upper respiratory diseases,
influenza, herpes simplex lesions, and tuberculosis.43 These psychologi-
cally induced altered immune states are probably mediated by changes in
lymphocytes. T lymphocyte function is significantly depressed in bereaved
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HEALTH CONSEQUENCES OF NUCLEAR WAR
spouses.44 Marked decreases in lymphocyte mitogenic activity have been
noted among patients with primary depressive illness.45 46 Suppression of
mitogen-induced lymphocyte stimulation in widowers has been associated
with bereavement.47 Clinically depressed patients have been shown to
have an increased mortality rate, cancer rate, and incidence of certain
viral infections.46 48
The mechanisms by which stress influences the immune system are
largely unknown. Neuroendocrine mediation has been suggested. Once
again, T lymphocytes appear to mediate the abnormal immunological state.
MALNUTRITION
It has long been recognized that nuclear war would have a major impact
on agriculture and world food supplies. More recently, Harwell~3 has
written that nuclear winter could result in termination of agricultural pro-
duction and distribution systems and that widespread starvation might
ensue. Specifically, he predicted that surviving populations would be
deprived of vitamins A, Bit, and C; riboflavin; and iron.
Each of these nutrients is important in maintaining a healthy immune
response. Studies in rats and mice indicate that vitamin B ~2 may be highly
important to T lymphocyte immune reactions.49 Riboflavin-deficient an-
imals are more susceptible to infection.S° Vitamin A deficiency in animals
leads to depleted numbers of T lymphocytes; depressed lymphocyte re-
sponse to certain mitogens; and an increased frequency and severity of
bacterial, viral, and protozoan infections.S° Iron deficiency is also accom-
panied by impaired in vitro lymphocyte responsiveness to mitogenic stim-
ulation.S° Abnormalities of T lymphocyte function have also been noted
in pyridoxine and zinc deficiency.S~ Based on epidemiologic observations,
the World Health Organization report on interactions between nutrition
and infectionS2 noted that severe ascorbic acid (vitamin C) deficiency
tends regularly to lower resistance to most infectious diseases.
There is epidemiological and clinical evidence that the cell-mediated
immune response is defective in protein-calorie malnutrition.S3 Individuals
with protein-calorie malnutrition have a high incidence of infection, par-
ticularly by mycobactena, viruses, and fungi; and they develop lympho-
penia with decreased cutaneous hypersensitivity to several antigens.s4 In
communities where protein-calorie malnutrition is prevalent, there is a
high mortality from infections which cause only minor illnesses in well-
nourished individuals.55
The diminished cellular immunity of protein-calorie malnutrition is as-
sociated with a marked decrease in the number of T lymphocytes.S6 Almost
every conceivable alteration of the T lymphocyte subpopulation and its
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THE IMMUNOLOGICAL IMPACT OF NUCLEAR WAR
323
function (as well as the B lymphocyte population and its function) can be
evoked through nutritional, protein, or caloric manipulation.57 In severe
protein-calorie deprivation, the entire lymphocyte population and T lym-
phocyte immunity can virtually be eliminated. The cellular immune def-
icits associated with protein-calorie maInu~ition correlate with the frequency
and severity of infections with Car~ida albicans, measles, and tubercu-
losis, all of which are T lymphocyte-mediated infections.
DISCUSSION
Sublethal injuries in combination can prove lethal. Since the five major
Injurious agents associated with nuclear warfare attack the same compo-
nent of the immune system, the T lymphocyte, and generally do so in a
similar manner by decreasing the helper-to-suppressor T lymphocyte ratio,
additive influences can be anticipated. Impairment of immunity to a variety
of infectious diseases and tumors is likely. Infections associated clinically
with depressed cell-mediated immunity have been those with intracellular
pathogens like tuberculosis, leprosy, and histoplasmosis;57 DNA-type vi-
rus infections (e.g., varicella-zoster virus, cytomegalovirus); and a variety
of rarer pathogens (e.g., Legionella, Pneumocystis, and Toxoplasma).
Abrams and Von Kaenel33 have suggested that in the post-nuclear-war
world, surviving populations would be particularly susceptible to tuber-
culosis.
A striking similarity exists between acquired immunodeficiency syn-
drome (AIDS) and the anticipated immunosuppressed condition of sur-
vivors of a nuclear war: both are characterized by absolute depression of
the helper T lymphocyte population, reduced helper-to-suppressor T lym-
phocyte ratios, reduced lymphocytic response to mitogens and antigens,
and reduced to absent antibody response following immunization. In AIDS,
the T lymphocyte abnormalities appear to be induced by infection with
the human T lymphocyte virus type III (HTLV-III), which kills helper T
lymphocytes. The resulting profound immunosuppression apparently pro-
duces enhanced susceptibility to other infections. These are listed in Table
2.
Patients with AIDS also experience increased incidences of malignan-
cies, especially Kaposi's sarcoma, which is thought to be caused by the
cytomegalovirus. AIDS patients frequently develop non-Hodgkins lym-
phomas, oral squamous cell carcinoma, and cloacogenic carcinomas.
Since large numbers of the survivors of nuclear war can be expected
to have immunologic deficits like those in individuals with AIDS, an
increase in the incidence of AIDS-related diseases should be anticipated.
The data of von Hippel~s and others suggest an immediate at-risk popu
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324
HEALTH CONSEQUENCES OF NUCLEAR WAR
TABLE 2 Principal Agents of Infection in Patients with
Acquired Immunodeficiency Syndrome (AIDS)
Viruses
Herpesvirus (types 1 and 2)
Cytomegalovirus
Varicella-zoster
Adenovirus
Epstein-Barr
Re~ovirus (HTLV-I, -III)
F.
ungl
Candida albicar~s
Cryptococcus neoforrnans
Nocardia
Protozoa
Pneumocystis carinii
Toxoplasma gondii
Isospora sp.
Cryptosporidium
Giardia iamblia
Entameeba histolytica
Mycobactena
Mycobacterium tuberculosis
Mycobacterium avium-
intracellulare
Mycobacterium kansasii
Legionella sp.
Spirochetes
Treponema sp. (including
Treponema pallidum)
Bactena
Campylobacter sp.
Neisseria sp. (including
Neisseria gonorrhoeae)
Shigella sp.
Salr~wnella sp.
Chlamydia
SOURCE: Ammann (1984: Table 22-10).58 Reproduced with permus-
sion, from Shtes, D.P., et al. (editors): Basic and Clinical Immunology,
5th ed. @) 1984 by Lange Medical Publications, Los Altos, California.
ration of at least 10 million Americans in an attack directed at strategic
targets only. Exposure to UV radiation, malnutrition, and stress could
increase this in the months and years following an attack.
SUMMARY AND CONCLUSIONS
Survivors of a nuclear attack would suffer from injuries caused by
ionizing and UV radiation, physical trauma, burns, malnutrition, and
psychosocial stress. Several independent lines of research have indicated
that these separate agents converge on the T lymphocyte component of
the immune system, generally causing a reduction in T lymphocytes and
a decrease in the ratio of helper-to-suppressor T lymphocytes.
T lymphocyte defects are associated with some of the most disabling
immunodef~ciencies. T lymphocytes are essential in the defense against
a variety of bacterial diseases and are vital in resistance to many viral and
fungal diseases. Patients with AIDS show depression of T lymphocyte
populations and reduced helper-to-suppressor T lymphocyte ratios similar
to those anticipated in millions of nuclear war survivors. There is con-
siderable experimental evidence that T lymphocytes provide immune sur
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THE IMMUNOLOGICAL IMPACT OF NUCLEAR WAR
325
veillance against cancer. T lymphocyte functional abnormalities may explain
some of the susceptibility to malignancy which is clinically associated
with exposure to ionizing and UV radiation.
Multiple factors converging on a single element of We immune system,
the T lymphocyte, can be expected to be additive. The possibility of
synergy has been raised by several observers,33 59 and this could magnify
Me impact. Severe immunodeficiencies of the T lymphocyte variety are
to be anticipated after exposure of human populations to nuclear war.
Epidemics of diseases in which T lymphocytes mediate the immune re-
sponse would be likely in Me months and years following a nuclear attack.
NOTES
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Representative terms from entire chapter:
immune response
