| A.
Immunosuppression Physical immunosuppression:
1. Surgical
manipulation can have a major impact on
immune responsiveness.
a.
Surgical
removal of the bursa, or the thymus, or both in
the neonatal period will block the development of
immunologic competence in the correspondingly
dependent lymphoid system. It is necessary that
these future antibody-producing cells receive
some influence from the bursa before they can
become responsive in peripheral lymphoid tissues.
Similarly, it is necessary for small lymphocytes
to differentiate in the thymus before they can
function in peripheral tissue.
b.
Surgical
removal of these tissues after immunologic
development, however, has very little effect on
immune competence, at least for a considerable
period. Lymphoid cells require central lymphoid
organ programming in order to differentiate
appropriately in response to antigen in
peripheral lymphoid tissues, but once that
programming has been achieved, cells react as
mature cells in peripheral tissues for months or
years.
2. Radiation acts on the lymphoid
cells and bone marrow. Shielding the lymphoid organs
from irradiation protects against diminished immune
capacity. Radiation damages DNA; thus, cells that are
in the process of division or that need to divide to
express their immunologic role will be most affected
by this exposure.
Chemical and biological
immunosuppressive agents include therapeutic agents for
autoimmune disease, some of which are also cancer
chemotherapeutics. Most anticancer agents have some
degree of immunosuppressive activity.
1. Since a role of the
immune response is limitation or protection against
infectious disease, the result of immunosuppression
with any of these drugs or with any other procedure
is increased incidence and chronicity of infectious
disease. When immunosuppressive agents are used, the
patient is more subject to infectious disease and
malignancy.
2. Action of
immunosuppressive agents
a. Lympholytic agents:
The two major types are ionizing radiation and
antiserum (i.e., antilymphocyte serum and
antithymocyte serum).
b.
Lymphocytotoxic
agents:
Antimetabolites,
such as purine and pyrimidine analogs and
folic acid antagonists (methotrexate),
interfere with DNA synthesis.
Alkylating
agents, such as
cyclophosphamide, interfere with cell
division by altering guanine so that base
pairing errors occur. They also can cross-link
the two strands, thus blocking DNA
replication.
Antibiotics,
such as cyclosporine, exert an inhibitory
effect on interleukin-2 action, thus blocking
the expansion of the helper/inducer T-cell
population. It is particularly effective in
suppression graft rejection reactions.
c. Cortisone
is immunosuppressive as well as anti-inflammatory.
It has the following effects:
- It
depresses macrophage chemotaxis and
interleukin-1 production.
- It
inhibits calcium ion influx into cells.
- It
depresses release and/or effect of
interleukin-2, lymphotoxin, macrophage
migration-inhibition factor (MIF), and
macrophage-activating factor (MAF).
- It
blocks cleavage of membrane phospholipids,
thus lowering prostaglandin and leukotriene
levels by inhibiting arachidonic acid release
from the membrane.
d. Antibodies:
Antibodies that react with lymphoid cells:
If
injected into the body, the antibodies
against T cells can find all the lymphocytes
in the lymph nodes, blood, and other
components of the reticuloendothelial system.
Antilymphocyte
serum, particularly antithymocyte serum, is
most useful in inducing immune deficiency in
transplant patients by suppression of all
cell-mediated immune responses.
If a
performed antibody is injected into an animal,
followed by injection of specific antigen,
the immune response in the host will be
blocked. The injected antibody binds up the
antigen and prevents its access to lymphoid
tissue. This is the principle through which
Rho(D) immunoglobulin (RhoGAM) was developed
to combat Rh incompatibility (erythroblastosis
fetalis). Antiserum against the immunogen (Rh
antigen) will neutralize the antigen through
some mechanism (probably by coating it in
such a way that it is cleared from the body
very rapidly); thus, an immune response is
aborted.
B.
Immunodefficiency Disorders
In view of the
complex nature of the immune response, it is not
surprising that a wide array of deficiencies exist,
heralded primarily by recurrent infection, chronic
infection, unusual (opportunistic) infecting agents, and
a poor response to treatment.
Congenital
Immunodeficiencies:
1. Bruton’s
hypogammaglobulinemia failure of development of B-cell
(humoral) immunity. These patients form antibodies
very poorly and suffer from repeated bacterial
infections.
2. DiGeorge
syndrome
failure of development of the third and fourth
pharyngeal pouches during embryogenesis. These
patients have a great deal of trouble with recurrent
viral diseases.
Malignancies are potentially
immunosuppressive, particularly if they involve lymphoid
tissues.
Infections:
1. Measles and certain
other viral diseases cause a transient depression in
cell-mediated immune responses.
2. Human T-cell
lymphotropic virus [(HTLV-III), also known as human
immunodeficiency virus (HIV)] infection causes a
profound immunosuppression which renders the host
susceptible to fatal infections caused by
opportunistic pathogens.
3. Specific anergy is seen
in lepromatous leprosy and the terminal stages of
tuberculosis.
Malnutrition:
1. Cell-mediated immunity
appears to be the most sensitive to nutritional
deprivation, but humoral immunity, complement, and
phagocytic functions are also affected.
Phagocytic cell defects:
1. Quantitative
defects. In
quantitative defects in Polymorphonuclear leukocytes
(neutrophils), referred to as neutropenia or
granulocytopenia, the total number of normal,
circulating cells is suppressed.
2. Qualitative
defects.
a.
Chronic granulomatous disease: Granuloma
formation occurs in many organs, and it appears
to reflect the inability of, first, neutrophils
and then tissue macrophages to kill ingested
microorganisms.
b.
Myeloperoxidase deficiency is an important
microbicidal agent contained in normal
neutrophils. Hydrogen peroxide is formed in these
patients in normal amounts; however, both
myeloperoxidase and hydrogen peroxide are
necessary for neutrophil killing function.
c.
Chediak-Higashi syndrome is a relatively
rare disease of humans and of a variety of
animals. The patient’s neutrophils contain
abnormal, giant lysosomes, which can apparently
fuse with the phagosome but which are impaired in
their ability to release their contents,
resulting in a delayed killing of ingested
microorganisms.
d.
Job’s syndrome,
hyperimmunoglobulinemia E (hyper-IgE)
syndrome. Neutrophils demonstrate normal
ingestion and killing activity by defective
chemotaxis. Serum levels of IgE are extremely
high in association with increased specificity
for staphylococcal antigens.
e.
Lazy leukocyte syndrome is characterized
by susceptibility to severe microbial infections,
neutropenia, defective chemotactic response by
neutrophils, and an abnormal inflammatory
response.
B-cell deficiency
disorders:
1. Bruton’s
X-linked hypogammaglobulinemia. The primary bacterial
infections do not induce immunoglobulin synthesis.
Cellular immunity is normal in these patients.
2. Transient
hypogammaglobulinemia of infancy results when the onset
of immunoglobulin synthesis, particularly IgG
synthesis, is delayed beyond the norm.
3. Common
variable hypogammaglobulinemia (acquired
hypogammaglobulinemia) resembles Bruton’s
disease except that symptoms first appear when the
patient is 20 to 30 years of age.
4. Selective
immunoglobulin deficiency (dysgammaglobulinemia)
describes a decrease in the serum level of one or
more immunoglobulins, but not all immunoglobulins,
with normal or increased levels of the others. The
most common form of this disorder is selective IgA
deficiency.
T-cell deficiency
disorders:
1. DiGeorge
syndrome (congenital
thymic hypoplasia) is due to faulty development of
the third and fourth pharyngeal pouches during
embryogenesis, with resulting absence or hypoplasia
of both the thymus and parathyroid glands.
Lymphocytopenia is usual in these patients. T cells
are diminished in number.
2. Chronic
mucocutaneous candidiasis is a syndrome of skin
and mucous membrane infection with Candida
albicans, which is associated
with a rather unique defect in T-cell immunity.
Although the total lymphocyte count appears to be
normal, the ability of the T cells to be activated by,
or to produce macrophage migration-inhibition factor
(MIF) in the presence of Candida antigen
is impaired, although their response to other
antigens may be normal.
Combined B-cell and T-cell
deficiency disorders
Severe combined
immunodeficiency disease (SCID) involves a combined defect
in both humoral (B-cell) and cell-mediated (T-cell)
immunity. Patients usually die within the first or second
year of life from viral, bacterial, fungal, or protozoan
infection. SCID may be inherited as an X-linked recessive
or autosomal recessive disease.
1. Nezelof’s syndrome. There is a marked
deficiency of T-cell immunity. B-cell deficiency
varies. The antibody response to specific antigens is
usually low or absent.
2. Wiskott-Aldrich
syndrome
comprises a triad of features including
thrombocytopenia, which is present at birth; eczema,
which usually is present at the age of 1 year; and
recurrent pyogenic infection (e.g., with S.
pneumoniae, Neisseria meningitidis,
or H. influenzae),
starting after 5 months of age. There is a variable
deficit in T-cell immunity.
3. Ataxia-telangiectasia is an autosomal
recessive disease and is characterized by
uncoordinated muscle movements (ataxia) and
dilatation of small blood vessels in the sclera of
the eye (telangiectasia). It is associated with
repeated sinopulmonary infections due to various
viral and bacterial agents. The neurologic, endocrine,
and vascular systems are involved. There is selective
IgA deficiency with variable abnormalities affecting
other immunoglobulins and, occasionally, an inhibited
antibody response to certain antigens. T-cell
deficiency is variable.
4. Enzyme
deficiencies have been reported to be the
cause of at least some degree of combined
immunodeficiency. Deficiencies of both adenosine
deaminase (ADA) and purine nucleoside phosphorylase (PNP)
are autosomal recessive traits. ADA and PNP are
necessary for the purine salvage pathway.
C.
Secondary Immunodeficiencies
Measles is an example of a disease
that induces immunosuppression. The infection induces a
transient suppression of delayed hypersensitivity
reactions. Lymphocytic response to antigens and mitogens
is reduced. The number of circulating T cells is
decreased. Similar effects may be seen following measles
immunization.
Leprosy is another infection with
associated immunodeficiency. Patients with lepromatous
leprosy have an impaired ability to develop delayed
hypersensitivity reactions. However, whether
immunosuppression leads to or is caused by leprosy is not
certain.
Tuberculosis and coccidioidomycosis are
other examples. Both impair delayed hypersensitivity
reactions.
Acquired immune
deficiency syndrome (AIDS) affects
primarily, but not exclusively, male homosexuals,
intravenous drug abusers, hemophiliacs, and other
individuals who receive transfusions. It is caused by a
retrovirus, which formerly was referred to as human T-cell
lymphotropic virus III (HTLV-III) or lymphadenopathy-associated
virus (LAV) but now is designated human immunodeficiency
virus (HIV). Patients demonstrate pronounced suppression
of the immune system and development of Kaposi’s
sarcoma, severe opportunistic infection (e.g., with Pneumocystis
carinii, Mycobacterium avium-intracellulare,
or Toxoplasma),
or both. Marked lymphopenia is associated with a
reduction in the level of CD4 cells and resultant
reversal of the CD4:CD8 ratio less than 0.5 (normal >
1.5). There is an impaired response of peripheral blood
lymphocytes to PHA and specific antigens. Specific
antibody production is impaired. The lymphocytes cannot
produce the normal amount of interleukin-2, and the
activity of natural killer (NK) cells is reduced.
HIV incorporates
itself into host cell genome (it lasts for life), attacks
and incapacitates the body’s central immune system.
Thus the body cannot fight diseases caused by
intracellular pathogens or even normally harmless
microbes. The HIV multiplies profusely in phagocytic
monocytes without killing them and so propagates
throughout the body and loads body fluids with virus,
induces body to attack itself (autoimmune inactivation of
IL-2, cytotoxic humoral antibodies killing lymphocytes,
CD8 cells killing CD4 cells), and is antigenically
variable.
AIDS has a long
incubation period (usually 3 years or longer) and appears
to be 100% fatal. HIV probably will cause the greatest
pandemic in human history: millions have been infected
and are spreading HIV, probably about 2 million in U.S.A.
alone; these infected people are carriers and potential
sources for life. There is no cure and no vaccine. HIV is
transmitted best by blood, probably by infected cells (T
cells and monocytes or macrophages).
Reaction of host
for infection of his own T cells and macrophages with the
transmitted ones (close cell-cell contact which part of
recognition/response mechanisms) promotes infection.
Initial multiplication of HIV in newly-infected subject
results in humoral Ab immune response (a few days after
infection) and probably promotes infection by increasing
HIV uptake by uninfected macrophages (by specific
opsonization). A cell-mediated immunity, probably
cytotoxic to infected lymphocytes, kills infected cells
and results in temporary control of the infection.
HIV selectively
attacks CD4 and macrophages because both have the CD4
antigen on them, and CD4 is the receptor for HIV.
Infection of the macrophages also is promoted by
antibodies made against HIV and by natural intimate
contact between macrophages and CD4 cells in induction
processes. HIV kills the CD4 cells directly and by
syncytial lysis, kills some of the macrophages but just
multiplies profusely to be shed in large numbers from
others. The mature/activated macrophage is the most
permissive for HIV. In the infected CD4 cell, HIV reverse
transcriptase incorporates HIV genes in host cell genome.
When the infected CD4 cell becomes activated (e.g., by
other antigenic stimulation), in replicating itself it
also replicates HIV, which kills it.
CD8 cells can
recognize HIV antigen on CD4 cells as foreign, and will
kill infected CD4 cells, adding to loss of these cells.
HIV glycoprotein in the envelope is homologous to IL-2.
Thus, HIV induces production of IL-2-neutralizing
autoantibodies. These antibodies plus complement can kill
IL-2-bearing cells.
While neutralizing
antibodies are made which can block HIV from infecting
new T cells, these cannot get at intracellular HIV.
Furthermore, HIV changes its surface antigenicity
frequently, making previously effective antibodies no
longer effective.
HIV causes flu-like
symptoms in about 2 weeks after initial infection, then
becomes dormant (perhaps in response to antibody and
cytotoxic immunity). In a mean time of 5 years later, it
emerges again in various disease forms, the most familiar
being lymphadenopathy ( AIDS-related complex) AIDS.
AIDS is said to
have developed when victim is overrun with opportunistic
infections, the most common of which are with Pneumocystis
carinii and M.
avium. Both of these microorganisms
probably are found in everyone but don’t cause
disease until the body becomes unable to develop any cell-mediated
immunity. HIV infection is detected by primary binding
tests, usually ELISA (screening test) and Western blot
for antibodies to specific viral envelope antigens (confirmatory
test). Anyone with these antibodies can (1) presume to
have been infected, (2) be infectious, and (3) be
expected to develop one or another of the fatal
manifestations of AIDS.
Plasma cell dyscrasias
represents a
group of diseases characterized by the overproduction of
immunoglobulins, or their fragments by a single clone of
plasma cells. The protein is called paraprotein. The most
important of the plasma cell dyscrasias is multiple
myeloma; other notable disorders include Waldenstrom’s
macroglobulinemia, benign monoclonal gammopathy, primary
amyloidosis, and heavy chain diseases.
Complement deficiencies.
Deficiency of
complement components and function has been associated
with increased susceptibility to infection, autoimmune
disease, and other disorders.
1. C1 esterase inhibitor
deficiency
2. C1q deficiency
3. C2 and C4 deficiencies
4. C3 deficiencies
5. C5 deficiency
6. C6, C7, and C8
deficiencies
|