Immunodeficiency Diseases Flashcards
Immunodeficiency Syndromes
mmunodeficiencies can be divided into primary (or
congenital) immunodeficiency disorders, which are genetically
determined, and secondary (or acquired) immunodeficiencies,
which may arise as complications of cancers, infections,
malnutrition, or side effects of immunosuppression, irradiation,
or chemotherapy for cancer and other diseases.
Primary Immunodeficiencies
Most primary immunodeficiency diseases are genetically
determined and affect the defense mechanisms of innate
immunity (phagocytes, NK cells, or complement) or the humoral
and/or cellular arms of adaptive immunity (mediated by B and T
lymphocytes, respectively). Although these disorders were once
thought to be quite rare, some form of mild genetic immune
deficiency is, in fact, present in many individuals.
Most primary
immunodeficiencies are detected in infancy
between 6 months
and 2 years of life, the telltale signs being susceptibility to
recurrent infections
Defects in Innate Immunity
nherited defects in the early innate immune response typically
affect leukocyte functions or the complement system, and all
lead to increased vulnerability to infections
Inherited defects in leukocyte adhesion
Defects in Leukocyte Function
leukocyte adhesion deficiency type 1
have a defect in the
biosynthesis of the β2 chain shared by the LFA-1 and Mac-1
integrins. L
Leukocyte adhesion deficiency type 2
caused by
the absence of sialyl-Lewis X, the fucose-containing ligand for
E- and P-selectins, as a result of a defect in a fucosyl
transferase, the enzyme that attaches fucose moieties to
protein backbones. The major clinical problem in both
conditions is recurrent bacterial infections due to inadequate
granulocyte function.
Chédiak-Higashi syndrome
an autosomal recessive
condition characterized by defective fusion of phagosomes and
lysosomes, resulting in defective phagocytes function and
susceptibility to infections. The main leukocyte abnormalities
are neutropenia (decreased numbers of neutrophils), defective
degranulation, and delayed microbial killing. Leukocytes
contain giant granules, which can be readily seen in peripheral
blood smears and are thought to result from aberrant
phagolysosome fusion
abnormalities in
melanocytes (leading to albinism), cells of the nervous system
(associated with nerve defects), and platelets (causing bleeding
disorders). The gene associated with this disorder encodes a
large cytosolic protein called LYST, which is believed to
regulate lysosomal trafficking.
Inherited defects in microbicidal activity
The importance
of oxygen-dependent bactericidal mechanisms is shown by the
existence of a group of congenital disorders called chronic
granulomatous disease, which are characterized by defects in
bacterial killing and render patients susceptible to recurrent
bacterial infection
Chronic granulomatous disease results from
inherited defects in the genes encoding components of
phagocyte oxidase, the phagolysosomal enzyme that generates
superoxide ( ). The most common variants are an X-linked
defect in one of the membrane-bound components (gp91phox)
and autosomal recessive defects in the genes encoding two of
the cytoplasmic components (p47phox and p67phox).
Defects in TLR signaling
Rare defects have been described
in various TLRs. Defects in TLR3, a receptor for viral RNA,
result in recurrent herpes simplex encephalitis, and defects in
MyD88, the adaptor protein downstream of multiple TLRs, are
associated with destructive bacterial pneumonias.
Deficiencies Affecting the Complement System
Hereditary deficiencies have been described for virtually all
components of the complement system and several of the
regulators. In addition, one disease, paroxysmal nocturnal
hemoglobinuria, is marked by an acquired deficiency of
complement regulatory factors.
Deficiency of C2
is the most common complement protein
deficiency. A deficiency of C2 or C4, early components of the
classical pathway, is associated with increased bacterial or viral
infections. However, many patients have no clinical
manifestations, presumably because the alternative
complement pathway is adequate for the control of most
infections
some of these C2 patients, as well as in
patients with C1q deficiency
the dominant manifestation is
SLE-like autoimmune disease, as discussed earlie
Deficiency of components of the alternative pathway
properdin and factor D
associated with recurrent
pyogenic infections.
The C3 component of complement
Classical and alternative pathways, and hence a deficiency of
this protein results in susceptibility to serious and recurrent
pyogenic infections. There is also increased incidence of
immune complex-mediated glomerulonephritis; in the absence
of complement, immune complex–mediated inflammation is
presumably caused by Fc receptor-dependent leukocyte
activation.
The terminal components of complement C5, 6, 7, 8, and 9
required for the assembly of the membrane attack complex
involved in the lysis of organisms.
With a deficiency of these
late-acting components, C5,6,7,8,9
increased susceptibility to
recurrent neisserial (gonococcal and meningococcal) infections;
Neisseria bacteria have thin cell walls and are especially
susceptible to the lytic actions of complement
Some patients
inherit a defective form of mannose-binding lectin,
the plasma
protein that initiates the lectin pathway of complement. These
individuals also show increased susceptibility to infections.
A deficiency of C1 inhibitor (C1 INH)
gives rise to hereditary
angioedema. This autosomal dominant disorder is more
common than complement deficiency states. The C1 inhibitor’s
targets are proteases, specifically C1r and C1s of the
complement cascade, factor XII of the coagulation pathway, and
the kallikrein system
deficiency of C1 INH
unregulated
activation of kallikrein may lead to increased production of
vasoactive peptides such as bradykinin. Although the exact
nature of the bioactive compound produced in hereditary
angioedema is uncertain, these patients have episodes of
edema affecting skin and mucosal surfaces such as the larynx
and the gastrointestinal tract. This may result in lifethreatening asphyxia or nausea, vomiting, and diarrhea after
minor trauma or emotional stress
Acute attacks of hereditary
angioedema can be treated with
C1 inhibitor concentrates
prepared from human plasma.
Deficiencies of other complement regulatory proteins are the
paroxysmal nocturnal hemoglobinuria (Chapter 14)
and some cases of hemolytic uremic syndrome
Defects in Adaptive Immunity
Defects in adaptive immunity are often subclassified on the basis
of the primary component involved (i.e., B cells or T cells or
both). However, these distinctions are not clear-cut; for instance,
T-cell defects almost always lead to impaired antibody synthesis,
and hence isolated deficiencies of T cells are often
indistinguishable clinically from combined deficiencies of T and
B cells. These immunodeficiencies result from abnormalities in
lymphocyte maturation or activation
Severe Combined Immunodeficiency
Severe combined immunodeficiency (SCID) represents a
constellation of genetically distinct syndromes, all having
in common defects in both humoral and cell-mediated
immune responses. Affected infants present with prominent
thrush (oral candidiasis), extensive diaper rash, and failure to
thrive.
Some patients develop a morbilliform rash shortly after
birth because
maternal T cells are transferred across the
placenta and attack the fetus, causing GVHD. Persons with SCID
are extremely susceptible to recurrent, severe infections by a
wide range of pathogens, including Candida albicans,
Pneumocystis jiroveci, Pseudomonas, cytomegalovirus, varicella,
and a whole host of bacteria
X-linked SCID
The most common form, accounting for 50%
to 60% of cases, is X-linked, and hence SCID is more common in
boys than in girls. The genetic defect in the X-linked form is a
mutation in the common γ-chain (γc) subunit of cytokine
receptors. This transmembrane protein is a signal-transducing
component of the receptors for IL-2, IL-4, IL-7, IL-9, IL-11, IL-15,
and IL-21. IL-7 is required for the survival and proliferation of
lymphoid progenitors, particularly T-cell precursors. As a result
of defective IL-7 receptor signaling,
a profound defect in
the earliest stages of lymphocyte development, especially T-cell
development. T-cell numbers are greatly reduced, and although
B cells may be normal in number, antibody synthesis is impaired
because of lack of T-cell help
IL-15 is important for the
maturation and proliferation of
K cells, and because the
common γ chain is a component of the receptor for IL-15, these
individuals often have a deficiency of NK cells as well.
Autosomal recessive SCID
. The remaining forms of SCID are
autosomal recessive disorders. The most common cause of
autosomal recessive SCID is a deficiency of the enzyme
adenosine deaminase (ADA). Although the mechanisms by
which ADA deficiency causes SCID are not entirely clear, it has
been proposed that deficiency of ADA leads to accumulation of
deoxyadenosine and its derivatives (e.g., deoxy-ATP), which are
toxic to rapidly dividing immature lymphocytes, especially those
of the T-cell lineage. Hence there may be a greater reduction in
the number of T lymphocytes than of B lymphocytes.
Mutations in recombinase-activating genes (RAG)
components of the antigen receptor gene recombination
machinery prevent the somatic gene rearrangements that are
essential for the assembly of T-cell receptor and Ig genes. This
blocks the development of T and B cells.
An intracellular kinase called Jak3
ssential for signal
transduction through the common cytokine receptor γ chain
(which is mutated in X-linked SCID, as discussed above).
Mutations of Jak3 therefore have the same effects as mutations
in the γc chain.
X-Linked Agammaglobulinemia (Bruton
Agammaglobulinemia)
X-linked agammaglobulinemia is characterized by the
failure of B-cell precursors (pro-B cells and pre-B cells) to
develop into mature B cells
