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
t is one of the more common
forms of primary immunodeficiency
X-Linked Agammaglobulinemia (Bruton
Agammaglobulinemia)
During normal B-cell
maturation in the bone marrow
Ig heavy-chain genes are
rearranged first, in pre-B cells, and these are expressed on the
cell surface in association with a “surrogate” light chain, where
they deliver signals that induce rearrangement of the Ig lightchain genes and further maturation. This need for Ig-initiated
signals is a quality control mechanism that ensures that
maturation will proceed only if functional Ig proteins are
expressed.
X-linked agammaglobulinemia is caused by mutations
in a cytoplasmic tyrosine kinase, called
Bruton tyrosine kinase
(Btk); the gene that encodes it is located on the long arm of the
X chromosome at Xq21.22. Btk is a protein tyrosine kinase that
is associated with the Ig receptor complex of pre-B and mature B
cells and is needed to transduce signals from the receptor
As an X-linked disease, this disorder is seen almost entirely in
males, but sporadic cases have been described in females,
possibly caused by mutations in some other genes that function
in the same pathway.
The disease usually does not become
apparent until
about 6 months of age, as maternal
immunoglobulins are depleted.
Almost always the causative organisms are
Haemophilus
influenzae, Streptococcus pneumoniae, or Staphylococcus
aureus. These organisms are normally opsonized by antibodies
and cleared by phagocytosis. Because antibodies are important
for neutralizing infectious viruses that are present in the
bloodstream or mucosal secretions or being passed from cell to
cell, individuals with this disease are also susceptible to certain
viral infections, especially those caused by enteroviruses, such
as echovirus, poliovirus, and coxsackievirus
in patients with X liknked aggamaglobulinemia immunization with live poliovirus carries the risk of
paralytic poliomyelitis, and
echovirus can cause fatal encephalitis
Giardia lambliA
an intestinal protozoan that is normally resisted
by secreted IgA, causes persistent infections in persons with this
disorder. In general, however, most intracellular viral, fungal,
and protozoal infections are handled quite well by the intact T
cell–mediated immunity
The classic form of B-aggama disease has the following
characteristics:
• B cells are absent or markedly decreased in the circulation,
and the serum levels of all classes of immunoglobulins are
depressed. Pre-B cells, which express the B-lineage marker
CD19 but not membrane Ig, are found in normal numbers in the
bone marrow.
• Germinal centers of lymph nodes, Peyer’s patches, the
appendix, and tonsils are underdeveloped.
• Plasma cells are absent throughout the body.
• T cell–mediated reactions are normal.
Autoimmune diseases, such as arthritis and dermatomyositis
occur in as many as 35% of individuals with this disease, which
is paradoxical in association with an immune deficiency
DiGeorge Syndrome (Thymic Hypoplasia)
DiGeorge Syndrome (Thymic Hypoplasia)
individuals with this syndrome have a
variable loss of T
cell–mediated immunity (resulting from hypoplasia or lack of the
thymus), tetany (resulting from lack of the parathyroids), and
congenital defects of the heart and great vessels. In addition,
the appearance of the mouth, ears, and facies may be abnormal.
Absence of cell-mediated immunity is caused by low numbers of
T lymphocytes in the blood and lymphoid tissues and
poor
defense against certain fungal and viral infections. The T-cell
zones of lymphoid organs—paracortical areas of the lymph
nodes and the periarteriolar sheaths of the spleen—are depleted.
Ig levels may be normal or reduced, depending on the severity of
the T-cell deficiency
DiGeorge syndrome is not a familial disorder. It
results from a deletion that maps to chromosome
22q11, This
deletion is seen in more than 50% of patients, and DiGeorge
the syndrome is now considered a component of the 22q11 deletion
syndrome,
One gene in the deleted
region is TBX1
which is required for development of the
branchial arch and the great vessels. Notably, TBX1 is involved
by loss-of-function mutations in a few cases of DiGeorge
syndrome that lack 22q11 deletions, strongly suggesting that its
loss contributes to the observed phenotype.
bare lymphocyte syndrome
is usually caused by
mutations in transcription factors that are required for class II
MHC gene expression. Lack of expression of class II MHC
molecules prevents the development of CD4+ T cells. CD4+ T
cells are involved in cellular immunity and provide help to B
cells, and hence class II MHC deficiency results in combined
immunodeficiency. Other defects are caused by mutations in
antigen receptor chains or signaling molecules involved in T- or
B-cell maturation.
Hyper-IgM Syndrome
In this disorder the affected patients make IgM antibodies
but are deficient in their ability to produce IgG, IgA, and
IgE antibodies
It is now known that the defect in this disease
affects the ability of
f helper T cells to deliver activating signals to
B cells and macrophages
CD4+ helper T cells require the
engagement of
CD40 on B cells, macrophages and dendritic cells
by CD40L (also called CD154) expressed on antigen-activated T
cells. This interaction triggers Ig class switching and affinity
maturation in B cells, and stimulates the microbicidal functions
of macrophages.
Approximately 70% of individuals with hyperIgM syndrome have the
X-linked form of the disease, caused by
mutations in the gene encoding CD40L located on Xq26. In the
remaining patients the disease is inherited in an autosomal
recessive pattern. Most of these patients have loss-of-function
mutations involving either CD40 or the enzyme called activationinduced cytidine deaminase (AID), a DNA-editing enzyme that is
required for Ig class switching and affinity maturation.
The serum of persons with this syndrome contains
normal or
elevated levels of IgM but no IgA or IgE and extremely low
levels of IgG, although the number of B and T cells is norma
Clinically, patients present with recurrent pyogenic infections
the level of opsonizing IgG antibodies is low
CD40L mutations
susceptible to
pneumonia caused by the intracellular organism Pneumocystis
jiroveci, because CD40L-mediated macrophage activation, a key
reaction of cell-mediated immunity, is also defective
IgM antibodies react with blood cells
rise to autoimmune hemolytic anemia, thrombocytopenia, and
neutropenia. In older patients there may be a proliferation of
IgM-producing plasma cells that infiltrates the mucosa of the
gastrointestinal tract.
Common Variable Immunodeficiency
This relatively frequent but poorly defined entity
encompasses a heterogeneous group of disorders in which
the common feature is hypogammaglobulinemia, generally
affecting all the antibody classes but sometimes only IgG.
In contrast to X-linked
agammaglobulinemia
most individuals with common variable
immunodeficiency have normal or near-normal numbers of B
cells in the blood and lymphoid tissues. These B cells, however,
are not able to differentiate into plasma cells
The clinical manifestations of common variable
immunodeficiency are caused by antibody deficiency, and hence
they
resemble those of X-linked agammaglobulinemia. The
patients typically present with recurrent sinopulmonary
pyogenic infections. In addition, about 20% of patients have
recurrent herpesvirus infections. Serious enterovirus infections
causing meningoencephalitis may also occur. Individuals with
this disorder are also prone to the development of persistent
diarrhea caused by G. lamblia
In contrast to X-linked
agammaglobulinemia
common variable immunodeficiency
affects both sexes equally, and the onset of symptoms is later, in
childhood or adolescence.
Histologically the B-cell areas of the
lymphoid tissues
hyperplastic
enlargement of B-cell areas may
reflect
incomplete activation, such that B cells can proliferate in
response to antigen but do not produce antibodies.
As in X-linked agammaglobulinemia, these patients have a
high frequency of autoimmune diseases (approximately 20%),
including rheumatoid arthritis. The risk of lymphoid malignancy
is also increased, and an increase in gastric cancer has been
reported.
Isolated IgA Deficiency
Isolated IgA deficiency is a common immunodeficiency. In the
United States it occurs in about 1 in 600 individuals of European
descent. It is far less common in blacks and Asians. Affected
individuals have extremely low levels of both serum and
secretory IgA.
It may be familial or acquired in
association
with toxoplasmosis, measles, or some other viral infection. The
association of IgA deficiency with common variable
immunodeficiency was mentioned earlier. Most individuals with
this disease are asymptomatic.
IgA is the major
antibody in
external secretions, mucosal defenses are weakened,
and infections occur in the respiratory, gastrointestinal, and
urogenital tracts. Symptomatic patients commonly present with
recurrent sinopulmonary infections and diarrhea. Some
individuals with IgA deficiency are also deficient in the IgG2 and
IgG4 subclasses of IgG.
IgA-deficient
patients have a high frequency of
respiratory tract allergy and a
variety of autoimmune diseases, particularly SLE and
rheumatoid arthritis. The basis of the increased frequency of
autoimmune and allergic diseases is not known. When
transfused with blood containing normal IgA, some of these
patients develop severe, even fatal, anaphylactic reactions,
because the IgA behaves like a foreign antigen (since the
patients do not produce it and are not tolerant to it).
X-Linked Lymphoproliferative Syndrome
X-linked lymphoproliferative disease is characterized by
an inability to eliminate Epstein-Barr virus (EBV),
eventually leading to fulminant infectious mononucleosis
and the development of B-cell tumors. In about 80% of
cases, the disease is due to mutations in the gene encoding an
adaptor molecule called SLAM-associated protein (SAP) that
binds to a family of cell surface molecules involved in the
activation of NK cells and T and B lymphocytes, including the
signaling lymphocyte activation molecule (SLAM)
cluding the
signaling lymphocyte activation molecule (SLAM). Defects in
SAP contribute to
attenuated NK and T cell activation and result
in increased susceptibility to viral infections. SAP is also
required for the development of follicular helper T cells, and
because of this defect XLP patients are unable to form germinal
centers or produce high affinity antibodies, additional
abnormalities that also likely contribute to susceptibility to viral
infection.
The X-Linked Lymphoproliferative Syndrome is most commonly manifested
by
severe EBV infection, including severe and sometimes fatal
infectious mononucleosis (Chapter 8), but not other viral
infections, for reasons that are not clear.
Job
syndrome
Many rare cases of lymphocyte activation defects have been
described, affecting antigen receptor signaling and various
biochemical pathways. Defects in TH1 responses are associated
with atypical mycobacterial infections and defective TH17
responses are the cause of chronic mucocutaneous candidiasis
as well as bacterial infections of the skin
Immunodeficiencies Associated with
Systemic Diseases
In some inherited systemic disorders, immune deficiency is a
prominent clinical problem.
Wiskott-Aldrich Syndrome
Wiskott-Aldrich syndrome is an X-linked disease
characterized by thrombocytopenia, eczema, and a marked
vulnerability to recurrent infection, resulting in early
death
The thymus is morphologically normal
at least early in
the course of the disease, but there is progressive loss of T
lymphocytes in the peripheral blood and in the T-cell zones
(paracortical areas) of the lymph nodes, with variable defects in
cellular immunity.
Patients with WAS
do not make antibodies to
polysaccharide antigens, and the response to protein antigens is
poor. IgM levels in the serum are low, but levels of IgG are
usually normal. Paradoxically the levels of IgA and IgE are often
elevated. Patients are also prone to developing B-cell
lymphomas
The Wiskott-Aldrich syndrome is caused by
mutations in the gene encoding
Wiskott-Aldrich syndrome
protein (WASP), which is located at Xp11.23. WASP belongs to a
family of proteins that are believed to link membrane receptors,
such as antigen receptors, to cytoskeletal elements.
The only treatment of WAS
HSC TRans[lant
Ataxia Telangiectasia
Ataxia telangiectasia is an autosomal-recessive disorder
characterized by abnormal gait (ataxia), vascular
malformations (telangiectases), neurologic deficits,
increased incidence of tumors, and immunodeficiency.
The
immunologic defects are of variable severity and may affect both
B and T cells. The most prominent humoral immune
abnormalities are defective production of isotype switched
antibodies, mainly IgA and IgG2.
T cell defects, which are
usually less pronounced, are associated with
thymic hypoplasia
upper and lower respiratory tract bacterial infections
multiple autoimmune phenomena
cancers with advancing age
The gene responsible for
this disorder is located on
chromosome 11 and encodes a
protein called ATM (ataxia telangiectasia mutated) that is
related structurally to phosphatidylinositol-3 (PI-3) kinase, but is
a protein kinase
ATM protein is a sensor of DNA damage
(double-strand breaks) and it activates
53 by phosphorylation,
which in turn can activate cell cycle checkpoints and apoptosis
in cells with damaged DNA. ATM has also been shown to
contribute to the stability of DNA double-strand break
complexes during V(D)J recombination. Because of these
abnormalities in DNA repair, the generation of antigen receptors
may be abnormal.
