Immunodeficiency Diseases

Bharati B
Learning objectives
List the immunodeficiency diseases resulting from defects in
phagocytic cells, B cells, T cells, T cells and B cells combined
and complement
Describe the molecular defects of each of the
immunodeficiency diseases
Recognize the infections most likely to be seen in each of
immunodeficiency diseases
Recognize/ identify a immunodeficiency disease from the
signs and symptoms associated with the defect and the
specific molecular defect
Immunodeficiency
Failure of the immune system to protect against disease or malignancy
Result of a genetically incompetent or deregulated immune system


May result from abnormalities of:
Phagocytes, Complement, B cells, production of antibodies, and T cells
due to defects in their maturation, activation or deficiency


May be recognized because of:
Increase in incidence of infections
Increase in severity of infections
Unusual etiology of infection (opportunistic infections)
Dysfunction/ abnormality of cells or organs not directly related to the
immune system

Immunodeficiency
Primary Immunodeficiency
Congenital immune deficiencies or
developmental defects in immune
system
These defects are present at birth but
may show up later on in life
Generally present with:
Recurrent ear infections/yr
Sinus infections, pneumonias,
meningitis, or sepsis/yr
Recurrent abscesses
Persistent thrush

Secondary immunodeficiency
Loss of immune function that develops
later in life as a direct consequence of
some other recognized cause
Acquired immune deficiencies that arise
from:
Medical intervention (iatrogenic)
Antirejection drugs post transplant
Immunomodulating drugs for
autoimmune conditions
Chemotherapy & radiation for
malignancy
Infections/ cancers/Myeloma, leukemia
HIV/AIDS, other viruses
Metabolic/ toxic
Diabetes, renal & hepatic failure Aging

2 general types: Primary (Congenital) & Secondary (Acquired)

General Features of Immunodeficiency diseases
Principal consequence of immunodeficiency is an increased
susceptibility to infections
Type of infection depends on the nature of immunodeficiency.
Defects in humoral immunity results in increased susceptibility
to infection with encapsulated, pus forming bacteria and some
viruses
Defects in cell mediated immunity lead to infection with viruses
and intracellular microbes
Increased susceptibility to certain types of cancer
Increased incidence of autoimmunity
Immunodeficiency may result from defects in lymphocyte
development or activation or from defects in the effector
mechanisms of innate and adaptive immunity

Features of Immunodeficiency affecting T or B
lymphocytes, phagocytes
Type of
pathogen
T-cell defect B-cell defect
Granulocyte
defect
Complement
defect
Bacteria Bacterial sepsis Streptococci,
Staphylococci,
Haemophilus
Staphylococci,
Pseudomonas
Neisserial
infections, other
pyogenic bacterial
infections
Viruses CMV, EBV, severe VZV,
chronic infections with
respiratory &
intestinal viruses
Enteroviral
encephalitis

Fungi &
parasites
Candida,
Pneumocystis jiroveci
Severe intestinal
giardiasis
Candida,
Nocardia,
Aspergillus

Special
features
Aggressive disease
with opportunistic
pathogens, failure to
clear infections
Recurrent
sinopulmonary
infections, sepsis,
chronic meningitis

Examples of Infections in Immunodeficiency
Congenital Disorders of Innate Immunity
Congenital Disorders of Innate Immunity
Defective production of reactive oxygen species by
phagocytes resulting in recurrent catalase positive bacterial
& fungal infections
Recurrent infections with cat+
Staphylococcus aureus
Pseudomonas species
Serratia species
Klebsiella species
Candida species

Chronic Granulomatous Disease (CGD)
Neutrophils, Macrophages are
affected
Poor intracellular killing and
low respiratory burst.

In majority of these patients, the deficiency is due to:
A defect in NADPH oxidase that participate in phagocytic
respiratory burst
(Phagocytic oxidase enzyme complex) phox
Defective reactive oxygen species production

Infections not controlled by
phagocytes, so T-cell mediated
activation is turned on
Exhibit inflammatory reaction
resulting in the formation of
granulomas (macrophages, T
cells)
Characterized by marked
lymphadenopathy,
hepatosplenomegaly and chronic
draining lymph nodes
Autosomal recessive or X-
linked trait

Treatment with IFN-

Chronic Granulomatous Disease (CGD)
Respiratory Burst triggered in
macrophages and neutrophils cause
a transient increase in oxygen
consumption during production of
microbicidal oxygen metabolites
which ultimately kill microbes
through
Reactive Oxygen species (ROS)
Nitric Oxide (NO)
Individuals who have defective
NADPH will not produce H
2
O
2

(hydrogen peroxide)

Bacteria produce some hydrogen
peroxide which is used by
myeloperoxidase
Infections with catalase positive
bacteria will destroy the hydrogen
peroxide and therefore no substrate
for myeloperoxidase

Mechanism of Respiratory Burst
14

Nitroblue tetrazolium test

CGD patients can be diagnosed on
the basis of poor Nitroblue
tetrazolium (NBT) reduction which
is a measure of respiratory burst
negative reaction in the nitroblue
tetrazolium test which in normal
individual turns blue due to
reduction by superoxide anions.
Step1: neutrophils placed on slide
with an activator to induce
activation of NADPH
Step 2: Drop of nitroblue
tetrazolium (yellow color) added to
the slide
In the presence of normal NADPH
the yellow dye turns purple
(positive test)
In the absence it remains yellow
(negative test)
Patients with CGD the test is
negative (yellow)
NBT reduction
Positive reaction in the nitroblue
tetrazolium test normal cells
turns blue due to reduction by
superoxide anions.

Negative reaction in the nitroblue
tetrazolium test in which abnormal
cells are yellow due to absence of
superoxide anions.

Myeloperoxidase deficiency:
Myeloperoxidase is green
contributes to the color of pus
Individuals with
myeloperoxidase deficiency can
still kill bacteria but more slowly
(no ClO- produced)

Individuals with myelperoxidase
deficiency will be susceptible to
bacterial infections
Will be positive by NBT test
Chronic Granulomatous Disease (CGD)
Inherited defect (autosomal
recessive) in phagolysosome
function:
Affected gene encodes LYST
protein that regulates lysosomal
trafficking
Defective fusion of phagosome-
lysosome in phagocytes
Reduced intracellular killing and
chemotactic movement
Defective degranulation
Delayed microbial killing
Neutropenia

Giant lysosomes are often seen
and fail to function (Granule
structural defect).
Extremely large granules are
seen in the cytoplasm of
granulocytes.
Result from abnormal fusion of
granules during their formation
The respiratory burst is normal.
Resulting in recurrent infections
with pyogenic bacteria,
especially in the skin &
respiratory tract





Chdiak-Higashi Syndrome
Giant granules
A history of recurrent bacterial infections and giant
granules seen in peripheral blood leukocytes is
characteristic for Chediak-Higashi syndrome.
Other cells affected by this disorder
Melanocytes (partial albinism)
Platelets (bleeding disorders)
Cells of the nervous system; Schwann cells
(neuropathy),
NK and cytotoxic T cells (aggressive
lymphoproliferative disorder).

Chdiak-Higashi Syndrome
Jobs syndrome (hyper-IgE
syndrome):
TH1 cells can not make IFN-,
which reduces the ability of
macrophages to kill bacteria. This
leads to an increase in TH2 cells
and high level IgE level.
Increased IgE causes histamine
release, which blocks certain
aspects of the inflammatory
response and inhibits neutrophil
chemotaxis
Patients have recurrent cold
staphylococcus abscesses,
eczema, & high IgE

Other Phagocyte Deficiencies
Kaplan Medical USMLE step 1;
Immunology and Microbiology lecture
notes
Biological function of TH1 and TH2 subsets
22
TH1 TH2
Fig 31 Fig 30.
LFA-1: CD11a CD18
Mac-1: CD11b CD18

LAD-1: Mutation in gene
encoding common chain
(CD18) of a few integrins
including LFA-1 and Mac-1 that
mediate adhesion to
endothelium and other cells


Cells affected:
Neutrophils, lymphocytes,
monocyte/macrophages, NK cells
Functional defects: mostly
adhesion-dependent leukocyte
functions are impaired
Chemotaxis, diapedesis,
adherence, phagocytosis, CTL &
NK cytotoxicity

Leukocyte Adhesion Deficiency Syndrome (LAD-1)
Associated features:
Delayed cord separation
(omphalitis), failure to form pus,
chronic skin ulcers, periodontitis,
leukocytosis, defective T & NK
cytotoxicity

Inheritance: Autosomal Recessive
Treatment is with bone marrow
(devoid of T cells and MHC-
matched) transplantation or gene
therapy.

Leukocyte Adhesion Deficiency Syndrome (LAD-1)
Defects in phagocytic cells are associated with
persistence of bacterial infection
Disorders of Complement System
C3b deficiency from insufficient C3 synthesis are particularly
susceptible to sepsis with pyogenic bacteria that may be
fatal
Shows importance of C3b in opsonization & enhanced
phagocytosis
Immune complex disease; SLE
C5, C6, C7, or C8 deficiency are prone to Neisseria infections

Defects in C components results in immunodeficiency
lead to increased susceptibility to bacterial infections.

Hereditary Angioedema
Autosomal dominant disease
Results from deficiency in C1
inhibitor deficiency (C1-INH)
which targets C1r, C1s, factor XII
of the coagulation pathway,
kallikrein pathway
In the absence of INH
C1 continues to act on C4 to
generate C4a
C4a subsequently triggers
vasoactive components C3a,
C5a
Bradykinin release

Lead to edema of skin and
mucosal surface of respiratory
and GIT following minor trauma
or emotional stress
Larygeal edema can be fatal
Nausea ,vomiting, diarrhea


Copyright 2011 by Saunders, an imprint of Elsevier Inc. Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7
th
edition. Copyright 2012 by Saunders, an imprint of Elsevier Inc.
Regulation of C1 Activity by C1 INH
Fig. 12-13
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acquired , clonal, hematopoietic
stem cell disorder
Somatic mutation of PIG-A gene
(phosphatidyl inositol glycan
class A gene) in a myeloid stem
cell clone
Codes for anchoring proteins GPI
(glycosyl phosphatidylinositol)
which anchors many proteins to
cell membrane example
CD 55 (DAF) inhibitors of C
CD 59 (membrane inhibitor
of reactive lysis)
CD 14 (Macrophages)
CD 16 (NK cells)
C8 binding proteins
Defect in anchoring of CD 55
and CD 59 on the surface of RBC,
Neutrophils and platelets
CD55 and CD 59 degrade C3 and
C5 convertase thus preventing
MAC deposition on normal cells
and their lysis

Intravascular complement
mediated lysis of RBC, platelets
and neutrophils
Occurs at night because
respiratory acidosis enhances
complement attachment



Copyright 2011 by Saunders, an imprint of Elsevier Inc. Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7
th
edition. Copyright 2012 by Saunders, an imprint of Elsevier Inc.
Inhibition of C3 Convertase Formation
Fig. 12-14
Copyright 2011 by Saunders, an imprint of Elsevier Inc. Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7
th
edition. Copyright 2012 by Saunders, an imprint of Elsevier Inc.
Regulation of MAC Formation
Fig. 12-16
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Clinical Findings:
Iron deficiency due to episodic
hemoglobinuria (microcytic
anemia)
Increased vessel thrombosis
(due to release of aggregating
agents from platelets)
Increaed risk of developing
acute myeloblastic leukemia (
because of defect in stem cell
Diagnosis: Flow cytometry for
CD55 and CD 59

Defects of Humoral Immunity
B cell & Antibody Deficiencies
Sites of lymphocyte development block in some primary immunodeficiency
diseases
ADA: adenosine deaminase
AID: activation-induced deaminase
Disease Functional Deficiencies Mechanism of Defect
Agammaglobulinemias
X-linked Brutons Decrease in all serum Ig isotypes;
reduced B cell numbers
Pre-B receptor checkpoint defect;
Btk mutation
Hypogammaglobulinemias/isotype defects
Selective IgA deficiency Decreased IgA; may be associated with
increased susceptibility to bacterial
infections and protozoa such as Giardia
lamblia
Failure to class switch
Selective IgG2 deficiency Increased susceptibility to bacterial
infections
Small subset have deletion in IgH 2
locus
Common variable
immunodeficiency
Low IgG ; IgA, variable IgM ; normal or
decreased B cell numbers
Hyper-IgM syndromes ( Combined B and T cell )
X-linked Defects in T helper cell-mediated B cell,
macrophage, and dendritic cell
activation; defects in somatic mutation,
class switching, and germinal center
formation; defective cell-mediated
immunity
Mutation in CD40L
B cell & Antibody deficiencies
X- Linked Agammaglobulinemia
Disorder: Brutons
agammaglobulinemia
The most severe
hypogammaglobulinemia
Functional deficiencies: absence
of antibody production, lack of B
cells
Mature B cells are absent as they
exist in the pre-B cell stage with
H, but not L, chains rearranged
Patients have failure of B-cell
maturation associated with a
defective B cell tyrosine kinase
gene (Btk)

BTK: phosphorylating enzyme
that Pre-B cells use to signal that
they have successfully put the
Pre-BCR on the B cell surface
Result: patients have no
Antibodies (all serum isotypes)
and suffer severe & recurrent
bacterial infections
May have small amount of IgM
FIGURE 7.1. Stages in differentiation of B lymphocytes. Dashed lines on
the pre-B cell indicate surrogate light chains. The two lines associated
with the cell surface heavy chain represent the signaling molecules Ig
and Ig (CD79a and b).
X-agammaglobulinemia Ig Levels
Maternal IgG
passively
acquired
Figure 12.8.
Immunoelectrophoresis
Diagnosis is based on enumeration of B cells &
Antibody measurement
Immunoelectrophoresis reveals the absence of several
distinct Abs in serum from XLA patient
Diagnosis is based on enumeration of B cells &
Ab measurement
Flow cytometry shows loss of B Cells in XLA
Selective immunoglobulin deficiency (IgA)
Hypogammaglobulinemias/
isotype defects:
IgA deficiency is the most
common of all primary
immunodeficiencies known
(1/700 of all Caucasians)
Results from a defect in heavy
chain class switching. Leads to
Failure to mature into plasma
cells, drop in secretory IgA.
IgA-deficient patients are very
susceptible to pyogenic bacterial
infections (especially in sinus and
lungs), gastrointestinal, eye and
nasopharyngeal infections.

Decrease in secretory and serum
IgA
Patients with IgA deficiency have
a high incidence of autoimmune
diseases (particularly immune
complex type) and lymphoid
malignancies.
Anaphylaxis on exposure to
blood products with IgA
Laboratory diagnosis is based on
IgA measurement.


Transient
hypogammaglobulinemia
Children, at birth, have IgG levels
comparable to that of the
mother.
Because the half life of IgG is
about 30 days, its level gradually
declines, but by three months of
age normal infants begin to
synthesize their own IgG.
In some infants, however, IgG
synthesis may not begin until
they are 2 to 3 years old.
This delay has been attributed to
poor T cell help.
This results in a transient
deficiency of IgG which can be
treated with gamma-globulin
Profound decrease in antibody
producing plasma cells
Low levels of all isotypes
Recurrent infections
Condition manifest late than
other immunodeficiency (teens
or twenties)
Late onset
hypogammaglobulinemia
Common Variable
immunodeficiency
Common variable immunodeficiency
Martha D., a 40-year-old woman, presents with recurrent
sinusitis requiring antibiotic treatment. She has had two
hospitalizations within the past two or three years for
bacterial pneumonia. She also reports symptoms of chronic
diarrhea, abdominal pain, weight loss, and fatigue.
Laboratory tests reveal evidence of malabsorption due to
infection with Giardia lamblia. Serum immunoglobulin
assessments reveal a significantly decreased level of IgG
and a mildly decreased level of IgA, consistent with
common variable immunoglobulin deficiency. She is treated
with passive immunoglobulin therapy, and her IgG level
increases to within normal range. She continues to receive
immunoglobulin therapy and remains free of significant
infection or diarrhea for several years thereafter.
Brutons X-linked agammaglobulinemia
Brutons X-linked agammaglobulinemia was named
after an American pediatrician, Dr. Ogden Carr Bruton.
In 1952, Dr. Bruton described the clinical case of an 8-
year-boy who had recurrent bacterial infections,
including many episodes of pneumococcal sepsis. Dr.
Bruton vaccinated the boy, the boy did not produce
anti-bodies to any antigen and had undetectable levels
of serum immunoglobulins. Dr. Bruton treated this
patient with monthly injections of exogenous gamma
globulin. The boy did not have any occurrences of
sepsis over the 14 months during which he received
injections. Because this condition was observed only in
male patients, it was determined to be X-linked
Defects of T cells
Combined T and B cell disorder
and Severe Combined deficiencies
Deficiencies associated with defects lymphocyte activation and effector functions
Disease Functional Deficiencies Mechanism of Defect
Defects in MHC expression
Bare lymphocyte
syndrome
Defective MHC class II expression and
deficiency in CD4
+
T cells; defective cell-
mediated immunity and T-dependent
humoral immune responses
Defects in transcription factors regulating
MHC class II gene expression,
MHC class I deficiency Decreased MHC class I levels; reduced CD8
+
T
cells
Mutations in TAP1, TAP2
Defective T cell signaling
Proximal TCR signaling
defects
Defects in cell-mediated immunity and T-
dependent humoral immunity
Mutations in CD3 genes, CD45,
Familial hemophagocytic lymphohistiocytoses
X-linked
lymphoproliferative
syndrome
Uncontrolled EBV-induced B cell
proliferation, uncontrolled macrophage and
CTL activation, defective NK cell and CTL
function
Mutations in SAP
Perforin deficiencies Uncontrolled macrophage and CTL activation,
defective NK cell and CTL function
Mutations in PERFORIN
Granule fusion Uncontrolled macrophage and CTL activation,
defective NK cell and CTL function
Defective cytotoxic granule exocytosis;)
Defects in T cell Activation
Disease Functional Deficiencies Mechanism of Defect
Defects in cytokine signaling
X-linked SCID Marked decrease in T cells; normal or
increased B cells; reduced serum Ig
Cytokine receptor common chain
mutations; defective T cell development in
the absence of IL-7-derived signals
Autosomal recessive
forms
Marked decrease in T cells; normal or
increased B cells; reduced serum Ig
Mutations in IL2RA, IL7RA, JAK3
Defects in nucleotide salvage pathways
Autosomal recessive
SCID due to ADA
deficiency
Progressive decrease in T, B, and NK cells;
reduced serum Ig
ADA deficiency caused by mutations in the
gene, leading to accumulation of toxic
metabolites in lymphocytes
Autosomal recessive
SCID due to PNP (purine
nucleoside) deficiency
Progressive decrease in T, B, and NK cells;
reduced serum Ig
PNP deficiency caused by mutations in the
gene, leading to accumulation of toxic
metabolites in lymphocytes
Defects in V(D)J recombination
RAG1 or RAG2 deficiency
recombination ;
(Omenns syndrome)
Decreased T and B cells; reduced serum Ig;
absence or deficiency of T and B cells
Cleavage defect during V(D)J
recombination; mutations in RAG1 or RAG2
Defective thymus development
Defective pre-TCR
checkpoint
Decreased T cells; normal or reduced B
cells; reduced serum Ig
Mutations in CD45,
DiGeorge syndrome Decreased T cells; normal B cells; normal or
reduced serum Ig
22ql 1 deletion;
Severe Combined Immunodeficiencies
Congenital Thymic Aplasia Thymic hypoplasia
Di George's syndrome:
autosomal dominant, caused by
deletions of various sizes in
chromosome 22
Most clearly defined T-cell
immunodeficiency
Both thymus & parathyroid fail to
develop properly: abnormal
development of the fetus (3rd
and 4th pharyngeal pouch) during
the 6-10 wk of gestation (forming
parathyroid, thymus, lips, ears
and aortic arch)

Circulating T cells are decreased
Circulating B cells normal
Serum antibodies are normal or
decreased
Associated features:
Hypoparathyroidism (tetany;
seizures in new born)
Absent thymic shadow on
radiograph
Congenital heart defects, low set
notched ears and fish shaped
mouth

DiGeorge Syndrome
Small Thymus, Low T Cell Development
BoneMarrow Thymus
Thymus Peripheral LN
Congenital Thymic Aplasia; Thymic hypoplasia
Early life infections with
Extracellular Bacteria
Viral infections: CMV, EBV,
Varicella
Fungi: Pneumocystis and Candida

Treatment:
Patients may be treated with a
thymic graft.
Thymic graft from an early fetus
(13-14 wk gestation) used for
treatment where as older grafts
may result in GVH reaction.
In severely immunodeficient
DiGeorge patients, live vaccines
may cause progressive infections.

Hyper IgM syndrome
Individuals with this type of
immunodeficiency have low IgA,
IgE and IgG concentrations with
abnormally high levels of IgM.
These patients cannot make a
switch from IgM to other classes
which is attributed to a defect in
CD40L on their CD4 cells.
Absence of co-stimulatory signal
of CD40-CD40L inhibits B cell
response to T-dependent
antigens


B cell response to T- independent
antigen is unaffected accounting
for the production of IgM
No class switching and failure to
produce germinal centers
They are very susceptible to
pyogenic infection and should be
treated with intravenous gamma-
globulins.

Helper T cell mediated
activation of B cells
57
Defects in IgG production and
affinity maturation in hyper
IgM syndrome

No class switching
No somatic hypermutation
Increased susceptibility to
extracellular bacteria and
some fungal infections
Severe Combined Immunodeficiency (SCID
Defective lymphoid progenitor
cells ; both the T & B cell lineages
are affected ; result in SCID
Less common but are very severe.
Infants suffer from recurrent
infections especially by
opportunistic microorganisms
(bacterial, viral, mycotic,
protozoan)
Immunodeficiency is X-linked or
autosomal
Characterized by an absence of T
cell and B cell immunity and
absence (or very low numbers) of
circulating T and B lymphocytes.


Thymic shadows are absent on x-
rays.
Diagnosis is based on
enumeration of T and B cells and
immunoglobulin measurement.
Treatment is by gene therapy or
stem cell transplantation.
SCID patient must not receive live
vaccine as it will result in
progressing disease

SCID Defect: ADA deficiency
Adenosine deaminase (ADA)
deficiency
ADA: enzyme responsible for
converting adenosine to inosine.
Ada deficiency leads to
accumulation of adenosine which
results in production of toxic
metabolites that interfere with
DNA synthesis.
Defects in adenosine deaminase
(ADA) or purine nucleoside
phosphorylase (PNP) genes
which results is accumulation of
dATP or dGTP, respectively, and
cause toxicity to lymphoid stem
cells.

The patients have defects in T, B
and NK cells
Clinical manifestations include
skin, mouth & throat lesions,
opportunistic fungal infections,
chronic diarrhea, low levels of
circulating lymphocytes

Autosomal SCID patients with
ADA deficiency have been treated
with a retroviral vector
transfected with the gene with
some success.
SCID Defect: Common gamma chain of IL-2 R
Common gamma chain of IL-2 R
(present in receptors for IL-4, -7,
-9, -15)
X-linked severe SCID
IL-2R may be lacking in patients
thereby preventing signaling by
IL-2 and other growth factor
cytokines
Lead to defect in the proliferation
of T cells, B cells and NK cells.
Clinical manifestations include
skin, mouth & throat lesions,
opportunistic fungal infections,
chronic diarrhea, low levels of
circulating lymphocytes

SCID Defect: Rag1 or Rag2 mutations
Rag1 or Rag2 gene nonsense
mutations
Total absence of B & T cells
Patients having both T and B cell
deficiency lack recombinase
activating genes (RAG1 and 2)
that are responsible for the T cell
receptor and Ig gene
rearrangements.
These patients are athymic and
are diagnosed by examining the
TCR gene rearrangement.
This is an autosomal recessive
trait
They also lack B cells although
they do have Abs in early infant
life because of passive transfer
from mother. NK cells are normal
in these patients.

Omenns syndrome: increased
susceptibility to opportunistic
infections and clinical feature
similar to GVH disease with rash,
eosinophilia, diarrhea and
enlargement of LN
RAG-1 or RAG-2 defect can make
some amount functional Rag
protein. Allow small amount of
VD-J recombination

X-linked SCID
Timmy K., a 4-month-old male, presents with severe
diarrhea andfailure to thrive. Over the past two months, he
has had two episodes of ear infections requiring antibiotic
therapy. Examination reveals a poorly nourished child with
minimal tonsillar tissue and the presence of oral thrush.
Blood tests reveal lymphocyte counts significantly below
normal with an absence of T cells (CD3+) and NK cells
(CD16+, CD56+) and significantly reduced numbers of B
cells (CD19+).
A further workup by an immunology consultant results in a
diagnosis of X-linked SCID.
The hematology/immunology trans-plant team is notified,
and the patient receives a bone marrowtransplant.B.
B- and T-cell disorders associated with other
diseases
Disease Defect Presentation Labs
Ataxia-telangiectasia Defect in DNA repair
enzymes.
Triad: Cerebellar
defects (ataxia),
Spider angiomas
(telangiectasia),
IgA deficiency.
IgA, IgE deficiency.
Normal IgM
Wiskott-Aldrich
syndrome
X-linked recessive defect.
Progressive deletion of B and
T cells.
TCR-dependent actin-
cytoskeletal rearrangements
are defective because of
mutations in WASP

Triad (TIE):
Thrombocytopenic
purpura,
Infections,
Eczema.
IgE, IgA; IgM.
Ataxia-Telangiectasia
Deficiency of T cells associated
with a lack of coordination of
movement (ataxis) and dilation
of small blood vessels of the
facial area, eyes (telangiectasis).
Defective CMI: T-cells and their
functions are reduced to various
degrees.
B cell numbers and IgM
concentrations are normal to low.
IgG is often reduced and IgA is
considerably reduced (in 70% of
the cases).
There is a high incidence of
malignancy, particularly leukemia,
in these patients.
The defects arise from a breakage
in chromosome 14 at the site of
TCR and immunoglobulin heavy
chain genes.
Mutations in genes coding for
DNA repair enzymes


Wiskott-Aldrich Syndrome
Defect in cytoskeletal
glycoprotein, CD43
Mutant gene encodes a protein
involved in actin filament
assembly in cytskeleton of all
hematopoietic cells
Defect in cell migration and
signal transduction
Gradual loss of humoral and
cellular responses: inability of T
cells to provide help to B cells
Associated with normal T cell
numbers with reduced functions,
which get progressively worse.

TRIAD: (TIE) Thrombocytopenia,
Infections, Eczema
IgM reduced, IgG normal, IgA &
IgE elevated
X-linked disorder
Boys with this syndrome develop
severe eczema, Petechia (due to
platelet defect) and bleeding
from thrombocytopenia. They
respond poorly to bacterial
polysaccharide antigens
(pneumococci) and are prone to
pyogenic infection and
respiratory infections.

MHC Deficiencies
MHC-II Deficiency
Circulating T cells normal
decreased CD4 T cell numbers
Circulating B cells normal
Serum Ig normal or decreased
Associated features:
Bare Lymphocyte Syndrome, lack
of T-cell responses to antigens,
Hepatic disease from chronic
cryptosporidia or CMV infection
MHC-I Deficiency
TAP 1/2 Deficiency
Circulating T cells: decreased
CD8, normal CD4
Circulating B cells an serum Ig
normal
Associated features:
respiratory infections, vasculitis,
with few viral infections
Reading
Chapter 12 Abbas and Lichtman; 3
rd
or 4
th

edition
Robbins 8
th
edition , Chapter 6