Download Krishnaswamy

Guha Krishnaswamy, M.D., FACP., FCCP., FAAAI, FACAAI
08/01/2010
The Primary Immune Deficiencies
Macrophage
T cell
Immunodeficiency
•Mechanisms
•Presentations
•When to suspect
•How to treat
• Definition
– Immunodeficiency is the result of a
diverse group of abnormalities of the
immune system resulting primarily in an
increased incidence of infection
Pneumococcus
• Primary Immunodeficiency
– Congenital and hereditary
Guha Krishnaswamy, M.D., FACP., FCCP., FAAAI, FACAAI
Professor of Medicine
Chief of Allergy and Immunology
Editor-In-Chief, Clinical Molecular Allergy
Quillen College of Medicine
James H. Quillen VA Medical Center
• Secondary Immunodeficiency
– Acquired on a transient or permanent
basis
August 10
Guha Krishnaswamy, M.D.
2
Innate-Adaptive Immunity Interactions
Adaptive
Immunity
8/2/2010
3
4
Disorders Diagnosed In Appalachia
• Humoral
– CVID, subclass defects, selective polysaccharide defects, selective IgM and
IgE deficiency, Mixed defects
• Cellular
– SCID, HIGM, Ommen syndrome, DiGeorge’s syndrome
• Complement
– Component (C1, C4, C8), MBL, HAE/AAE
• Phagocyte
– CGD, Hyper-IgE, MPO defect
• Secondary
– Glucocorticoids, chemotherapy/mixed, paraproteinemias, DM,
hematological dyscrazias, malignancies, iatrogenic (Gold, seizure
medications), nephrosis, cirrhosis, ADEH
• Structural and others
5
8/2/2010
– Immotile cilia syndrome
Pathogen Patterns In Immune Deficiency
Pathogen Type
T-cell Defect
B-cell Defect
Granulocyte Defect
Complement Defect
Bacteria
Bacterial sepsis
Staphyloccus,
Hemophilus
Streptoccus
Staphylococcus
Pseudomonas
Neisseria
Pyogenic bacteria
Virus
CMV, EBV, VZ
CEMA
---
---
Fungi
Candida
---
Candida, Aspergillus
---
Parasite
PCP
PCP, Giardia
---
---
Acid Fast
AFB
---
Nocardia
---
August 10
Guha Krishnaswamy, M.D.
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1
Guha Krishnaswamy, M.D., FACP., FCCP., FAAAI, FACAAI
08/01/2010
Primary Immunodeficiency
Cellular
10%
Combined
20%
Phagocytic
18%
Complement
2%
Antibody
50%
•
•
•
•
Primary Immunodeficiency Disorders
Frequency
Italy
1:77,000
Japan
p
1:200,000
,
Switzerland 1:54,000
Sweden
1:55,000
B-cell disorders
• Selective IgA deficiency (1:333)
– XLA 1:100,000
– CVID 1:75,000
T cell disorders
T-cell
– SCID 1:100,00
Phagocytic disorders
– CGD 1:200,000
Complement disorders
– very rare
Guha Krishnaswamy, M.D.
7
August 10
Case 1
Guha Krishnaswamy, M.D.
8
What is the single test that is most likely to
confirm the underlying diagnosis?
• A 16 year old girl
presents with her third
episode ankle arthritis
with fever. Examination
reveals
l a rash.
h Gram
G
stain
i
of the joint aspirate is
shown in the slide
A. Neutrophil count
B. NBT assay
C. Oxidative burst of
neutrophil
D CH50
D.
E. IgG level
C1q, C1r, C1s
0%
ev
el
0%
O
xi
Ig
G l
ur
s..
.
0%
C
H5
0
u.
..
l c
o
Immune complex
A. Stroke
B. Premature coronary artery
disease
C. Paroxysmal cold
hemoglobinuria
D. Paroxysmal nocturnal
hemoglobinuria
E. Gram negative sepsis
N
BT
ph
i
tro
N
eu
Defects in DAF/CD55 and HRF/CD59 lead to:
0%
as
sa
y
0%
da
t iv
e b
August 10
7
MBL,MASP1,MASP2
C2,C4
DAF/CD55
C1 inhibitor
C3
e
ro
k
0%
0%
0%
C5-C9
Homologous
Restriction factor
CD59
P
re
m
at
ur
e c
St
0%
or
o.
P
..
ar
ox
ys
m
al co
P
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ar
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ox
ys
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al no
G
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ra
.
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n
eg
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ive
..
.
0%
D,B,C3b,P
7
MAC
CELL LYSIS
2
Guha Krishnaswamy, M.D., FACP., FCCP., FAAAI, FACAAI
08/01/2010
Complement Component Deficiency
Case 2
• CTC is a 4 month old male admitted for a pneumonia
• Prior hx: repaired imperforate anus, hydronephrosis
• Lab reports show:
• Early complement deficiency is associated with
recurrent pyogenic infection and connective
tissue disease (especially C2 and C4)
• Complement deficiency of components 5 through
8 is associated with recurrent Neisseria species
infection
• Deficiency of the complement regulatory protein
C1 esterase inhibitor associated with angiodema
(hereditary angiodema)
• Deficiency of DAF/CD55 and HRF/CD59
associated with PNH
–
–
–
–
–
–
–
–
–
–
Blood sugar N
Sodium 145 mmol/L (N)
Calcium 6.1 mg/dL (9-11 N)
Ionized calcium low 0.93L (N=1.12-1.32)
Intact PTH 14 pg/ml (N=15-75)
CD4+ T cells 688 (N=575-1070/cumm)
CD8+ T cells 140 (N=190-860/cumm)
WBC= 9600/cumm (N)
ECHO: shows VSD, pulmonic stenosis
IgG, A and M normal; poor vaccine response
Typical finding in this disease is:
Elevated PTH level
Absence of a cleft palate
Vitiligo
Deletion of Tuple gene
Elevated TRECs
n o
te
d T
f T
0%
RE
Cs
u.
..
go
0%
ev
a
7
El
El
ev
0%
D
el
et
io
ce
o
f a
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.
0%
A
bs
en
at
ed
P
TH
l.
..
0%
V
it i
li
A.
B.
C.
D.
E.
CXR In DIGeorge Syndrome
All the following defects are seen except:
ar
s
pe
d m
ou
th
0%
sh
‐sh
a
th
i
Lo
og
na
M
icr
0%
w
se
t e
ow
sh
ad
0%
a
0%
Fi
ce
o
f t
h
ym
ic ex
t ro
ca
rd
i
a
0%
D
C.
D.
E.
Dextrocardia
Absence of thymic
shadow
Micrognathia
Low set ears
Fish-shaped mouth
A
bs
en
A.
B.
7
http://www.hawaii.edu/medicine/pe
diatrics/pemxray/v2c02.html
8/2/2010
18
3
Guha Krishnaswamy, M.D., FACP., FCCP., FAAAI, FACAAI
08/01/2010
Fish del
(22)(q11.2q11.2)(TUPLE1-)
DiGeorge Anomaly
Normal interphase Deleted interphase
– Dysmorphic facies
(micrognatia)
– Hypocalcemia (lack of
parathyroids)
– Depressed T-cell immunity
(absent thymus)
– Congenital heart disease
11.2
13
22
Probes:
• Defect in embryogenesis,
3rd and 4th pharyngeal
pouches
• Clinical features:
8/2/2010
TUPLE1
TUPLE1--22q11.2 (orange)
ARSA--22q13.3(green)
ARSA
19
Courtesy: Reid Myer, MAYO
• Presents in first few days
of life (tetany)
• Diagnosed immediately by
lateral chest x-ray
(absence of thymic
shadow)
Case 3
DiGeorge Anomaly: Partial vs Complete
Partial DGA
• Most frequent
• Thymic hypoplasia
• Normal corticomedullary
differentiation
• Presence of Hassall
Hassall’ss
corpuscles
• Normal thymic function
• CD4 cells > 400/mm3
• T-cell function adequate
• B-cell numbers and function
normal
• Usually free of infections
Complete DGA
Uncommon
Thymic aplasia
CD4 cells < 400/mm3
B-cell numbers normal
Antibody response
decreased
• Susceptible to
infections
• Susceptible to GVHD
•
•
•
•
•
• Ataxia-telangiectasia (A-T)
is characterized by
CVID
T cell dysregulation
Low interferon gamma
IgA
g deficiency
y
Mannose binding lectin
deficiency
0%
en
cy
in
di
M
an
n
os
e b
ic i
de
f
Ig
A gu
...
rfe
in
te
w
Lo
0%
– Progressive cerebellar ataxia
•
beginning between one and
four years of age
•
– Oculomotor apraxia
– Frequent infections
– Choreoathetosis
•
– Telangiectasias of the
conjunctivae
– Patients with A-T are
unusually sensitive to ionizing •
radiation and malignancy
n.
..
0%
ro
n.
..
0%
ys
re
T
ce
ll d
C
VI
D
0%
– a staggering gait
– finger-nose
incoordination
Ataxia Telangiectasia
The typical immune defect seen in
these patients is:
A.
B.
C.
D.
E.
• A patient who has
recurrent
sinopulmonary
infections
demonstrates this
ocular finding
• He also has
ATM gene: 11q22.3
Karyotype: 7;14
chromosomal
translocation
Alpha fetoprotein
elevated in >90% of
patients
IgA deficient
7
4
Guha Krishnaswamy, M.D., FACP., FCCP., FAAAI, FACAAI
08/01/2010
Case 4
The best diagnostic test is:
• A 16 year old male
patient presents with
recurrent purulent
bronchitis and failure
to thrive
• HRTSCT chest
h
demonstrates saccular
bronchiectasis
• Sinus CT scan and
CXR are shown in
next slide
A. Echocardiogram and
endomyocardial biopsy
B. Saccharin test
C. IgG level
D Transbronchial
D.
T
b
hi l bi
biopsy and
d
electron microscopy
E. Nasal biopsy
N
as
al
b
io
ps
y
l
...
al
ev
e
ch
i
Ig
G l
sb
ro
n
ra
n
T
...
gr
am
cc
ha
rd
io
C
D1
1/
C
D1
8 fl
ev
ph
i
N
eu
tro
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ow
.. .
0%
l o
xi.
..
el
0%
Ig
G l
Sa
ho
ca
Ec
•
•
•
•
•
•
•
•
CH50
CD4 cell count
IgG level
Neutrophil oxidative burst
CD11/CD18 flow
cytometry
C
H5
0
C
D4
ce
ll c
ou
nt
0%
7
Labs
The best diagnostic test would be:
0%
0%
• AS is a 11 month old
Caucasian female
admitted with fever,
diarrhea, bilateral
pneumonitis, bilateral
otitis media and
pansinusitis
i ii
• CXR is shown in
adjoining picture
• Bronchoscopy was
carried out and cultures
grew H. influenzae
• This is her third bout of
bacterial pneumonia
• Dyskinetic cilia syndrome is the result of an
abnormality in ciliary structure which results in
abnormal ciliary motion.
• The ultrastructural abnormality is related to a
deficiency of the dynein arms (which are normally
p
for ciliary
y bending),
g) absent or short radial
responsible
spokes (which prevent buckling of the cilia), and
absent central microtubules.
• Patients have chronic rhinitis, sinusitis, otitis,
recurrent bronchial infections, bronchiectasis, male
sterility, and corneal abnormalities.
• Situs inversus or dextrocardia is present in 50% of
cases and this is the form originally described by
Kartagener.
0%
0%
Case 5
Kartageners Syndrome
A.
B.
C.
D.
E.
0%
rin
te
st
0%
IgE undetectable
IgG <200 mg/dL (L)
IgM <30 mg/dL (L)
I A <12 mg/dL
IgA
/dL (L)
Serum protein and albumin are normal
CD8 1656 cells/cumm (High)
CD4 3373 cells/cumm (High)
CD19 797 cells/cumm (High)
7
5
Guha Krishnaswamy, M.D., FACP., FCCP., FAAAI, FACAAI
08/01/2010
The next most important step is:
The Most Likely Diagnosis is:
A. Brutons disease
B. Hyper-IgM syndrome
C. Common variable immune
deficiency
D Nephrotic
D.
N h i syndrome
d
E. None of the above
0%
0%
0%
0%
0%
0%
b.
..
B
ro
nc
ho
sc
M
op
ea
y
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en
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.
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ea
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G ha
...
e a
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on
e of
th
iab
sy
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tic
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o
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ep
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.
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va
r
C
om
m
on
s d
ise
gM
sy
r‐I
ru
to
n
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yp
e
B
0%
nd
...
as
...
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A. Bronchoscopy
B. Measurement of functional
antibody response
C. Stool for alpha-1
p
antitrypsin
yp
D. Start intravenous
immunoglobulin right away
E. Measure IgG half life to
monitor catabolism
7
7
Common Variable Immunodeficiency (Late-Onset
Hypogammaglobulinemia)
Predominantly Antibody Deficiencies
•
•
•
•
•
Onset usually in 2nd or 3rd decade of life
We have seen several cases of infantile CVID
90% sporadic, 10% TACI/ICOS/BTK mutations
40% have T cell defects
Recurrent sinopulmonary infections (usually bacterial
in origin) and sepsis
• Gastrointestinal, endocrine, hematologic disorders can
be associated
• May follow Epstein-Barr infection , sIgA-D, Iatrogens
(Gold, Dilantin sodium)
• Reduction in 2 or more isotypes and normal
or low numbers of B lymphocytes
– CVID (Variable inheritance)
– ICOS deficiency (AR) mutation in ICOS
– TACI deficiency* (AD/AR): mutation in
TNFRF13B
– CD19 deficiency (AR): mutation in CD19
– BAFF receptor deficiency (AR): mutation in
TNFRF13C
• Treated with IGIV infusions (IV or SQ)
* Very common
8/2/2010
Management
•
•
•
•
Diagnose ID by PCR or culture not serology
IGIV 400-600 mg/Kg/month
Avoid live vaccines
No evidence for prophylactic or rotating
antibiotics
• Use higher IGIV dose for bronchiectasis or
suppurative lung disease
33
August 10
Guha Krishnaswamy, M.D.
34
Case 6
• PC is a 9 year old male with a
prior history of recurrent
pneumonitis, otitis and sinusitis
• He is admitted with the
following CXR findings
• Examination reveals a thin,,
febrile male child
• Thoracenthesis shows
empyema and cultures grow
Pneumococcus
• A maternal uncle died of
hypogammaglobulinemia and a
cousin carried the diagnosis of
cystic fibrosis
6
Guha Krishnaswamy, M.D., FACP., FCCP., FAAAI, FACAAI
08/01/2010
Laboratory Results
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to
...
x.
..
.. .
0%
ep
es
sio
ec
ll r
ce
T
f .
..
nd
e
in
g o
0%
C
D4
0 m
qu
en
c
Se
Se
ru
0%
ex
pr
0%
C
D4
0 IgG <200 mg/dL
IgA undetectable
IgM
g <40 mg/dL
g
(N
( >50-250))
Tetanus antibody “0”
H. Influenza B low (<0.1)
ESR 44 mm/hour
Sweat chloride normal
p
ro
t
•
•
•
•
•
•
•
lig
a
A. Serum protein
electrophoresis
B. Sequencing of BTK gene
for mutation
C CD40 ligand expression by
C.
flow
D. CD40 expression by flow
E. T cell receptor
rearrangement study for
clonality
Immune
CD4 1468 cells/cumm (H)
CD8 1996 cells/cumm (H)
CD3 3675 cells/cumm ((H))
CD19 0 cells/cumm (L)
CD16/56 566 cells/cumm (N)
WBC 8200 cells/cumm
ei
n ...
Flow cytometry
•
•
•
•
•
•
The confirmatory test of choice is:
7
X-Linked Agammaglobulinemia
Predominantly Antibody Deficiencies
• Gene defect chromosome location: Xq 21.3-22; B-cell
tyrosine kinase deficiency
• Infections begin at 4 - 6 months of life when maternal
IgG wanes
• Absent circulating mature B-cells
• All major classes of immunoglobulin affected
(IgG, IgM, IgA)
• Lack of ability to make an antibody response to antigen
• Pyogenic infections: Otitis, pneumonia, sinusitis
• Post-vaccinal poliomyelitis
We have summarized
• Neutropenia in 25%
Several leaky phenotypes
• Enterovirus+++ (CEMA)
Guha Krishnaswamy, M.D.
40
All the following facts about this condition
are true except:
0%
0%
0%
ie
s i
ss
s
ec
t l
de
f
he
C
la
T
0%
n f c
ho
ice
..
0%
ex
pr
w
itc
es
A
...
h de
ut
os
fe
ct
om
is
al
s
m
ee
od
n
es
o
f i
nh
.. .
A. It is often X-linked
B. The treatment of choice is
gene therapy
C. The defect lies in expression
of either CD40 or its ligand
on lymphocytes
D. Class switch defect is seen
E. Autosomal modes of
inheritance may also be seen
nk
ed
• RC is a 10 month old
• Laboratory
male admitted with
– WBC 2600 cells/cumm
fever, severe peri-rectal
– ANC 270 cells/cumm
and pharyngeal
– IgG <200 mg/dL (L)
ulceration, neutropenia,
– IgA <6.0 mg/dL (L)
and bibasilar pneumonia
– IgM 89 mg/dL (N)
• He has a prior history of
pneumonia, otitis media
– CH50 normal
and one bout of severe
pharyngitis
August 10
tm
en
t o
Case 7
39
X‐
li
8/2/2010
n Thymoma with Ig deficiency
fte
 heavy chain deficiency (5%)
 5 deficiency
Ig deficiency
Ig deficiency
BLNK deficiency (B cell linker protein)
ea
AR
he
tr
Btk phosphorylates PLC2
85% familial;; 15% spontaneous
p
mutation
T
Btk deficiency (XLA) 85%
It
is
o
• Severe reduction in all isotypes and decreased or
absent B cells: AGAMMAGLOBULINEMIA
7
7
Guha Krishnaswamy, M.D., FACP., FCCP., FAAAI, FACAAI
08/01/2010
HIGM Syndrome
• X-linked CD40L
deficiency
• Low IgG and IgA
• Normal or high IgM
• Neutropenia
• Autoimmunity
• Opportunistic
infections
• Rx IGIV
• BMT
HIGMS: Molecular Defect
• AR CD40 deficiency
– Same as XL
• AR AID deficiency
– Adenopathy/T cell intact
– Milder
Mild disease
di
• AR UNG deficiency
– Adenopathy/T cell intact
– Milder disease
AID=Activation induced cytosine deaminase
UNG=Uracil N-glycosylase
Both required for Ig CSR/somatic hypermutation
44
http://emedicine.medscape.com/article/889104-media
Selective IgA Deficiency
Predominantly Antibody Deficiencies
• Most frequently occurring immunodeficiency
• Serum IgA concentration <5 mg / dL. No other
isotype immunoglobulin deficiency
• 15% of cases associated with IgG subgroup
deficiency
g deficiencyy are
• Some ppatients with IgA
asymptomatic
• Associated with recurrent sinopulmonary infections
and autoimmune, GI tract, and endocrine disorders
• Development of anti-IgA antibodies may lead to
severe anaphylactic reactions with blood
transfusions
• Isotype or light chain deficiencies with normal B
cells
– IgG heavy chain mutations/deletions* (AR): absent IgG
and/or IgA subclasses and IgE
– Isolated IgG subclass deficiency
– Selective IgA deficiency
– Selective IgM deficiency
– Selective IgE deficiency
– Transient hypogammaglobulinemia of infancy
– Specific antibody deficiency with normal Ig
concentrations and normal B cells*
* Relatively common
45
8/2/2010
August 10
Guha Krishnaswamy, M.D.
46
IgG Subclass Deficiency
• IgG antibody can be divided into subclasses - IgG1,
IgG2, IgG3, IgG4
• Deficiency in IgG subclasses has been reported in
some individuals
• Recurrent pyogenic infection has been associated with
IgG subclass deficiency in some individuals
– IgG2 and IgG4: capsulated pathogens
– IgG1 and IgG3: Viral pathogens
• Individuals with IgG subclass deficiency also found to
be asymptomatic
• Relationship of IgG2 deficiency to IgA deficiency
• Clinical significance of IgG subclass deficiency is
variable
August 10
Guha Krishnaswamy, M.D.
47
August 10
Guha Krishnaswamy, M.D.
48
8
Guha Krishnaswamy, M.D., FACP., FCCP., FAAAI, FACAAI
08/01/2010
Case 8
• Baby N is a 2 day old
child, sibling of a baby
diagnosed with JAK3
SCID
• Due to family history
of SCID, we were
consulted by Dr.
Devoe
• There is no diarrhea,
pneumonia or
opportunistic infection
Immune Tests
STAT LABS drawn
CD4 20 cells/cumm
CD8 275 cells/cumm
WBC 22,400 cells/cumm
Hgb 18
18.5
5 g/dL
MPV 7.2 fl (L)
IgG 780 mg/dL
IgM <25 mg/dL
PAN T CD3 %
< 1* % (58-69)
CD3 #/CUMM
< 17* #/cumm (1700-3600)
T HELPER CD4 %
< 1* % (30-50)
T HELPER CD4 #/CUMM < 17* #/cumm (1000-2800)
CD8(CD3+)/CD45 %
< 1* % (18-32)
C 8(C 3 )/C 4 #/C
CD8(CD3+)/CD45
#/CUM < 17*
1 * #/cumm
#/
(800-1500)
(800 1 00)
CD16+56 (NK) %
13
% (8-17)
CD16+56 #/CUMM
218
#/cumm (200-700)
PAN B CD19 %
82*
% (19-31)
CD19 #/CUMM
1378
#/cumm (500-1500)
T-cell Dysfunction : Clinical Characteristics
The most likely diagnosis is:

A. DiGeorge syndrome
B. Severe combined
immunodeficiency (SCID)
C. Sarcoidosis
D HIV
D.
0%
H
IV
Sa
rc
oi
do
s is
ro
m
e
sy
nd
0%
co
m
bi
n
rg
e
0%
Se
ve
re
D
iG
eo
ed
im
m
u.
..
0%
Infections with intracellular microorganisms
– Viruses (HSV, V-Z, CMV, EBV)
– Protozoa (Cryptosporidium, toxoplasma)
– Mycobacteria
– Fungal (Candida, pneumocistis carinii)
– Bacteria, gram negative enteric (T-cell)
– Bacteria, polysaccharide encapsulated (Bcell)
7
T-cell Dysfunction: Clinical Characteristics
Severe Combined Immunodeficiency
Designation
• Anergy to recall antigens
• Graft versus host disease
• Failure to thrive (especially with
diarrhea))
• Increased B-cell malignancies
• Eosinophilia, thrombocytopenia
• Eczema, alopecia
Inh
Ig
Phenotype
Reticular dysgenesis
c chain deficiency
AR
XL


JAK3 deficiency
AR

Swiss type
AR

IL-7R deficiency
AR

Adenosine deaminase
deficiency
ZAP 70 deficiency
Omenn syndrome
AR

T-NKB
T-NK
B
T-NK
B
T,NK
B
T, nlNK
nl B
TB
AR
AR
NI

MHC Class II deficiency AR

Comments
stem cell defect
 IL-2R, IL-4R, IL-7R, IL-9R,
IL-15R
Janus kinase 3 defect
RAG 1/2 deficiency
in some
 ADA in RBC
 CD8
nl T-NK-B RAG 1/2 defect
T, 
 IgE, eosinophilia
NK B
class II transactivator
RF-X defects
nl T-B
9
Guha Krishnaswamy, M.D., FACP., FCCP., FAAAI, FACAAI
Severe Combined Immunodeficiencies
• IVIG
JAK3 deficiency
• Avoidance live viral vaccines
• Irradiation blood products
• Prophylactic antibiotics
IL--7R
IL
7R
 deficiency
Omenn
The diagnosis is best established by:
Fl
ow
cy
to
HIES
• Three variants :
• AD/Job syndrome- High IgE,
poor antibody functional
response, pneumatoceles, coarse
facies, scoliosis, osteoporosis and
mutations
t ti
iin STAT3
• AR-HIES: Elevated IgE, no
skeletal disease, TYK2 mutation,
mycobacterial and viral infection
• AR-HIES: DOCK8 mutation,
severe atopy, skin viral and
staphylococcal infection
0%
hy
...
0%
0%
0%
C
. .
D4
.
, C
D8
an
d N.
..
0%
ns
fo
r
A. Flow cytometry for Tolllike receptor
B. IgE level
C. PCR for staphylococcus
aureus
D. Mutations for Btk
E. CD4, CD8 and NK cell
counts
m
et
ry
...
• A 12 year old girl has
recurrent lung infections
with staphylococcus
aureus and her CXR is
shown.
• She has had skin
infections and cutaneous
abscesses
• Spine films show scoliosis
and osteoporosis.
c - chain deficiency
tio
Case 9
Rag 1 and 2
recombination deficiency
• Enzyme replacement (PEGADA)
XL SCID)
• Gene therapy (ADA, XL-SCID)
M
ut
a
NK
NK--cells +
Rag 1 and 2 deficiency
ve
l
B
B--cells low
• BMT/Stem cell transplantation
Ig
E le
T-cells +
Syndrome
(clonal)
NK
NK--cells
+
ADA deficiency
st
ap
B-cells
+
NK
NK--cells
–
Reticular
dysgenesis
fo
r
T-cells –
NK
NK--cells
+
Severe Combined Immunodeficiency
Treatment
P
CR
B-cells
–
NK
NK--cells
–
08/01/2010
7
Case 10
• A patient presents with high
fever, sinusitis, pneumonitis
and sterile skin abscesses
• He has poor healing after
injury
• Severe
S
periodontitis
i d i i has
h been
b
a
problem (Figure)
• The mother claims he had an
infected umbilical stump for 2
months after childbirth
• Infections are characterized by
severe leukemoid reactions
10
Guha Krishnaswamy, M.D., FACP., FCCP., FAAAI, FACAAI
08/01/2010
Leukocyte Adhesion Deficiency
The diagnosis is best established by:
• Absent beta subunit (CD18) of 3 cell
surface glycoproteins (CD11 family)
• Gene defect chromosome location:
21q22.3; gene product: CD18
• Neutrophils cannot migrate toward
i fl
inflammatory
t
stimuli
ti li or adhere
dh to
t
vascular endothelium
• Diagnosis suggested by:
0%
–
–
–
–
0%
ss
ay
ai
n fo
r m
ye
l. .
.
m
et
ry
...
0%
St
G
6P
D a
o.
..
t u
m
fo
r
Fl
ow
cy
to
A
ss
ay
0%
m
et
ry
...
0%
Fl
ow
cy
to
A. Assay for tumor necrosis
factor
B. Flow cytometry for
CD18
C. Flow cytometry for NFkappaB
D. G6PD assay
E. Stain for
myeloperoxidase
7
Recurrent soft tissue infections
Delayed umbilical cord separation
Severe peridontal disease
No pus formation despite high
white blood cell counts
T-B Interactions and Defects
8/2/2010
63
11