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‫מי אינו סובל‬
‫מחסר חיסוני ?!‬
‫פרופ' עמוס עציוני‬
Patient 1
• Lihi – 1y 4 month, parents not related.
• Normal development + immunization.
• No previous infections.
• 3 days high fever + Meningeal signs.
• Purulent meningitis due to Step. Pneumonia
• Full recovery with antibiotics.
Patient 2
• 2 healthy siblings.
• Parents not related.
• 6 month of age-pneumococcal meningitis.
• 1y osteomyelitis.
• From 1y up to now 8 years old- normal
development no infections.
•Normal CBC.
•Humoral immunity: IgG+A+M serum levels and specific
antibody response (including polysaccharides + anti
pneumococcal antibodies) – normal.
•Cellular Immunity: T cell subsets and mitogen response normal.
Science March 2003
Proinflammatory Cytokines
Decrease mortality due to:
1.Hygiene understanding – Mid 19th
century.
2.Vaccination – Early 20th century.
3.Antibiotics – Early-mid 20th century.
No genetic changes in last 100 years.
Genetic and environmental influences
on premature death in adult adoptee.
Sorensen T et al. NEJM 1988
•1003 adoptee born between 1924-1926 in
Denmark.
•The study compared causes of death in the
adoptee and the biological or adoptive parents.
•Cause of death:
1) Infections – biological parents
2) Vascular – both biological and adoptive parents.
3) Cancer – Adoptive parents.
Good mutations in protection against
infections.
•CCR5 – AIDS
•DUFFY - Malaria
O’Brien & Nelson, Nat.Gen 2004
Nat Med. 2005 Nov;11(11):1170-2.
Efficacy of short-term monotherapy with
maraviroc, a new CCR5 antagonist, in patients
infected with HIV-1.
Conventional PID classification:
Cellular immune defects
Humoral immune defects
Complement defects
Phagocyte defects
etc
Journal clinical investigation Nov 2005
SEVERE COMBINED IMMUNODEFICIENCY
Reticulum Dysgenesis
NK ADA Def.
RAG1 and 1 Def.
BNK +
RAG 1 and 2 recombination
Tcell –
gamma c chain Def.
NK -
B+
Tcell +
B
NK +
JAK 3 Def.
IL-7R Def.
NK +
Omen Synd.
The same RAG1 mutation (R561H) –
Different clinical presentation
Pt1
Symptoms
CMV, EBV
Erythroderma
—
Eosinophils
420
CD3
CD19
N
Mitogen response
IgG
N
IgE
Specific ab
+
Diagnosis
?
JCI 2005
Pt2
Staph sepsis
++
4,550
190
—
Omen Syn
Pt3
Dermatitis, Candida
—
0
—
classical AR SCID
Monocyte-chemoattractant
Protein-1(MCP-1) influences
the level of IL-12 which is
crucial for the normal immune
defense against
mycobacterium tuberculosis.
MCP-1 genotype G is associate with pulmonary TB
Healthy
control
(N=176)
PPD+
(N=334)
Pulm. TB
(N=435)
P value
Rantes-471
A
G
26%
74%
27%
73%
27%
73%
Not
significant
MIP-1459
C
T
87%
13%
85%
15%
86%
14%
Not
significant
MCP-1-2518
A
G
49%
51%
49%
51%
28%
72%
0.0003
Allele
JEM 202,2005
Neutralization of MCP-1 increases IL-12Lp40 production
Monocytes from MCP-1
homozygous AA:
No antibody (ab) Control
Isotype ab Control
Anti-MCP-1 neutralizing ab
Monocytes from MCP-1
homozygous GG:
No antibody (ab) Control
Isotype ab Control
Anti-MCP-1 meutralizing ab
MCP-1 and IL-12p40 levels in TB patients
Genotype
MCP-1
IL-12p40
AA
1108
1470
AG
1424
1348
GG
1975
1178
P value
0.0001
0.004
Flores – Villanueva et al JEM 2005 (202;1649)
Conclusion:
“MCP-1 2518G has a dose effect on the
of progression of TB infection to disease
in Mexicans and Koreans”
Flores-Villanueva, JEM, 202, 2005
Journal clinical investigation 1998
Rate of major chronic GI
complications in patients with CGD
with specific host defense molecule
genotype.
Molecule
MPO
FcR III b
FcR II b
IL-1R
TNF - 
MBL
JCI 1998
Association
P=0.003
P=0.007
P=0.05
P=0.34
P=0.42
P=0.55
•IgA deficiency – Immunodeficient ?
Dying from infection with no defect
– Immunocompentent?
Immunocompetant – The ability to
mount a normal immune response to a
pathogen.
Immunodeficiency – classical definition
– A patient with a known defect in the
immune system.
– proposed definition
– A patient who does not survive on
infectious episode.
Non conventional PID
classification.
Host defect towards specific
pathogen
“Mendelian susceptibility to
mycobacterial diseases”
IL-2
IL-2R
IFN
T / NK
IL-12R


18
?
IL- 15
IFNR
STAT1
1 2
IL-12
NEMO
AFB
Salm.
TNF
NRAMP1
M
CD14
TNFR
TLR
LPS
Differential Modulation of endotoxin
responsiveness by human caspare-12
polymorphisms.
Saleh M et al Nature 429, 75, 2004
Caspases mediate essential key proteolytic
events in the inflammatory cascades
(cytokine maturation -1-4-5) and in the
apoptotic cell pathway (-2-3-6-7-8 -9-10) .
Caspase 12 may therefore be important in
the host response to infections or in the
pathogenesis of Alzheimer’s disease.
Decrease cytokine
response to LPS from
caspase 12L individuals
Human caspase 12 Is not involved in apoptosis
Caspase-12 genotype and Alzheimer or severe sepsis
Casp-12S
HeteroCas-12L
HomoCasp-12L
Total
Reference group
(African American)
499 (78.1%) 113 (18.1%) 11(1.8%)
623
Alzheimer
141(76.7%) 40(21.7%)
3(1.6%)
184
Sepsis
23(60.5%)
4(10.5%) 38
(p=0.002)
Death from sepsis
17%
11(29%)
54%
“Inborn errors of immunity
are – unfortunately but
inevitably - the rule rather
than the exception”
JL Casanova & Abel 2005