Innate Immunity: Innate Immunity: The First Line Against Infectio The First Line Against Infection n Pablo Horcajada. n Pablo Horcajada. dad de Enfermedades Infecciosas dad de Enfermedades Infecciosas pital Universitario Marqués de Valdecilla pital Universitario Marqués de Valdecilla tander. Spain. tander. Spain.
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Innate Immunity: The First Line Against Infections
Innate Immunity: The First Line Against Infections. Juan Pablo Horcajada. Unidad de Enfermedades Infecciosas Hospital Universitario Marqués de Valdecilla Santander. Spain. Relevance. In adults there are important differences in susceptibility to infections - PowerPoint PPT Presentation
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Innate Immunity: Innate Immunity: The First Line Against InfectionsThe First Line Against Infections
Innate Immunity: Innate Immunity: The First Line Against InfectionsThe First Line Against Infections
Juan Pablo Horcajada. Juan Pablo Horcajada. Unidad de Enfermedades InfecciosasUnidad de Enfermedades InfecciosasHospital Universitario Marqués de ValdecillaHospital Universitario Marqués de ValdecillaSantander. Spain.Santander. Spain.
• In adults there are important differences inIn adults there are important differences in
– susceptibility to infectionssusceptibility to infections
– outcome of infections under treatmentoutcome of infections under treatment
• Innate immune system is the “third column” of the immun Innate immune system is the “third column” of the immun
system system
• There are new therapeutical possibilities There are new therapeutical possibilities
• In adults there are important differences inIn adults there are important differences in
– susceptibility to infectionssusceptibility to infections
– outcome of infections under treatmentoutcome of infections under treatment
• Innate immune system is the “third column” of the immun Innate immune system is the “third column” of the immun
system system
• There are new therapeutical possibilities There are new therapeutical possibilities
RelevanceRelevance
CellularCellularImmunityImmunity
Humoral Humoral InmunityInmunity
Innate immunityInnate immunity
• The innate immune systemThe innate immune system
• Mannose-binding lectinMannose-binding lectin
• MBL deficiency and infections: susceptibility and severityMBL deficiency and infections: susceptibility and severity
• Special populations: Special populations:
– Bone marrow transplant patientsBone marrow transplant patients
– HIV-infected patientsHIV-infected patients
• The innate immune systemThe innate immune system
• Mannose-binding lectinMannose-binding lectin
• MBL deficiency and infections: susceptibility and severityMBL deficiency and infections: susceptibility and severity
• Special populations: Special populations:
– Bone marrow transplant patientsBone marrow transplant patients
– HIV-infected patientsHIV-infected patients
IndexIndex
ImmunityImmunity
InnateInnate AdaptativeAdaptative
SpecificSpecificGenerates memoryGenerates memory
HumoralHumoralresponseresponse
CellularCellularresponseresponse
AntibodiesAntibodies LymphocytesLymphocytes
Non-specificNon-specificDoes not generate memoryDoes not generate memory
Alpha helix region. Interacts with CRDAlpha helix region. Interacts with CRD and determines its spatial orientationand determines its spatial orientationAlpha helix region. Interacts with CRDAlpha helix region. Interacts with CRD
and determines its spatial orientationand determines its spatial orientation
Collagen region. Functions: fagocytosis, opsonizationCollagen region. Functions: fagocytosis, opsonizationand protease binding for complement activation and protease binding for complement activation
Collagen region. Functions: fagocytosis, opsonizationCollagen region. Functions: fagocytosis, opsonizationand protease binding for complement activation and protease binding for complement activation
Terminal NH2 segment. Oligomerization through Terminal NH2 segment. Oligomerization through N-terminal cisteins by disulfur bondsN-terminal cisteins by disulfur bonds
Terminal NH2 segment. Oligomerization through Terminal NH2 segment. Oligomerization through N-terminal cisteins by disulfur bondsN-terminal cisteins by disulfur bonds
MBL gen polymorphismsMBL gen polymorphismsMBL gen polymorphismsMBL gen polymorphisms
Serum MBL levels related with different haplotipesSerum MBL levels related with different haplotipesSerum MBL levels related with different haplotipesSerum MBL levels related with different haplotipes
High
(>1000 ng/ml)
HYPA
LYQA
LYPA
Homozygous
Sufficient
High
(>1000 ng/ml)
HYPA
LYQA
LYPA
Homozygous
Sufficient
Medium
(500-1000 ng/ml)
HYPA
LYQA
LYPA
LXPA
Heterozygous
sufficient
Medium
(500-1000 ng/ml)
HYPA
LYQA
LYPA
LXPA
Heterozygous
sufficient
Low
(200-500 ng/ml)
HYPD
LYQC
LYPB
HYPA
LYQA
LYPA
Heterozygous
Sufficient-insufficient
Low
(200-500 ng/ml)
HYPD
LYQC
LYPB
HYPA
LYQA
LYPA
Heterozygous
Sufficient-insufficient
Very Low
(<200 ng/ml)
HYPD
LYPB
LYQC
LXPA
Homozygous
insufficient
Very Low
(<200 ng/ml)
HYPD
LYPB
LYQC
LXPA
Homozygous
insufficient
MBL levels in relation with haplotypesMBL levels in relation with haplotypesMBL levels in relation with haplotypesMBL levels in relation with haplotypes
Homozygous defficientHomozygous defficient
MBL binding to different microorganismsMBL binding to different microorganismsMBL binding to different microorganismsMBL binding to different microorganisms
+++
Candida
Aspergillus
S. aureus
S. pyogenes
Bifidobacterium
Veillonella
+++
Candida
Aspergillus
S. aureus
S. pyogenes
Bifidobacterium
Veillonella
++
E. coli
Klebsiella
Haemophilus influenza B
++
E. coli
Klebsiella
Haemophilus influenza B
+
S. agalactiae
S. pneumoniae
S. epidermidis
Pseudomonas
Enterococcus
Clostridium
Bacterioides
+
S. agalactiae
S. pneumoniae
S. epidermidis
Pseudomonas
Enterococcus
Clostridium
Bacterioides
MBL defficiency and susceptibility MBL defficiency and susceptibility to to bacterial infectionsbacterial infections
MBL defficiency and susceptibility MBL defficiency and susceptibility to to bacterial infectionsbacterial infections
Meningococcal InfectionMeningococcal Infection
Frequency of homozigous MBL-variants alleles in Frequency of homozigous MBL-variants alleles in hospitalized hospitalized patientspatients
7,7% vs. 1,5% in non-infectious controls7,7% vs. 1,5% in non-infectious controlsOR 6,5 p = 0.0006OR 6,5 p = 0.0006
Frequency in Frequency in general populationgeneral population::8,3% vs. 2,3% in healthy controls8,3% vs. 2,3% in healthy controls
OR 4,5 p = 0.06OR 4,5 p = 0.06
Hibberd ML. Lancet 1999;353:1049
Pneumococal infectionPneumococal infection
Defficient homozygousDefficient homozygous ControlsControls OR OR p p
MBL defficiency and susceptibility MBL defficiency and susceptibility to to bacterial infectionsbacterial infections
MBL defficiency and susceptibility MBL defficiency and susceptibility to to bacterial infectionsbacterial infections
Roy S. Lancet. 2002;360:1176.
MBL levels in MBL levels in elective abdominal surgeryelective abdominal surgeryand incidence of bacterial infectionsand incidence of bacterial infections
MBL levels in MBL levels in elective abdominal surgeryelective abdominal surgeryand incidence of bacterial infectionsand incidence of bacterial infections
N=172 patientsN=172 patients N infections: 10 (0,58%)N infections: 10 (0,58%)
M. Siassi. Biochem Soc Tras 2003;31:774
MBL defficiency associated with MBL defficiency associated with recurrent bacterial infectionsrecurrent bacterial infections
MBL defficiency associated with MBL defficiency associated with recurrent bacterial infectionsrecurrent bacterial infections
Polymorphisms of the Mannose-Binding Lectin Gen and Susceptibility to Opportunistic Infections
in HIV-Infected Patients
0/0n=39
527 (252)
36579 (152237)
CD4 count, mean (SD)
Viral load, mean (SD)
A/A or A/0n=151
460 (304)
48831 (154112)
p
0.21
0.66
Genotypes
JP Horcajada et al. ICAAC 2004JP Horcajada et al. ICAAC 2004
S. pneumoniae
0/0n=39
7 (18)
1 (2.5)
7 (18)
Pneumococcal bacteremia
Recurrent pneumococcal
bacteremia
Recurrent pneumonia
A/A or A/0n=151
32 (21)
5 (3.3)
17 (11)
p
0.65
1
0.28
Genotypes
JP Horcajada et al. ICAAC 2004JP Horcajada et al. ICAAC 2004
Candidiasis
0/0n=39
1 (2.5)
5 (13)
1 (2.5)
7 (18)
Oral (Muget), n(%)
Esophageal, n(%)
Vaginal, n(%)
Any candidiasis, n(%)
A/A or A/0n=151
7 (4.6)
18 (12)
4 (2.6)
29 (19.2)
p
1
1
1
0.96
Genotypes
JP Horcajada et al. ICAAC 2004JP Horcajada et al. ICAAC 2004
Virus
0/0n=39
1 (2.5)
4 (10.2)
5 (13)
1 (2.5)
0
Cytomegalovirus
Herpes Zoster
Recurrent Herpes simplex
Progressive multifocal
leukencephalopathy
Molluscum contagiosum
A/A or A/0n=151
7 (4.6)
32 (21)
5 (3.3)
2 (1.3)
4 (2.6)
p
0.20
0.15
0.03
0.50
0.58
Genotypes
JP Horcajada et al. ICAAC 2004JP Horcajada et al. ICAAC 2004
Other OI
0/0n=39
1 (2.5)
3 (7.7)
1 (2.5)
3 (7.7)
2 (5.1)
0
Toxoplasmosis
Pneumocystis carinii
MAI
Hairy leukoplakia
Condiloma
Non-TB Mycobacteria
A/A or A/0n=151
6 (3.9)
10 (6.6)
2 (1.3)
3 (1.9)
13 (8.6)
1 (0.6)
p
10.52
0.50
0.10
0.73
1
Genotypes
JP Horcajada et al. ICAAC 2004JP Horcajada et al. ICAAC 2004
Tuberculosis
0/0n=39
1 (2.5)
1 (2.5)
0
0
2 (5.1)
Pulmonary, n(%)
Lymph node, n(%)
Bone, n(%)
Milliary, n(%)
Any TB, n(%)
A/A or A/0n=151
15 (10)
3 (1.9)
1 (0.6)
8 (5.3)
27 (18)
p
0.20
1
1
0.35
0.048
Genotypes
JP Horcajada et al. ICAAC 2004JP Horcajada et al. ICAAC 2004
• MBL is a key protein of the innate immune systemMBL is a key protein of the innate immune system
• MBL serum level is genetically determinedMBL serum level is genetically determined
• Genetic polymorphisms are very prevalent Genetic polymorphisms are very prevalent
• There is a higher predisposition for some infections in There is a higher predisposition for some infections in
MBL-deficient patients MBL-deficient patients
• MBL is a key protein of the innate immune systemMBL is a key protein of the innate immune system
• MBL serum level is genetically determinedMBL serum level is genetically determined
• Genetic polymorphisms are very prevalent Genetic polymorphisms are very prevalent
• There is a higher predisposition for some infections in There is a higher predisposition for some infections in
MBL-deficient patients MBL-deficient patients
Conclusions (I)Conclusions (I)
• MBL defficiency is associated with MBL defficiency is associated with higher severityhigher severity of of infections infections
• In bone marrow transplant MBL deficiency is associated In bone marrow transplant MBL deficiency is associated
with a higher incidence of with a higher incidence of invasive fungal infectionsinvasive fungal infections..
• No relation between low MBL levels and the incindenceNo relation between low MBL levels and the incindence
bacterial / viral infections and in these patientsbacterial / viral infections and in these patients
• MBL defficiency is associated with MBL defficiency is associated with higher severityhigher severity of of infections infections
• In bone marrow transplant MBL deficiency is associated In bone marrow transplant MBL deficiency is associated
with a higher incidence of with a higher incidence of invasive fungal infectionsinvasive fungal infections..
• No relation between low MBL levels and the incindenceNo relation between low MBL levels and the incindence
bacterial / viral infections and in these patientsbacterial / viral infections and in these patients
Conclusions (II)Conclusions (II)
• In HIV-infected patients MBL deficiency is associated with In HIV-infected patients MBL deficiency is associated with
a higher incidence of a higher incidence of recurrent herpesrecurrent herpes..
On the contrary, tuberculosis is more frequent in patientsOn the contrary, tuberculosis is more frequent in patientsWith With normal or high MBL levelsnormal or high MBL levels. .
• MilliaryMilliary tuberculosis is not detected in MBL-deficient tuberculosis is not detected in MBL-deficient
HIV-infected patients.HIV-infected patients.
• In HIV-infected patients MBL deficiency is associated with In HIV-infected patients MBL deficiency is associated with
a higher incidence of a higher incidence of recurrent herpesrecurrent herpes..
On the contrary, tuberculosis is more frequent in patientsOn the contrary, tuberculosis is more frequent in patientsWith With normal or high MBL levelsnormal or high MBL levels. .
• MilliaryMilliary tuberculosis is not detected in MBL-deficient tuberculosis is not detected in MBL-deficient