innate immunity: the first line against infections
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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 PresentationTRANSCRIPT
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
HumoralHumoralfactorsfactors CellsCells
External barriersExternal barriers
ComplementComplementAcute phase proteinsAcute phase proteins
NeutrophilsNeutrophilsMonocytesMonocytesNK CellsNK Cells
CLASSIC PATHWAYCLASSIC PATHWAYAg-Ab ComplexesAg-Ab Complexes
CLASSIC PATHWAYCLASSIC PATHWAYAg-Ab ComplexesAg-Ab Complexes
MBL-MASP1MBL-MASP1MBL-MASP1MBL-MASP1C3bC3bC3bC3b
C3C3C3C3
C1qC1qC1rC1rC1qC1qC1rC1r
C4C4C4C4 C2C2C2C2
C2aC2aC2aC2a
C3bC3bC3bC3bC3a, C5aC3a, C5aC3a, C5aC3a, C5a C5b-C9C5b-C9C5b-C9C5b-C9
Membrane attack complex, Membrane attack complex,
pathogen lysispathogen lysisMembrane attack complex, Membrane attack complex,
pathogen lysispathogen lysisInflamation, fagocyte Inflamation, fagocyte
recruitmentrecruitmentInflamation, fagocyte Inflamation, fagocyte
recruitmentrecruitmentOpsonization, eliminationOpsonization, elimination
of immunocomplexesof immunocomplexesOpsonization, eliminationOpsonization, elimination
of immunocomplexesof immunocomplexes
MBL PATHWAYMBL PATHWAYMicrobial surfacesMicrobial surfacesMBL PATHWAYMBL PATHWAY
Microbial surfacesMicrobial surfacesALTERNATIVE PATHWAYALTERNATIVE PATHWAY
Microbial surfacesMicrobial surfacesALTERNATIVE PATHWAYALTERNATIVE PATHWAY
Microbial surfacesMicrobial surfacesMBL-MASP2MBL-MASP2MBL-MASP2MBL-MASP2
C1sC1sC1sC1s
C4bC4bC4bC4b
THE COMPLEMENT SYSTEMTHE COMPLEMENT SYSTEM
MBL TETRAMER
N-terminal
collagen first region
DRC
Bacterial surface
Proteases (masp)
hexose
Disulfur bond
Activation C’
collagen second region
BBBB
AAAA
CCCC
DDDD
Structure of MBL polipeptidic chain Structure of MBL polipeptidic chain Structure of MBL polipeptidic chain Structure of MBL polipeptidic chain
Carbohidrate Recognition Domain (CRD)Carbohidrate Recognition Domain (CRD)Carbohidrate Recognition Domain (CRD)Carbohidrate Recognition Domain (CRD)
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
PromotorPromotorPromotorPromotor Exon 1Exon 1Exon 1Exon 1
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
28/229 (12%)28/229 (12%) 18/353 (5%)18/353 (5%) 2,592,59 0.0020.002
11/108 (10%)11/108 (10%) 36/679 (5%)36/679 (5%) ------ 0.0460.046
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
Gomi K. Chest 2004; 126:95–99
Recurrent vaginal candidiasisRecurrent vaginal candidiasis
Babula CID 2003 Sep 1;37(5):733 Babula CID 2003 Sep 1;37(5):733
MBL defficiency and susceptibility MBL defficiency and susceptibility to to fungal infectionsfungal infections
MBL defficiency and susceptibility MBL defficiency and susceptibility to to fungal infectionsfungal infections
Chronic necrotizing pulmonary AspergillosisChronic necrotizing pulmonary Aspergillosis
Defficients Haplotypes Defficients Haplotypes In ControlsIn Controls ppin CNPAin CNPA
7/10 (70%)7/10 (70%) 20/82 (25%)20/82 (25%) 0,0040,004
Crosdale JID 2001Crosdale JID 2001
MBL defficiency and susceptibility MBL defficiency and susceptibility to to fungal infectionsfungal infections
MBL defficiency and susceptibility MBL defficiency and susceptibility to to fungal infectionsfungal infections
MBL defficiency and MBL defficiency and severityseverity of infections of infections
Low MBL (n=13) 9 (33.3) 4 (11.4)
Normal MBL (n=49) 18 (67.6) 31 (88.6)
Bacteraemic PyelonephritisN = 27
Non Bacteraemic PyelonephritisN = 35
P=0.036 2 test
Smithson A. 2005 ECCMID . P-1824
MBL defficiency and MBL defficiency and severityseverity of infections of infections
Low MBL (n=13) 4 (57) 9 (16.3)
Normal MBL (n=49) 3 (43) 46 (83.7)
Pyelonephritis with septic shockN = 7
Pyelonephritis without septic shockN = 55
P=0.030 Fisher exact test
Smithson A. 2005 ECCMID . P-1824
CellularCellularImmunityImmunity
Humoral Humoral InmunityInmunity
Innate immunityInnate immunity
Prospective study (feb-oct 2005) BMT and infectionsFollow-up 6 months Periodic MBL serum levels determinations
RESULTS
- 12 (50%) autologous and 12 (50%) alogenic.
- 55% of infectious episodes: during neutropenic period.
- 63% bacterial; 26% viral, 9% fungal
- 6 (25%) died because an infectious complication
MBL Serum levels and Susceptibility to opportunistic Infections in bone marrow transplant patients
MBL<1000 *gram positive inf Crosstabulation
Count
8 3 11
7 2 9
15 5 20
no
si
MBL<1000
Total
no yes
gram positive infection
Total
MBL<1000 * gram negative infec Crosstabulation
Count
4 7 11
3 6 9
7 13 20
no
si
MBL<1000
Total
no yes
gram negative infection
Total
P = 1
P = 0.16
MBL<1000 * infeccion viral Crosstabulation
Count
4 6 10
8 2
12 8 20
no
si
MBL<1000
Total
n0 si
infeccion viral
Total
P = 0,16
10
P = 1
0
500
1000
1500
2000
2500
3000
3500
4000
4500
Maximum MBL serum levelsng/mL
Confirmed fungal infection-Pulmonary Aspergilosis -Pulmonary Mucormicosis-Systemic Candidiasis
MBL<1000 fungal infection no/yes Crosstabulation
Count
11 11
6 3 9
17 3 20
no
si
MBL<1000
Total
no yes
fungal infection no/yes
Total
P = 0,07
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
HIV-infected patients.HIV-infected patients.
Conclusions (III)Conclusions (III)