Sin ttulo de diapositiva

1
Innate Immunity The First Line Against
Infections
Juan Pablo Horcajada. Unidad de Enfermedades
Infecciosas Hospital Universitario Marqués de
Valdecilla Santander. Spain.
2
Relevance

• In adults there are important differences in
• susceptibility to infections
• outcome of infections under treatment
• Innate immune system is the third column of
  the immun system
• There are new therapeutical possibilities

3
Innate immunity
Cellular Immunity
Humoral Inmunity
4
Index

• The innate immune system
• Mannose-binding lectin
• MBL deficiency and infections susceptibility
  and severity
• Special populations
• Bone marrow transplant patients
• HIV-infected patients

5
Immunity
Innate
Adaptative
Specific Generates memory
Non-specific Does not generate memory
Humoral factors
Cells
External barriers Complement Acute phase proteins
Neutrophils Monocytes NK Cells
6
CLASSIC PATHWAY Ag-Ab Complexes
THE COMPLEMENT SYSTEM
MBL PATHWAY Microbial surfaces
ALTERNATIVE PATHWAY Microbial surfaces
MBL-MASP2
MBL-MASP1
C3b
C1q C1r
C1s
C4
C2
C3
C4b
C2a
C3a, C5a
C3b
C5b-C9
Inflamation, fagocyte recruitment
Membrane attack complex, pathogen lysis
Opsonization, elimination of immunocomplexes

7
MBL TETRAMER
Disulfur bond
Proteases (masp)
N-terminal
Activation C
collagen first region

collagen second region
DRC
hexose
Bacterial surface
8
Structure of MBL polipeptidic chain
D
Carbohidrate Recognition Domain (CRD)
C
Alpha helix region. Interacts with CRD and
determines its spatial orientation
Collagen region. Functions fagocytosis,
opsonization and protease binding for complement
activation
B
Terminal NH2 segment. Oligomerization through
N-terminal cisteins by disulfur bonds
A
9
(No Transcript)
10
MBL gen polymorphisms
Promotor
Exon 1
11
Serum MBL levels related with different haplotipes
High (gt1000 ng/ml) HYPA LYQA LYPA Homozygous
Sufficient
Medium (500-1000 ng/ml) HYPA LYQA LYPA LXPA He
terozygous sufficient
Low (200-500 ng/ml) HYPD LYQC LYPB HYPA LYQA LYP
A Heterozygous Sufficient-insufficient
Very Low (lt200 ng/ml) HYPD LYPB LYQC LXPA Homo
zygous insufficient
12
MBL levels in relation with haplotypes
Homozygous defficient
13
MBL binding to different microorganisms
Candida Aspergillus S. aureus S.
pyogenes Bifidobacterium Veillonella
E. coli Klebsiella Haemophilus influenza B
S. agalactiae S. pneumoniae S.
epidermidis Pseudomonas Enterococcus Clostridium B
acterioides
14
MBL defficiency and susceptibility to bacterial
infections
Meningococcal Infection Frequency of homozigous
MBL-variants alleles in hospitalized
patients 7,7 vs. 1,5 in non-infectious
controls OR 6,5 p 0.0006 Frequency in
general population 8,3 vs. 2,3 in healthy
controls OR 4,5 p 0.06
Hibberd ML. Lancet 19993531049
15
MBL defficiency and susceptibility to bacterial
infections
Pneumococal infection
Defficient homozygous Controls OR p 28/229
(12) 18/353 (5) 2,59 0.002 11/108
(10) 36/679 (5) --- 0.046
Roy S. Lancet. 20023601176.
16
MBL levels in elective abdominal surgery and
incidence of bacterial infections
N172 patients N infections 10 (0,58)
M. Siassi. Biochem Soc Tras 200331774
17
MBL defficiency associated with recurrent
bacterial infections
Gomi K. Chest 2004 1269599
18
MBL defficiency and susceptibility to fungal
infections
Recurrent vaginal candidiasis
Babula CID 2003 Sep 137(5)733
19
MBL defficiency and susceptibility to fungal
infections
Chronic necrotizing pulmonary Aspergillosis
Defficients Haplotypes In Controls p in
CNPA 7/10 (70) 20/82 (25) 0,004
Crosdale JID 2001
20
MBL defficiency and severity of infections    
Low MBL (n13)
9 (33.3)
4 (11.4)

Normal MBL (n49)
18 (67.6)
31 (88.6)

 


  P0.036 ?2 test
Smithson A. 2005 ECCMID . P-1824
21
MBL defficiency and severity of infections    
Low MBL (n13)
4 (57)
9 (16.3)


Normal MBL (n49)
3 (43)
46 (83.7)

 


  P0.030 Fisher exact test
Smithson A. 2005 ECCMID . P-1824
22
Innate immunity
Cellular Immunity
Humoral Inmunity
23
MBL Serum levels and Susceptibility to
opportunistic Infections in bone marrow
transplant patients
Prospective study (feb-oct 2005) BMT and
infections Follow-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

24
MBLlt1000 gram positive inf Crosstabulation
Count
gram positive infection
no
yes
Total
no
MBLlt1000
8
3
11
si
7
2
9
P 1
Total
15
5
20
MBLlt1000 gram negative infec Crosstabulation
Count
gram negative infection
no
yes
Total
no
MBLlt1000
4
7
11
si
3
6
9
P 1
Total
7
13
20
P 0.16
25
MBLlt1000 fungal infection no/yes Crosstabulation
Count
fungal infection no/yes
no
yes
Total
no
MBLlt1000
11
11
si
6
3
9
P 0,07
Total
17
3
20
Maximum MBL serum levels
ng/mL

• Confirmed fungal infection
• -Pulmonary Aspergilosis
• Pulmonary Mucormicosis
• Systemic Candidiasis

26
Polymorphisms of the Mannose-Binding Lectin Gen
and Susceptibility to Opportunistic Infections
in HIV-Infected Patients
A/A or A/0 n151 460 (304) 48831 (154112)
0/0 n39 527 (252) 36579 (152237)
p 0.21 0.66
Genotypes
CD4 count, mean (SD) Viral load, mean (SD)
JP Horcajada et al. ICAAC 2004
27
S. pneumoniae
p 0.65 1 0.28
A/A or A/0 n151 32 (21) 5 (3.3) 17 (11)
0/0 n39 7 (18) 1 (2.5) 7 (18)
Genotypes
Pneumococcal bacteremia Recurrent pneumococcal
bacteremia Recurrent pneumonia
JP Horcajada et al. ICAAC 2004
28
Candidiasis
p 1 1 1 0.96
A/A or A/0 n151 7 (4.6) 18 (12) 4 (2.6) 29
(19.2)
0/0 n39 1 (2.5) 5 (13) 1 (2.5) 7
(18)
Genotypes
Oral (Muget), n() Esophageal, n() Vaginal,
n() Any candidiasis, n()
JP Horcajada et al. ICAAC 2004
29
Virus
p 0.20 0.15 0.03 0.50 0.58
A/A or A/0 n151 7 (4.6) 32 (21) 5 (3.3) 2
(1.3) 4 (2.6)
0/0 n39 1 (2.5) 4 (10.2) 5 (13) 1 (2.5) 0
Genotypes
Cytomegalovirus Herpes Zoster Recurrent Herpes
simplex Progressive multifocal leukencephalopathy
Molluscum contagiosum
JP Horcajada et al. ICAAC 2004
30
Other OI
p 1 0.52 0.50 0.10 0.73 1
A/A or A/0 n151 6 (3.9) 10 (6.6) 2 (1.3) 3
(1.9) 13 (8.6) 1 (0.6)
0/0 n39 1 (2.5) 3 (7.7) 1 (2.5) 3 (7.7) 2
(5.1) 0
Genotypes
Toxoplasmosis Pneumocystis carinii MAI Hairy
leukoplakia Condiloma Non-TB Mycobacteria
JP Horcajada et al. ICAAC 2004
31
Tuberculosis
p 0.20 1 1 0.35 0.048
A/A or A/0 n151 15 (10) 3 (1.9) 1 (0.6) 8
(5.3) 27 (18)
0/0 n39 1 (2.5) 1 (2.5) 0 0 2 (5.1)
Genotypes
Pulmonary, n() Lymph node, n() Bone,
n() Milliary, n() Any TB, n()
JP Horcajada et al. ICAAC 2004
32
Conclusions (I)

• MBL is a key protein of the innate immune
  system
• MBL serum level is genetically determined
• Genetic polymorphisms are very prevalent
• There is a higher predisposition for some
  infections in
• MBL-deficient patients

33
Conclusions (II)

• MBL defficiency is associated with higher
  severity of
• infections
• In bone marrow transplant MBL deficiency is
  associated
• with a higher incidence of invasive fungal
  infections.
• No relation between low MBL levels and the
  incindence
• bacterial / viral infections and in these
  patients

34
Conclusions (III)

• In HIV-infected patients MBL deficiency is
  associated with
• a higher incidence of recurrent herpes.
• On the contrary, tuberculosis is more frequent
  in patients
• With normal or high MBL levels.
• Milliary tuberculosis is not detected in
  MBL-deficient
• HIV-infected patients.