Post on 29-Dec-2015
Alcohol and the immune system
Gyongyi Szabo, MD PhDUniversity of Massachusetts
Medical School
RSA 2008
http://www.ephidrina.org/alcohol/history.html
-The first brew was probably date palm wine, originating in Mesopotamia. - We know that the ancient Egyptians were drinkers, because they invented the first straws, for drinking beer that still contained wheat-husks. - Some of Egyptian texts refer to the social problems associated with drunkenness, so they were no strangers to recreational drinking. - The Babylonians, in the world's first legal text, included a law regulating drinking houses.
Heiroglyph from Memphis, the capital of ancient Egypt, drawn in approximately 3700BC:depicts a temple priest called Ruma showing typical clinical signs of paralytic poliomyelitis.
Infectious Disease in History
Ancient times:
Koch's postulates :
i. The agent must be present in every case of the disease. ii. The agent must be isolated from the host & grown in vitro. iii. The disease must be reproduced when a pure culture of the agent is inoculated into a healthy susceptible host. iv. The same agent must be recovered once again from the experimentally infected host.
’Germ theory' of disease was introduced in the 1880s byRobert Koch & Louis Pasteur
Louis Pasteur (1822-1895)Robert Koch (1843-1910)
Koch observed:-Significant mortality of alcoholics during the cholera epidemics of 1884.-Showed that rats experimentally treated with alcohol were more susceptible to cholera.
Sir William Osler:-“ The most potent predisposing factor is perhaps the lowered resistance to alcohol” - in pneumonia.Principles and Practice of Medicine (1909)
1849-1919
Alcohol, inflammation and immune response
Clinical observations
• Reduced antimicrobial defense– Increased incidence of bacterial pneumonias– Increased incidence of M. tuberculosis infection– Suscepibility to infection with Listeria monocytogenes
• Reduced anti-viral immunity– Increased susceptibility to HIV infection– Higher rate of chronic hepatitis C viral (HCV) infection
and accelerated liver injury in alcoholics
• Increased inflammatory pathway activation– Increased post-trauma immunosuppression
• Higher rate of major complications, prolonged disease course
Pathogens
Immune response
BacteriaVirusesFungiParasites, etc
Pathogen elimination
Innate immunityNeutrophils
Monocytes/MacrophagesDendritic cells
Natural killer cellsInterferonsInterleukinsCytokinesChemokinesReactive oxygen substances
Adaptive immunity
T lymphocytesCD4+CD8+
Regulatory T cells
Humoral Cellular
B lymphocytesantibodies
Immune response to pathogens
Host cell
CD4+Th cell
B cell
CD8+CTL
MHCClass I
Th1 cytokines(IL-2, IFN-)
TCR
TCR
Th2 cytokines(IL-4, IL-5, IL-10)
DendriticCell
MHC Class II
Monocyte
Macrophage
NKcellIFN-
antibodies
Adaptive immunity Innate immunity
PhagocytosisReactive oxygen radicals
Cytokines(TNF, IL-1, IL-6, IL-10)
ChemokinesInterferons
PMNL
TLR2/6
TLR2/1
TLR5Flagellin
Triacyl peptides Diacyl
PeptidesZymosan
TLR4LPS
DNA
TLR3dsDNA
TLR9 TLR7/8Endosome
CpG ssRNA
MyD88
NF-B
Pro-inflammatory cytokines
IRAK-1
TRAF6
IBCytoplasm
Nucleus
Extracellular space
IRF7
IRF7
MyD88
TRIF
Type I IFNs
IRF3
IRF3 IRF3
TRAM
Toll-like receptors in pathogen recognition
Adaptive immunity Antigen presentation and T cell
activation
Microbes Viral products
CytokinesEtc.
Th1
Th2IL-12, IL-18, IL-6, IL-8,
TNF-, IL-10
CD8+MHC Class I
Naïve Th0CD4+
Co-stimulatory signals
MHC Class IICD80, CD86
MonocytesDendritic cells
APC T cells
IFNIL- 2
IL-10IL- 4
Alcohol reduces host antimicrobial defense
– Increased incidence of bacterial pneumonias• Pneumococcus, Klebsiella, Hemophilus
influenzae, Legionella, other Gram negative organisms
– Increased incidence of infection with
Pneumococcus
Klebsiella
M. tuberculosis
Listeria monocytogenes
Alcohol use and M. tuberculosis
• Acute and chronic alcohol predisposes to TB disease through alterations of the specific and non-specific immune response to MTB.
• Alcohol use predisposes to a more severe form of TB• Heavy alcohol use (>3 drinks/day) was associated
with an increased risk of TB
Alcohol feeding increases susceptibility to Listeria
Monocytogenes
Alcohol Clin Exp Res. 1993 Feb;17(1):75-85
Liver enzyme levels in mice 5 days after infection(5 mice/group)
AS
T
Bacterial colony counts in livers and spleens(5 mice/group)
Nu
mb
er o
f co
lon
ies/
gram
of
tiss
ue
Human data: mortality from listeric meningitis or sepsis is 10.7% in non-alcoholics and 24% in alcoholics
Experimental data in mice
• Image Removed – Awaiting Copyright Permissions
Chronic alcohol feeding increases susceptibility to respiratory syncytial
virus infection in mice
Increased virusreplication
after alcohol feeding
Increased early Type I Interferon
production after alcohol feeding
Chronic alcohol feeding increases susceptibility to influenza virus infection
in mice
Increased lethality and magnitude of
infection
Progressive loss of CD8+ T cell function
with prolonged alcohol
The Journal of Immunology, 2008, 181: 641-648.
Increased lung injury and neutrophil infiltration
Impairment of pulmonary host defense from alcohol abuse
OropharynxSaliva production, poor dentationBacterial pathogen colonization Glottis
Consciousness, cough reflexAspiration
Airspaces/Innate Immunity Alveolar macrophages Neutrophils
Adhesion molecules, ChemotaxisPhagocytosis, antimicrobial activity
Cytokines (TNF, IL-12, GM-CSF)Chemokines (MIP2/IL-8/CINC/Gro-
Bone marrow PMNL response to infection
Adaptive ImmunityCellular immunity Humoral immunityT cell proliferation B cell numbersInflammatory cytokines Airspace levels ofIFN, IL-17 IgG and IgG1Anti-inflammatory Cytokines (IL-10)
AirwaysMucosiliary function
Happel & Nelson 2005
Treatment options for alcohol-induced immune defects in
pneumonia
• Antibiotics
• G-CSF administration to alcohol-fed mice with Klebsiella pneumoniae infection– Increased PMNL recruitment to lungs– Increased pulmonary host defense
• Replacement of the reduced glutathione levels with N-acetylcystein feeding reversed decreased alveolar macrophage phagocytosis in the lung.
Alcohol use and Human Immunodeficiency Virus infection
• Association between alcohol use and risk of being infected with HIV
• Incidence of alcohol abuse among HIV-infected individuals is greater than the population as a whole
• 82% if HIV positive patients consume alcohol and 41% met criteria for alcoholism (Michigan test)
• Miami HIV-infected Drug Abuser Study >60% of HIV+ patients reported heavy alcohol use
• Fong described a heavy alcohol user patient who developed accelerated HIV progression to AIDS in a 3-months period.
Alcohol Clin Exp Res. 2006 Oct;30(10):1781-90
The adverse effects of alcohol on the HIV-infected patient as it relates to immunity and disease progression are poorly understood.
Chronic alcohol worsens infection with Simian Immunodeficiency
Virus
• Increased viral load• Decreased circulating
CD4+/CD8+ lymphocyte ratio• Increased lymphocyte
proliferation• Increased muscle TNF
mRNA expression at 10 months after infection
• More rapid development of end-stage disease
Alcohol Clin Exp Res. 2006 Oct;30(10):1781-90.
Percent survival as a function of days after SIV inoculation inmacaques receiving ethanol or sucrose. Statistical difference by Lifetest,p<0.05.
Image Removed – Awaiting Copyright Permissions
Alcohol and trauma
• Alcohol abuse has a detrimental outcome on traumatic injury.
• Alcohol abuse is estimated in nearly 50% of burn and trauma admissions
• Decreased survival • Higher number of complications including
– infection, sepsis, pneumonia, prolonged hospitalization
http://www.photovault.com/Link/Health/Emergency/Paramedics/HEPVolume01.html
J Trauma 64:230-240.Alcohol 28:137-149.
Alcohol Clin Exp Res 31:704-715.
Immune regulation in trauma
J Trauma 64:230-240.Alcohol 28:137-149.Alcohol Clin Exp Res 31:704-715
Image Removed – Awaiting Copyright Permissions
Moderate alcohol consumption and immunity
• Moderate drinkers were more resistant than abstainers to common cold virus (non-smokers)
• Wine consumption, especially red wine, decreases the incidence of common cold
• Moderate wine or beer consumption was associated with lower levels of systemic inflammatory markers in three different European areas (Germany, Scotland, France)
• After moderate alcohol consumption there is a decrease in TNF induced adhesion in monocytes to endothelial cells
• Beer down-regulates activated peripheral mononuclear cells Most studies show an anti-inflammatory effect of acute, moderate consumption of
alcoholic beverages.
Alcohol and TNF a master regulator of inflammatory
responses
• Dose-dependent inhibition of TNF production in monocytes
• Inhibits TNF converting enzyme (TACE) - reversible
• Acute in vivo alcohol inhibits LPS-induced TNF in the serum or lung
•Increased serum and monocyte TNF in alcoholic hepatitis•Increased TNF producion by Kupffer cells in the liver•Increased TNF production by human monocytes
Acute (moderate)
Opposite effects
Chronic (excessive)
Toll-like receptor 4 signaling
TLR4CD14 MD-2
LPS
TBK-1
IKKi
IRF3
IRF3 IRF3IFNß
TRAM
TRIFMyD88
TIRAP
IRAK1/4TRAF6
MAPK
IkB
NF-B
NF-BAP-1
Inflammatory genes
TNFα
Toll-like receptor 4 signaling
TLR4CD14 MD-2
LPS
TBK-1
IKKi
IRF3
IRF3 IRF3IFNß
TRAM
TRIFMyD88
TIRAP
IRAK1/4TRAF6
MAPK
IkB
NF-B
NF-BAP-1
Inflammatory genes
TNFα
- transiently-formed, dynamic plasma membrane microdomains enriched in sphingolipids and cholesterol (Mouritsen OG et al., 2004)
- represent ~30-50% of the plasma membrane
- platforms for various cellular events, such as membrane trafficking and signaling
- GPI-linked proteins and Src-family kinases, are constitutively expressed in rafts, while others, like T cell receptors, associate with rafts upon engagement with specific ligands for the purpose of signal transduction
- lipid rafts play a pivotal role in lymphocyte and monocyte/macrophage functions and may interfere with TLR-mediated signaling
Razaqq TM et al., 2004; Schmitz, 2002; Triantafilou M, 2003; Dai Q, 2005
Lipid rafts
Opposite effects of acute and chronic alcohol on monocyte TNF production
Acute alcohol also inhibits while chronic alcohol increases activation of NF-B, a nuclear regulatory
factor in TNF regulation.J Immunol. 2007 178:7686-93
Inflammation
TLR4
Pro-inflammatoryTNF, IL-1 Anti-
inflammatoryIL-10
LPS
Acute alcohol
Inflammation
TLR4
Pro-inflammatory
TNF
Anti-inflammatory
LPS
Chronic alcohol
Alcohol Clin Exp Res. 2006 Apr;30(4):720-30.
Mechanisms of alcoholic liver injury
PMNL HepatocyteAlcohol
Gut
Endotoxin(LPS)
Kupffer Cell
IL-8MCP-1 Stellate Cell
TNFROSTGF
Collagen
TLR4
NADPHNF-kBAP-1
Adachi et al, Gastro 1995;108:218-224.
Kupffer cell activation in alcoholic liver disease
TNF
Courtesy of L. Nagy (Cleveland Cilinic)J Gastroenterol Hepatol. 2007 Jun;22 Suppl 1:S53-6
Hepatitis C and Alcohol Use
• 30% of alcoholic patients with liver disease are HCV infected (Rosman AS,1996, Am.J.Gastroenerology)
• USA: 70% of HCV infected patients have alcohol use/abuse history (Schiff ER, 1999, Am.J.Med)
• Clinical progression and liver disease with alcohol use is accelerated in HCV(Tanaka T, 2000, Alcohol Clin.Exp.Res)
• Prolonged alcohol use is an independent risk factor for HCV progression (Regev A, 1999 Alcohol Clin.Exp.Res)
• Ongoing moderate alcohol consumption affects hepatic inflammatory activity (Day CP, 2001 Gut)
• IFN therapy is ineffective in patients with ongoing alcohol use (Newmann A.U, 1998, Science)
p< .001
010
30
50
70
Pro
life
rati
o n (
cpm
x 10- 3
)
Control DC
Control DC+alcohol
HCV DC
HCV DC+alcohol
p< .001 p< .01
p< .022
Additive inhibition of dendritic cell allostimulatory capacity
by HCV infection and alcohol treatment
Dolganiuc et at. Alcoholism: Clin. & Exp. Research, 2003
HCV DC
Control DC
0
0.25
0.5
0.75
1
1.25
HCV DC+alcohol
All
osti
mu
lato
ry c
apac
ity
*
**
02
46
81012141618
20
T cells
DC (TT)
DC (TT)
Et-DC(TT)
43 ±
2.3
%
Th
ymid
ine
in
corp
ora
tio
n
(cp
m x
10-3
)
+ T cells
Th
ymid
ine
in
corp
ora
tio
n
(cp
m x
10-3
)
Dendritic cells (X 104/well)T cells: 2x 105/well
I-DC
EtOH-I-DC
0
10
20
30
40
*
*
*
1 2 4
Ethanol inhibits myeloid dendritic cell antigen presentation and T cell
activation
J Immunol 173:3398-3407.
Adaptive immunity Antigen presentation and T cell
activation
Microbes Viral products
CytokinesEtc.
Th1 IL-12, IL-10
Naïve Th0CD4+
Co-stimulatory signals
MHC Class IICD80, CD86
APC
Antigen-specific T cell proliferation
Th2Naïve Th0
CD4+
Co-stimulatory signals
MHC Class IICD80, CD86
APC
Low IL-12, High IL-10
T cell anergy
Alcohol consumption inhibits dendritic cell antigen presentation in
mice-Alcohol feeding in mice resulted in decreased : -bone marrow-derived DC generation- expression of the co-stimulatory molecules, CD80, CD86 on DCs- induction of T cell proliferation-IL-12 production
J. Leukoc. Biol. 79: 941–953;
Increased:- IL-10 production
Image Removed – Awaiting Copyright Permissions
Image Removed – Awaiting Copyright Permissions
Chronic alcohol exposure affects dendritic cell functions in the skin
• Decreased numbers and migration of Langerhans cells and dermal dendritic cells in mice after 4-8 weeks of alcohol feeding
Alcohol Clin Exp Res, Vol 32, No 3, 2008: pp 1–12
Image Removed – Awaiting Copyright Permissions
Immature DC
Mature (stimulatory) DC
High intracellular MHC IILow CD 80, 86, 54Low CD83Endocytosis, FcR
Inhibitory DC
High surface MHC IIHigh CD80, 86, 54High CD83Low endocytosis, FcRHigh IL-12, low IL-10IFNT cell priming, activation
High Surface MHC IIReduced CD80, 86Low IL-12 High IL-10Reduced T cell activationT cell anergy
Alcohol
Alcohol use affects adaptive immunity in humans
• B cell defects:– Polyclonal hyperglobulinemia– Immunoglobulin A deposition in tissues
• Increased percentage of activated CD8+ T cell
• Shift from “naïve” (CD45RA+) to the “memory” phenotype of T cells (CD45RO+) - both in CD4+ and CD8+ population
Clin Exp Immunol 103:304-310.
Adaptive immunity - animal data
• 4-6 weeks alcohol feeding decreased the splenic, thymic and bone marrow T cell populations
• Increased CD4/CD8 T cell ratios• Increased memory/naïve T cell
ratios• Abnormal antigen-specific
responses
Clin Exp Immunol 103:304-310.
Methods Mol Biol. 2008;447:277-94.
Antigen presentation &Induction of adaptive
immunity
Alcohol impairs innate and adaptive immunity
Inflammatory response
Pathogen eliminationAdaptive immune responses
Pro-inflammatory cytokines
NF-B activation
T cell proliferationIL-12Co-stimulatory molecules
Change in Th1/Th2 cytokine profile (?)
T cellCD4+
APCPathogen