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Pathogenesis of

Various immunodeficiencies

Hyperinflammatory but inadequate

immune response

Clinical picture of (Hemophagocytic

lymphohistiocytosis) HLH
Variable course of disease

Rapidly progressive leading to death within

Transient improvements with unspecific
Disappearance of symptoms without therapy
Disappearance of symptoms with immuno-
suppressive/immunomodulatory drugs

Genetic, primary HLH Acquired, secondary HLH

- Perforin mutations (chr.10) Exogenous agents
- infectious organisms, toxins
- Chromosom 9 linkage (VAHS, IAHS)

- Unknown mutations HLH Endogenous products

- tissue damage
- radical stress
- Immune deficiencies - metabolic products
Griscelli syndrome Rheumatic disorders
XLP Malignancies
Diagnostic criteria Histiocyte Society 1991

Fever > 38.5
Cytopenia of => 2/3 cell lines
Hypertriglyceridemia and/or
Hemophagocytosis in bone marrow
or spleen or liver or lymphnode

Strong supportive evidence are spinal fluid pleocytosis, liver

histology resembling chronic persistent hepatitis, low natural
killer cell activity
h Cytostatic and immunsuppressive/
immunomodulatory drugs:
Corticosteroids, Cyclosporin A,
Immunoglobulins, Antithymocyte globulin

h Bone marrow transplantation


In 20% no response to therapy

After BMT 60-70% relapse-free survival

Thickening and loss of elasticity of arterial
Hardening of the arteries

Greatest morbidity and mortality of all

human diseases via
Atherosclerotic Disease

In US there are 6 million with CAD
3 million Americans have had strokes

1.5 million deaths/yr in US due to
myocardial infarction
0.5 million deaths/yr in US due to strokes
Three patterns of arteriosclerosis

The dominant pattern of arteriosclerosis
Primarily affects the elastic (aorta, carotid,
iliac) and large to medium sized muscular
arteries (coronary, popliteal)
Monckeberg medial calcific sclerosis
Arteriolosclerosis small arteries and
arterioles (hypertension and DM)
Non-Modifiable Risk Factors

A dominant influence
Atherosclerosis begins in the young, but does not
precipitate organ injury until later in life
Men more prone than women, but by age 60-70
about equal frequency
Family History
Familial cluster of risk factors
Genetic differences
Modifiable Risk Factors
(potentially controllable)
Cigarette smoking
Diabetes Mellitus
Elevated Homocysteine
Factors that affect hemostasis and
Infections: Herpes virus; Chlamydia
Obesity, sedentary lifestyle, stress
AHA Classification of atherosclerosis

Fig. 11.7
Normal Artery
Normal Artery
A disease of the intima
A disease of the intima
A disease of the intima

Atheromas, atheromatous/fibrofatty
plaques, fibrous plaques
Narrowing/occlusion; weakness of wall
Major components of plaque
Cells (SMC, macrophages and other WBC)

ECM (collagen, elastin, and PGs)

Lipid = Cholesterol (Intra/extracellular)

(Often calcification)
Two major processes in plaque

Intimal thickening (SMC proliferation and

ECM synthesis)

Lipid accumulation
Consequences of plaque

Leading to specific problems:

Myocardial and cerebral infarcts
Aortic aneurysms
Peripheral vascular disease
Fatty Streak-Aorta
Fatty Streak-Coronary Artery
Altered Vessel Function
Vessel change Ischemia, turbulence
Plaque narrows
Aneurysms, vessel
Wall weakened
Narrowing, ischemia,
Breaking loose of
plaque Increase systolic blood
Loss of elasticity pressure
Late Changes
An example of dystrophic calcification
Cracking, ulceration, rupture
Usually occurs at edge of plaque
Thrombus formation
Caused by endothelial injury,ulceration, turbulence
Organization of thrombus
More thrombus
Weakens vessel wall
Ulceration, cracking and angiogenesis
Pathology, Pathogenesis, Complications, Natural History
Fibrous Plaques Complicated Lesions
Fibrous cap Elastin membrane Calcification
Cholesterol clefts destroyed Inflam. cells
Hemorrhage into Plaque
Ulceration/Hemorrhage/Cholesterol Crystals
Complicated Lesion/Calcification
Foam Cells/Cholesterol Crystals
Cholesterol Crystals/Foam Cells
Thrombosis/Complicated Lesion
Complicated Lesion/Ulceration/Thrombosis
Aortic Aneurysm
Aortic Aneurysm
Pathogenesis of Atherosclerosis

Current hypothesis: Response to Injury
Initiated by endothelial dysfunction
Disease of the intima
Intimal thickening
Intra- and extra-cellular lipid accumulation
Chronic Inflammation
Basic Lesion: is termed atheroma, fibro-fatty
plaque, or atheromatous plaque
Response to injury hypothesis
* Injury to the endothelium
(dysfunctional endothelium)
* Chronic inflammatory response
* Migration of SMC from media to intima
* Proliferation of SMC in intima
Excess production of ECM
Enhanced lipid accumulation
Response to injury hypothesis (I)

1. Chronic EC injury (subtle?)

EC dysfunction
Increased permeability
Leukocyte adhesion (via VCAM-1)
Thrombotic potential
Response to injury hypothesis (II)

2. Accumulation of LDL (cholesterol)

3. Oxidation of lesional LDL
4. Adhesion & migration of blood
monocytes; transformation into
macrophages and foam cells
5. Adhesion of platelets
6. Release of factors from platelets,
macrophages and ECs
Response to injury hypothesis (III)

7. Migration of SMC from media to intima

8. Proliferation of SMC
9. ECM production by SMC
10. Enhanced lipid accumulation
Intracellular (SMC and macrophages)
Endothelial dysfunction
Induced by oxidized LDL, can be worsened by
cigarette smoking, and can be reversed with
correction of hyperlipidemia by diet or by therapy
with a statin, which increases the bioavailability of
nitric oxide, with ACE inhibitors, or with
antioxidants such as vitamin C or flavonoids
contained in red wine
Anderson et al., 1996; Harison et al 1987; John et al., 1998; Mancini et al 1996; Levine
et al 1996
Endothelial dysfunction
Expression of VCAM-1 on endothelial
surfaces is an early, and necessary, step in
the pathogenesis of atherosclerosis.
Increased cellular adhesion and associated
endothelial dysfunction then sets the stage
for the recruitment of inflammatory cells,
release of cytokines and recruitment of lipid
into the atherosclerotic plaque.
Li et al., 1993
Lipid abnormalities play a critical role in
the development of atherosclerosis
Early experiments demonstrated accelerated
atherosclerosis with a high cholesterol diet.
Epidemiologic studies showed increasing
incidence of atherosclerosis when serum
cholesterol above 3.9 mM
High levels of LDL and low levels of HDL
important risk factors for atherosclerosis
Macrophage uptake of LDL may initially be
adaptive response, which prevents LDL-induced
endothelial injury
However, cholesterol accumulation in foam cells
leads to mitochondrial dysfunction, apoptosis, and
necrosis, with resultant release of cellular
proteases, inflammatory cytokines, and
prothrombotic molecules
Oxidized LDL can cause disruption of the
endothelial cell surface, promote
inflammatory and immune changes via
cytokine release from macrophages and
antibody production and increase platelet
HDL, in contrast to LDL, has
antiatherogenic properties that include
reverse cholesterol transport, maintenance
of endothelial function, protection against
thrombosis, and maintenance of low blood
viscosity through a permissive action on red
cell deformability
Best evidence supporting the importance of
inflammation in the pathogenesis of
atherosclerosis comes from the observation
that markers of increased or decreased
systemic inflammation are directly
associated with the risk of atherosclerosis
Inflammation and chronic
endothelial injury
VCAM-1 expression increases recruitment of
monocytes and T-cells to sites of endothelial
Subsequent release of MCP-1 by leukocytes
magnifies the inflammatory cascade by recruiting
additional leukocytes, activating leukocytes in the
media, and causing recruitment and proliferation
of smooth muscle cells
Atherosclerosis is initiated when
leucocytes adhere to the
endothelium as a result of
expression of adhesive proteins.

Crowther et al., 2005

Inflammation and chronic
endothelial injury
Monocytes adhere to the endothelium and
then migrate through the endothelium and
basement membrane by elaborating
enzymes, including locally activated matrix
metaloproteinases (MMP) that degrade the
connective tissue matrix

Crowther et al., 2005

Leucocytes than cross the
endothelial barrier and begin to

Crowther et al., 2005

Inflammation and chronic
endothelial injury
Macrophages both release additional cytokines
and begin to migrate through the endothelial
surface into media of the vessel.
This process is further enhanced by the local
release of M-CSF, which causes monocytic
Local activation of monocytes leads to both
cytokine-mediated progression of atherosclerosis,
and oxidation of LDL
Crowther et al., 2005
Monocytes within the sub-
endothelial space subsequently
orchestrate the development of
atherosclerosis through cytokine
Crowther et al., 2005
Inflammation and chronic
endothelial injury
CD40L elaborated within the plaque has
been shown to increase the expression of
tissue factor in atherosclerotic plaques
anti-CD40L abrogates evolution of
established atherosclerotic lesions in animal

Schonbeck et al., 2000

Clinically apparent disease if first
noted as a result of the
accumulation of foam cells.

Crowther et al., 2005

Inflammatory mediators
Include IL-1, TNF and , IL-6, M-CSF,
MCP-1, IL-18 and CD-40L.
The impact of these mediators is diverse
and includes mitogenesis, intracellular
matrix proliferation, angiogenesis and foam
cell development

Crowther et al., 2005

The clinically important lesion is characterized by
intimal narrowing, many foam cells,
neovascularization and flow limiting narrowing.
However, this stage of the disease is sufficiently
advanced that treatments aimed at it do not
impact the pathogenesis of the underlying disorder.
CRP may be only a marker of inflammation and
thrombotic risk
CRP binds to LDL, allowing LDL to be taken up
by macrophages without the need for modification
CRP induces adhesion molecule expression and
production of IL-6 and MCP-1 in human
endothelial cells; these effects might enhance a
local inflammatory response within the
atherosclerotic plaque by the recruitment of
monocytes and lymphocytes
The proinflammatory and prothrombotic effects of
CRP on monocytes and endothelial cells in vivo
by subjecting wild-type mice, which do not
express CRP, and human CRP-transgenic (CRPtg)
mice to two models of arterial injury.
In an arterial injury model complete thrombotic
occlusion of the femoral artery at 28 days was
seen in 17% of wild-type mice compared with
75% of CRPtg arteries.

Danenberg et al., 2003

Multivariable-adjusted relative risks of
cardiovascular disease according to levels of CRP
and the estimated 10-year risk based on the
Framingham Risk Score. CHD indicates coronary
heart disease. Data from Ridker and colleagues
IL-1 and TNF-alpha
Enhance expression of cell surface
molecules such as ICAM-1, VCAM-1,
CD40, CD40L, and selectins on endothelial
cells, smooth muscle cells, & macrophages
Induce cell proliferation, contribute to the
production of ROS, stimulate matrix
metalloproteinases, & induce TF expression
Leukocyte activation
mRNA profiles showing increased levels of
most inflammatory mRNAs in individuals
with prior AMI
Toll-like receptor 4
Polymorphisms in the toll-like receptor 4 gene that
confer differences in the inflammatory response to
Gram negative pathogens
Carriers of the Asp299Gly polymorphism,
compared to wild-type alleles, have reduced
circulating levels of inflammatory markers,
including CRP, adhesion molecules, and IL-6, and
a reduced incidence of carotid atherosclerosis
Molecular Targets to address chronic
Peroxisome proliferator-activated receptors
(PPARs) have emerged as important anti-
atherogeneic targets
Endothelial specific roles of PPAR- include
inhibition of adhesion molecules, including VCAM-1
increased endothelial NO release
reduced foam cell formation
reduced uptake of glycated LDL and triglyceride-rich
remnant lipoproteins
Ligands of PPAR- include fatty acids and
the oral hypoglycemic drugs belonging to
the glitazone family
PPAR- is expressed in numerous cell types
found within the atherosclerotic lesion,
including endothelial cells, smooth muscle-
cells, macrophages, and T cells
Potential anti-atherogenic activities of peroxisome
proliferator-activated receptors (PPARs)

1. Increased nitric oxide synthesis and release

2. Decreased recruitment of T cells
3. Reduced angiogenesis
4. Inhibition of smooth muscle cell (SMC) migration
5. Decreased SMC expression of matrix-degrading enzymes
6. Decreased macrophage-dependent expression of matrix
metalloproteinase (MMP)-9 and osteopontin
7. Enhanced release of the interleukin-1 receptor antagonist
8. Enhanced reverse cholesterol transport
Lucas et al., 2006
Angiogenic signaling and proliferation of
microvessels within the plaque is only now
beginning to be understood
Plaque hemorrhage is likely attributable to
bleeding from fragile microvessels that
proliferate within the plaque itself,
presumably in response to local angiogenic
Kockx et al identified intraplaque hemorrhage
from microvessels triggering macrophage
activation and foam cell formation in carotid
These authors propose that intraplaque
microhemorrhage may initiate platelet and
erythrocyte deposition, lead to iron deposition,
activate macrophages and contribute to foam cell
Kockx et al.,2003
The importance of angiogenesis in the
pathogenesis of plaque growth was recently
bolstered by the finding that intra-plaque
microvessels were an independent predictor of
plaque rupture
The potential importance of angiogenesis in the
development of atherosclerosis is found in
experiments that demonstrate that antiangiogenic
therapy reduced atherosclerotic lesion
development in a placebo controlled trial in
atherosclerosis prone mice
Moreno et al., 2004; Chew
et al 2003
Moreno et al., 2006
General features of insulin signal transduction pathways.
PI 3-kinase branch of insulin signaling regulates GLUT4
translocation and glucose uptake in skeletal muscle and NO
production and vasodilation in vascular endothelium. MAPkinase
branch of insulin signaling generally regulates growth and
mitogenesis and controls secretion of ET-1 in vascular
Endothelium Kim et al., 2006
Kim et al., 2006
Shared and interacting mechanisms of
glucotoxicity, lipotoxicity, and inflammation underlie
reciprocal relationships between insulin resistance
and endothelial dysfunction that contribute
to linkage between metabolic and cardiovascular
diseases. CAD indicates coronary artery disease
Mechanisms for the contribution of
insulin resistance to atherosclerosis.
VSMC indicates vascular smooth
muscle cell; CHF, congestive heart

Kim et al., 2006

Tissue factor: A key regulator of coagulation. Tissue factor (TF) is a key
initiator of the coagulation cascade. Formation of a complex with factor VIIa
(FVIIa) leads to activation of factor IX (FIX) and factor X (FX), resulting in
thrombin generation and, ultimately, clot formation. Tissue factor pathway inhibitor
(TFPI), the endogenous inhibitor of TF activity, is synthesized and secreted mainly by
endothelial cells. TFPI binds to FXa and thereby inhibits TF/FVIIa activity.

Steffel et al; 2006

Induction of tissue factor expression and activity. Induction of tissue factor (TF) is
exemplified in an endothelial cell. Various mediators induce TF expression through
activation of their receptors. Induction of TF primarily occurs at the transcriptional
level, resulting in an increase in TF mRNA and, eventually, TF protein expression. TF
is distributed in three cellular pools as cytoplasmatic TF, surface TF, and encrypted TF.
Moreover, TF-containing microparticles are released from the cell. Alternative splicing
results in a soluble secreted form of TF (asTF). IL-1 indicates interleukin-1; LPS,
lipopolysaccharide; TNF-, tumor necrosis factor ; VEGF, vascular endothelial growth
factor; HB1B, histamine HB1B-receptor; 5-HTB2aB, 5-hydroxytryptamineB2aB
receptor; IL1-R, interleukin-1 receptor; TLR-4, toll-like receptor 4; PAR, protease-
activated receptor; KDR, VEGF receptor-2. Steffel et al; 2006
Tissue factor in the atherosclerotic plaque. In the inflammatory environment of atherosclerotic
plaques, tissue factor (TF) is present at high levels in endothelial cells, vascular smooth muscle
cells, macrophages/foam cells, and in the necrotic core. TF induction is exemplified by selected
mediators in endothelial cells (EC, left panel), macrophages (M, middle panel), and vascular
smooth muscle cells (VSMC, right panel). On plaque rupture, highly procoagulant material
including TF-containing microparticles is released into the blood, leading to rapid initiation of
coagulation, platelet aggregation, and, ultimately, thrombus formation with vessel occlusion.
Steffel et al; 2006
Therapeutic approaches. Several therapeutic strategies have been developed to specifically interfere with
the action of tissue factor (TF). Molecular approaches such as ribozymes or antisense oligonucleotides
specifically inhibit TF production. Monoclonal or polyclonal anti-TF antibodies directly target and inactivate
the TF protein. Site-inactivated factor VIIa (FVIIai) binds to TF but lacks catalytic activity for conversion of
factor X (FX) or factor IX (FIX). Recombinant tissue factor pathway inhibitor (rTFPI) interferes with the
activity of the TF/FVIIa complex by binding to the active site of factor Xa (FXa), leading to formation of a
quaternary inhibitory complex with TF/FVIIa. Similarly, recombinant nematode anticoagulant protein c2
(rNAPc2) interferes with the TF/FVIIa complex by binding to FXa or FX before formation of a quarternary
inhibitory complex with TF/FVIIa. Steffel et al; 2006
Response to Injury
Endothelial Dysfunction
Initiation of Fatty Streak
Fatty Streak
Fibro-fatty Atheroma
Summary of Atherosclerotic Process

Multifactorial process (risk factors)

Initiated by endothelial dysfunction
Up regulation of endothelial and leukocyte adhesion
Macrophage diapedesis
LDL transcytosis
LDL oxidation
Foam cells
Recruitment and proliferation of smooth muscle cells
(synthesis of connective tissue proteins)
Formation and organization of arterial thrombi
Is Atherosclerosis
Primate experiments
High fat diet discontinued; atherosclerotic lesions
Decrease fat and caloric intake (wars, famine,
wasting disease), atheromas decrease.
Angiography after cholesterol lowering, plaque
size decreases
What has to happen for plaques to regress?
LDL lowered
Mac ingest lipids
Reverse cholesterol transport, depends on HDL