Transcript Immunology in Rheumatic Diseases

Disorder of immune system
Yeong-Wook Song, MD
Division of Rheumatology
Seoul National University
The Immune System
Objectives
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3
4
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Define the terms infection, pathogen, and
antigen, tolerance, autoimmunity, rheumatic
disease.
List and describe mechanism of the
nonspecific and specific body defense
mechanisms.
Explain the signs and causes of inflammation.
Define B cells and T cells and describe their
locations and functions.
Explain the importance of MHC proteins.
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The Immune System
Objectives (cont.)
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List the different types of T cells and describe
their functions.
List the different types of antibodies and explain
how they differ and how they fight infection.
Define complement and give its functions.
Explain the difference between innate and
adaptive immunity.
Describe the signs and symptoms of common
immune disorders (rheumatoid arthritis, lupus,
ankylosing spondylitis scleroderma, myositis).
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Introduction
Immune system - protects the body against
Bacteria
Viruses
Fungi
Toxins
Parasites
Cancer
4
Defenses Against
Disease
Nonspecific defenses
- mechanisms to
protect us against
pathogens in general
Nonspecific Defenses
 Species Resistance
 Mechanical Barriers
 Chemical Barriers
 Fever
 Inflammation
 Phagocytosis
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Specific Defenses
Against Disease
Specific defenses are Lymphocytes and
macrophages are
called immunities and
the major white
protect the body
blood cells
against very specific
involved in specific
pathogens
defenses.
Antibodies and
complement are
the major proteins
involved in specific
defenses
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Inflammation
Causes:
 Injured or
infected with
a pathogen,
inflammation
can result
Signs:
 Redness
 Heat
 Swelling
 Pain
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Immunity Can Be Divided Into
2 Main Components:
1. Innate immunity
•
Rapid acting, nonspecific
2. Specific or adaptive immunity
•
Slower onset of action
•
Targets pathogens that escape the innate
immune system
•
Activated by the innate immune system
Innate
IMMUNITY
Physical barrier
Complement
NK cells
Phagocytic cells
- neutrophils
- macrophages
Eosinophils
Mast Cells
Humoral ( B cells)
Specific
CMI ( T cells)
B Cells & T Cells
Two major types of lymphocytes
B Cells and T Cells
Recognize antigens in the body
B cells
Respond to antigens
by becoming plasma
cell - make antibodies
against the specific
antigen
T Cells
Cell-mediated
bind to antigens on
cells and attack
them directly
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T Cells
Helper T cells
 increase antibody formation, memory cell
formation, B cell formation, and phagocytosis
Memory T cells
 memory cells “remember” the pathogen that
activated the original T cell
 person is later exposed to the same pathogen,
memory cells trigger an immune response that
is more effective than the first immune
response
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Antibodies
IgG - recognizes bacteria, viruses, and toxins.
It can also activate complement.
IgA - found in secretions of the body such as
breast milk, sweat, tears, saliva, and mucusprevents pathogens from entering the body.
IgM - very large - primarily binds to antigens
on food, bacteria, or incompatible blood
cells- activates complement.
IgE - found wherever IgA is located- involved
in triggering allergic reactions.
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Major Immune System
Disorders
Diseases and disorders that challenge
the immune system: (the following are
the most significant)
 HIV/AIDS
 Infections
 Autoimmune disease
 Cancer
 Allergies
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Acquired Immune Deficiency
Syndrome (AIDS)
Caused by human
immunodeficiency
virus (HIV) infection
Most common routes of
transmission are
through sexual
contact, blood, or
from mother to child
during pregnancy or
breast-feeding.
Can have infection for
years before
developing any
symptoms of this
disease
Less common routes of
transmission are through
accidental needle sticks,
artificial insemination, and
organ transplants.
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Acquired Immune Deficiency
Syndrome (AIDS) (cont.)
AIDS virus affects
the immune system
 Counts of CD4
cells are used to
diagnose the stage
of HIV infection. If
below 200 patient
has AIDS


CD4 cells are types
of T cells and are
important for the
functions of other
components of the
immune system.
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Acquired Immune Deficiency
Syndrome (AIDS) (cont.)
Signs and Symptoms of AIDS:
 Low T cell counts
 Frequent infections
 Fever
 Some rare forms of
cancer
 Profuse sweating
 A common form of
 Weakness
cancer is called
 Weight loss
“Kaposi’s” sarcoma.
 Swollen glands
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Allergies
Allergic reaction is an
immune response
to a substance
Allergens - trigger of
allergic responses
Anaphylaxis - blood
vessels dilate
quickly causing
blood pressure to
drop too quickly
for organs to
adjust. This
condition is life
threatening.
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Allergies
(cont.)
Allergic reactions involve
IgE antibodies and
mast cells.
IgE antibodies bind to
allergens, they cause
mast cells to release
histamine and
heparin
These chemicals trigger
allergic reactions.
If a person is receiving
allergy shots, he is
being injected with
tiny amounts of the
allergen and reduces
symptoms
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Immunology in Rheumatic
Diseases
Toll like receptors (TLRs)
Value of the Immune System
Macrophages & toll-like receptors (TLRs)
10-12 different TLRs can (collectively) bind a wide range of
pathogens
Each macrophage has all of the set of TLRs
TLRs and Autoimmunity

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Clear evidence they play a role in SLE
and RA
Clear evidence that intrinsic molecules
trigger TLRs in RA and SLE
Targeted inhibitors of TLRs are in Phase
II trials
Agonists of TLRs are being used as
vaccine and tumor adjuvants
Antigen Presenting Cells



Unlike the other cells, TH cells only
recognize antigen that is properly
presented with MHC by other cells
These specialized cells are called
antigen presenting cells
They include macrophages, B cells,
fibroblasts & dendritic cells
Major Histocompatibility
Complex (MHC)

Antigen is ingested by the antigen
presenting cell then presented on its
surface in molecules called major
histocompatibility complex

MHC are also the molecules responsible for
rejection in transplant organs
Major Histocompatibility
Complex




MHC proteins =HLA(Human
Leucocyte Antigen) in
humans
Molecules on cell surfaces
which can display antigen
Products of a region of
highly polymorphogenic
genes on chromosome 6
2 types :
Class I &
Class II
Comparison of MHC Class I & II Molecules
Class I
Class II
Genes
HLA A/B/C
HLA D
Expressed on
All nucleated cells
APCs – B cells,
macrophages &
dendritic cells
Size
9 to 10 amino acids
(smaller)
12 to 28 amino acids
(larger)
Intracellular eg viral
infections
Extracellular eg
bacterial infections
Source of antigen
displayed
Antigen presented to CD8+ T cells
CD4+ cells
( APC = Antigen presenting cell)
Activation of the Adaptive
Immune System


Antigens that escape the innate
immune system encounter the
adaptive system
Adaptive immune system – powerful
must be activated
Activation of the Adaptive Immune
System
In this diagram, the macrophage represents the innate system
& the TH cell, the adaptive system
3. T cell recognizes
its cognate Ag
2. Ag presented
on cell surface
with MHC
1.
4. 2nd signal required
= protein on APC +
a TH cell receptor
APC eg
Macrophage
ingests Ag
5. ACTIVATION
&
6. Cytokine production
Cytokines

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Cells of the immune system communicate
with each other using cytokines
Protein hormones
Mediate the effect of the innate &
specific immunity
Autocrine/ paracrine/endocrine
Effects include cell activation, division,
apoptosis, movement
Cytokine types



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
Interleukins –
– produced by leucocytes & have effects mainly
on WBC
Chemokines –
– chemoattractants
Colony stimulating factors –
– differentiation & proliferation of stem cells
Interferons –
– interfere with viral replication
Eg.
Il-2 = a growth factor that stimulates CTLs & NK
cells to proliferate
TNF activates primed macrophages & NK cells
Cells & cytokine production
Cells produce different subgroups of cytokines which will
instruct the innate & adaptive systems to produce cells &
antibodies against specific antigens.
Here is an example
Cells
TH1
(CD4)
Cytokines
IL2
IFN 
TNF
TH2
(CD4)
IL 4
IL 5
IL10
Antigen
Viruses
Bacteria
TH0
Parasites
T Cell Subsets – the Family Grows
5
10
44
28.2
CM
Naive
EM
TEM
4
< CCR7 >
10
3
10
2
10
0
23.1
4.73
2
0 10
3
10
4
10
5
10
< CD45RA>
Naïve (CD45RA+CCR7+)
CM: central memory (CD45RA-CCR7+)
EM: effector memory (CD45RA-CCR7-)
TEM: terminal effector memory (CD45RA+CCR7-)
IL-12
IL-23
p40
IL-12Rβ1
p35
p19
p40
IL-12Rβ2
IL-23R
NK or T cell
membrane
Signal
Signal
IL-1
IL-6
INF
Th1 cell proliferation
Th17 cell proliferation
IL-22
2. Tolerance Is…………….
the immunologic unresponsiveness
to self antigens




It allows the immune system to protect the
body without turning against itself
The focus is on the adaptive immune system
T & B cells must be able to discriminate self
from non self
This occurs centrally & peripherally
Central T Cell
Tolerance




NEJM 2001;344(9): 655 – 664.
T cells are produced in
the bone marrow &
migrate to the thymus.
Here they go through a
rigorous selections
process.
Only T cells that react
to antigen but not self
exit.
The rest die by
apoptosis.
Peripheral T Cell Tolerance
If autoreactive T cells enter the circulation,
there are several mechanisms that can prevent an
autoimmune reaction.
NEJM 2001;344(9): 655 – 664.
B Cell Tolerance
 CENTRAL
–Clonal deletion of autoreactive B
cells in the bone marrow, spleen
& lymph nodes.
PERIPHERAL
–Lack of help from T cells is the
predominant factor.
Breakdown in peripheral tolerance
3. Autoimmunity

Breakdown in mechanisms preserving
tolerance to self

Severe enough to cause a pathological
condition
Autoimmune diseases

Organ specific e.g.
– Insulin dependant diabetes
– Myasthenia gravis

Multisystem e.g.
– Rheumatoid arthritis
– SLE
Mechanisms
GENETIC FACTORS
Aberant MHC/HLA present self peptide
Autoreactive T & B cells

ENVIRONMENTAL
FACTORS
Infectious/ noninfectious
triggers
Hypothesis : Molecular
mimicry

AUTOIMMUNE DISEASE
Molecular mimicry :
The antigen looks similar to a self-peptide. As a result, the body produces an
immune response to the trigger factor as well as to self.
The Major Theories in the Development of
Autoimmune Diseases

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Release of the normally sequestered antigens
Increased expression of autoantigen/cryptic
epitope/MHC II
Molecular mimicry, Epitope spreading
Defects in apoptosis
Decreased cell numbers or function of suppressor
and/or regulatory cells
Altered Th1 and Th2 cytokine pattern
Increased expression of costimulatory molecules
Release of inflammatory mediators
Autoantibodies in Connective Tissue
Diseases




Produced by B cells
May be pathogenic eg.
– Form immune complexes in lupus nephritis
Markers of certain diseases
May not be diagnostic
– Apart from rheumatic disorders, they may be
found in normal population & with other
conditions
– Therefore only test when clinically indicated.
Autoantibodies associated with
disease
DISEASE
AUTOANTIBODY
Rheumatoid Arthritis
Rheumatoid factor
SLE
ANA,dsDNA, Smith
Scleroderma
ANA,centromere,
topoisomerase
Antiphospholipid
Syndrome
Sjogren’s syndrome
Anticardiolipin (ACLA)
Polymyositis
Jo-1
Dermatomyositis
Mi-2
Wegener’s granulomatosis
c-ANCA
Ro, La
Cellular Targets for autoantibodies
Ab to intracellular proteins
-proteinase 3
•cANCA
Ab to cell membrane
Proteins
•ACLA
Ab to IgG
•Rheumatoid factor
Antinuclear antibodies (ANA)
•dsDNA
•ENA – Smith, Ro , La, RNP
•Centromere, topoisomerase
Ribosomal &
lysosomal components
-t RNA synthetase
• AntiJo 1
This diagram depicts the autoantibodies & their respective
target antigens
1.
2.
3.
Immune Mechanisms
Tolerance
Autoimmunity
4. Rheumatologic conditions
–
–
–
–
–
Rheumatoid arthritis
Systemic Lupus Erythematosis
Spondarthropathies
Inflammatory myopathies
Systemic sclerosis
The above disease will be used to highlight some of
the concepts of Immunology in Rheumatology.
Note that the details of each pathway does NOT have
to be memorized.
Rheumatoid Arthritis
Chronic autoimmune
disorder
 Affects 1% of
population
A symmetrical peripheral
polyarthritis of unknow
n etiology that leads
to joint deformity &
destruction due to
erosion of cartilage &
bone

Inflammation Drives Arthritis
The inflammatory process results in damage to cartilage
& bone
NEJM 2001; 344 (12): 907 – 916.
Rheumatoid Factor




Rheumatoid Factor
is an autoantibody
produced in RA
It is however
produced in several
other conditions
 Clinical features
are important in
making the
diagnosis
Anti-CCP Ab
Rheumatoid Arthritis

Current therapies
– Nonsteroidal anti-inflammatory drugs (NSAIDs)
– Oral corticosteroids
– Disease-modifying antirheumatic drugs (DMARDs)
 D-penicillamine, auranofin, hydroxychloroquine,
azathioprine, MTX
 MTX has the most rapid onset of action and is well
tolerated with long-term use
 Many patients receiving DMARD therapy show only
partial symptom relief and still exhibit features of active
disease
New Agents for the Treatment
of RA

Cytokine inhibitors
–
–
–
–



Human monoclonal Ab to TNFα
PEGylated anti-TNFα
Monoclonal antibody to IL-6 receptor
JAK3 inhibition
Co-stimulatory molecule blockers-abatacept
Targeted B-cell therapy- anti-CD20
yOther unique mechanisms of action
Systemic Lupus Erythematosus
A generalized connective tissue
disorder affecting many organs
and characterized by the
production of many autoantibodies
Signs:
Arthritis
“Butterfly” rash on face
Sensitivity to sunlight
Renal failure
Headaches
Mental disorders
Systemic lupus erythematosus classification
criteria (SOAP BRAIN MD)
1. Serositis:
(a) pleuritis, or
(b) pericarditis
2. Oral ulcers
3. Arthritis
4. Photosensitivity
10. Malar rash
11. Discoid rash
". ..A person shall be said to have SLE
if four or more of the 11 criteria are
present, serially or simultaneously,
during any interval of observation."
5. Blood/Hematologic disorder:
(a) hemolytic anemia or
(b) leukopenia of < 4.0 x 109
(c) lymphopenia of < 1.5 x 109
(d) thrombocytopenia < 100 X
9
10
6. Renal disorder:
(a) proteinuria > 0.5 gm/24 h or
3+ dipstick or
(b) cellular casts
7. Antinuclear antibody (positive ANA)
8. Immunologic disorders:
(a) raised anti-native DNA
antibody binding or
(b) anti-Sm antibody or
(c) positive anti-phospholipid
antibody work-up
9. Neurological disorder:
(a) seizures or
(b) psychosis
Lupus Nephritis

The kidney biopsy on the right is from a patient
with diffuse proliferative lupus nephritis shows
massive deposits of IgG on immunofluorescence
Ankylosing
Spondylitis
AS is a chronic inflammatory disease of the axial
skeleton manifested by back pain & progressive
stiffness of the spine
Ankylosing
Spondylitis

The prevalence of
the MHC,HLA-B27
is high in
Caucasians
but rare in Black
populations with
Ankylosing Spondy
litis
Dermatomyositis
An idiopathic inflammatory myopathy associated
with certain characteristic cutaneous manifestations
Note: the inflammatory infiltrate in the muscle
biopsy of this patient with Dermatomyositis
Scleroderma
The term encompasses a heterogeneous group of
conditions linked by the presence of thickened
sclerotic skin lesions
The inflammatory process in Scleroderma results a marked
fibrotic precess responsible for many of the clinical features
Scleroderma Lung Disease
2 important lung diseases which occur due to the
inflammatory process in Scleroderma
Summary
Medical Assistant
Knowledge of the immune system forms the basis of
understanding many of the diseases and disorders of
the immune system and has become the focus of many
exciting new treatment strategies.
You must have knowledge of this system when assisting
the physician during the examination of a patient who is
having problems with their immune system.
85
Apply Your Knowledge
Your 18-year-old patient states
that he thinks his right big toe is
inflamed. What symptoms would
you expect to see?
86
Apply Your Knowledge
Answer
-
Your 18-year-old patient states that
he thinks his right big toe is inflamed.
What symptoms would you expect to
see?
Redness, heat, swelling, and pain
87
Apply Your Knowledge
How can a patient contract HIV?
88
Apply Your Knowledge
Answer
-
How can a patient contract HIV?
Most common routes of transmission are
through sexual contact, blood, or from mother
to child during pregnancy or breast-feeding
89
Apply Your Knowledge
As you are taking your patient to the
exam room, you notice that she has
“Butterfly” rash on her face. What
disorder exhibits this sign?
90
Apply Your Knowledge
Answer
-
As you are taking your patient to the
exam room, you notice that she has
“Butterfly” rash on her face. What
disorder exhibits this sign?
Lupus
91
References
1.
2.
3.
4.
5.
Sompayrac L. How the Immune System works.
Blackwell Science, Inc. 1999
Roitt IM. Roitt’s Essential Immunology 10th ed
. Blackwell Science 2001
Hochburg et al. Rheumatology 3rd ed. Mosby
2003
UpToDate 12.3
Kalla AA. Rheumatology Handbook. Rheumatic
Diseases Unit Univrersity of
Cape Town. 20
03
References (cont)
6.
7.
8.
9.
10.
Parkin J, Cohen B. An overview of the immu
ne system. Lancet 2001;357: 1777-1789.
Mackay IR, Rosen FS. Tolerance and
Autoimmunity. NEJM 2001;344(9): 655 – 66
4.
Mackay IR, Rosen FS. Autoimmune disease
s. NEJM 2001; 345(5): 340-350.
Epstein FH. Cytokine pathway and Joint
Inflammation in Rheumatoid Arthritis. NEJM
2001; 344 (12): 907 – 916.
Yuan G et al. Immunologic Intervention in
the Pathogenesis of Osteoarthritis. Arthritis
& Rheumatism 2003; 48(3) 602- 611.
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