Transcript Principles of Autoimmune diseases

Principles of Autoimmune
diseases
ID# 3092
Raja’a Al-Attiyah
Dept. Microbiology
Objectives
 Define autoimmunity
 Describe the various mechanisms by which autoimmune
reactions may be induced
 Describe the various mechanisms of tissue damage in the
autoimmune diseases
 Understand the concepts of organ-specific and non-organ-
specific autoimmunity with classic examples
A failure to control the function of self-reactive cells
(which escaped to the periphery) results in
Autoimmune response
(AUTOIMMUE DISEASE)
Autoimmune Disease=A condition in which the
pathological tissue damage occurs as a result of an
immune response directed to self
Autoimmunity:
• may arise by different mechanisms
• is affected by various environmental & genetic factors
• These factors work to break down self tolerance
MECHANISMS OF INDUCTION
OF AUTOIMMUNITY
(Loss of self-tolerance)
1. Release of Sequestered Auto-antigens:
e.g.
•
Release of myelin basic protein (MBP) in infection
•
Exposure of Eye lens protein after trauma
•
Vasectomy can lead to exposure of sperms
•
Exposure of heart muscle Ag after
myocardial
infarction
2. Cross-reactive Auto-antigens: (Molecular mimicry)
Viruses and bacteria may have antigenic determinants that are
identical or similar to those of normal host cells
e.g. Rheumatic fever - b hemolytic Streptococci and
heart auto-Ag
3. Autoimmunity and Heat Shock Proteins (HSP)molecular mimicry
• HSP are normally produced in response to high
temperature and stress
• Conserved in mammals and microbes and
Immunodominant
• Infections may stimulate HSP which may stimulate autoreactivity
e.g. Rheumatoid Arthritis - T cell reactivity to HSP
induced by Mycobacterium tuberculosis
4. Inappropriate Expression of Class II MHC:
Cells which do not normally express MHC-II present autoantigens+MHC-II to Th cells. Th cells get activated and
may then activate B, Tc
b cell
e.g.
In IDDM, b cells from pancreas
express high levels of Class I
and Class II MHC molecules
Self-reactive Th
5. Cytokine Imbalance
Increased production of cytokines may result
in excessive T and B cell activation and
subsequent damage
e.g.
Increased level of IL-4 & IL10 in Systemic Lupus
Erythematosus (SLE)
6. Defects in T cell Immunoregulation
e.g. low levels of Treg and high levels of Tc in thyroiditis in
Obese chickens
7. Polyclonal Activation
Some viruses and bacteria
non-specific polyclonal activation of B-cell
Proliferation of numerous clones of B cells
including B cells reactive to self-antigens
Release IgM in the absence of Th cells
e.g. EBV, CMV - stimulate antibodies to self-Ag (e.g. antinuclear antibodies)
Often more than one mechanism is involved in
the initiation of disease
Release of
sequestered
antigens
Cross-reactive
Antigens
Inappropriate
expression of
MHC
Cytokine
Imbalance
SELF-REACTIVE-Th CELLS
B cells
Tc
auto-Ab
Induction of Auto-immunity
Tissue damage
T DTH
Auto-Ab
Plasma cells
B cells
Activated Tc
Tc cells
self-reactive
Th cells
TDTH
• ADCC
• MAC
• Immune
complexes
Activated MQ
TISSUE
DAMAGE
Inflammation
DTH
Mechanisms of pathology of
Autoimmune Diseases
Pathological changes in auto-immune diseases can be
mediated by variable immune responses
1. Antibody-Mediated Autoimmune Diseases
autoAb bind to hormone receptors and prevent hormone from
binding to receptor
e.g .Myasthenia gravis-AutoAb to Acetylcholine receptor on
muscles
No activation of muscles
2. Immune-Complex-Mediated Autoimmune diseases
Formation and deposition of immune complexes (auto-Ab+
auto-Ag) followed by widely spread tissue damage
e.g. Systemic Lupus Erythematosus (SLE)
AutoAb to nuclei, DNA, RBCs, leukocytes
Immune complex deposition in blood vessels
3. T cell-Mediated Autoimmune diseases
Cellular damage by inflammation
e.g .Insulin-dependent-diabetes mellitus (IDDM)
Infiltration of the pancreas by lymphocytes
and plasma cells
b cells are destroyed
4. Immune-complexes & T cell-Mediated Autoimmune
Diseases
Widespread tissue damage due to hyperactive T & B cells
e.g. Rheumatoid arthritis
• Chronic inflammation
• Rheumatoid factor-AutoAb to Fc region of IgG
• Immune complex deposition in joints
Spectrum of auto-immune diseases
Autoimmune diseases exist in a spectrum, organ-specific
diseases at one end & the non- organ-specific diseases at the
other end
ORGAN-SPECIFIC AUTOIMMUNITY:
Autoimmunity limited to a single organ/gland e.g. thyroid, adrenal,
pancreas, stomach.
NON -ORGAN SPECIFIC AUTOIMMUNITY:
Broad range of target Ag involving a number of organs and tissues e.g.
skin, joints, kidney, liver
Examples
ORGAN-SPECIFIC AUTOIMMUNITY:
Pernicious anemia
Insulin-dependent diabetes mellitus
Stomach
Pancreas
NON -ORGAN SPECIFIC AUTOIMMUNITY:
Systemic lupus erythematosus (SLE)
Rheumatoid arthritis
Kidney
Joints
Comparison of organ specific and non-specific
disorders
Organ specific
Antigen
Essentially localized
to given organ
Lesions
Antigen in a specific
organ is target for
immunological attack
Non-organ
specific
Widespread
throughout the
body
Complexes
deposit
systemically
particularly in
kidneys, joints
and skin