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Transcript
AUTOIMMUNITY- I
Autoimmunity Part-1

At the end of the session the student should be able
to:
a. Define and classify autoimmunity
 b. Explain Immunological tolerance
 c. Discuss the mechanism of autoimmunity

Suggested readings: Robbins’s basic pathology, 8th edition.
I. Autoimmune disease Definition
is a problem of Self/Non-self Discrimination
 Autoimmune disease - an immune reaction
against “self-antigens”:
 Failure of SELF RECOGNITION
 Failure of SELF TOLERANCE
 can be single organ or multisystem diseases.
 can be more than one autoantibody in a given
disease.”

Just like we said “EVERY disease is a genetic
disease”, we can also say “EVERY disease is an
‘immune’ disease
Autoimmunity
Frequently in women (2\3 of cases) vs men.
 Left handed vs Right handed.
 Secondary to certain diseases?
 More than 40 human diseases autoimmune
in origin.

“true” autoimmunity, difficult to ascertained.
 Autoimmunity- considered as grouped under

immune-mediated inflammatory diseases. This
indicate the role of chronic inflammation in
autoimmunity Pathogenesis.
Autoimmune diseases Classification



immune-mediated inflammatory diseases classify
as follow:
1) Diseases mediated by antibodies and immune
complexes:
- Organ specific
- Non-organ specific (multi-organs)
2) Diseases mediated by T cells:
- Organ specific
- Non-organ specific (multi-organs)
II. Autoimmune disease Classification
Immune-mediated inflammatory diseases divided:
Diseases mediated by antibodies and immune complexes
a) Organ specific autoimmune:
Autoimmune hemolytic anemia
Myasthenia gravis
Graves’ disease.
Goodpasture syndrome.
b) Systemic “Non organ specific” autoimmune:
-
-
SLE
c) Disease cause by reaction to microbial Ag
- Polyarteritis nodosa
II. Autoimmune disease Classification
Second: Diseases mediated by T cells
a) Organ-specific autoimmune diseases
DM- type-1
Multiple sclerosis.
-
-
b) Systemic autoimmune diseases
SLE
Rheumatoid arthritis.
Sjogren syndrome.
-
-
c) Diseases caused by autoimmunity or by
reactions to microbial antigens

- Inflammatory myopathies

- inflammatory bowel disease
Autoimmunity Part-1

At the end of the session the student should be able
to:
a. Define and classify autoimmunity
 b. Explain Immunological tolerance
 c. Discuss the mechanism of autoimmunity

Suggested readings: Robbins’s basic pathology, 8th edition.
Immunological “self” tolerance

Definition: Lack of immune responsiveness
to an individual’s own tissue antigens.
Mechanism of self tolerance: Classified into
Tow types:
 I. CENTRAL tolerance(Thymus- T cells and BM: B cells).
 II. Peripheral tolerance(Secondary lymphoid tissue, sites of
inflammation)

Immunological “self” tolerance
I. CENTRAL tolerance:
 defined as negative selection or deletion
process
 Goal: elimination of self-reactive T,B cells.
Mechanism:
 1- Deletion of self-reactive T & B lymphocytes
during their maturation in central lymphoid
tissues(Thymus: T cells and BM: B cells).
 2- Any self reactive cells undergoes
apoptosis & death.
 3- Escape cells >> peripheral tolerance.

Immunological “self” tolerance
II. PERIPHERAL tolerance:

definition: handling of escape cells “central control”
Role: suppression of B&T cells in peripheral tissue.

Mechanisms: several mechanisms

1) Anergy – lack of co-stimulatory.

2) Peripheral Suppression - regulated by CD4 T cell

3) Deletion- post-activation induced cell death.

Immunological “self” tolerance
II. PERIPHERAL tolerance- Mechanisms:
1) Anergy -prolonged irreversible functional inactivation
T-cell activation requires 2 signals. Absence of second
signal (from antigen presenting cells) leads to anergy.
2) Peripheral Suppression by regulatory T -CD4 cells:Regulatory T-cells can modulate the function of other cells.
Certain cytokines elaborated from these cells e.g. IL 10, TGF
beta, can affect T-cell responses.
3) Deletion (peripheral deletion) : post-activation
induced cell death – apoptosis of autoreactive
lymphocyte.
Autoimmunity Part-1

At the end of the session the student should be able
to:
a. Define and classify autoimmunity
 b. Explain Immunological tolerance
 c. Discuss the mechanism of autoimmunity

Suggested readings: Robbins’s basic pathology, 8th edition.
III. The mechanism of autoimmunity: define as
Loss of self-tolerance= breakdown of tolerance
Predisposition of most autoimmune diseases
is due to combined effect of:
1) Combination of the inheritance of
susceptibility genes. (single or multiple)
.
2) Immune regulation machines- persistence and
uncontrolled activation of self-reactive lymphocytes (Defective
elimination\ escape tolerance \ production of antinuclear
autoantibodies\ failur of clearning Imm.complex)
3) Environmental factors (tissue damage,
infections, hormone, trauma, drug, radiation etc..)
Autoimmunity: Part 2
At the end of the session the student should be able to:
• a. List the Genetic factors in autoimmunity
• b. Discuss the Role of infections and tissue
injury.
• Suggested readings: Robbins basic pathology, 8th edition.
Page:138 – 139
Mechanisms of autoimmunity




Genetic factors
- Antigen generated by molecular changes.
Infection factors.
- Molecular mimicry.
- Ag released from hidden location.
Enviromental factors
- Hormonal
- Radiation, trauma, others….
We deeply covered the first two????
1) Role of Genes Susceptibility-1
a)
HLA genes “disease-associated alleles”:
b) Non-HLA gene defects
c) Single gene defect
1) Role of Genes Susceptibility-1
a)
HLA genes “disease-associated alleles”:
Important genes that regulate the development of
autoimmunity are located within MHC.

MHC have got critical role in{ maturation of T cell}
& {induction of Immune response}.

MHC ll genes are responsible for auto-antigen
processing and presentation.

Examples: (HLA: B27, DR2,DR3,DR3\4)- SLE: DLAA7- mechanism remain obscure
Role of Genes Susceptibility- 2.
a) HLA genes “disease-associated alleles” (cont.):
Mechanism: remain obscure but postulated that presence
of MHC alleles defects are lead to
1) Affects the negative selection of T cells in the thymus .
2) Affect the development of regulatory T cells.
b) Non-HLA genes: recent Family & Twins studiesreveals multiple disorders specially gene defect
proved to be among monozygotic greater than > 4
The mechanism
of autoimmunitytimes III.
in dizygotic
twins.
– three
recentof
examples.........................................cont.)
Loss
self-tolerance= breakdown of
Role of Genes Susceptibility-3.
b) Non-HLA genes (cont.) Recent examples: 1- Polymorphisms in a gene called PTPN-22 (most
frequently implicated with AD, a\w RA & type 1 DM.
Mechanism : defect in encoded phosphatase >
defect in control of tyrosine kinases activity>defect
of lymphocyte responses>> excessive activation
2- Polymorphisms in the gene for NOD-2 (NOD-2 is a
cytoplasmic sensor of microbes) , a\w Crohn disease.
Mechanism : NOD-2 defect>> ineffective at sensing
III. microbes>>
The mechanism
of autoimmunityintestinal
entry of microbes>>
chronic
Loss of
self-tolerance=
breakdown
of
inflammatory
responses
against well-tolerated
commensal
bacteria
Role of Genes Susceptibility-4
c) Single gene mutation (rare in AD):
A few number of autoimmune diseases
caused by single gene defect e.g.:
( AIRE= Defect in central tolerance and IL2 and its
receptor D25)
Diseases example: multiple sclerosis, &
other
OUTCOME> These cytokines may control the
maintenance of regulatory T cells
2) Role of infection:
mechanisms postulated:

I. up-regulate the expression of co-stimulators on
APCs >> (via drugs, microorganisms)

II. Molecular mimicry: Some microbes may
express Ags that have the same amino acid
sequences as self-antigens e.g. RHD with postthroat streptococcal infection.

III. Some viruses, such as (EBV)& (HIV), cause
polyclonal B-cell activation, which may result in
production of autoantibodies.
2) Role of Infection (cont.):
IV. Infection induce tissue injury> release hidden Ag:
Tissue injury release “Emergence of sequestered
antigen-= previously unscreened self Ag” - lead to
“not tolerant” T cell activation.

V. Cytokines-induced by Infections- that recruit
lymphocytes, including potentially self-reactive
lymphocytes, to sites of self-antigens.
Ag related from hidden location
Many self Ag are found in hidden location eg. C N S
,TESTES ,EYE (CORNEA)
organ damage
Hidden Ag released
Reaches blood stream
Encounter Ag sensitive cells
Stimulate autoimmunity
End