Tolerance and autoimmune diseases

- Immune Tolerance : unresponsiveness to an antigen

- Tolerogens : Antigens that induce tolerance
- failure of self-tolerance immune reactions against self-Ag = autoimmunity

- Main contributor to tolerance is T cells because :

a- MHC relation to autoimmune diseases
b- T cell is the key regulator of immune response to proteins

- Tolerance in CD4+ helper T lymphocytes

a- effective way of preventing both CMI and humoral IR to auto protein Ags
b- because helper T cells are necessary inducers of all responses

Central Tolerance
- Immature T cell in thymus exposed to self-Ags, if they react to them they die
- In T cell selection stage: Medullary thymic epithelial cells can express antigens that related to specific
organs
- Controlled by many genes one is called (Aire)
- Aire deficient cause :
a- Polyendocrinopathy syndrome
b- Addison
c- hypoparathyroid
d- chronic candidiasis

Peripheral tolerance for autoreactive T cells

- Absence of co-stimulatory signals (B7-1 and B7-2) on APC carrying self-Ag that bind CD28 on T cells
(signal 2) prolonged activation by Signal 1 then cell inhibition by CTLA-4

- Expression of inhibitory receptor CTLA-4 instead of CD28 anergy

- Polymorphisms in the CTLA4 gene lymphoproliferation and several autoimmune diseases in humans
type 1 diabetes and Graves disease

- In CD4+ T cells, the most important death receptor is Fas (CD95), and its ligand is Fas ligand (FasL).
a- Fas : member of the TNF receptor family
b- FasL is homologous to TNF
c- When T cells are repeatedly activated, FasL is expressed on the cell surface, and it binds to surface
Fas on the same or adjacent T cells activation caspases apoptosis
d- Mutation in gene coding for FAS or Fas L leads to autoimmune lymphoproliferative syndrome
(ALPS).
 T regulatory
- Some self-reactive CD4+ T cells that see self-Ag in the thymus are not deleted
- but instead differentiate into regulatory T cells
- actively suppress self-Ag-specific lymphocytes in periphery
- Their production need both IL-2 and TGF-B.
- they produce immunosuppressive cytokines IL-10 and TGF-

TGF-
- inhibits the proliferation of T cells and the activation of macrophages
- stimulates production of IgA antibodies
- IgA is the major antibody required for mucosal immunity & associated with oral tolerance
- promotes tissue repair after local immune and inflammatory reactions subside

IL-10
- inhibits the production of IL-12 by DC and macrophages.
- inhibits the expression of costimulators and class II MHC molecules on dendritic cells and macrophages
- leads to T cell anergy
- IL-12 + IFN- secretion important role in innate and adaptive IR against intracellular microbes

Peripheral Tolerance in CD8+ T Lymphocytes

- if CD8+ T cells recognize MHC I associated Peptides without costimulation or T cell help anergy
- Inhibitory receptors (PD-1) suppress the activation of CD8+ T cells
- regulatory T cells can directly inhibit the activation of CD8+ T cells
- CD8+ T cells that are exposed to high concentrations of self-Ag apoptosis

B lymphocytes tolerance
- Central Editing, deletion and anergy
- Peripheral :
a- Fas on B cell and Fas L on T helper
b- inhibitory receptor CD22 and inhibitory Fc receptor (FcRIIB).
- polymorphism of FcRIIB associated with SLE in humans

Artificial induction of tolerance

- Useful in
1- preventing IR to the products of newly expressed genes in gene therapy
2- preventing reactions to injected proteins in patients with deficiencies of these proteins
3- promoting acceptance of stem cell transplants
4- immunotherapy for allergy to foreign proteins.
- Ways of induction tolerance
1- high doses of protein antigens administered cutaneously without adjuvants
2- Immunosuppression by total body irradiation
3- Immunosuppression by drugs
a- cyclosporin
b- anti-lymphocytic antibodies as anti-CD4
c- soluble CTLA-4
d- steroids
4- Oral administration of antigens ( lead to increase in IgA and IL-10 and TGF-beta)

Autoimmune diseases

- Etiology
1- Release of sequestrated antigens as a result of tissue injury (After infection, trauma or surgery)
a- Posttraumatic uveitis
b- Posttraumatic orchitis
c- Antigens of nucleus in SLE that immune system did not expose to before

2- molecular mimicry : exposure to MO Ags that cross react with self-Ag (strep-pyogenes & rheumatic
fever.

3- Bystander activation : Infection enhanced expression of costimulators in tissues activation of T

cells that are not specific for the pathogen bystander activation.

4- Genetic pre-disposition (Polygenic)

a- Rheumatoid arthritis (RA)in HLADR4
b- thyroiditis in HLA DR5
c- multiple sclerosis in HLA DR2
d- systemic lupus erythromatosus (SLE) in HLA DR3
e- Type 1 diabetes in HLA DR3 and 4

5- Other genetics (single gene) : loss of fas, fasL expression, AIRE gene, C4 gene (SLE) and CTLA-4 gene
mutations
6- Hormonal factors, RA and SLE more in females
- Autoimmune diseases, classification
1- Organ-specific disorders (localized)
a- Addisons disease (adrenal glands)
b- celiac disease (gastrointestinal tract)
c- Crohns disease (gastrointestinal tract)
d- multiple sclerosis (MS)(brain/spinal cord)
e- type 1 diabetes (pancreas ilets Beta cells)
f- ulcerative colitis (gastrointestinal tract)

2- Non-organ-specific disorders (systemic)

a- Rheumatic fever (joints ,skin and heart)
b- lupus (SLE) (joints, skin, kidneys, heart, brain and others)
c- Rheumatoid arthritis (RA) (joints, skin, muscles)

- Autoimmune diseases , Mechanisms of tissue damage

1- EFFECTOR MECHANISMS: auto-Ab , effector auto-T cells and immune complexes
2- Type 2 hypersensitivity to self-tissue as in
a- hemolytic anemia
b- myasthenia gravis
c- thyroiditis
d- thrombocytopenic purpura
e- pemphigus vulgaris
f- Goodpasture syndrome
g- Acute rheumatic fever

3- Immune complex deposition : type 3 hypersensitivity

a- SLE
b- RA
c- Mixed essential cryoglobulinemia

4- Cell mediated (Type 4 hypersensitivity)

a- Multiple sclerosis (MS)
b- ulcerative colitis
c- experimental autoimmune encephalitis
d- insulin-dependent DM (type1)

- Notes
a- Once autoimmune disease start it become chronic and progressive due to epitope spreading as a
result of tissue damage
b- The symptoms is on and off, when it is on it is called flare up.
- Autoimmune diseases , lab diagnosis
1- Elevated levels of immunoglobulins and auto T cells
2- High CRP, ESR
3- Auto-antibodies; anti-nuclear, anti-smooth muscle, anti-mitochondrial, rheumatoid factor
4- Complement levels may decreased
5- Biopsy; immune complex or lymphocyte infiltration

- Autoimmune diseases , management

1- Anti-inflammatory drugs; aspirin, corticosteroids
2- Immuno-suppressive drugs, azathioprine
3- Plasmapheresis

- Autoimmune diseases , examples

1- Myasthenia gravis : Ab against acetylcholine receptor of neuromuscular junction, block receptor
and cause muscle weakness
2- Gravis disease : Antibodies against thyroid stimulating hormone receptor cause long lasting
activation and hyperthyroidism

3- Idiopathic thrombocytic purpura (platelet antigen) low platelet count+bleeding

4- Good pasteur syndrome (renal and lung basement membrane collagen) lung and kidney bleeding;
anti-glomerular basement membrane (GBM)

5- Vitiligo (Ab against melanocytes) lead to depigmentation of skin

6- SLE (Lupus)
a- Red flush on face as wings of butterfly, disease attack many organs as CNS, heart and kidney
b- Mechanisms; 95% of patients have Abs to DNA and RNA (anti-nuclear Ab (ANA), and more
specific anti-ds-DNA antibody
c- Circulating immune complexes deposit in skin (vasculitis, skin rass), basement membrane of
kidney (lampy bumpy deposits) lead to glumerolonephritis and proteinuria
d- Diagnosis :
i- Symptoms as skin rash, proteinuria and edema
ii- Tissue biobsy; immunoflourescence microscope (granular appearance) to see ANA,
iii- Blood levels of ANA and anti-DS DNA antibody
iv- low complement levels

7- Rheumatoid arthritis
a- Synovium full with lymphocytes leading to destruction of bone and cartilage
b- Causes
i- Auto-antibodies mainly IGM but may be IGG, against Fc portion of self IGG (rheumatic
factor) and this factor present in 90% of patients
 ii- Tissue damage by Type 3 hypersensitivity reaction (Immune complexes),
iii- Or Type 4 reaction; TH1, CD8 cells, IL-12 and TFN gamma cytokines against antigens in
synovial membrane of the joint
c- anti-nuclear Abs (ANA) in 50% of patients
d- Stiff painful joints, malformation in Joint x-ray
e- Diagnostic test, positive RF latex agglutination test
f- disease modifying agents
i- Corticosteroids
ii- pain killers
iii- methotrexate (it is an anti-folate that inhibit synthesis of DNA, and RNA) and
iv- anti-inflammatory drug sulfasalazine

8- Rheumatic fever
a- inflammatory disease that occurs following a Streptococcus pyogenes infection, such as strep
throat or scarlet fever
b- caused by antibody cross-reactivity that can involve the heart, joints, skin, and brain
c- the illness typically develops two to three weeks after a streptococcal infection
d- commonly appears in children between the ages of 6 and 15
e- only 20% of first-time attacks occurring in adults
f- Diagnosis
i- Elevated anti-ASO titer or Anti-streptolysin O (ASO or ASLO) : the antibody is produced
against an antigen of the group A streptococci
ii- Presentation, recent sore throat plus painful joint, chest pain, skin nodule and heart
murmur
iii- Diagnostic test, positive ASO latex agglutination test plus clinical symptoms and signs.