2. Points to be discussed…
• What is autoimmunity ?
• Mechanisms of autoimmunity
• Animal models
• Organ specific diseases
• Systemic disease
• Diagnosis
• Therapy
3. Introduction
• Paul Ehrlich – ‘Horror Autotoxicus’
• Adaptive immunity double edged sword
• Recently role of innate immunity reported
• Failure of self-tolerance in T & B cells
• Beneficial autoimmunity!!! (Band 3 of RBC)
• Environmental
• Familial association
4.
5.
6. AUTOIMMUNITY
Normal IR
Hidden antigens
Tissue alterations
Molecular alteration
Newly synthesized
antigens
Molecular
mimicry
Abnormal IR
Failure of regulatory
control
Micriochimerism
Failure of
Apoptosis
Lymphoid tumors
Self-reactive T
cells
Virus infections
Genetic
predisposition
Hormonal
influences
7.
8. Hidden antigens
• Hidden antigens
– Myelin basic protein – autoimmune encephalitis
– Injury to testis
– Chronic hepatitis
– TB, Trypanosomiasis
• Molecular changes
– Rheumatoid factor (RF) - Ab to Fc part of IgG
– Immunoconglutinins (IK) – C2, C4, C3
10. • Epitope spreading – normal IR to exogenous antigen
that subsequently spreads to recognize self antigens –
Thyrotoxicosis, Diabetes
• Receptor editing
• MHC expression
– High levels of MHC I, II - Pancratic β cells IDDM
– Thyroid acinar cells – MHC II Grave’s disease
– PHA MHC II
– IFN γ MHC II SLE
11. • Virus induced
– Due to molecular mimicry & bystander activation
– Reovirus polyendocrine disease
– Type C retrovirus auto-Ab to nucleic acids,
RBC
• Microchimerism
– Exchange of cells between mother and foetus
– Women Scleroderma
– Boys Dermatomyositis
12. Failure of regulatory control
• Autoimmune proliferative syndrome/ ALPS
– Mutation in Fas (lpr/lpr mice)
• APECED
– Mendelian inheritance
– Defect in gene encoding AIRE, expressed in thymus,
pancreas, adrenal cortex
– Expression of peripheral tissue self antigen on thymic
medullary epithelial cells
– Central tolerance
• IPEX, Scurfy mice
– Mutation in Foxp3 gene leads to defects in formation
of CD4+/CD25+ T reg cells
13. Animal models
• Non-obese diabetic (NOD) mouse - IDDM
• (NZB NZW)F1 mouse - SLE
• Obese strain chicken (OS) – Hashimoto’s
Thyroiditis
• Bio breeding rats (BB rat) - Spontaneous
autoimmune type I diabetes
• New Zealand Black mouse – Spontaneous
autoimmune haemolytic anemia
14. Role of immune cells and its products
• Animal models implicated the role of
CD4+
• TH1/TH2 balance
• TH1 cells and cytokines promotes (IL 2,
TNF α, IFN γ)
• TH2 cells and cytokines inhibits (IL 4)
15. Based on Immunopathology
TYPE I HS TYPE II HS TYPE III HS TYPE IV HS
Milk allergy Autoimmune
hemolytic
anemia
SLE IDDM
Autoimmune
thrombocytopen
ic purpura
Rheumatoid
arthritis
Rheumatoid
arthritis
Goodpasture’s
syndrome
Pemphigus
vulgaris
Acute
rheumatic fever
16. Organ specific diseases
Disease Self antigen Immune response
Addison’s diseases Adrenal cells Auto-Ab
Autoimmune haemolytic
anemia
RBC membrane proteins Auto-Ab
Goodpasture’s disease Renal & lung basement mem Auto-Ab
Grave’s disease TSH receptor Auto-Ab (Stimulating)
Myasthenia gravis Ach receptor Auto-Ab (Blocking)
Idiopathic
thrombocytopenia purpura
Platelet mem proteins Auto-Ab
Pernicious anemia Gastric parietal cells, intrinsic
factor
Autoantibodies
IDDM Pancreatic beta cells TH1 cells, auto Ab
Hashimoto’s thyroiditis Thyroid proteins and cells TH1 cells, auto Ab
17. • Grave’s disease
– Stimulatory auto Ab binds to TSH receptor
• Myasthenis gravis
– Inhibitory auto Ab binds to Ach receptor blocks
Ach binds, later lysis of cells
– Weakening of muscle
– Tensilon Test
•anticholinesterase agent edrophonium chloride
regaining of muscle strength but not long time
electromyography repetitive nerve stimulation
progressive decline in the muscle action
20. Autoimmune anemia
• Pernicious anemia
– Auto-Ab to intrinsic factor in gastric parietal cells
blocks Vit B12 absorption
• Autoimmune hemolytic anemia
– Coombs test - RBC incubated with anti-human
IgG antiserum if auto-Ab present on RBCs, cells
agglutinate
• Drug induced
– Penicillin, Methyl dopa binds to RBC make them
antigenic
21. Autoimmune hemolytic anemia
Class Antibody Activity Optimal
temp (°C)
Site of
RBC
removal
Clinical effect
I G>>M Agglutinin 37 Spleen I/V
agglutination
II M Hemolysin 37 Liver I/V hemolysis
III G Incomplete 37 Spleen Anemia
IV M Agglutinin 4 Liver Cyanosis of
extremities
V M Incomplete 4 liver anemia
22. • Goodpasture’s syndrome
– Auto-Ab to basement of kidney glomeruli, alveoli
– Activation of C’
– Accumulation of C’ split products C3a, C5a attract
neutrophils aggravate the condition
• IDDM (Type I DM)
– Destruction of pancreatic beta cells
– Auto-Ab to enzyme glutamic acid decarboxylase
– CTL attack insulinitis
– Activation of MΦ release of cytokines TNF-α, IFN-γ,
IL1 along with auto-Ab cause DTH
26. Systemic lupus erythematous
• Auto-antibodies
– Specific RBC, platelets, leukocytes
– Nonspecific nuclear antigens, cytoplasmic
antigens
– Discoid lupus erythematous – dog, cat, horse, human
only facial skin involvement no other organs
• Diagnosis
– ANA to DNA, histones in serum indirect
immunofluoresence assay
– LE cell test phagocyte with opsonized nuclei
– Lupus band test – direct immunofluoresence test of
skin deposition of Ig at the dermo-epidermal
junction
27. Rheumatoid arthritis
• Rheumatoid factor IgM reactive with Fc region of
IgG
• This IgM-IgG complex deposit on joints activates C’
leads to type III HS
• Diagnosis
– Agglutination test isologous IgG on latex beads with
Fc part exposed binds with RF cause agglutination
– Rose Waaler test – sheep RBC coated with canine
anti-sheep RBC IgG
– Mucin clot test – synovial fluid has mucin which is
absent in RA so formation of non-friable clot upon
addition of glacial acetic acid
28. • Multiple sclerosis
– Autoreactive T cells to myelin sheath
– EBV DNA polymerase molecular mimicry
• Sjogren’s syndrome
– Triad of keratoconjunctivitis, xerostomia
and rheumatoid factor
– Conjunctival dryness, mouth dryness
– Often associated with RA
30. • Statins - decrease CRP RA
• mAb Rituxan – kills B cells thr. CD20 B cell
non-Hodgkin’s lymphoma
• Monoclonal antibodies to activated T cells
• Anti- CD 25 antibodies (α subunit of IL 2)
• mAb to appropriate MHC
• Oral antigens induce tolerance
