autoimmune diseases
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AUTOIMMUNE DISEASES
Elamurugan. A1559, VIM
PhD Scholar
Points to be discussed…
• What is autoimmunity ?• Mechanisms of autoimmunity• Animal models• Organ specific diseases• Systemic disease• Diagnosis• Therapy
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
Maintenance of self-tolerance
Breakdown of self-tolerance
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
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
Molecular mimicryHit-and-run process
• Tryp. cruzi – cardiac muscle• M protein of Strep. – cardiac myosin• EBV DNA polymerase – MBP Multiple sclerosis• Polio virus VP2 – Ach Myasthenia gravis• Omp of Borrelia – LFA-1 Lyme disease• Microbial HSP RA, SLE• Mycoplasma hyopneumoniae – pig lungs enzootic
pneumonia• Leptospira interrogans Perioidic ophthalmia• Klebsiella – HLA B27 Ankylosing spondylitis
• 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
• 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
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
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
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)
Based on Immunopathology
TYPE I HS TYPE II HS TYPE III HS TYPE IV HS
Milk allergy Autoimmune hemolytic anemia
SLE IDDM
Autoimmune thrombocytopenic purpura
Rheumatoid arthritis
Rheumatoid arthritis
Goodpasture’s syndrome
Pemphigus vulgaris
Acute rheumatic fever
Organ specific diseasesDisease 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
• 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
LATS
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
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
• 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
• Autoimmune thrombocytopenia– Auto-Ab to platelets– Multiple petechiae
• Hashimoto’s Thyroiditis– Auto-Ab & TH1 DTH– Destruction of thyroid peroxidase,
thyroglobulin involved in I2 uptake– Hypothyroidism
Pemphigus complex
• Pemphigus vulgaris – most severe– Bullae at muco-cutaneous junctions– Auto-Ab to desmoglein 3
• Pemphigus foliaceous– Auto-Ab to desmoglein 1
• Pemphigus vegetans• Pemphigus erythematosus• Bullous pemphigoid
– Tense bullae under subepidermal region
Systemic diseasesDisease Self antigen Immune response
Scleroderma Nuclei, heart, lungs, GIT, kidney
Auto-Ab
Sjogren’s syndrome Salivary gland, liver, kidney, thyroid
Auto-Ab
Rheumatoid arthritis Connective tissue, IgG Auto-Ab, Immune complex
SLE DNA, nuclear protein, RBC, platelet mem
Auto-Ab, Immune complex
Ankylosing spondylitis Vertebrae Immune complex
Multiple sclerosis Brain or white matter TH1 cells, TC cells, Auto-Ab
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
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
• 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
Treatment
• Immunosuppressive drugs - – Corticostreoids, Cyclophosphamide,
Cyclosporin, FK506• Thymectomy – Myasthenia gravis• Plasmapheresis - Immune complex
mediated diseases• Anti-CD4 antibodies• Blockers of TNF-α – Enbrel, Remicade,
Humira• IL-1 receptor antagonists
• 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
Thank you
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