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