Autoimmune DiseaseDefinition

• Ehrlich referred to this phenomenon as horror autotoxicus

• specific adaptive immune response directed against self antigen(s) with loss of tolerance, usually peripheral, not central

• trigger(s) is usually unknown (seed)

• immune response involves both environmental and genetic factors (soil)

• female predominance

Autoimmune DiseaseCharacteristics

• remissions and exacerbations

• organ specific or organ non-specific

• persistence of antigen due to lack of clearance

• tissue damage is produced by:• antigen specific cytotoxic T cells (CD8+)• antigen-non-specific NK cells and

macrophages • immune complexes• autoantibodies , and/or• granulocytes

Autoimmunity requires aloss of self-tolerance

Two types of tolerance:

• central (thymus and bone marrow)• peripheral

Possible Pathogenic Defects Human Autoimmunity

• Multiple genes are involved in human autoimmune disease e.g. IDDM (type I), especially involving the MHC

• Defects in several of these genes may:

– disrupt multiple tolerance pathways and

– contribute in an additive or synergistic way to these polygenic diseases

• Important individual roles for:

• Fas-FasL

• IL-2/IL-2RAICD)

• BCTLA-4 interaction

This suggests that each role may be involved in different pathways of tolerance, perhaps for distinct types of self antigens

Human Autoimmune Diseases

Organ Non-Specific Diseases

• SLE (systemic lupus erythematosus)

• RA (rheumatoid arthritis)

Human Autoimmune Diseases Organ Specific Diseases

• Central nervous system (multiple sclerosis)

• Thyroid (Grave’s disease-thyrotoxicosis, Hashimoto’s thyroiditis)

• Adrenal (Addison’s disease)

• Muscle (Polymyositis)

• Platelets (ITP, idiopathic thrombocytopenic purpura)

• Glomerular basement membrane (Goodpasture’s syndrome)

Human Autoimmune Diseases

Systemic Lupus Erythematosus

SystemicLupus

Erythematosus(SLE)

Systemic Lupus Erythematosus Possible Provocative and Environmental

Factors

Immune Complexes

Systemic Lupus ErythematosusPlacental Transfer of Specific Autoantibodies

IgG antibody crosses the placenta and can bind to fetal tissues causing:

• Cardiac disease (binding to conduction pathways anti-Ro and -La)• Low platelets and hemolytic anemia• Skin rash

Bind to cell membrane protein leading to:• complement activation and cell destruction e.g. red cell destruction (lysis)• damage by NK cells with Fc receptors e.g. ADCC• cellular penetration, enter the nucleus and regulate transcription

Bind to cell receptor leading to:• activation, e.g. TSH receptor (thyrotoxicosis), or• loss of receptor e.g. acetylcholine (myasthenia gravis)

Bind to soluble antigen or tissue fixed antigen forming immune complexes e.g. DNA

How do Antibodies result in Human Autoimmune Disease?

Complement Pathways in SLE

• immune complexes activate the classical and alternative pathways• patients with C1q deficiency and also C4 and C2 deficiency can develop SLE

SLEGENETIC

ASSOCIATIONS• C1q deficiency leading to impaired removal of apoptotic blebs (96% have SLE)• HLA-DR3• C2, C4 deficiencies• reduced TNF• CR1 (C3b receptor) deficiency

Protective genes

Multiple SNPs (single nucleotide polymorphisms)

Human Autoimmune Diseases

Rheumatoid arthritis

Rheumatoid arthritisSynovial Lymphocyte Population• CD4 positive T lymphocytes are

the most common cells in the synovium

• recent studies have described a CD4+, CD28 null cell population that is:– clonally restricted– a high -IFN producer– present in the active atherosclerotic

plaque (patients with RA usually die from atherosclerotic vascular disease)

• numerous B cells an plasma cells

Rheumatoid ArthritisPossible Mechanisms for

Autoimmunity

• molecular mimicry• arthritogenic viruses• superantigens

Rheumatoid ArthritisViruses causing Joint Inflammation

in Humans

• rubella• parvovirus B19• arboviruses• hepatitis B and C• EBV• HTLV 1

Rheumatoid arthritisPossible Superantigens

• mycoplasma• EB virus• lipopolysaccharide• bacterial cell wall peptidoglycans

Rheumatoid ArthritisMycoplasma Species

Human Autoimmune Disease

Ankylosing Spondylitis

Human Autoimmune Disease

Multiple Sclerosis

Human Autoimmune Disease

Myasthenia Gravis

Human Autoimmune Disease

Thyroid and Adrenal Disease

Addison’s Disease

A mutation in AIRE, a transcription factor which promotes ectopic expression of organ-specific proteins in thymus results in a failure of negative selection for these antigens