Autoimmune Disease Definition

1
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

2
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

3
Autoimmunity requires a loss of self-tolerance

• Two types of tolerance
• central (thymus and bone marrow)
• peripheral

4
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-2R (AICD)
• B7-CTLA-4 interaction
• This suggests that each role may be involved
  in different pathways of tolerance, perhaps for
  distinct types of self antigens

5
Human Autoimmune Diseases

• Organ Non-Specific Diseases
• SLE (systemic lupus erythematosus)
• RA (rheumatoid arthritis)

6
Human Autoimmune Diseases

• Organ Specific Diseases
• Central nervous system (multiple sclerosis)
• Thyroid (Graves disease-thyrotoxicosis,
  Hashimotos thyroiditis)
• Adrenal (Addisons disease)
• Muscle (Polymyositis)
• Platelets (ITP, idiopathic thrombocytopenic
  purpura)
• Glomerular basement membrane (Goodpastures
  syndrome)

7
Human Autoimmune Diseases

• Systemic Lupus Erythematosus

8
Systemic Lupus Erythematosus (SLE)
9
Systemic Lupus Erythematosus Possible
Provocative and Environmental Factors
10
Immune Complexes
11
Systemic Lupus Erythematosus Placental 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

12
How do Antibodies result in Human Autoimmune
Disease?

• 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

13
(No Transcript)
14
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

15
SLE GENETIC ASSOCIATIONS

• C1q deficiency leading to impaired removal of
  apoptotic blebs (96 have SLE)
• HLA-DR3
• C2, C4 deficiencies
• reduced TNFa
• CR1 (C3b receptor)
• deficiency
• Protective genes
• Multiple SNPs (single nucleotide polymorphisms)

16
Human Autoimmune Diseases

• Rheumatoid arthritis

17
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 g-IFN producer
• present in the active atherosclerotic plaque
  (patients with RA usually die from
  atherosclerotic vascular disease)
• numerous B cells an plasma cells

18
Rheumatoid ArthritisPossible Mechanisms for
Autoimmunity

• molecular mimicry
• arthritogenic viruses
• superantigens

19
Rheumatoid ArthritisViruses causing Joint
Inflammation in Humans

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

20
Rheumatoid arthritisPossible Superantigens

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

21
Rheumatoid ArthritisMycoplasma Species
22
Human Autoimmune Disease
Ankylosing Spondylitis
23
Human Autoimmune Disease

• Multiple Sclerosis

24
Human Autoimmune Disease
Myasthenia Gravis
25
Human Autoimmune Disease

• Thyroid and Adrenal Disease

26
Addisons 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