General Pathology

Autoimmune Disorders
 Autoimmune Disorders
(immune reaction to self-antigens)

• Disorders in which the immune system produces auto-

antibodies to an endogenous antigen
• Immune system of the body reacts against its own
tissue  destruction
• N.B. presence of auto-reactive antibodies or T-cells
does not equate to autoimmune disease
• Non-pathogenic auto-antibodies are demonstrated in
otherwise healthy individuals
• Many disorders have an auto-immune aetiology
suspected, but not proven
• Autoimmune diseases range from:
– Localised tissue damage
• Specific immune response directed against one particular
organ or cell type

– Multisystem diseases
• Characterised by lesions in many organs and associated
with a multiplicity of auto-Ab’s or cell-mediated reactions
• Changes principally in CT & blood vessels of organs
involved  ‘collagen vascular’ or ‘ CT disorders’

• Therefore autoimmunity implies loss of self-

tolerance
 Classification of Autoimmune Diseases
Local  single organ Systemic  multiple sites
Probable: Probable:
- Hashimoto thyroidistis - Systemic Lupus Erythematosus
- Autoimmune haemolytic anaemia - Rheumatoid arhtritis
- Autoimmune atrophic gastritis - Sjogren’s syndrome
(pernicious anemia) - Reiter syndrome
- Autoimmune encephalomyelitis
- Autoimmune orchitis
Possible:
- Goodpasture syndrome
- Inflammatory myopathy
- Autoimmune thrombocytopaenia
- Systemic sclerosis (scleroderma)
- Type I DM (IDDM)
- Polyarteritis nodosa
- Myasthenia gravis
- Graves disease

Possible:
- Primary biliary cirrhosis
- Chronic active hepatitis
- Ulcerative colitis
- Membranous glomerulonephritis
 Immunological Tolerance
• State in which an individual is capable of developing an
immune response against a specific antigen

• Self- tolerance specifically refers to a lack of immune

responsiveness to one’s own tissue antigens

• Immunologically competent cells learn to recognize the

body’s own antigens at an early stage

• Central vs peripheral tolerance

 Central Tolerance
Clonal deletion
• Deletion of self reactive T- & B-lymphocytes during
their maturation in central lymphoid organs
• T-lymphocytes with receptors for body’s own
antigens are removed/destroyed in thymus during
maturation of T-cells
• Many self antigens not present in thymus  T-cells
bearing receptors for autoantigens escape into the
periphery
• Similar ‘slippage’ in B-cell system
 Peripheral Tolerance
(Self-reactive T-cells that escape negative selection in thymus)

Anergy
• Prolonged/irreversible inactivation of lymphocytes induced by
encounter with antigens
• Inactivated cells can’t amplify the immune response
• Cells do not react to presentation of antigen
– Lack of T-cells co-stimulants
– Immature B-cells

Apoptosis  activation induced cell death

Peripheral suppression
• CD8+ suppressor T-cells
• Prevent autoimmune reactions if potentially self-reactive cells are not
eliminated by clonal deletion
• Regulatory T-cells  modulate function of other cells
• Cytokines can dampen variety of T-cell responses (e.g IL-10; TGF-β)
• Regulatory T-cells also modulate T-cell activity (cell-cell contact)
 Failure in Tolerance

• Failure in activation-induced cell death (apoptosis)

• Breakdown of T-cell anergy
• Bypass of B-cell requirement for T-cell help
• Failure in T-cell mediated suppression
• Polyclonal lymphocyte activation
• Release of sequestered antigens
• Exposure of cryptic self & epitope speading
Mechanisms leading to loss of Self-Tolerence
breakdown of 1 or more mechanisms of self-tolerance leading to immune attack on self tissues

Release of sequested antigens

• Normally maintained in isolation from immune mechanisms
• Hidden/sequestered antigens may not be recognised as self (such as intracellular
substances)
• E.g spermatazoa; myelin protein; lens material

Breakdown of T-cell helper tolerace

• TH-cells need to assist specific B-cells in the production of antibodies
• Can be overcome
– Alteration in body’s own molecule (e.g viruses; drugs)
– Cross reactions
• Exogenous Ag can stimulate formation of an Ab
• Ab can cross-react with body’s own tissue
• E.g. steptococcal Ab  heart (Rheumatic fever)
– Stimulation of anergic self specific immune cells (e.g. endotoxins; EBV)
 T-cell suppressor function
• Autoimmune reaction balanced by action of specific suppressor T-cells

Genetics
• Familial clustering
– Relatives of patients with autoimmune disease often show high incidence of
same type of auto-Ab
– Woman > men (5:1)
• HLA  esp class II (e.g. HLA-B27)
• Genetic predisposition not enough  need enviromental factors
Infection  not clearly implicated in aetiology
• Viruses 7 other microbes may share cross-reacting epitomes with self-antigens
– E.g. strptococci; Klebsiella

• Microbial antigens & autoantigens may become associated to form immunogenic units &
bypass T-cell tolerance

• Some organisms/products are non-specific polyclonal B-cell or T-cell mutagens

– may induce formation of autoantibodies and/or
– break T-cell anergy
– E.g. EBV

• Tissue necrosis & inflammation (due to microbial infection)

– can cause up-regulation of molecules on resting APC’s (Ag presenting cell) in tissue  breakdown
T-cell anergy

• Local inflammation may facilitate presentation of cryptic antigens & thus induce epitome
spreading
Autoimmune Disorders & Mechanisms
• Hashimoto’s thyroidistis  cell mediated & humoral cytotoxicity

• SLE  circulating & locally generalised immune complexes

• Goodpasture syndrome  anti-basement membrane Ab

• Grave’s disease  TSH receptor Ab (stimulatory)

• Myasthenia gravis  Ach receptor Ab

• Insulin resistance  insulin receptor Ab

• Autoimmune haemolytic anaemia  phagocytosis of Ab-

sensitised RBC’s

• Autoimmune thrombocytopenic purpura  phagocytosis of Ab-

sensitised platelets
• Rheumatoid arthritis  immune complexes in joints

• SLE  circulating & locally generalised immune complexes

• Goodpasture syndrome  anti-basement membrane Ab

• Grave’s disease  TSH receptor Ab (stimulatory)

• Myasthenia gravis  Ach receptor Ab

• Insulin resistance  insulin receptor Ab

• Autoimmune haemolytic anaemia  phagocytosis of Ab-

sensitised RBC’s

• Autoimmune thrombocytopenic purpura  phagocytosis of

Ab-sensitised platelets
General Pathology

Immunological Antibodies & HLA

 Rheumatoid Factor
• Rheumatoid factor (RF or RhF) is an antibody against the Fc portion of
IgG, which is itself an antibody
• Usually IgM (can be any class)
• Rheumatoid factor and IgG join to form immune complexes which
contribute to rheumatological diseases.
• Rheumatoid factor can be measured in patients with suspected
rheumatoid arthritis (RA).

• Associations with RhF

– Rheumatoid arthritis (80%)
– Lupus; scleroderma; Sjogrens syndrome; Dermatomyositis
– Chronic infection
• Bacterial endocardidits
• Viruses  rubella; cytomegalovirus; infectious mononucleosis
• parasites
– Neoplasms
– Hyperglobulinaemic states
• Chronic liver disease
 Antinuclear Antibody
• Anti-nuclear antibodies are any antibodies directed against the
nucleus

• The ANA test measures the pattern and amount of autoantibody

which can attack the body's tissues as if they were foreign
material.

• Associations with ANA

– SLE (100%)
– Rheumatoid arthritis
– Sjogrens syndrome
– Polymyositis
– Polyarteritis nodosa
– Juvenile idiopathic arthritis
– Chronic active hepatitis
– Autoimmune thyroid disease
– Myasthenia gravis
– Extensive burns
 Pansma autoantibodies & Disease Association
• Antinuclear Antibody (ANA)
– SLE (99%)
– Rheumatoid arthritis (32%)
– Juvenile rheumatoid arthritis (76%)
– Chronic active hepatitis (75%)
– Sjogrens syndrome (68%)
– Systemic sclerosis (64%)

• Smooth Muscle Antibody (SMA)

– Chronic active hepatitis (40-90%)
– Primary biliary cirrhosis (30-70%)
– Idiopathic cirrhosis (25-30%)
– Viral Infections (80%)
– Normal controls (3-12%)

• Mitochondrial Autoantibody (AMA)

– Primary biliary cirrhosis (60%)
– Chronic active hepatitis (25%)
– Idiopathic cirrhosis (25-30%)
– Normal controls (0.8%)
• Gastric Parietal Cell Antibody
– Pernicious anaemia (>90%)
– Atrophic gastritis (60%)
– Autoimmune thyroid disease (33%)
– Normal controls (2-16%)

• Rheumatoid Factor (Rh)

– Rheumatoid arthritis (70-80%)
– Sjogrens syndrome (up to 100%)
– Systemic sclerosis (30%)
– Infective endocarditis (50%)
– SLE (40%)
– Normal controls (5-10%)

• Gastric Parietal Cell Antibody

– Chronic active hepatitis (40-90%)
– Primary biliary cirrhosis (30-70%)
– Idiopathic cirrhosis (25-30%)
– Viral Infections (80%)
– Normal controls (3-12%)
• Thyroid Antibodies
– Hashimoto’s thyroiditis (70%)
– Grave’s disease (50-80%)
– Myxoedema (40-65%)
– Thyrotoxicosis (37-54%)
– Pernicious anaemia (55%)
– Normal Controls (10-13%)

• Rheumatoid Factor (Rh)

– Rheumatoid arthritis (70-80%)
– Sjogrens syndrome (up to 100%)
– Systemic sclerosis (30%)
– Infective endocarditis (50%)
– SLE (40%)
– Normal controls (5-10%)

• Classical Antineutrophil cytoplasmic antibody (cANCA)

– Wegener’s disease (>90%)

• Perinuclear Antineutrophil cytoplasmic antibody (pANCA)

– Pauci-immune cresentric GN (80%)
– Systemic vasculotides
– Churg-Straus (pulmonary infiltrates & asthma that occurs with vasculatides)
 Human Leukocyte Antigen (HLA)

• The human leukocyte antigen system (HLA) is the name of the human major
histocompatibility complex (MHC).

• This group of genes resides on chromosome 6, and encodes cell-surface

antigen-presenting proteins and many other genes

• The major HLA antigens are essential elements in immune function

• Different classes have different functions

– class I antigens (A, B & C) - Present peptides from inside the cell
(including viral peptides if present)

– class II antigens (DR, DP, & DQ) - Present phagocytosed antigens from
outside of the cell to T-lymphocytes

• HLAs also have a role in:

– disease defense
– reproduction (may be involved in mate selection)
– cancer (may be protective or fail to protect)
– human disease:
• in autoimmunity - known to mediate many autoimmune diseases
• as antigens - responsible for organ transplant rejection.
 HLA – B27

• Class I surface antigen encoded by the B locus in the major

histocompatibility complex (MHC) on chromosome 6

• Presents microbial antigens to T-cells.

• HLA-B27 strongly associated with a certain set of autoimmune diseases

referred to as the seronegative spondyloarthropathies – e.g.:
– Ankylosing spondylitis
– Reiter’s syndrome
– Psoriatic arthritis
– Arthritis associated with IBD

• Mechanism for disease association is unclear

– Aberrant response to infection in predisposed individuals
– Triggering organism may be identified (e.g. Reiter’s disease)

• Strong familial aggregation of these conditions