Lecture 20 - Autoimmune Diseases -26 Sep 2006

AUTOIMMUNITY AND AUTOIMMUNE DISEASES

•Concept of autoreactivity •Mechanisms of induction of autoimmunity •Mechanisms of tissue autoimmune diseases

damage

•Role of HLA •Spectrum of autoimmune diseases Organ-specific and organ non-specific diseases •Examples •Diagnostic value of auto-antibodies •Treatment

in

The

developing

immune

system

produces

populations of cells with an infinite array of recognition receptors which do not recognize self components as foreign. If self-reactive cells escape to the periphery, their function must be controlled. A failure to do so results in AUTOIMMUE DISEASE

MECHANISMS OF INDUCTION OF AUTOIMMUNITY ))Loss of self-tolerance

1. Release of Sequestered Auto-antigens: e.g. •

Release of myelin basic protein (MBP) in infection

•

Release of sperm Ag after vasectomy

•

Exposure of Eye lens protein after trauma

•

Exposure of heart muscle Ag after myocardial infarction

2. Cross-reactive Autoantigens: Viruses and bacteria may have antigenic determinants that are identical or similar to those of normal host cells e.g. Rheumatic fever - Streptococci and heart autoAg

3. Inappropriate Expression of Class II MHC: Auto-antigens+MHC get presented to Th cells by cells which do not normally express high levels of MHC. Th cells get activated and may then activate B, Tc and TDTH cells. e.g. In IDDM, β cells from pancreas express high levels of Class I and Class II MHC molecules

4. Lymphokine Imbalance • Increased production of cytokines may result in excessive T and B cell activation and subsequent damage. e.g. • Increased IL-2 levels in SLE

5. Autoimmunity and Heat Shock Proteins )HSP)-molecular mimicry • HSP are normally produced in response to high temperature and stress • Conserved in mammals and microbes and Immunodominant • Infections may stimulate HSP which may stimulate auto-reactivity e.g. Rheumatoid Arthritis - T cell reactivity to HSP induced by Mycobacteria

6. Polyclonal Activation •

Some viruses and bacteria non-specifically and poly-clonally activate B cells

• These activated cells secrete IgM which may lead to damage •

e.g. EBV, CMV - stimulate anti-T, anti-B reactivity and anti-nuclear antibodies etc

Indection of Auto-immunity By:

Sequestered Antigens Cross-reactive Antigens Inappropriate expression of MHC Lymphokine Imbalance

SELF-REACTIVE-Th CELLS

ive Th cells

cell IFN-γ Tc cells

d MQ

B cells

Activated Tc

ation, DTH ed lysis( ADCC )Immune Complexes

Plasma cells Ab

TISSUE DAMAGE

Role of HLA

ORGAN-SPECIFIC AUTOIMMUNITY: Autoimmunity limited to a single organ/gland e.g. thyroid, adrenal, pancreas, stomach.

NON -ORGAN SPECIFIC AUTOIMMUNITY: Broad range of target Ag involving a number of organs and tissues e.g. skin, joints, kidney, liver

Comparison of organ specific and nonspecific disorders Organ specific Antigen

Essentially localized to given organ

Lesions

Antigen in a specific organ is target for immunological attack

Non-organ specific Widespread throughout the body Complexes deposit systemically particularly in kidneys, joints and skin

Mechanisms of pathology of Autoimmune Diseases

Pathological changes in auto-immune diseases can be mediated by variable immune responses

2. Antibody-Mediated Autoimmune Diseases 1.1. Stimulating AutoAbSome autoAb bind to hormone receptors and stimulate inappropriate activity e.g. Grave’s disease-AutoAb to receptor for TSH disease Overproduction of thyroid hormones Hyperthyroidism (hyperactive gland) Complement-mediated damage

1.2. Blocking AutoAbSome autoAb bind to hormone receptors and prevent hormone from binding to receptor e.g. Myasthenia gravis-AutoAb to Acetylcholine gravis receptor on muscles No activation of muscles

2. T cell-Mediated Autoimmune diseases Cellular damage by inflammation e.g. Hashimoto’s thyroditisthyroditis Infiltration of the thyroid by lymphocytes, MQ, AFC Auto-Ab are also detected leads to Hypothyroidism e.g. Insulin-dependent-diabetes mellitus (IDDM) Infiltration of the pancreas by lymphocytes and AFC β cells are destroyed

3. Immune-Complex-Mediated Autoimmune diseases Widespread tissue damage due to the formation of AutoAb and the deposition of immune complexes e.g. Systemic Lupus Erythematosus (SLE) AutoAb to nuclei, DNA, RBCs, leukocytes Immune complex deposition in blood vessels, Activation of C, chemotaxis of neutrophils Joint pain, Hemolytic anemia, Kidney dysfunction

4. Immune-complexes & T cell-Mediated Autoimmune Diseases Widespread tissue damage due to hyperactive T & B cells e.g. Rheumatoid arthritis Rheumatoid factor-AutoAb to Fc region of IgG Immune complex deposition in joints Chronic inflammation of joints

Diagnostic and Prognostic value of autoantibodies The use of auto-Ab as diagnostic markers e.g. 1. anti-acetylcholine receptor Ab

MG

2. anti-nuclear Ab (ANA)

SLE

3. Rheuamtoid factor (RF)

RA

Treatment 1. Metabolic control Thyroxine

Hypothyroidism

2. Anti-inflammatory

RA

3 . Immunosuppression antimitotic drugs 4 . Plasmapheresis

SLE Organ-specific diseases