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Autoimmune Disease

Joko Anggoro Bagian Ilmu Penyakit Dalam FK Unram/RSUP NTB

A disease that results from autoimmunity, when pathogenic autoantibodies or autoreactive T cells (cell-mediated autoimmune disease) can reach corresponding targets (epitopes) with the appropriate configuration or presentation in host tissues

WHAT IS AN AUTOIMMUNE DISEASE?

A situation characterised by the development of one or several abnormal immune responses, directed against antigenic components of the host. Autoimmunity can lead to autoantibodies (antibodies against host antigens) or to autoreactive T cells (lymphocytes). Autoimmunity is not a rare event, particularly later in life. Autoimmunity does not always result in autoimmune disease

WHAT IS AUTOIMMUNITY?

an antibody (a type of protein) manufactured by the immune system that is directed against one or more of the individual's own proteins.

AN AUTOANTIBODY IS

Background
A combination of genetic predisposition and

environmental factors contribute to the

development of autoimmune disease. 58% of the population in the United States and are the third most common category of disease in industrialized countries following cardiovascular disease and cancer.
DeLisa Fairweather, ENCYCLOPEDIA OF LIFE SCIENCES & 2007, John Wiley & Sons, Ltd. www.els.net

Autoimmune disease

The development of autoimmune disease depends on a combination of genetic and environmental factors

Genes 30%

Environment 70%

Autoimmune disease

DeLisa Fairweather, ENCYCLOPEDIA OF LIFE SCIENCES & 2007, John Wiley & Sons, Ltd. www.els.net

External environmental factors

Hormones Diet

Environment

Toxin/drugs Infection

DeLisa Fairweather, ENCYCLOPEDIA OF LIFE SCIENCES & 2007, John Wiley & Sons, Ltd. www.els.net

Genetics
Most autoimmune diseases are thought to be polygenic. Monozygotic twins found a concordance rate in the range of 1050% in different studies and 240% for dizygotic twins. Thus, heredity accounts for only about one-third of the risk of developing an autoimmune disease, while noninherited, environmental factors account for the remaining 70% risk

Clinical reports that patients often

describe a family history of autoimmune diseases. Higher probability that other family

members without autoimmune

disease will develop increased levels of autoantibodies. Human lymphocyte antigen, or

HLA haplotype, is the best

available predictor of developing an autoimmune disease.

DeLisa Fairweather, ENCYCLOPEDIA OF LIFE SCIENCES & 2007, John Wiley & Sons, Ltd. www.els.net

Hormones
Most autoimmune diseases (80%) are more

prevalent in women than men.

Exceptions include diabetes mellitus, ankylosing spondylitis and inflammatory heart disease, which occur more frequently in men. Sex hormones (natural and synthetic) directly

interact with cells of the immune system via

receptors on the surface or inside immune cells.

Diet
prevalence of autoimmune thyroid disease in U.S and Coeliac disease resulting from gluten-sensitivity also has the

Western European populations

has been associated with use of iodized salt. Iodine-thyroglobulin (thyroid hormone precursor) making it a target for the immune system resulting in increased

hallmarks of an autoimmune
disease. Hypersensitivity to wheat gluten and similar proteins of barley, rye and oats resulting in inflammation of the intestine and autoantibodies against the enzyme

autoantibodies and recruitment of

inflammation to the thyroid gland.

transglutaminase.

DeLisa Fairweather, ENCYCLOPEDIA OF LIFE SCIENCES & 2007, John Wiley & Sons, Ltd. www.els.net

Toxin/drugs
Drugs like procainamide and hydralazine can induce autoantibodies and lupus-like disorders in patients.

Penicillamine has been associated with myasthenia gravis and amethyldopa is known to cause a form of haemolytic anaemia. However, in all cases of drug-induced autoimmune diseases

described thus far, the disease disappears when the drug is

removed. Various heavy metals, such as mercury, silver or gold, can induce

an autoantibody response to cell nuclear antigens in susceptible

strains of mice.

Infections
Bacterial and viral infections were some of the first agents associated with autoimmune diseases more than a century ago.

1.

Diabetes has been associated with coxsackievirus and cytomegalovirus

infections,

2.

Multiple sclerosis with EpsteinBarr virus and measles virus infections,

3.
4.

Rheumatoid arthritis with mycobacteria and Epstein Barr infections and

Myocarditis with coxsackievirus and cytomegalovirus infections.

Direct viral damage, release of cryptic self-peptides, antigenic spread, molecular mimicry, bystander activation and the adjuvant effect.

THE LANCET Published online June 3, 2003 http://image.thelancet.com/extras/02art9340web.pdf

Immunity mechanism

Autoimmune Disease mechanisms

A common feature of all autoimmune diseases is the presence of autoantibodies and inflammation,

Including :
1. 2. Mononuclear phagocytes, Autoreactive T lymphocytes and

3.

Plasma cells (autoantibody producing B cells).

Autoimmune diseases can be classified as organ-specific or nonorganspecific depending on whether the autoimmune response is directed against a particular tissue like the thyroid in Hashimotos thyroiditis, or against widespread antigens such as cell nuclear antigens in lupus

DeLisa Fairweather, ENCYCLOPEDIA OF LIFE SCIENCES & 2007, John Wiley & Sons, Ltd. www.els.net

Antibody-mediated damage
Antibodies or immunoglobulins are a family of glycoproteins present in the serum and tissue fluids of all mammals.

Antibodies can be carried on the surface of B cells, acting as receptors, or

free in the blood or lymph. Specific binding of antigens (self or foreign) causes B cells to produce large

amounts of antigen-specific antibody.

Antibodies provide critical protection microorganisms immediately following infection and are the key protective immune response induced by vaccination. Similarly, self-reactive or autoantibodies are important in clearing cellular debris induced by inflammation or physical damage to the body.

DeLisa Fairweather, ENCYCLOPEDIA OF LIFE SCIENCES & 2007, John Wiley & Sons, Ltd. www.els.net

Autoantibodies effect
Due to the chronic nature of most autoimmune diseases, autoantibodies appear long before clinical symptoms, providing a good predictive marker

for the potential to develop disease.

The risk of developing an autoimmune disease rises from about 10% if one autoantibody is present to around 6080% if three autoantibodies. Autoantibodies can induce damage to the body by binding to self-tissues, activating the complement cascade and inducing lysis and/or removal of cells by phagocytic immune cells. Self-antigen, autoantibodies and complement can combine to form injurious immune complexes that deposit in vessels or joints as is observed in lupus, inflammatory heart disease and arthritis.

DeLisa Fairweather, ENCYCLOPEDIA OF LIFE SCIENCES & 2007, John Wiley & Sons, Ltd. www.els.net

Cell-mediated damage
Damage induced by cells of the immune system play a major pathogenic role in many autoimmune diseases.

The predominant infiltrating cells include

1. 2. Phagocytic macrophages, Neutrophils,

3.
4.

Self-reactive CD4+ T helper cells and self-reactive CD 8+ cytolytic T cells,

with smaller numbers of natural killer cells, mast cells and dendritic cells.

Immune cells damage tissues directly by killing cells or indirectly by

releasing cytotoxic cytokines, prostaglandins, reactive nitrogen or oxygen

intermediates.

DeLisa Fairweather, ENCYCLOPEDIA OF LIFE SCIENCES & 2007, John Wiley & Sons, Ltd. www.els.net

Macrophages
Tissue macrophages and monocytes can act as antigen-presenting cells to initiate an autoimmune response, or as effector cells once an immune

response has been initiated.

Macrophages act as killer cells through antibody-dependent cell-mediated cytotoxicity and by secreting cytokines, such as tumour necrosis factor (TNF) or interleukin (IL)-1, which act as protein signals between cells. Macrophages and neutrophils damage tissues (and microorganisms) by releasing highly cytotoxic proteins like nitric oxide and hydrogen peroxide. Cytokines and other mediators released by macrophages recruit other inflammatory cells, like neutrophils and T cells, to the site of inflammation.

DeLisa Fairweather, ENCYCLOPEDIA OF LIFE SCIENCES & 2007, John Wiley & Sons, Ltd. www.els.net

Self-reactive CD4+ T helper cells

CD4+T cells have been classified as T helper 1 (TH1) or T helper 2 (TH2) cells depending on the release of the cytokines interferon- (IFN-) or IL-4, respectively. IFN- is a proinflammatory cytokine associated with many organspecific autoimmune diseases like type I diabetes and thyroiditis, while IL-4 activates B cells to produce antibodies and is associated

with autoantibody/immune complex-mediated autoimmune diseases

like lupus and arthritis.
DeLisa Fairweather, ENCYCLOPEDIA OF LIFE SCIENCES & 2007, John Wiley & Sons, Ltd. www.els.net

Self-tolerance
Mechanisms of self-tolerance, defined as a state of nonresponsiveness to self, can be divided into central and peripheral tolerance. In central tolerance, immature lymphocytes in the bone marrow (B cells) and thymus (T cells) that recognize self-antigens with high affinity die by apoptosis or programmed cell death. In peripheral tolerance, mature self-reactive lymphocytes are inactivated, killed or turned off by regulatory mechanisms including functional anergy,

ignorance and suppression by regulatory T cells.

Defects in tolerance leading to autoimmune disease may occur in one or multiple tolerance mechanisms.

DeLisa Fairweather, ENCYCLOPEDIA OF LIFE SCIENCES & 2007, John Wiley & Sons, Ltd. www.els.net

Ann Rheum Dis 2004

What diseases have been proven to have an autoimmune basis?

1. 2. 3. 4. 5. Systemic lupus erythematosus, Type 1 diabetes (insulin dependent diabetes), Graves disease and Hashimotos thyroiditis, Rheumatoid arthritis, Autoimmune thrombocytopenia and haemolytic anaemia,

6.
7.

Multiple sclerosis
Myasthenia gravis

The clinical condition in which IgG and/or IgM antibodies bind to RBC surface antigens and initiate RBC destruction via the complement system and the reticuloendothelial system.

AUTOIMMUNE HEMOLYTIC ANEMIA

Gehrs & Friedberg, 2002

Patogenesis anemia hemolitik autoimun

autoantibodi IgG subklas IgG1, IgG3 IgM komplemen C3b dan C4b

reseptor Fc dan reseptor komplemen pd makrofag

Fagositosis, eritrosit lisis oleh efek litik (hemolisis intravaskuler)

Retikuloendotelial (limpa & hepar) Hemolisis ekstravaskuler

Anemia hemolitik autoimun

bentuk eritrosit menjadi sferosit

Gehrs & Friedberg, 2002

Diagnosis AHA
Hepatosplenomegali, ikterus, konjungtiva anemis Anemia makrositik hiperkromik (MCV>96 fl dan MCH> 32 pg), LDH > 450ng/ml, Bilirubin total > 2mg/dl dgn dominasi bilirubin indirek, Retikulosit > 2 %, Tes Coombs direk dan indirek positif (PMI)

Terapi AHA
Terapi lini pertama pada AHA adalah kortikosteroid dengan dosis setara prednison 1 mg/kgBB/hr Transfusi sel darah merah (PRC) bila Hb <6,5g/dl

Type 1 Diabetes mellitus

(IDDM, or, formerly, juvenile diabetes) is a form of diabetes

mellitus that results from

autoimmune destruction of insulinproducing beta cells of the pancreas. An expansion of autoreactive CD4+ and CD8+ T helper cells, autoantibody-producing B cells

and activation of the innate

immune system.

 The classical symptoms are polyuria (frequent urination), polydipsia (increased thirst), polyphagia (increased hunger), and weight loss
Normal

2006 WHO Diabetes criteria

Condition 2 hour glucose mmol/l(mg/dl) <7.8 (<140) <7.8 (<140) 7.8 (140) 11.1 (200) Fasting glucose mmol/l(mg/dl) <6.1 (<110) 6.1(110) & <7.0(<126) <7.0 (<126) 7.0 (126)

Impaired fasting glycaemia Impaired glucose tolerance Diabetes mellitus

Laboratory examination: low

C-peptide, islet cell autoantibodies, insulin

autoantibodies,

Graves disease
This is caused by autoantibodies (TSHR-Ab) that activate the TSH-receptor (TSHR), there by stimulating thyroid hormone synthesis and

secretion, and thyroid growth

(causing a diffusely enlarged goiter).

5-10 times as common in

females as in males

http://www.zuniv.net/physiology/book/chapter28.

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Terima kasih

ANNE DAVIDSON AND BETTY DIAMOND N Engl J Med, Vol. 345, No. 5 August 2, 2001 www.nejm.org