kp 9 autoimmune diseases_htr

Autoimmune Diseases

HTR_UMM

Pendahuluan

Penyakit Autoimmune terjadi dari kerusakandalam tubuh dengan adanya autoantibodiesatau autoreactive cells

Sekitar 2% populasi terkena penyakit ini

Terjadinya self tolerance pada individu ini

Self tolerance merupakan mekanisme clonal deletion dari sel efektor, pengaturan aktif oleh selT dan pengaturan melalui jalur idiopatik

Umumnya sel T yang diproses memalui Thymus tidak bertahan dan self reactive T cells dihancurkan

Kehilangan sel T autoAbs

Introduction

Pendahuluan

Terjadi situasi dimana antibody diproduksi

untuk melawan antibody itu sendiri

Ketika antibody diproduksi pertama kalinya,

area tersebut dikenali sebagai benda asing

oleh host

Kemudian host akan memproduksi antibody

untuk melawannya

anti-idiotypic Ab mungkin memiliki reaksi

melawan self Ags

Pendahuluan

Anti-idiotypic Abs ditemukan pada penyakitseperti myasthenia gravis, diabetes mellitus, and Graves’ disease

Kerusakan pada NK sel, dalam sekresi interleukin, dalam phagocytosis dan complements dapatterjadi

Hormon khususnya estrogen ditemukan untukmeningkatkan aktivasi sel B dan menekanpengaturan aktivitas sel T

Kondisi lingkungan seperti agen-agen infeksiseperti virus, bakteri dan obat dapatmenyebabkan autoimunitas

Systemic Lupus Erythematosus

Peradangan sistemik kronis yang ditandai olehexaserbasi dan remisi

1/2000 orang terinfeksi

Usia biasanya 20-40 tahun

Wanita lebih tinggi dari pria (13/1)

Penyebab tidak diketahui tetapi kemugkinankarena genetic dan faktor2 lingkungan

Pada orang berkulit putih kemungkinan besardihubungkan dengan HLA-DR3 or DR2 danDQB1

Systemic Lupus

ErythematosusClinical Signs:

The first signs to appear are usually nonspecific such as fatigue, weight loss, malaise, fever, and anorexia

Joint involvement of small joints of the hands, wrist and knees is reported in over 90% of cases

A skin manifestation of an erythematous rash may appear in the area of body exposed to UV light

A classic butterfly rash across the nose and cheeks which is responsible for the name lupus may appear

Some patients may also exhibit renal involvement


Renal involvement is usually in the form of lesions the most dangerous of which is glomerulonephritis

Immune complexes may deposit in the subendothelial tissue and thickening of the basement membrane results

All of these can result in renal failure and death

There might also be cardiac involvement with pericarditis, tachycardia, or ventricular enlargement.

CNS manifestation such as seizures, psychoses, or depression

Hematologic abnormalities such as anemia, leukopenia or lymphopenia are exhibited


Immunological Findings:

The LE cell is a neutrophil that has engulfed the

antibody-coated nucleus of another

neutrophil

SLE is associated with more than 28

autoantibodies

Lupus patients appear to have overactive B

cells especially the subset with the CD5 marker

which increase in number


The increased prevalence of the disease in women may be traced to the fact that estrogen enhance B cell activity

Estrogen also suppresses regulator activities of T cells as a result, there is a decrease in the absolute number of T cells

Complement is activated which results in decrease in the serum level of complement components

At the same time there is an increase in the level of breakdown products of complements such as C3d and C3a

IgG is most pathogenic and it forms complexes that are deposited in the glomerular basement membrane


Accumulation of immune complex with complement activation is responsible for the damage to the kidney

Drug induced lupus differs from the chronic form of the disease: when the drug is withdrawn symptoms disappear

It is a milder form of the disease and manifest as arthritis or rashes

Drugs that have been implicated include procainamide hydrochloride, hydralazine hydrochloride, methyldopa etc.


Laboratory Diagnosis of SLE:

A screening test for antinuclear antibody (ANA) is

usually the first test done

Fluorescent antinuclear antibody (FANA) testing is

most widely used

The test is sensitive but the specificity is low because

many of the Abs are associated with other diseases

The test is an indirect IFA test which employs

antihuman globulin tagged with a fluorescent

marker.

If FANA is positive, then a profile testing should be

done for individual Abs

More than 99% of patients with SLE will have a

positive result for one or more tests

Rheumatoid Arthritis

Rheumatoid arthritis is a systemic autoimmune disorder

It involves the synovial membrane of multiple joints

Women are more likely to be affected than men and usually strikes between the ages of 20 and 40

Spontaneous remission may be experienced by some patients otherwise the disease may progress and result in deformity and disability

RA has been associated with certain of the HLA class II molecules.

HLA-DR1 and DR4 occur in 70% of patients with RA


Clinical Signs:

Symptoms include morning stiffness around the joints lasting at least 1 hour, swelling of the soft tissue around three or more joints

Others include swelling of the proximal interphalangeal, metacarpophalangeal, or wrist joints, symetric arthritis, subcutaneous nodules, a positive RF test

Also included is a radiographic evidence of erosion of the joints of the hands, the wrist, or both


Usually begins with nonspecific symptoms such as fever, malaise, weight loss, and transient joint pain

Stiffness and joint pain that gradually improves during the day are characteristics exhibited by most patients

Joint are involved progressively to larger joints in a symmetric manner from the knees, hips, elbows, shoulders and cervical spine

About 25% of patients have nodules over the bones

Nodules may also be found in the myocardium, pericardium, heart valve, pleural, lungs, spleen, and larynx


Immunologic Findings:

The main immunologic finding is the presence

of RF

It has been suggested that RF may be anti-

idiotypic antibodies involved in the regulation

of immune response

In RA, polyclonal activation of B cells may

occur resulting in overwhelming amount of

antibody to IgG


These Abs may cause immune complex

formation with the activation of complement

which contribute to pathogenesis

Joint damage is due to invasion of inflammatory

cells such as neutrophils, and macrophages

Proliferation of fibroblast, macrophages, mast

cells, and stellar cells result in the formation of a

pannus, an organized mass of cells that grow

into the joint space

Laboratory Diagnosis of Rheumatoid

Arthritis:

Diagnosis is based on a combination of clinical

manifestations, radiographic findings and lab tests

Laboratory screening test for RF

Quantitative test are also available which involve

nephelometry and ELISA techniques

RF is found in other diseases such as syphilis, viral

infections, leprosy, chronic liver disease, neoplasm

and other inflammatory processes

C-reactive protein and Erythrosit sedimentation

rate (ESR) are usually elevated and complements

are normal or elevated


Treatment:

Treatment include palliatives with rest and

nonsteroidal anti-inflammatory drugs like salicylates

and ibuprofen

Slow-acting antirheumatic drugs (SAARDS) may

also be used to treat the condition

New therapy include the use of monoclonal Abs

that target T cells

Hashimoto’s Thyroiditis

Hashimoto’s thyroiditis and Graves’ disease are organ specific autoimmune diseases

Both diseases interfere with the thyroid gland function

The thyroid gland located in the anterior region of the neck consist of units called follicles

Follicles are lined with cuboidal epithelial cells and filled with colloid

The primary constituent of colloid is thyroglobulin which is made up of triiodothyronine (T3) thyroxine(T4)

TRH acts on the pituitary gland to induce the release of TSH


TSH binds to receptors on the cell membrane of the thyroid gland causing break down of thyroglobulin into T3 and T4

AutoAbs may interfere with this process and cause under or overactivity of the thyroid

Hashimoto’s thyroditis is most often seen in womenbetween the ages of 30 and 40 years

Patients develop a combination of goiter or enlarged thyroid, hypothyroidism and thyroid autoantibodies

An association with HLA antigens DR4 and DR5 has been noted. DQA1 and DQB1 genes seem to confer resistance



Lymphocytic infiltration is seen with development of germinal centers that almost replace the normal glandular architecture of the thyroid

Cell infiltrates include T and B cells, macrophages and plasma cells

Both CD4 and CD8 cells are found thus the disease is characterized by a cellular and a humoral response

Autoantibodies are found in up to 80% of cases


Laboratory Testing:

The autoantibodies present include Abs to

thyroglobulin and to thyroid microsomal antigen

now known as thyroid peroxidase

Some peroxidase Abs inhibit enzyme activity while

others may mediate the cytotoxicity due to natural

killer cells

Abs to thyroglobulin help to produce hypothyroid

conditions

Other Abs include colloid Ab (CA2) thyrotropin-

binding inhibitory immunoglobulin (TBII)


Others are thyroid stimulating immunoglobulin (TSI) and thyroid growth-stimulating immunoglobulin (TGSI)

Peroxidase Abs can be measured by particle agglutination assays, complement fixation, RIA and Indirect IFA

Abs to thyroglobulin can be measured by precipitaion in agar, indirect IFA, passive agglutination, RIA, and EIA

Indirect IFA use human or monkey thyroid tissue fixed to a slide

Antithyroglobulin Abs are found in about 80% of patients with the disease

Graves’ Disease

Graves’ disease is another autoimmune disease that affects the thyroid gland

Graves’ disease produces hyperthyroidism

It the most common cause of hyperthyroidism and affects about 0.5% of the population

Women are more susceptible than men by a margin of 7:1 and usually present between the ages of 30 and 40.

In whites, the disease is associated with the HLA antigen DR3 while in Asians HLA Bw35 and Bw36 occur more frequently

Graves’ Disease

HLA DQB1 appears to confer resistance to the disease

Clinical Signs:

Disease is presented as thyrotoxicosis with a diffusely enlarged goiter that is soft instead of rubbery

Signs include nervousness, insomnia, depression, weight loss, heat intolerance, sweating, rapid heart beat

Other signs include fatigue, cardiac dysrhythmias, restlessness, and exopthalmus

Graves’ Disease


The thyroid presents with Hyperplasia with a patchy infiltration of lymphocytes

Both CD4 and CD8 cells are present and the T cells appear to play a central role in the pathogenesis of the disease

The most significant Ab present is thyroid stimulating hormone receptor antibody (TRab)

Ag-Ab combination result in the stimulation of the receptor resulting in the release of the thyroid hormones

Another group of Abs called thyroid stimulating antibodies or immunoglobulins (TSab or TSI) may have different specificity

Graves’ Disease

Laboratory Diagnosis:

A key finding in Graves’ disease is elevated levels of total and free T3 and T4

In addition, TSH levels are low due to Ab stimulation of the thyroid

Measurement of the thyroid Abs may be undertaken if the above assays are unclear

Treatment:

Antithyroid medication may be employed. Radioiodine which emits beta particles may be used. Surgery is also an option.

Insulin-Dependent Diabetes

This disease is characterized by insufficient

production of insulin due to an autoimmune

destruction of the beta cells of the pancreas

Peak onset is b/w 10 and 14 years of age

Disease may be attributed to genetic and

environmental conditions

About 95% of white diabetics carry the HLA-DR3

or DR4 genes

It appears that true susceptibility genes for

IDDM may occur in the HLA-DQ region


Viral infections have been linked with diabetes

Mumps virus, rubella virus, CMV, and Coxsakie B4 virus have all been inconclusively linked to diabetes

Congenital rubella infection is the only one for which a link has been definitively identified

There appears to be similarity between coxsakieviral protein P2-C and the enzyme glutamic acid decarboxylase.

Antibodies are formed against glutamic acid decarboxylase in IDDM

Molecular mimicry could initiate Ab production against self Ag


Immunopathology:

Inflammation of the islets of Langerhans in the pancreas leads to fibrosis and destruction of most of the beta cells

CD4 and CD8 B cells and macrophages are all involved in the destructive process of the islet cells

Cellular and humoral immunity are involved in this process

The subset of T cells that is activated determines whether the response is cellular or humoral


Laboratory Testing:

IDDM is usually diagnosed by the presence of

hyperglycemia

Abs to islet cells may be screened for by

indirect IFA with human or rat islet cells

Islet cell may be detected in the sera of newly

diagnosed diabetic cases

Abs to insulin may be detected by ELISA or RIA

methods


Treatment:

Insulin has been the standard form of

treatment

New treatment methods center around the use

of immunosuppressive agents

Agents that have been tried include

azathioprine, cyclosporine A and prednisone

All these agents have potentially toxic effects

Multiple Sclerosis

Destruction of the myelin sheath results in the formation of lesions known as plaques in the white matter of the brain and spinal cord

Genetic and environmental factors predispose one to this disease

MS is associated with the inheritance of HLA antigen DRw15 and DRw6

An inflammatory response to bacteria or virus may trigger the autoimmune process

Disease is most often seen in those b/w the ages of 20 & 50 and is more common in women

Multiple Sclerosis

90% of patients alternate between remissions and

relapses for many years

Within the plaques, CD4 cells, plasma cells and

macrophages are found along with immunoglobulin

Immunoglobulin is increased in the spinal fluid in 60

to 80% of patients

They usually produce oligoclonal bands on protein

electrophoresis

RIA (radioimuno assay) is used to detect the Abs

Therapy include use of corticosteroids

Myasthenia Gravis

Symptoms of disease include facial weakness, difficulty in chewing, and swallowing, difficulty breathing

Others include inability to maintain support of the trunk, the neck or the head

Antibody mediated damage to the acetylcholine receptors in the skeletal muscle leads to muscle weakness

May be associated with the presence of other autoimmune diseases such as SLE

Appears to be linked with either HLA-B8 or DRw3 antigens

Myasthenia Gravis

80 to 90% of patients have Abs to acetylcholine

receptors which may be the main contributor

to pathogenesis

Combination of the Abs to the receptors blocks

the binding of acetylcholine which destroy the

receptors

Abs can be detected with RIA methods

Anticholinesterase agents are employed in

therapy

Goodpasture’s Syndrome

Goodpasture’s syndrome is a

glomerulonephritis due to Abs reacting

specifically with Ags in the kidney

Necrosis of the glomerulus is triggered by an

Ab that reacts with glycoprotein present in

the basement membrane of the glomerulus

Results in immune complex deposit and

complement fixation which causes the

damage to the kidney

This may eventually produce renal failure

kp 9 autoimmune diseases_htr

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