Assoc. Prof. Ma. Jennifer R.

Tiburcio, MSMT Department of Med Tech UST Faculty of Pharmacy

Requirements for the development of an autoimmune disease

Defect in underlying self recognition

(auto tolerance, self tolerance)

IMMUNE RESPONS E
HUMORAL
(Circulating antibodies, immune complexes)

CELLULAR
(delayed hypersensitivity)

Diseases are due to the loss or breakdown of self tolerance

SELF TOLERAN CE

Clonal deletion of relevant effector cells Active regulation by T suppressor cells Regulation through idiotypic networks

Genetic Variation in MHC antigens also seems to account for increased susceptibility in some individuals

IMMUNOLOGIC ETIOLOGY BALANCE MAY ARISE FROM:

1. An excess of self reactive helper T-cell activity induced 2. A bypass of the lack or requisite self reactive TH cell activity or bypass of the need for such TH cell activity via polyclonal activation 3. A deficiency of suppressor TS cells

4. Release of sequestered antigen

ALL AUTOIMMUNE DISEASE SHARE SOME COMMON FEATURES

There is a strong genetic predisposition of autoimmune disease. It is associated with those genes (HLA-DR) that code for the immune response to antigen.
Most autoimmune diseases are commoner in females

Hypergammaglobulinemia is usually present

Autoantibodies are a constant feature and useful diagnostic markers, through their presence alone is not diagnostic of disease.

The tendency to develop organ specific antibodies and diseases cluster in families; the same applies to non-organ specific autoimmune disease The course of autoimmune diseases is variable and not always progressive

AUTOIMMU NE DISEASE
ORGAN SPECIFIC Respect with tissue of one organ
SYSTEMIC OR NON ORGAN SPECIFIC In respect of a tissue element present throughout the body

GENERAL SIGNS OF AUTOIMMUNE DISEASE THAT MAY BE OF DIAGNOSTIC IMPORTANCE

Elevated serum gamma globulin levels Depressed levels of serum complement Depressed levels of TS cells Various antibodies

Immune complexes in serum Lesions detected on biopsy

AUTOANTIBODIES ARE PRODUCED

If the antigenicity of tissue protein is altered due to degenerative lesions or the attachment of a hapten

If a tissue antigen is anatomically isolated from the immunologically competent cells the release of this antigen into the tissues following an injury results in the formation of auto antibodies

If a cell protein is no longer recognized Antibodies are directed against hapten rather than thereactivity normal tissue due toagainst altered of proteins the immune mechanism

Implications of an association of disease with autoimmunity

Autoimmunity may produce the disease The disease is responsible for the generation of autoimmunity The third factor may lead to both

Antigen Lesion

ORGAN SPECIFIC Localized to given organ Antigen organ is target for immunological attack

NON ORGAN SPECIFIC Widespread throughout the body Complexes deposit (systemically particularly in kidneys, skin and joints)

Overlap

With other organ- With other nonspecific antibodies organ specific and diseases antibodies and diseases

Specificity Organ Specific

Disease Hashimotos Thyroiditis Graves Disease

Target Tissue Thyroid Thyroid

Pernicious Anemia Cells

Addisons Disease Type 1 Diabetes Mellitus Myasthenia Gravis Multiple Sclerosis

Gastric Parietal
Adrenal Glands Pancreas Nerve-muscle Synapses Myelin Sheath of Nerves

Autoimmune Hemolytic Anemia

Idiopathic Thrombocytopenic Purpura Goodpastures Syndrome Rheumatoid Arthritis Scleroderma Systemic Systemic Lupus Erythematosus

Red Blood Cells

Platelets Kidney, Lungs Joints, Lungs, Skin Skin, Gut, Lungs, Kidney Skin, Joints, Kidney, Brain, Heart, Lungs

SPECIFICITY DISEASE
Organ specific Hashimotos thyroiditis Graves disease Pernicious Anemia Addisons disease Insulin-dependent diabetes mellitus Myasthenia gravis Multiple sclerosis Idiotypic thrombocytopenic purpura Goodpasteurs syndrome Rheumatoid arthritis Sclerodema Systemic Systemic lupus erythematosus

TARGET-TISSUE
Thyroid Thyroid Gastric parietal cells Adrenal glands Pancreas Nerve-muscle synapses Myelin sheath of nerves Platelets Kidney, lungs Joints, skin, Lungs Skin, gut, lungs, kidney Skin, joints, kidney, brain, heart, lungs

Systemic Lupus Erythematosus

A chronic inflammatory disease
Characterized by joint involvement, an erythematous (butterfly or malar) rash that appears on exposure to sunlight & deposition of immune complexes in the kidney to cause glomerulonephritis

Systemic Lupus Erythematosus

The first clue in the mystery of lupus was the discovery of LE cell LE cell is a neutrophil that has engulfed the antibody coated nucleus of another neutrophil. Strong association w/ HLA-DR3 or DR2

Systemic Lupus Erythematosus

Discoid Lupus

Laboratory diagnosis

Screening test
Test for anti-nuclear antibodies (ANA) Fluorescent anti-nuclear antibodies (FANA) most widely used and accepted Easy to perform and extremely sensitive test but it has low diagnostic specificity.

Common Antinuclear Antibody

Autoantibody Characteristics of Antigen
Anti- ds-DNA Anti-ss-DNA Anti-histone Anti-DNP Anti-Sm Anti-RNP Anti-SS-aRo Anti-SS-bLa Anti-nucleolar Anti-Scl-70 Anti-Jo-1 Specific for ds-DNA Related to purines and pyrimidines Different classes of histones DNA-histone complex Extractable nuclear antigen (RNA component) Proteins complexed with nuclear RNA Proteins complex to RNA Phosphoprotein complexed to RNA polymerase RNA polymerase, nucleolar protein DNA topoisomerase I Histidyl-t RNA synthetase

Immunofluorescent pattern
Peripheral/homogenous Not detected on routine screen homogenous/peripheral Homogenous Speckled Speckled Speckled or negative Speckled Nucleolar Atypical speckled Cytoplasmic

Disease Association
Only in SLE SLE, many other diseases Drug-induced SLE, other diseases SLE, drug-induced SLE Diagnostic for SLE SLE, mixed connective tissue disease SLE, Sjogrens syndrome, others SLE, scleroderma Scleroderma Polymyositis

Anti-nuclear Antibodies

1. FANA testing - Double Stranded DNA antibodies are the most specific for SLE because they are seen only in patients w/ lupus and levels correlate w/ disease activity. Diagnostic for SLE specially in combination w/ C3. They produce homogenous staining pattern on Indirect Immunofluorescence (IIF).

IIF patterns

Homogeneous ANA

Staining of the entire nucleus

Anti-ds-DNA Anti-histones Anti-DNP

Only in SLE Drug-induced SLE, other diseases Connective tissue disorders

IIF patterns

Nucleolar

Staining of the nucleolus

Anti-nucleolar SLE & Scleroderma

IIF patterns

Discrete speckled pattern staining of centromeres

Rheumatoid arthritis
Affects the synovial lining of joints, necrotic areas are surrounded by granulation of tissue that eventually leads to disintegration of the joint

Rheumatoid arthritis

Polyarthralgia or Arthritis (joint involvement)

Rheumatoid arthritis
The main immunologic finding in RA is the presence of rheumatoid factor (RF) Associated w/ HLA-DR1 & DR4 Diagnosis: clinical manifestation & positive RF test

Hashimotos thyroiditis
An organ-specific condition that affects the thyroid gland & causes it to be enlarged & rubbery
Lymphocyte infiltration in the thyroid w/ the presence of antithyroglobulin Ab leads to gradual destruction of the thyroid

Hashimotos thyroiditis
Clinical symptoms consistent w/ hypothyroidism
Associated w/ HLA-DR4 & DR5

Diagnosis: detection of antithyroglobin & antiperoxidase

Graves Disease
The hyperthyroidism that is evident in graves disease produces symptoms such as nervousness, insomnia, weight loss, heat intolerance, sweating, rapid heart beat, cardiac dysrhythmias, & bulging eye balls

Graves Disease
Associated with HLA-DR3, HLA-Bw35 & HLA-Bw36
Thyroid stimulating hormone receptor antibody stimulates receptors, causing continuous release of thyroid hormones

Elevated levels of thyroid hormones are the key laboratory findings & testing for autoantibodies is done only when results of hormone assays are unclear

Insulin-dependent diabetes mellitus

Characterized by insufficient insulin production caused by selective destruction of beta cells of the pancreas. Associated w/ HLA-DR3 or DR4

Insulin-dependent diabetes mellitus

The progressive destruction of beta cells in the pancreas results in lack of insulin production & symptoms of hyperglycemia Abs to islet cells are detected by IIF using human or rat cells while RIA or ELISA is used to identify Abs to insulin

Multiple sclerosis
An inflammatory autoimmune disorder of the central nervous system.
Characterized by the formation of lesion called plaques in the white matter of the brain and spinal cord, resulting of progressive destruction of myelin sheath of axons. Symptoms: visual disturbances, weakness in extremities, locomotor incoordination & sensory abnormalities such as tingling or pins and needles that runs down the spine or extremities and flashes of light seen on eye movement

Multiple sclerosis
Ab directed against myelin basic protein & myelin oligodendrocyte glycoprotein causes destruction of the myelin sheath of axons with the formation of lesions called plaques
Associated with HLA-DRw15 & DQw16

Multiple sclerosis

Multiple sclerosis

Multiple sclerosis

Myasthenia gravis
A neuromuscular disorder characterized by weakness and fatigability of skeletal muscles Antibody-mediated damage to acetylcholine receptor in skeletal muscles leads to this progressive weakness. By combining with the receptor site, Ab blocks the binding of acetylcholine & the receptors are destroyed due to activation of complement Another antibody present is the anti-muscle-specific-kinase (MUSK)

Associated with HLA-DRw3 & B8

Myasthenia gravis

Myasthenia gravis
drooping of eyelids
inability to retract the corners of the mouth, often result to snarling appearance. difficulty in speech, chewing and swallowing inability to maintain support of the trunk, the neck or the head.

Goodpasteurs syndrome
Characterized by severe necrosis of the glomerulus triggered by an antibody that reacts with glycoprotein in the glomerular basement membrane
The result is glomerulonephritis in which immune deposits accumulate & complement fixation causes injury to the tissue eventually producing renal failure This antibody can also react with lung tissue, producing pulmonary hemorrhage. Antibasement antibody is usually detected by IIF & RIA Associated w/ HLA-DR2

Goodpasteurs syndrome

Deposits of IgG antibodies

basement membrane thickening

Pulmonary bleeding

 A chronic inflammatory disease that affects the exocrine glands (lacrimal & salivary glands) Most patients are women

Sjogren syndrome
(Sicca syndrome)

Sjogren syndrome
Symptoms: - Dry mouth - Dry eyes - Dental cavities - Fatigue - Skin rashes or dry skin - Vaginal dryness - Joint pain

Sjogren syndrome

Sjogren syndrome
Diagnosis: Blood tests Eye tests Imaging Biopsy Urine sample

 Patients demonstrate hypergammaglobulinemia due to increased B cell activity Serum of patients w/ Sjogrens syndrome contain RF, ANAs & Abs to salivary duct epithelium The affected glands are infiltrated w/ plasma cells, B cells & T cells

Acute Disseminated Encephalomyelitis

May occur after vaccination (e.g. rabies immunization) or viral infection (e.g. measles, influenza The disease represents a cell-mediated allergic response to myelin basic protein

Guillaine-Barre Syndrome
(Acute Idiopathic Polyneuritis)
This occurs after infectious disease (e.g. measles, hepatitis or after vaccination (e.g. influenza) This is a self-limiting paralytic syndrome that occurs rarely (1per 100,000 vaccines)

Pernicious Anemia
This results from defective RBC maturation caused by faulty absorption of Vit B12

The hallmark of the disease is the progressive distribution of gastric glands and the associated loss of parietal cells.
The consequent lack of intrinsic factor leads to failure of Vit B12 absorption

Scleroderma
It is a slowly progressive, chronic, disabling disease characterized by abnormally increased collagen deposition in the skin & occasionally in the internal organs Symptoms: CREST syndrome Calcinosis, Raynauds phenomenon, Esophageal dysmotility, sclerodactily, telangiectases

Autoimmune Hemolytic Disease

This include warm-antibody hemolytic anemia (most common), cold Ab hemolytic anemia & paroxysmal cold hemoglubinuria

Idiopathic Thrombocytopenic Purpura

This may be either acute or chronic, and a result of Ab-mediated platelet destruction

Bullous (Vesicular diseases)

These are chronic dermatologic problems that result when destruction of intercellular bridges (desmosomes) interferes with cohesion of the epidermis This process leads to the formation of blisters (bullae)