Monday 10/16/00



Monday 10/16/00 Richard Wang

Pathology 8:00 AM Calvin Kuo

Immunopathology Part III – Autoimmune Disease

Dr. Pence followed his notes pretty closely starting on page 106 of the packet. I have expounded upon on what he mentioned in class. I have bolded the topics that he emphasized, and I have also included charts and topics that he deemed not worthy of memorization and regurgitation. It would behoove you to follow along with the notes to see what he did not mention and to see the complete lists of stuff in the notes.

I. Immune Tolerance

A. Know the difference between these!

1. Immune tolerance – Unresponsiveness of the immune system to a substance that is normally antigenic

2. Densitization – Temporary state of immune unresponsiveness induced in an already immunized person by large doses of antigen (Ag) administrated in a relative innocuous manner over period of time

B. Mechanisms of immune tolerance – don’t worry about regurgitation

1. Clonal deletion

2. Clonal anergy

3. Peripheral suppression by T cells

C. Not responsible for chart on p. 107

II. Autoimmunity and Disease

A. Autoimmunity – immune response to self Ag due to loss of tolerance to own tissue Ag

B. Mechanisms of Autoimmune (AI) Diseases

1. loss of self tolerance

2. microbial agents

3. genetic factors

C. Postulated mechanisms

1. Loss of self tolerance – will not have to regurgitate; be aware of different mechanisms

2. Microbial agents – same as above

3. Genetic factors

a. There is familial clustering of AI diseases linked with either class I or II HLA Antigens

b. Class I HLA linked AI disease– occurs more commonly in men

1. Ankylosing spondylitis

2. Reiter’s syndrome

3. Common psoriasis

c. Class II HLA linked AI disease– occurs more commonly in women

1. mostly systemic AI diseases

2. Systemic lupus erythematosis (SLE)

3. Rheumatoid arthritis (RA)

4. Systemic Sclerosis (SS or sclerodoma)

5. Sjogren’s syndrome

III. Classification of AI Diseases

A. Single organ or tissue (localized) AI diseases

1. Don’t worry about probable vs possible, just be aware of what diseases are considered AI. Also, we will get a lot more of single organ and tissue AI diseases later in organ system pathology.

a. Hasamito’s thyroiditis

b. AI hemolytic anemia

c. AI thrombocytopenia

d. Insulin dependent diabetes mellitus

e. Myasthenia gravis

f. Grave’s disease

g. Ulcerative cholitis

h. Chronic hepatitis

B. Systemic AI disease

1. We will talk about some of these today since these disease involve systems

a. SLE

b. RA

c. Sjogren’s syndrome

d. Reiter’s syndrome

e. Sclerodoma

(He skipped to page 113 without mentioning anything about the information on pages 111 and 112)

IV. Systemic Lupus Erythematosis (SLE)

A. SLE is a common, remitting and relapsing febrile multisystemic inflammatory AI disease of multiple origin

B. Organs SLE likes to infect

1. Kidney

2. Joints

3. Serosal membranes

4. Skin

5. These are places were type III hypersensitivity Ab-Ag complexes congregate

C. Clinical manifestations

1. Arthritis

2. Skin changes

3. Kidney damage

4. Inflamed serosal membranes

5. Fever

6. Mental changes which include fatigue

D. Epidemiology

1. Up until some years ago 5 year survival rate was 50% from time of diagnosis. Now 10 year survival rate is 90% from time of diagnosis.

2. Occurs mostly in young women 30-40 years old with a 9:1 female to male ratio (wrong in notes)

3. 1 in 1000 women has SLE

4. Many different postulated etiologies, multiple origins

5. Strong genetic disposition

E. Mechanisms of Pathogenicity

1. Auto-antibody (Auto-Ab) is formed against many things including

a. Plasma proteins – complement components, clotting factors

b. Cell surface Ag – lymphocytes, neutrophils, platelets, RBCs

c. Intracellular components – microtubules, lysosomes, microfilaments, ribosomes

d. Most important nuclear components – DNA, RNA, histones

2. KNOW THIS! ( Auto-Ab against double stranded DNA (dsDNA) and Smith Ag (Sm Ag) - cytoplasmic RNA are most important. Used for diagnosis.

3. Many curious Auto-Ab are formed

4. Type III hypersensitivity results in immune complex tissue injury from acute vasculitis with necrosis, inflammatory response, and macrophage infiltration in organs and tissues

F. Lesions of SLE

1. Blood vessels in many areas of body develop

a. Acute necrotizing vasculitis - due to type III hypersensitivity reaction (learn to associate vasculitis with type III hypersensitivity)

b. Fibrinous necrosis

2. Spleen lesions

a. Chronic vasculitis

b. Fibrosis of pencillary arteries in spleen

c. SLIDE - Fibrosed arteries around spleen

3. Impaired kidney function – cause of death among SLE patients

a. Anti-tubular Ab causes lupus interstitial nephritis

b. Acute vasculitis

c. Fibrinoid necrosis

d. SLIDE: Immunofluorescence of kidney with SLE (Robbins fig 7-26)

4. Phototrophic skin rashes

a. Skin lesions often the one of first symptoms to show up

b. Due to auto-Ab forming in basement membrane between dermis and epidermis

c. Phototrophic rash – mainly found on face, hands, and other parts of body exposed to sunlight ( sometimes to point of skin ulceration

d. Sometimes ulcerative lesions with rash + vasculitis

e. SLIDE: Butterfly rash on cheeks across nose on exposure to sun (phototrophic rash)

f. SLIDE: Immunofluorescence of basement membrane (Robbins Fig 7-29B)

g. SLIDE: Sometimes more papillar rash is seen

h. SLIDE: Ulcerative lesion

5. Arthritis or inflammation of joint tissues– also one of first things to show up

a. non-suppurative, not a fixed joint, not like RA

b. just joint aches and pains

c. not mutilating

6. Pleural and pericardial inflammation

a. Libman-Sacks endocarditis (Robbins Fig 7-30)

7. Chronic fatigue – often presenting complaint and one of first things to show up

a. Probably from anemia and generalized joint pain

8. Mental changes

a. Convulsions

3 things seen first with SLE

1. Skin rash 2. Fatigue 3. Arthritis

H. Don’t worry too much about the chart on p 115. Just be aware of the common ones ( arthritis, skin changes, fever, kidney changes

I. Statistics on p 115 have changed. Now, 90% of diagnosed patients are alive after 10 years due to better management of disease, more effective treatment, earlier diagnosis ( but not necessarily a cure

J. Diagnosis

1. LE cell test (lupus erythematosus) - LE cell is any phagocytic leukocyte that has engulfed the denatured nucleus of an injured cell. Not sensitive nor specific.

2. Hemotoxylin body (cell with lots of eosinphilic material inside)

a. Indicative (but no specific) of SLE if found in bloodstream

b. But if hemotoxylin body found in tissue, that is specific for SLE

3. ANA (indirect immunofluorescent test) – Nonspecific test

a. 99% of SLE have it, but 10% of population has it also and it’s found in other AI disease like

1. RA, Systemic Sclerosis, Polymyositis Sjogren’s Syndrome, and even Mononucleosis.

2. Drug induced (hydrazines)

b. Staining patterns of ANA

1. Homogenous – anti RNA and histone

2. Rim – anti dsDNA or anti Smith Ag ( most specific for SLE

a. stain around edges ( remember this one

3. Speckled – non DNA nucleoprotein

4. Nucleoid – nucleolar RNA staining

K. Lab findings

1. Erythrocyte sedimentation rate (ESR) is increased to near 100%

2. Positive ANA in 100% of cases

3. Positive Rheumatoid Factor (RF)

4. Positive Anti dsDNA Ab and Anti Smith Ab

5. Increase in IgG, IgM levels

6. Inflamed joint fluid

SLE-like Diseases

1. Chronic discoid lupus erythematosus (DLE)

a. SLE with the skin lesion but without the systemic problems

b. may develop into system, but rarely

2. Drug induced lupus erythematosus

a. Occurs in people that are “slow acetylators” of hydrazines

b. Same as SLE without the renal damage

c. Have positive ANA, positive smith Ag Ab, positive ds DNA Ab

Question from the class: Is drug induced lupus temporary or permanent?

Answer: If you take the drug away, the symptoms will eventually go away.

V. Rheumatoid Arthritis (RA)

A. RA is a systemic chronic inflammatory disease with a genetic predisposition

B. Characterized by immune mediated destruction of cartilage in the joints with necrotizing vasculitis

1. Nonsuppurative synovitis causing symmetrical arthritis of principally joints

2. Extra-articular lesions including ulcerative skin, lesions on legs similar to diabetes, heart problems with serosal membrane, and mental problems

C. Epidemiology

1. Disease present in about 1% of population with onset in 4th or 5th decade of life

2. More common in women than in men (3 to 5 times more likely)

3. Don’t worry about specific genes (HLA-DR4, HLA-DR1)

D. Pathogenesis

1. Activation of T helper cells by some arthrogenic microbe causing cytokine release which causes

a. Activates macrophages in joint space leading to inflammation

b. Activated B cells producing Auto-Ab ( leading to Ag-Ab deposits in the joints

2. Auto-Ab is an Anti-IgG called Rheumatoid Factor (RF)

3. Over time, the nonsuppurative proliferative synovitis leads to

a. Destruction of auricular cartilage

b. Disabling arthritis

4. Joints become Stiff, Enlarged, Immobile, and Painful (Classic RA)

5. Eventually undergoes complete ankylosis resulting in a permanently severely crippled person.

6. Vasculitis results in

a. Raynaud’s phenomenon– decreased vascular response in extremities and results in light colored areas in hands and feet

b. Leg ulcers

c. GI erosions

d. Infarcts

e. Anemia – very common

7. Anemia and vasculitis are hallmarks of RA other than arthritis

E. Diagnosis – Don’t worry about regurgitation but note some of the similarities to SLE

F. Don’t worry about chart at top of p 118

G. Variants of RA – just be aware of what variants occur, don’t worry about details

1. Juvenile RA

2. Still’s Disease

3. Felty’s Syndrome

4. These usually disappear when person reaches older 20’s

VI. Spondyloarthropathies

A. Ligamentous diseases associated with various joints

B. Marked by absence of Rheumatoid Factor (RF) ( seronegative spondyloarthropathies

C. Often associated with uveitis

D. Examples of spondyloarthropathies

1. Anykylosing spondylitis

2. Reiter’s syndrome

3. Psoriatic arthropathy

4. Reactive arthritis

VII. Sjogren’s Syndrome

A. Occur mostly in women

B. Clinical Triad – Classical symptoms of Sjogren’s

1. Dry mouth – Xerostomia

2. Dry eyes – Xeropthalmia

3. Non-destructive arthritis

C. Dry mouth & Dry eyes known as sicca’s syndrome

D. Pathogenesis

1. There are several Auto-Ab against cell cytoskeleton ( particularly ANA anti-ss-A and anti-SS-b (against host RNA Ag)

2. Activated CD4+ helper cells, B Cells, and some cytotoxic T cells infiltrate lachrymal and salivary glands and release Auto-Ab locally( cause lymphocytic infiltrations ( glands undergo ductal hyperplasia and obstruction ( result in sicca’s syndrome.

E. SLIDE – picture of woman with no tears and mouth cracked at corners

VIII. Systemic sclerosis or sclerodoma

A. Occur mostly in women

B. 2 clinical variants

1. Diffuse - widespread skin and visceral involvement

2. Limited – mostly hands and face, benign course

C. Pathogenesis

1. Excessive deposition of collagen in skin and internal organs

2. Fibrosis secondary to immune complex vasculitis

3. Delayed hypersensitivity reactions

4. Other unknown immunologic derangements (possibly altered collagen synthesis)

D. Don’t worry about chart on bottom of p 121

E. Clinical Correlations

1. Lesions are fairly unique – Blood vessels, heart, lungs, peripheral nerves

2. Excessive fibrosis occur in

a. GI tract

b. Muscles

c. Lungs

d. Kidneys

e. Especially in the skin

3. With progressive collagen deposition, you get

a. CREST syndrome

1. C – calcinosis in the skin

2. R – Raynaud’s phenomenon - vasoplastic disorder affecting small vessels

3. E – Esophageal dysfunction

4. S – Sclerodactyl – progressive loss of skin flexibility, hand is fixed in claw like manner

5. T – Telangiectasia – red spot on skin from by dilated capillary

b. All of the above will lead to

1. Progressive loss of skin flexibility

2. Cutaneous ulcerations

3. Auto-amputation of extremities

4. Arthritis + vasculitis + fibrinoid necrosis ( connective deposition in organs and tissue

F. Slides

1. Calcinosis in dermis

2. Raynaud’s phenomenon – hand with some digits that are very pale and others normal

3. Sclerodactyl – fixed claw-like hand; peripheral nerves are shot so don’t feel very much (like leprosy); therefore subject to trauma since they cannot sense (Robbins Fig 7-34)

4. Fixed stare position – similar to the inflexibility of skin on hand, but occurs in the face; owl-like fixed appearance

5. Telangiectasia – blotching of the skin do to rupture of vessels near surface

IX. Inflammatory Myopathies

A. Mostly in women

B. 3 heterogeneous disorders ( polymyositis, inclusion body myositis, dermatomyositis

C. Polymyositis and inclusion body myositis – w/o dermal involvement

1. Mechanism of pathogenesis

a. Type IV hypersensitivity mediated muscle cell injury ( will see inclusion bodies in muscle section

b. Infiltration of CD8+ cells, cytotoxic T cells, and macrophages into the muscle

c. Increase HLA class I on sarcolemma

2. Clinical manifestations

a. Loss of muscle mass

3. There is more inflammation associated with these 2 than with dermatomyositis.

D. Dermatomyositis – w/ dermal involvment

1. Mechanism of pathogenesis

a. T cell mediated immune response with CD4+ cells and B cells in muscle tissue causing damage

2. Clinical manifestations

a. Rash on eyelids causing periorbital edema

b. Erythematous rash

c. Phototrophic rash

d. Loss of muscle mass

E. There is a childhood and adult form

F. Muscle weakness and loss of function major symptom for all types

G. SLIDE - Loss of muscle tissue and replaced by connective tissue

X. Mixed Connective Tissue Disease (MCTD)

A. Complicated disease with overlapping clinical features of SLE, SS, and inflammatory myopathy

B. But RARELY see kidney damage

C. Affects mostly female (again)

XI. Polyarthritis Nodosa

A. Necrotizing inflammation of small/med size vessels of multiple origin

B. Inflammation resembles fibrinoid necrosis like Type III hypersensitivity immune complex damage

C. Kidney damage and disease seen

XII. Wegener’s Granulomatosis

A. Will be lectured on at another time so don’t worry about it

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