Autoimmune diseases

SLIDE 3: Introduction to autoimmune diseases

•Chronic

•Sometimes relapsing : and remitting. which means that they present as attacks

•Progressive damage

•Epitope spreading…more and more damage : As it damages more tissue, the antigens that induce unwanted

immune response increase leading to more damage

•Actions may be by: -autoantibodies -Th1 & Th17 cells -CD8 cells -both cellular and humoral

SLIDE 4: •Autoimmune diseases may be Systemic

Tend to involve: - connective tissues -blood vessels (we call them:collagen vascular diseases & connective tissue diseases )

examples: SLE, systemic sclerosis, polymyositis .. etc We will discuss some of these

Organ-specific

SLIDE 5. Examples •Systemic lupus erythematosus (SLE) •Sjogren syndrome •Systemic sclerosis

SLIDE 6 •Systemic lupus erythematosus (SLE)

Features:

- Autoantibodies/immune complexes : Antibodies bind self-antigens leading to the formation of

immune complexes that cause damage to the tissue. We call this reaction (Type III

hypersensitivity)

- Onset: acute or insidious

- Typically: chronic, remitting and relapsing

- Often febrile illness

- 20s & 30s

- F:M ratio: 9:1…in reproductive age : Before and after reproductive age the ratio decreases to 2:1

- Blacks & Hispanics more

Can affect: *…Skin …joints …kidney …serosal membrane …any other organ

The American college of rheumatology made this criteria to diagnose a patient with SLE. The patient must

meet 4 out of the 11

1. Inflammation in the pleurae, pericardium or peritoneum.

When we use the stethoscope we can hear a click at the end of inspiration, which is called a pleural rub. it

accompanies pleuraitis

There's also pericardial rub that occurs with pericarditis

2. In SLE oral ulcers are PAINLESS

3. Affects 2 joints and more. non erosive with effusion in the joint, erythema and swelling

5. blood cells also get attacked by the immune complexes leading to leukopenia, lymphopenia,

thrombocytopenia, hemolytic anemia

6. -presistant proteinuria (more than 0.5 g/dl protein in the urine OR +3 on spot urine test)

- presence of cellular cast in the urine.

From google: (Urinary casts are tiny tube-shaped particles that can be found when urine is examined

under the microscope during a test called urinalysis)

7. Most important ANAs in SLE are:

Anti-dsDNA & Anti-smith antibodies

*Anti non-histone proteins sub types: - Anti-smith(Anti-Sm)/ Anti-ro(SS-A) / Anti-la(SS-B)

elevated.

such as:

- Anti histone protein antibodies

- Anti dsDNA antibodies

- Anti non-histone proteins antibodies (ribonucleoproteins)

- Anti-Nucleolus Antibodies

- Anti-centromere antibodies

9. like seizures or psychosis(impaired relationship with reality).

*make sure it's not caused by other reasons such as drugs.

10. Butterfly appearance, sparing the nasolabial fold. (The picture on the left)

11. Elevated crusty patches appears mainly in the face and scalp. (The picture on the right)

SLIDE 9. Investigations, indirect immunofluorescence: We use this test -that we talked about before- to detect the

ANAs.

Each group of the ANAs has a specific pattern

Homogenous : used for: AntiHistone and Anti dsDNA antibodies.

There's another pattern for the Anti dsDNA called peripheral.

Speckled : For Anti non-histone proteins

Centromeric : for anti-centromere antibodies

Nucleolar: for Anti-nucleolus antibodies

SLIDE 10. Investigations, cont’d •Antibodies to double-stranded DNA and the so-called Smith (Sm) antigen are virtually diagnostic of SLE •In addition to ANAs, 30-40% of lupus patients also have autoantibodies against proteins complexed with phospholipids Plasma proteins: -prothrombin -annexin V -Beta 2-glycoprotein I : Its Ab also binds to cardiolipin antigen

Antibodies againt Beta 2-glycoprotein also bind cardiolipin antigen which is found in Treponema pallidum

the bacteria that causes syphilis.

So patients with SLE might have false positive tests for syphilis because they have antibodies againt the

antigen that is found in Treponema pallidum. -protein S -Protein C

Lupus anticoagulant ………?Anti-phospholipid antibodies are also called lupus

anticoagulants because in vitro they increase the PTT. BUT in reality they are associated with

hypercoagulation in the patient. And that's why patients with anti-phospholipid antibodies are prone to

recurrent miscarriages.

SLIDE 11. Risk factors •Genetic susceptibility…HLA-DQ polymorphisms

…inherited deficiencies of C2, C4, or C1q : Because C2 & C4 are important in removing immune complexes.

C1q is important in phagocytosis of apoptitic cells, so impairment in it's function increases antigens that induce

immune response. …others

•Environmental factors are more important…UV light and drugs : UV light destroys cells,induces apoptosis and

causes changes in the DNA to make it antigenic and immunogenic.

It also induces fromation of IL-1 by keratinocytes which induces inflammation.

•Immunological factors: -Failure of self-tolerance in B cells : Main factor in SLE.

Leads to formation of autoantibodies and Type III hypersensitivity which we mentioned earlier

-CD4+ helper T cells

-Role of TLRs : have a role in inflammation (innate immunity) and stimulating B lymphocytes.

*B cells have TLR and Fc receptors

-Role of type I interferons : Released mainly by dendritic cells -Role of BAFF: Type of the TNF family.

has a role in activation and survival of B lymphocytes

SLIDE 12. Mechanisms

•Systemic lesions…mostly by type III hypersensitivity: mainly in the kidney causing lupus nephritis. •Opsonization of blood cells by autoantibodies

•Antiphospholipid antibody syndrome : Could be primary, if it's present alone. Or secondary if it's present as part of

SLE. One of the important causes of recurrent miscarriages

SLIDE13. Sjogren syndrome: Autoimmune diseases in which there's lymphocytic infiltration of the glandular epithelium of the lacrimal and salivary

glands leading to dry eyes and dry mouth

•Most commonly in women between the ages of 50 and 60 •Dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia)

•Primary or secondary : If it accompanies another autoimmune disease, mainly: Rheumatoid arthritis.

•Lymphocytic infiltration and fibrosis of lacrimal and salivary glands : lymphocytic infiltration of the salivary gland

is one of the main marks of the disease •Mainly CD4+…and B cells : Starts as polyclonal infiltration •75% are positive for rheumatoid factor : Even if it's Primary and the patient doesn't have rheumatoid arthritis •ANAs in 50-80%

To diagnose the patient with Sjogren syndrome we take a biopsy (slide 16)

•The most important antibodies are: But not specific. because they might be elevated in SLE SS-A(-earlier onset -longer disease duration -extraglandular manifestations)( Anti-Ro)( Affects prognosis leads to worse

prognosis) & SS-B…90% (Anti-la)

•HLA association •Viral infection may be the initial trigger

•Sjogren syndrome-like disease is seen in some patients with AIDS & hepatitis C

•Extraglandular disease in 1/3 of patients -synovitis -pulmonary fibrosis -neuropathy SLIDE16

•Biopsy of the lip : we took a biopsy from the lip because lips have minor salivary glands.

duct looking abnormal because metaplastic changes occurred

late in the course of the disease we can see fibrosis around the duct

when lymphocytes invade the duct epithelium we call it histologically: lymphoepithelial lesion.

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In some cases, if we stain this lesion by immunohistochemical stain and we find that all the cells are CD20+ and CD3

negative (Monoclonal) then we suspect lymphoma, which might exacerbate Sjogren syndrome. In this case the

lymphoma is called (Extranodal marginal zone B cell lymphoma).

SO sjogren syndrome might be followed by lymphoma.

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Extranodal marginal zone B cell lymphoma can also occur in the thyroid gland as an exacrebation of Hashimoto

Thyroiditis.

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*CD20 is a marker for B cells

SLIDE 17

Systemic sclerosis (scleroderma)

•50s-60s •M:F 1:3

•Its distinctive features are the striking cutaneous changes, notably skin thickening : because of the fibrosis by

collagen

•3 main problems: -Inflammation : CD4+…also humoral roles -Small blood vessel damage : Leads to malignant hypertension

-Interstitial and perivascular fibrosis in skin and other tissues

•The majority: also kidney, heart, lung and GI involvement…but late

•Diffuse(Affects most of the skin, and the extra-cutaneous involvement is early) VS limited(may affect forearms or

fingers .. etc , with late extra-cutaneous involvement) scleroderma : Some patients: CREST syndrome C: calcinosis (soft tissue masses made by calcium)

R: Raynaud phenomenon

E: esophageal dysmotility

S: sclerodactyly

T: telangiectasia

•Raynaud phenomenon…virtually in all patients …precedes other manifestations in 70% of the cases

•Dysphagia is an important symptom…50% •Nephrotic syndrome is rare

•The most dangerous risk: malignant hypertension SLIDE 20

Two ANAs are important in diagnosing systemic sclerosis 1- against DNA topoisomerase I (anti-Scl 70)…highly specific …10-20% of diffuse disease

…prognostically important : If it's positive then the prognosis is bad.

2-anticentromere antibody…20-30% …more with CREST syndrome