Autoimmune Diseases Flashcards
Autoimmune Intro
Immune reactions to self antigens (= Autoimmunity) affect at least 1 to 2% of the US population.
–A growing number of diseases are attributed to autoimmunity without definitive evidence.
–Innocuous autoantibodies can be found in normal individuals, particularly in the elderly.
To categorize a disease as Autoimmune, it should meet the following requirements:
1) Evidence of an Autoimmune Reaction
2) Evidence that such a reaction is not secondary to tissue damage.
3) No evidence of well-defined cause.
Factors resulting in Autoimmune diseases
Autoimmune diseases may result from a variety of factors leading to bypass of immunological tolerance, not from a single factor.
These factors fall into these categories:
- -Inheritance of Susceptibility Genes, mostly HLA alleles
- -Environmental Triggers, such as Infection (or Trauma)
HLA Alleles Associated with Autoimmune Disease
- Systemic Lupus Erythematosus (SLE) occurs more often in patients with
- -*Specific Types of *HLA-DQ alleles and
- -*Deficiencies of Complement *C2, *C4, and *C1q
- Rheumatoid Arthritis (RA) occurs more often in patients with
- -*HLA-DRB1 gene of *Specific alleles, such as 0401 and 0404.
*Sjogren Syndrome (SS) occurs more often in patients with certain HLA alleles, such as *B8, *DR3, and *DRW52, or *DQA1 and *DQB1.
Anti-Nuclear Antibodies (ANA) in Autoimmune Diseases ***
1) Anti-ds DNA, Anti Smith(Speckled):
- -Specific for SLE
2) Anti-Histone (Homogenous):
- -Drug-induced SLE
3) Anti-IgG (IgM anti-IgG = RF) (Rheumatoid Factor):
- -Rheumatoid Arthritis (RA)
- -Sjogren Syndrome
4) Anti-Centromere:
- -Scleroderma CREST
5) Anti-DNA Topoisomerase (Anti-Asl70):
- -Diffuse Scleroderma (Systemic)
6) Anti-Jo1:
- -Polymyositis / Dermatomyositis
7) Anti-SSA (Anti-Ro) (Speckled):
- -Sjogren
8) Anti-SSB (Anti-La) (Speckled):
- -Sjogren
9) Anti-U1 RNP (Speckled):
- -MCTD, Mixed Connective Tissue Disease
Anti-Nuclear Antibodies (ANA) Indirect Immunofluorescence Test
1) Homogenous Diffuse Nuclear Staining:
- -Due to Antibody to *Chromatin, *Histones, and *ds-DNA
2) Rim of Peripheral Nuclear Staining:
- -Due to Antibody to *ds-DNA
3) Speckled Pattern:
- -Due to Antibody to *Non-DNA Nuclear Components, such as *Smith Antigen (Sm antigen), *SS-A, *SS-B, and *Ribonucleoproteins.
4) Nucleolar Pattern:
- -Due to Antibody to *Nucleolar RNA (place of active transcription)
SLE Autoantibodies
1) Form Immune Complexes and elicit:
2) *Type III Hypersensitivity immune rxns.
3) **Antibodies to *ds-DNA and to *Smith Antigen:
= Diagnostic of SLE (Specific)
4) *ANA Immunofluorescence Test is POSITIVE for almost every SLE patient:
- -Very Sensitive
- -Not Specific; other autoimmune ds pts score positive.
5) **Anti-Phospholipid Antibodies:
- -Not directed against phospholipids, but against Phospholipid-Bound Proteins: e.g. Prothrombin, Annexin V, Beta2 glycoprotein I
6) (Binds Cardiolipin, gives
* FALSE POSITIVE SYPHILIS VDRL TEST!!), Protein S, Protein C.
- -These Antibodies are called
- *Lupus Anticoagulants because they interfere with Clotting Tests in vitro.
- -But induce
7) **HYPERCOAGULABLE STATE in vivo!! - -> Embolism
Other Autoantibodies:
- -Against RBCs, Platelets, Lymphocytes
- -Against Phospholipids (40-50%)
8) LE cell or Hematoxylin Bodies:
- -Neutrophils that have been phagocytosed by Macrophages b/c they have been Opsonized by ANAs. (We don’t use hematoxylin body test anymore though.
High Titers of ds-DNA Antibodies:
–Associated with Renal Disease
Anti-SS-B Antibodies:
–Indicate Low Risk of Nephritis
SLE Clinical Course
- Acute or Insidious Onset.
- Chronic Disease
- Flare-ups and Remissions.
Females in 20s / 30s.
(Female:Male 9:1)
African Americans: more common, more severe.
1) Young woman with
2) Butterfly Rash @ Face,
3) Fever,
4) Joint Pain without deformity.
Injury to
- -*Skin,
- -*Joints,
- -*Kidney,
- -*Serosal Membranes.
ANAs test positive in almost 100% of patients:
–Anti ds-DNA and Sm antigen more Specific!!
Renal:
1) Renal Hematuria with Red Cell Casts;
2) Proteinuria or
3) Nephrotic Syndrome.
Blood: (very common)
1) Anemia or
2) Thrombocytopenia
Mental Alterations: e.g.
Convulsions/Seizures or Psychosis.
Treatment:
1) Corticosteroids and
2) Immunosuppressive drugs to improve inflammatory responses.
Most Common Causes of Death: #1) Renal Failure #2) Infections. (Infections due to immune deficiency due to ANA attack on Neutrophils or Lymphocytes.
SLE Manifestations
1) ***Immune complexes @ Blood Vessels, Kidneys, Skin, Connective Tissues.
- -Immune complexes identified by Immunofluorescence.
–Histologic patterns of Vasculitis range from Leukocytoclastic to Lymphocytic and may occur in any organ.
2) ***Facial Butterfly Erythema Rash:
- -Very Characteristic!!!
- -50% of patients
–Skin lesions demonstrate Hydropic Degeneration of the Basal Layer, Upper Dermal Edema, Purpura, and Vasculitis.
(Abs attack keratinocytes in basal layer of skin, leaving behind little holes in the skin.)
3) ***Discoid Lupus E (DLE):
- -Involves the skin without visceral involvement
- -Negative for ANAs
- -5-10% develop SLE after many years.
4) Glomerulonephritis:
- -Common!!
- -Can result in End-Stage (fatal) Renal Disease!!
–WHO classifies Lupus Nephritis in Grades I-VI according to severity of Glomerular damage.
5) Serositis: (very common!!) --**Pericarditis --or **Pleuritis @ First, Fibrinous Then, Fibrous.
6) **Arthritis:
- -Usually Non-erosive
- -With little deformity
7) Endocarditis or **Libman-Sacks Disease:
- -may occur
- -clinically insignificant
8) Spleen:
- -Lymphoid Hyperplasia,
- -Concentric Periarteriolar Fibrosis or “Onion-Skinning”
Criteria for SLE
Minimum of 4/11 = SLE
Mneumonic:
SOAP BRAIN MD
- Serositis: Pleuritis or Pericarditis
- Oral Ulcers
- Arthritis: Non-erosive
- Photosensitivity
- Blood Disorders: any cytopenia
- Renal Disorder: Proteinuria or Urine Casts
- Anti-Nuclear Antibody (immunofluorescence)
- Immunologic Phenomena: (Anti-dsDNA, Anti-Sm, False Positive Syphilis Test, LE Hematoxylin cell)
- Neurologic Disorder: Seizures or Psychosis
- Malar Rash
- Discoid Rash
SLE Risk Factors
1) Family members have increased risk of developing SLE.
2) Specific Alleles of HLA-DQ
3) Deficiencies of Complement *C2, *C4, and *C1q
4) UV Light exposure
5) Drugs: (Anti-Histone ANA) (Homogenous Nuclear Stain)
- -Hydralazine
- -Procainamide
- -Isoniazid
- -D-penicillamine
- -others
Scleroderma
Chronic disease.
***Abnormal FIBROSIS: @ Skin, Blood Vessels, Multiple Organs: --GI --Kidneys --Heart --Muscles --Lungs
Two Major Forms:
1) Diffuse Scleroderma:
- -Wide Skin involvement
- -AND *Rapid Progression to Visceral Involvement.
* **Anti-DNA Topoisomerase Antibody
2) Limited Scleroderma:
- -Skin involvement confined to fingers, forearms, and face.
- -Visceral involvement *Late and with *Benign course.
* **Anti-Centromere Antibody
Diffuse Scleroderma
Inappropriate activation of Humoral immunity with *Circulating ANAs in virtually all patients.
- **Anti-DNA Topoisomerase Antibody:
- -Specific for Diffuse Scleroderma!!
**Diffuse, More Extensive Organ involvement, including Pulmonary and Renal Disease.
- -Wide *Skin involvement
- -*AND *Rapid Progression to Visceral Involvement.
Limited Scleroderma
CREST Syndrome
- **Anti-Centromere Antibody:
- -Specific for *Limited CREST Syndrome!!:
- Skin involvement confined to fingers, forearms, and face.
- -*Visceral involvement *Late and with *Benign course.
Calcinosis Raynaud's phenomenon Esophageal dysfunction Sclerodactyly Telangiectasia
Systemic Scleroderma at the Vascular level
**Excessive Fibrosis due to Abnormal Immune responses causing Vascular Damage.
(Fibrosis results from long-lasting, chronic inflammation)
- *Fibrosis mediated by
- TGF-beta, *PDGF, *IL-13. (Production of Fibroblasts and increase in ECM.)
–Microvascular disease is always present Early.
–Intimal proliferation is seen in 100% of Digital Arteries.
–Widespread Narrowing of Microvasculature leads to Ischemic injury and Scarring.
Systemic Scleroderma Clinical Course
HyperGammaGlobulinemia with Elevated IgG
Has many features similar to SLE, RA, and Polymyositis.
***Distinctive Feature:
CUTANEOUS THICKENING.
- **Raynaud Phenomenon:
- -Episodic Vasoconstriction and Vasodilation of Arteries @ Extremities
- -Seen in 70% of patients Before other symptoms appear.
