Ch 6: Immunopathies (Part 3 - Autoimmune diseases) Flashcards
What is central tolerance?
Learns to tolerate self-ag prior to release from generative lymphoid organs
What is peripheral tolerance?
Learns to tolerate self-ag during on-going regulation in peripheral tissues
What is the mechanism behind central tolerance in the thymus/bone marrow?
Thymus:
Production of TCRs that cross-react with self-ag detected and apoptosed
Dev. of Tregs
Bone marrow:
Receptor editing
Apoptosis
What are the mechanisms behind peripheral tolerance?
For T-cells:
Anergy
Suppression by t-Regs
Apoptosis
For B-cells:
Anergy
Describe how anergy occurs.
T-cells have inhibitory receptors: CTLA AND PD-1
Help t-cell downregulate when self-ag are present
CTLA binds B7(CD80) which prevents T-cell activation b/c B7 can’t attach to CD28 (activator)
How do cancer evade T-cell killing? How can this be solved?
Uses PD-1 binding to PD-1L to evade T-cell
Anti-PD-1 (and 1L) can reverse this
Also anti-CTLA4
Describe T-Regs. Induced by? Positive for? Express? Actions?
Induced by TGF-B
Positive for CD4
Express CD25 and FOXP3
Actions = cytokine immunosupression (using IL-10 AND TGF-B), CTLA-4 inhibition
What is AIRE? What is its purpose and where does it assert its effects? A mutation here causes what?
AIRE = autoimmune regulator
It stimulates expression of some “peripheral tissue-restricted” self-Ag in thymus and is responsible for deletion of immature T-cells specific for those Ags
Mutation leads to polyendocrine disorders due to autoimmunity
What is IPEX? What mutation is involved? What normal process fails?
IPEX = immune dysregulation, polyendocrinopathy, enteropathy, x-linked
Mutations in FOXP3 cause this
This leads to loss in maintenance of T-regs, which leads to attacks on normal cells.
What 3 requirements are there to define an autoimmune disease?
Immune rxn is directed against a self-Ag
Immune rxn primarily responsible for pathologic condition
There is no other pathophysiology responsible
What are required for genesis of an autoimmune disease?
Combo of:
Genetic susceptibility
Immune regulation
Environmental contribution - infection, damaged tissue
What is Ankylosing Spondylitis? What gene is it associated with?
Hereditary inflammatory condition of joints, particularly spine
Inflammation leads to degeneration and fusion of vertebrae
Strongly associated with Class 1 HLA allele B27
What is Crohn’s disease? What gene is associated?
Polymorphisms in NOD2 gene render panted cells in intestinal epithelium ineffective at microbial killing
Defective killing and cleanse allows accusation of bacteria and exaggerated immune response
Describe what happens with OLP and epitope spreading.
With OLP, there is an initial T-cell response leading to keratotic lesions in oral and conjunctival mucosa
Basement membrane disruption exposes antigenic proteins
A secondary B-cell response occurs
What is ANA? What can it test for?
Anti-nuclear antibody test
SENSITIVITY
Tests for multiple autoimmune diseases:
Systemic lupus erythematous (SLE) - discoid and drug-induced
Sjogren syndrome
Systemic sclerosis
For SPECIFICITY, what can you use to test for SLE?
Anti DS DNA
Anti Smith
For SPECIFICITY, what can you use to test for Sjogren syndrome?
Anti Ro/SS-A
Anti Ro/SS-B
For SPECIFICITY, what can you use to test for Systemic sclerosis?
Anti DNA topoisomerase (Scl-70)
What is SLE?
Autoimmune disease associated with vast array of auto-ab
Genetic and environmental influences combine to degrade self-tolerance
Genetic association = family patterns, HLA-DQ
Female bias = X-chromosome
UV light
Multiple immune mechanisms involved:
B-cells and CD4 T-cells
Immune complex formation
When do you start to suspect Lupus?
Requires 4 or more criteria (ex: discoid rash, malar rash)
Prevalent: Arthritis Skin rashes - malar rash Fever Fatigue Hemolytic anemia Edema
What is the first class of lupus nephritis? Last class?
Minimal mesangial lupus first
Advanced Sclerosing lupus last
fibrosis often end-stage process
Describe Diffuse Lupus Nephritis (Class 4).
MOST COMMON
Pts symptomatic = proteinuria, hematuria
Glomeruli show increased cellularity
Proliferation of endothelial, mesangial, and epithelial cells
EM shows immune deposits in subendothelium
Describe the skin changes you see with SLE.
Basal layer degeneration of skin - vacuolated spaces b/w degenerating cells
Malar rash
What are some cardiovascular complication with SLE?
Libman-Sacks endocarditis: Verrucous (warty) valve deposits Comprised of fibrin Not infective Can embolize (rare)
Coronary artery disease
What is an L-E cell? Is it still used for diagnosis?
Neutrophil or macrophage that ingest nucleus of damaged cell.
It is not used for diagnosis but may be seen in blood or body fluids
How does Discoid Lupus erythematosus differ from SLE in regards to characteristics seen?
It does have:
discoid rash
positive ANA
positive immunofluorescence
Discoid DOESN’T have malar rash, renal disease, heart disease, hematologic disorders or positive ds DNA associated with it like SLE does
Describe Discoid lupus.
Typically, just face and scalp are affected
Positive ANA
Negative Anti-DS DNA
Progression is possible
Disseminated skin lesions
Systemic organ involvement
How does Drug-induced Lupus erythematosus differ from SLE in regards to characteristics seen?
It has: Arthralgia (joint aches), fever Positive ANA Discoid rash Hematologic disease Positive immunofluorescence
DOESN’t have:
renal and CNS disease, positive ds DNA
What is Drug-induced lupus (DIL)?
Meds induced breakdown of self tolerance (procainamide, hydralazine)
HAs Arthralgia, fever, positive ANA
Positive anti-histone Ab
Resolves with drug discontinuation
What is the relationship between certain drugs and HLA allele with risk of DIL?
Hydralazine = high risk of DIL in ppl with HLA-DR4 allele
Procainamide = high risk of DIL in ppl with HLA-DR6 allele
What is Sjogren syndrome?
Autoimmune diease resulting in destruction of lacrimal and salivary gland tissue
What is the pathogenesis of Sjogren syndrome?
B and T cell mediated inflammatory rxn to target tissues with inflammatory damage followed by fibrotic destruction
What clinical presentations do you see with Sjogren syndrome?
Dye eyes - due to decreases lacrimal secretions
Dry mouth (xerostomia)
Difficulty swallowing
Root caries - due to dry mouth
Smooth tongue with candida yeast infection due to dry mouth
How do you diagnose Sjogren syndrome?
Anti-Ro/SS-A and Anti-La/SS-B
Biopsy of lip to look for inflammation of minor salivary gland tissue
What are some further complications that can arise with Sjogren syndrome?
Extraglandular disease = pulmonary fibrosis
Lymphoid proliferation becoming clonal = lymphoma
What is systemic sclerosis (scleroderma)?
Fibrosis throughout body (skin, GI tract, kidneys, heart, lungs)
Can occur in limited form = skin + late visceral involvement
Can be part of CREST syndrome
What 3 things need to occur for systemic sclerosis to occur?
Microvasculopathy
Immune dysregulation
Fibrosis
What histological characteristics are seen with systemic sclerosis?
Dense collagenous deposition consistent with subcutaneous fibrosis
Vascular hyalinizaion
What clinical presentations can be seen with systemic sclerosis?
Clubbing of fingers
Progression to Raynaud phenomenon = cold, ischemic fingers become necrotic and distal phalangeal bone undergoes ischemic resorption
GI = GI reflux, esophageal ulceration
Renal vascular disease
Pulmonary = Pulmonary HTN and fibrosis
What test is used for systemic sclerosis? What is the ANA pattern?
Anti Scl-70 (DNA topoisomerase)
ANA = speckled pattern
When and using what test would you see an centromere ANA pattern?
Using Anticentromere antibody
CREST syndrome
What is CREST syndrome? What does it stand for?
Unique form of limited sclerosis
Better prognosis than diffuse sclerosis
C = calcinosis - calcium deposits in skin R = Raynaud phenomenon - spasm of blood vessels in response to cold or stress E = esophageal dysfunction - acid reflux and decrease in motility of esophagus S = sclerodactyly - thickening and tightening of skin on finger and hands T = tenlangiectasia - dilation of capillaries causing red marks on surface of skin
What is mixed connective tissue disease? Has a high titer for?
A combination of SLE, systemic sclerosis, and polymyositis
Arguing in favor of it being unique entity
High titer for Anti-ribonucleoprotein (RNP)
What is a common presenting feature of mixed connective tissue disease?
Raynaud phenomenon
What is IgG4-related disease?
Newly understood
Unites pathophysiology tying together many disease we know about
What diseases are being tied into IgG4-related disease?
Autoimmune pancreatitis Reidel thyroiditis Mukulicz's syndrome Idiopathic retroperitoneal fibrosis Inflammatory pseudotumors Inflammatory aortitis
What is the pathophysiology behind IgG4-related disease?
IgG4-producing plasma cell + T-cells, fibrosis
Eventual fibrotic scarring and irreversible damage to involved area
