Diseases of Immunity Pt 2 Flashcards
Requirements to characterize autoimmune disease
presence of immune reaction specific for self ag or tissue, evidence that a rxn is not secondary to tissue damage but is of pathogenic significance, absence of another well-defined cause of disease
Immunologic tolerance
unresponsiveness to ag induced by exposure of lymphocytes to ag
Self tolerance
lack of responsiveness to individual’s own ag
Central tolerance
learned tolerance prior to release from generative lymphoid organs
Negative selection
process responsible for eliminating self-reactive lymphocytes from T-cell pool
AIRE
autoimmune regulator, protein that stimulates expression of some “peripheral-tissue-restricted” self ags in thymus and is critical for deletion of self-reactive T cells
Receptor editing
reactivation of B cell machinery to create a new antigen receptor gene rearrangement, not specific for self antigens
Peripheral tolerance
ongoing regulation in peripheral tissues
Anergy
lymphocytes rendered functionally unresponsive
Inhibitory T cell receptors
CTLA, PD-1; downregulate T cells when self ags are present
Most common regulatory T cell features
induced by TGF-B, CD4+, express CD25 and FOXP3
Actions of regulatory T cells
cytokine immunosuppression (IL-10, TGF-B), CTLA-4 inhibition
Mutations in AIRE cause what?
autoimmune polyendocrinopathy
IPEX
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked; systemic autoimmunity
IPEX mutation
FOXP3
What factors contribute to the genesis of autoimmune diseases?
susceptibility genes, infection, damaged tissues
Pathology of ankylosing spondylitis
inflammatory condition of joints that leads to degeneration and fusion of vertebrae
Etiology of ankylosing spondylitis
typically hereditary, associated with Class I HLA allele B27
Etiology of Crohn disease
polymorphisms in NOD-2 gene render paneth cells in intestinal epithelium ineffective at microbe killing
Pathogenesis of Crohn disease
defective killing and clearance allows accumulation of bacteria and an exaggerated immune response
Pathogenesis of oral lichen planus
epitope spreading; initial T cell response leads to keratotic lesions in oral mucosa, basement membrane disruption exposes antigenic proteins, secondary B cell response occurs and results in blistering
Autoimmune diseases with anti-nuclear antibody
SLE, Sjögren syndrome, systemic sclerosis
Sensitivity of ANA test
sensitive for multiple diseases, will be negative the patient does not have the disease, will prompt more specific testing
SLE tests
Anti DS DNA, Anti smith
Sjögren syndrome tests
anti Ro/SS-A, anti La/SS-B
Systemic sclerosis tests
anti DNA topoisomerase
Four staining patterns of ANAs
homogenous, speckled, nucleolar, centromere
Etiology of SLE
genetic associations: family patterns, HLA-DQ, X chromosome (female bias)
Environmental influences: UV light
Combine to degrade self tolerance
SLE criteria
malar rash, discoid rash, photosensitivity, oral ulcers, arthritis, serositis, renal disorder, neuro disorder, hematologic disorder, ANA, immunologic disorder
When to consider/suspect SLE
arthritis, skin rashes, fever, fatigue, hemolytic anemia, edema
What stage do people with SLE often present?
Class IV, patients are symptomatic (proteinuria, hematuria), glomeruli show increased cellularity, immune deposits in subendothelium, proliferation of endothelial, mesangial, and epithelial cells
Immunofluorescence pattern in diffuse lupus nephritis
Granular pattern of IgG antibody-containing complexes
Skin changes in SLE
basal layer degeneration of skin, vacuolate spaces between degenerating cells, positive immunofluorescence
CV complications in SLE
Libman-sacks endocarditis (verrucous valve deposits of fibrin) and coronary artery disease
L-E cell
neutrophil or macrophage that ingests nucleus of damaged cell
Similarities between SLE and DiscoidLE
discoid rash, positive ANA, positive immunofluorescence
Discoid lupus tests
positive ANA, negative anti-DS DNA
Similarities between SLE and Drug-inducedLE
arthalgias, fever, positive ANA, discoid rash, hematologic disease, positive immunofluorescence
Etiology of drug-induced lupus
medication-induced breakdown of self tolerance (procainamide, hydralazine)
Drug-induced lupus tests
positive ANA, positive anti-histone Ab
HLA risk linkage of drug-induced lupus in use of hydralazine
HLA-DR4 allele
HLA risk linkage of drug-induced lupus in use of procainamide
HLA-DR6 allele
Sjögren syndrome
autoimmune disease resulting in destruction of lacrimal and salivary gland tissue
Pathogenesis of Sjögren syndrome
B and T cell mediated inflammatory reaction to target tissues with inflammatory damage followed by fibrotic destruction
Sxs of Sjögren syndrome
dry eyes, dry mouth (resulting in root caries), smooth tongue(papillary atrophy)
Clinical presentation of Sjögren syndrome
dry, irritated eyes, dry mouth, difficulty swallowing
Diagnosis of Sjögren syndrome
anti-ro/ss-a and anti-la/ss-b, biopsy to look for inflammation of minor salivary gland tissue
Possible complications of Sjögren syndrome
extraglandular disease, pulmonary fibrosis, lymphoma
Systemic sclerosis
fibrosis throughout the body - skin, GI tract, kidneys, heart, lungs
Skin morphology of systemic sclerosis
dense collagenous deposition consistent with subcutaneous fibrosis, vascular hyalinization, sclerodactyly, Raynaud’s phenomenon
Manifestations of systemic sclerosis
GI reflux, esophageal ulceration, renal vascular disease, pulmonary hypertension, pulmonary fibrosis
Immunofluorescence ANA pattern for systemic sclerosis
speckled, anti Slc-70
Immunofluorescence ANA pattern for CREST syndrome
centromere, anticentromere antibody
Crest Syndrome
unique form of limited sclerosis - calcinosis, raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, telangestica
Mixed connective tissue disease
symptoms of SLE, systemic sclerosis, polymyositis; not well understood, high titer for anti-RNP; most common feature is Raynaud phenomenon
IgG4-related disease
group of diseases with common pathophys – autoimmune pancreatitis, Riedel thyroiditis, Mikulicz’s syndrome, idiopathic retroperitoneal fibrosis, inflammatory pseudotumors, inflammatory aortitis
Pathophys of IgG4 related disorders
IgG4-producing plasma cells, t lymphocytes, fibrosis, fibrotic scarring and irreversible damage to involved areas
Allorecognition
direct pathway: donor APC in the graft triggers a rejection response to donor tissues
Indirect pathway: recipient APC presents graft cell ag and triggers antibody production and macrophage activation
Timing of rejection
hyperacute rejection, acute rejection, acute ab-mediated rejection, chronic rejection, chronic ab-mediated rejection
Hyperacute rejection
occurs within minutes to hours, mediated by preformed antibodies, marked inflammation followed by thrombotic microvasculopathy
Acute ab-mediated rejection
inflammation with complement C4d breakdown product
Chronic ab-mediated rejection
fibrosis with primary effect on vessels
Acute cellular rejection
occurs within days, months, years of transplant; T-cell mediated response
Treatments for transplant rejection
corticosteroids (immunosuppressive), T lymphocyte-mediated cell rejection (Tacromilus), Ab-mediated rejection (immune globulin, rituximab
Hematopoietic stem cell transplant
therapy for hematologic malignancies, ablative chemo and radiation destroys recipient marrow, stem cell transplant administered and recipient essentially has a new immune system
Graft versus host disease
t-lymphocyte mediated response; skin rash, jaundice/cholestasis, bloody diarrhea->strictures
