Hypersensitivity, Autoimmunity and Immunodeficiency Part 2 Flashcards
what are autoimmune diseases
- immune reaction to self-antigens
- organ or cell specific disorders
- multi-system disorders (collagen vascular or connective tissue disease)
what are the different types of autoimmune disease
- immunologic tolerance
- self tolerance (central tolerance or peripheral tolerance)
what is central tolerance
- deletion of self reactive T and B cells during development
- thymus-negative selection by apoptosis of T cell expressing receptor for autologous antigens
- bone marrow-deletion of self reactive B cells by apoptosis
- slippage occurs
what is peripheral tolerance
-self reactive T cell escape negative selection in thymus and must be deleted from periphery
what is anergy
- encounter with Ag by APC lacking appropriate MHC molecule and costimulatory molecules for T cell
- lack of specific T helper cell for B cell functional inactivation not death
peripheral suppression is mediated by
regulatory T cells which express CD25, a chain of the IL-2 receptor, which require IL-2 for generation and survival
-also express transcription factor FoxP3
mutation of FoxP3 gene are responsible for what
systemic autoimmune disease called immune dysregulation, polyendocrinopahy, enteropathy X-linked syndrome (IPEX)
peripheral suppression excrete what
immunosuppressive cytokines IL-10 and TGF-B
what is activation-induced cell death
- apoptosis by Fas-Fas ligand system mutations of which cause lymphoproliferative syndrome
- peripheral suppression by regulatory T cells
what are the mechanisms of autoimmunity
- failure of tolerance:
- single gene mutation
- failure of activation - induced cell death
- breakdown of T cell anergy
- bypass of B cell requirement for T cell help
- failure of T cell mediated suppression
- molecular mimicry
- polyclonal lymphocyte activation
- release of sequestered antigens
- exposure of cryptic self and epitope spreading
what genetic factors are involved in autoimmunity
- Familial clustering
- Linkage with HLA antigens
a greater occurrence of familial clustering occur in
monozygotic than dizygotic twins
linkage of HLA antigens are common in what alleles
class II alleles (HLA-DR, HLA-DQ)
how do infections in autoimmunity act as triggers
- cross reacting epitopes
- bypass T cell tolerance by forming immunogenic units
- act as non-specific polyclonal B cell or T cell mitogens
- up-regulate co-stimulators via necrosis and inflammation
- facilitate cryptic antigen presentation and induce epitope spread
what is systemic lupus erythematosis (SLE)
-systemic disorder primarily affecting skin, kidneys, serosal membranes, joints and the heart
what type of antibody is involved with SLE
ANA -autonuclear antibody
who does SLE affect
- childbearing age
- African American women
- presents in second or third decade
9: 1 female to male
what is the diagnostic criteria for SLE
Patient is said to have SLE if any 4 or more of the 11 are present serially or simultaneously during any interval of observation
- macular rash
- discoid rash
- photosensitivity
- oral ulcers
- arthritis
- serositis
- renal disorder
- neurological disorder
- hematologic disorder
- immunologic disorder
- antinuclear antibod
SLE is caused by
- defect in self tolerance
- antinuclear antibody (ANA)
what is ANA
- anti DNA
- anti histone
- anti non histone proteins bound to RNA
- anti nucleolar antigens
what are the patterns of immunofluorescence used to diagnosis SLE
- homogenous or diffuse
- Rim or peripheral
- Speckled
- Nucleolar
what is homogeneous or diffuse patterns of immunofluorescence
-chromatin, histones and DS DNA antibodies
what is rim or peripheral patterns of immunofluorescence
-double stranded DNA (ds DNA) antibodies
what is speckled patterns of immunofluorescence
-most common, histones and ribonucleoprotein antibodies
what are nucleolar patterns of immunofluorescence
nucleolar RNA antibodies
what is immunoluorescence
- highly sensitive
- not highly specific
- patterns are not absolutely specific for types of antibody
- antibodies to DS DNA and to Smith (Sm) antigen (non-DNA) are virtually diagnostic of SLE
SLE have antibodies to what
RBC
WBC
platlets
40-50% of patients with SLE have what type of antibodies
antiphospholipid antibodies
patients with SLE have false positive
syphilis serology
what syndrome do SLE patients have
lupus anticoagulant or the antiphospholipid antibody syndrome
what are the genetic factors of SLE
25% concordance in monozygotic twins vs. 1 to 3% in disygotic twins
-increases risk of developing disease in family members with 20% unaffected showing autoantibodies
-association of HLA-DQ locus and SLE
~6% have deficiencies of complement
what non-genetic factors affect SLE
- drug induced lupus
- sex hormones
- UV exposure
what immunologic factors affect SLE
CD4 + T cell as effector cell
what is the mechanism of tissue injury in SLE
- autoantibodies as mediator
- visceral injury by type III hypersensitivity
- RBC, WBC, and platelet injury by type III hypersensitivity
SLE has what types of bodies or hematoxylin bodies in tissue or cells in vitro
LE
SLE is associated with deposition of what
immune complexes
- acute necrotizing vasculitis
- chronic stages with fibrosis and luminal narrowing
what does the skin look like in a SLE patient
-malar rash
why does the skin in lupus have a malar rash
- liquifactive degeneration of basal layer
- immune complexes and complement at dermal epidermal junction
what happens to the joints of SLE patients
-swelling with mononuclear cell infiltrate without destruction
how does SLE affect the CNS
- focal neurological deficit or neuropsychiatric symptoms
- intimal proliferation in small vessels due to antiphospholipid antibodies; anti-synaptic membrane protein antibodies have been found
what does the spleen of a SLE patient look like
- onion skin lesions
- splenomegaly with follicular hyperplasia and plasma cells in red pulp
how does SLE affect serosal membranes
- causes pericardium and pleura
- serous effusions
- fibrinous exudates
- fibrous obliterations of space
what effects does SLE have on the heart
can cause:
- pericarditis
- myocarditis
- Libman-Sacks endocarditis
- Coronary artery disease
- Hypertension
what is the most common cause of death in SLE patients
renal failure
what are the different glomerulonephritis in SLE
Class I - normal by LM, EM, IF (rare)
Class II - mesangial lupus nephrtis (20%)
Class III focal proliferative glomerulonephritis (25%)
Class IV - diffuse proliferative glomeruloephritis (~50%) MOST SERIOUS
Class V - membranous glomerulonephritis (15%)
what is the clinical course in SLE
- clinical manifestations
- difficult to diagnose in many cases
- protean organ and system involvement
what are the course variable in SLE
- benign, indolent
- malignant, rapid
- remissions and relapses
- Rx steroids/immunosuppressive
- 90% 5 year survival
- 80% 10 year survival
see clinical manifestations
see clinical manifestations
what are the major causes of death in SLE
- renal failure
- intercurrent infections
- diffuse CNS involvement
what is Sjogren Syndrome
- dry eyes (keratoconjunctivitis sicca)
- dry mouth (xerostomia)
- immune mediated destruction of lacrimal and salivary glands (ductal epothelial cells are primary target)
what is the primary form of Sjogren syndrome
sicca syndrome
what is the secondary form of Sjogren Syndrome
-associated w/ other autoimmune disorder esp. RA, SLE polymyositis, systemic sclerosis, vasculitis or thyroiditis in ~60% of patients
the autoantibodies of Sjogren syndrome are to
SS-A (Ro), SS-B (La) RNP ags
Sjogren syndrome are associated with what
systemic disease and high anti SS-A
RF is present in Sjogren syndrome in the absence of
RA
what cells proliferate in Sjogren syndrome
initial polyclonal B cell proliferation
what genetic factors affect Sjogren syndrome
- inheritance of certain MHC II molecules
- loss of tolerance of CD4 + T cells
what glands are affected in Sjogren syndrome
-lacrimal, salivary and other secretory glands
what is the morphology of Sjogren syndrome
- intense lymphocyte and plasma cell infiltrates with germinal center formation
- loss of normal architecture
- mucosal atrophy
- ulceration or perforation of nasal septum
- bronchitis, laryngitis, pneumonia
Sjogren syndrome has a ~25% involvement of what
the CNS, skin, kidneys and muscle
what is the kidney involvement in Sjogren syndrome
-usually mild interstitial nephritis
Sjogren syndrome can also cause what
synovitis, pulmonary fibrosis, peripheral neuropathy
Sjogren syndrome has a 40 fold increased risk of developing what
non-Hodgkin B cell lymphoma marginal zone lymphoma (MALT)
- 90% of cases in women btwn 35-45 yrs of age
- enlargement of salivary glands
- present with dry mouth and lack of tears
what are the different types of systemic sclerosis
- diffuse scleroderma
- limited scleroderma
- overlap syndromes
what is diffuse scleroderma
-systemic widespread skin fibrosis, with rapid progression and early visceral involvement
what is limited scleroderma
- CREST syndrome
- calcinosis, Raynaud’s Esophageal dysmotility, Sclerodactyly, Telangiectasia
what are overlap syndromes
-either diffuse or limited scleroderma with typical features of one or more other autoimmune diseases like MCTD
what are the anti nuclear protein antibodies in systemic sclerosis
- Scl-70
- Diffuse scleroderma (70%)
- DNA topoisomerase 1 - centromere
- limited scleroderma (90%)
visceral involvement of systemic sclerosis includes
GI tract, lungs, kidneys, heart and skeletal muscle
systemic sclerosis occurs most commonly in who
women in the 3rd to 5th decades
3:1 female to male
what is the mechanism of systemic sclerosis
- interaction of CD4+ T cells, endothelial injury and fibroblast activation by IL-1, TNF, PDGF, TGF-B and fibroblast growth factors
- B cell activation with ANAs and hypergammaglobulinemia
- microvascular disease present early on progressing to ischemic injury
what are the effects of systemic sclerosis on the skin
- diffuse sclerotic atrophy
- edema at first with ultimate claw like deformity
what are the effects of systemic sclerosis on the GI tract
90% of patients esp. esophagus –> Barrett’s small bowel loss of villi and microvilli –> malabsorption
what are the effects of systemic sclerosis on the musculoskeletal system
- synovial hyperplasia and inflammation w/o deformity
- 10% get inflammatory myositis
how does systemic sclerosis affect the lungs
50% of patients pulmonary HTN and/or interstital fibrosis
how does systemic sclerosis affect the kidney
2/3 patients change in interlobular arteries similar to those of malignant HTN
-HTN occurs in 30% and 20% of those develop malignant HTN–> renal failure and death
how does systemic sclerosis affect the heart
- patchy fibrosis and thickening of intramyocardial arteries in 1/3 “cardiac Raynaud”
- Cor pulmonale and RV hypertrophy due to lung changes
what is the clinical course of systemic sclerosis
- women 50-60 yrs of age
- nearly all develop Raynaud’s phenomenon
- hands atrophy and become immobile
- dysphagia from esophageal involvement
- malabsorption
- dyspnea and chronic cough
- pulmonary HTN with cor pulmonale
- renal failure may lead to malignant HTN
continuation of clinical course of systemic sclerosis
-most progress slowly and steadily downhill over many yrs
-life span normal if no renal involvement
-10 yr survival is 35-70%
CREST has much better prognosis
-begins frequently with Raynaud’s phenomenon with face and hand involvement only for many yrs
what is inflammatory myopathies
-rare disorders with immune mediated muscle injury and inflammation which occur alone or with other disorder such as systemic sclerosis
inflammatory myopathies can lead to
- polymyositis
- dermatomyositis - women have increased risk of developing visceral cancers (lung, ovary, stomach)
- inclusion body myositis
what is characteristic of inflammatory myopathies
-symmetric muscle weakness beginning in large muscles of trunk, neck and limbs with difficulty climbing stairs or rising from a chain
what will be seen histologically in inflammatory myopathies
-histology lymphocytic infiltration and degenerative and regenerating muscle fibers
what immunologic evidence in inflammatory myopathies
- immunological evidence of antibody mediated injury in dermatomyositis
- immunological evidence of T cell mediated injury in polymyositis and inclusion body myositis
what antibody is characteristic of inflammatory myopathies
Jo-1 antibodies (tRNA synthetase)
how do you diagnose inflammatory myopathies
- diagnosis on clinical features
- increase creatine kinase
- EMG
- biopsy
patients with mixed connective tissue disease have symptoms of
-autoimmune disease, high tigers and antibodies to RNP antigen UIRNP
mixed connective tissue disease responds well to what class of drug
corticosteroids
