Autoimmunity (Introduction, Systemic Autoimmune Disease) Flashcards
introduced “horror autotoxicus” or
“fear of self-poisoning” in 1900s
Paul Ehrlich
Immune responses are targeted toward self-antigens resulting to organ and tissue damage
Autoimmune diseases
Autoimmune diseases can be caused by
T-cell–mediated immune responses
Autoantibodies directed against host antigens
ETIOLOGY of autoimmunity
Self-Tolerance
Genetics
Other endogenous & environmental factors
ability of the immune system to accept self-antigens and not initiate a response against them
Self-Tolerance
a state of immune unresponsiveness that is directed against a specific antigen, in this case, a self-antigen
Immunologic Tolerance
2 levels of Immune Tolerance
Central Tolerance
Peripheral Tolerance
immune tolerance that occurs in central or primary lymphoid organs (thymus & BM)
Central Tolerance
involves negative and positive selection during T cell maturation
Central Tolerance
involves receptor editing in B cells
Central Tolerance
result from anergy caused by absence of costimulatory signal from an antigen-presenting cell (APC) or binding of inhibitory receptors such as CTLA-4
Peripheral Tolerance
specific state of unresponsiveness to the antigens
anergy
molecule that prevents T-cell activation
CTLA-4
in terms of genetics, autoimmunity is prevalent in these groups
family members and among monozygotic (genetically identical) twins
than dizygotic (non-identical) twins or siblings
Other Endogenous and Environmental Factors
Hormonal Influence
Tissue Trauma and Release of Cryptic Antigens
Microbial Infections
women are ___ more likely to acquire an
autoimmune disease than men
2.7x
___ of pt. with autoimmune dse are females
78%
female hormones that may place women at a greater risk for developing autoimmune dse
estrogen, androgen, prolactin
“immunologic tolerance” some self-antigens
may be cryptic, or hidden within host’s tissue
Tissue Trauma and Release of Cryptic Antigens
tissue damage could be caused by factors:
▪ infections
▪ contact with environmental toxins
▪ physical injury from UV radiation exposure
Mechanisms of Microbes in triggering autoimmune response
1) Molecular mimicry
2) Bystander effect
3) Superantigens
4) Epigenetics and Modification of Self-Antigens
5) Interactions Between Factors
many bacterial or viral agents contain antigens that closely resemble the structure or amino acid
sequence of self-antigens
Molecular mimicry
example of molecular mimicry
gram-positive bacterium S. pyogenes and
rheumatic fever (scarlet fever/pharyngitis)
production of antibodies to the M protein and N-acetyl glucosamine components of the bacteria, which crossreact with cardiac myosin, causing damage to the heart
Molecular mimicry in scarlet fever or pharyngitis
microorganism can induce a local inflammatory
response that recruits leukocytes and stimulates
APCs to release cytokines that nonspecifically
activate T cells
Bystander effect
proteins produced by various microbes that bind to both class II MHC molecules and TCRs, regardless of their antigen specificity
Superantigens
example of superantigen
staphylococcal enterotoxins
Epstein-Barr virus (EBV) and cytomegalovirus (CMV)
can cause polyclonal activation of B cells
Epstein-Barr virus (EBV) and cytomegalovirus (CMV)
superantigens produced can act as potent T-cell mitogens by activating a large number of T cells with different antigen specificities
staphylococcal enterotoxins
modifications in gene expression that are not caused by changes in original DNA sequence
Epigenetics
citrullination of collagen leads to
RA
glycosylation of myelin leads to
Multiple Sclerosis
complex interactions between genetic and environmental factors may cause break in
immunologic tolerance, autoreactive T cells recognize and proliferate in response to self-antigens and B cells develop into plasma cells that secrete autoantibodies
Interactions Between Factors
a chronic systemic inflammatory disease
SLE
peak age of onset of SLE
20-40 yo
W:M of SLE
9:1
5 yr survival rate of SLE
90%
etiology of SLE
complex interactions between environmental factors, genetic susceptibility, and abnormalities within immune system
genetic defects in genes coding for these increases the chance of developing lupus
HLA-A1, B8, DR3
result in uncontrolled autoreactivity of T and B cells, which leads to production of numerous autoantibodies in SLE
polymorphisms in genes
genes coding for various cytokines
genes involved in signaling of innate immune response
What will be the result if there is a hidden or cryptic self antigens?
T and B lymphocytes are shielded and not educated to become tolerant. (No recognition since hidden)
changes at protein level during epigenetics and modification of self-antigens
post translational modification
biochemical processes:
acetylation
lipidation
citrullination
glycosylation
Associated autoantibodies in SLE
Ab to dsDNA, histones, and other nuclear components
Autoantibody to lymphocytes
Autoantibody to erythrocytes
Autoantibody to platelets
Autoantibody to ribosomal components
Autoantibody to endothelium
Phospholipid Ab
RF
present in 70% of patients with lupus
Antibodies to dsDNA (AntidsDNA)
Ab highly specific for SLE
Antibodies to dsDNA (AntidsDNA)
found in immune complexes that are deposited in
organs such as kidneys and skin of patient with SLE
AntidsDNA
complement protein
most pathogenic, forms intermediate size complexes that become deposited in glomerular basement membrane (GBM)
Accumulation of IgG to dsDNA
activate complement and initiate an inflammatory response
Immune complexes
attracted to sites of inflammation and release cytokines that perpetuate the response, resulting in tissue damage
Leukocytes
Antibodies to RBCs indicates
hemolytic anemia
Antibodies to platelets indicates
thrombocytopenia
Antibodies to endothelial cells indicates
inflammation of blood vessels and vascular damage in lupus, vasculitis and neuropsychiatric symptoms
Phospholipid antibodies indicates
increased miscarriage, stillbirth, and preterm delivery in pregnant women with lupus
occurs in up to 8% of babies born to pregnant women with SLE, associated with antibodies to the nuclear antigens, SS-A/Ro and SS-B/La
Neonatal lupus
nuclear antigens where neonatal lupus antibodies are associated
SS-B/La
SS-A/Ro
serious complication that occurs in 2% of fetuses whose mothers have anti–SS-A antibodies
In utero heart block
clinical symptom in 90% of patients with SLE
polyarthralgias or arthritis
symmetric and involves small joints of the hands,
wrists, and knees
arthritis
may appear on any area of the body exposed to UV light in 80% of SLE patients
erythematous rash or butterfly rash
found in 50% of SLE patients
renal involvement leading to renal failure
end stage renal dse, deposition of immune complexes in subendothelial tissue and thickening of basement membrane
nephritis, diffuse proliferative glomerulonephritis
symptoms usually disappear once the drug is discontinued; milder form of the disease; manifested as fever, arthritis, or rashes; kidneys are rarely involved
drug-induced SLE
Systemic Lupus International Collaborating Clinics criteria (2012)
Clinical criteria
Immunologic criteria
give examples of clinical criteria and immunologic criteria
Clinical criteria
▪ acute cutaneous lupus
▪ chronic cutaneous lupus
▪ oral ulcers
▪ non-scarring alopecia (hair thinning/fragility)
▪ synovitis
▪ serositis
▪ renal involvement
▪ neurological symptoms
▪ hemolytic anemia
▪ leukopenia
▪ thrombocytopenia
Immunologic criteria
▪ elevated antinuclear antibody titer
▪ elevated anti-dsDNA titer
▪ presence of antibody to the Sm nuclear antigen
▪ presence of antiphospholipid antibody
▪ low complement levels
▪ + direct Coombs’ test in hemolytic anemia absence
what is needed to be classified as having SLE
4 of the 17 criteria, including at least 1 clinical criterion and 1 immunologic criterion
treatment for SLE with mild symptoms
high dose of aspirin (brings relief)
treatment for skin manifestations of SLE? what is the action?
Antimalarials (hydroxychloroquine/chloroquine and topical steroids)
Antimalarial drugs – inhibit signaling of TLR 7, 8, and 9
treatment for acute fulminant (severe & sudden) lupus, lupus nephritis, or CNS complications because these suppress immune response and lower antibody titers
Systemic corticosteroids
key or goal to successful treatment of SLE
prevent organ damage
achieve remission
SLE Laboratory Diagnosis
complete blood count (CBC)
platelet count
urinalysis
quantification of complement proteins (C3) - low
detection of specific autoantibodies
autoantibodies directed against antigens in the nuclei of mammalian cells
Anti-Nuclear Antibodies (ANA)
12 types of ANA
- Double-stranded DNA (dsDNA) antibodies
- Antihistone Antibodies
- Nucleosome antibodies
- Antibody to Sm antigen
- Anti-RNP (ribonucleoproteins) antibody
- Anti–SS-A/Ro
- Antibodies to SS-B/La
- Antibodies to both SS-A/Ro and SS-B/La
- Antibody to fibrillarin
- Antibodies to RNA polymerase
- Antibodies to the PM-1 antigen (aka PM/Scl)
- Anticentromere antibodies
produce a peripheral or a homogeneous staining pattern on indirect immunofluorescence (IIF)
Double-stranded DNA (dsDNA) antibodies
ANAs that produce homogenous IF pattern
Antihistone Antibodies
Anti-DNP
Anti-dsDNA
Nucleosome antibodies
Anti-PM-1 antigen (PM/Scl)
nucleoproteins; essential components of chromatin
Histones
5 major classes of histones
H1, H2A, H2B, H3, H4
Antibodies to H2A and H2B is detected in almost all
patients with
drug-induced lupus
supports the diagnosis of drug-induced lupus
antihistone antibody alone or combined with antibody to ssDNA
Also found in RA, Felty’s syndrome, Sjögren’s syndrome, systemic sclerosis, and primary biliary cirrhosis, but the levels are usually lower
Antihistone Antibodies
stimulated by DNA-histone complexes (nucleosomes, or deoxyribonucleoprotein [DNP])
Nucleosome antibodies
directed only against the complexes and not against DNA or the individual histones
Nucleosome antibodies
found in 85% of patients with SLE and their levels correlate with disease severity
Nucleosome antibodies
associated with uridine-rich RNA
ENA – extractable nuclear antigens
found in only 20 – 40% of patients with SLE, depending on the race of the population
Antibody to Sm antigen
first described in a patient named Smith
anti-Sm antibody
pattern of anti-Sm antibody in IIF
coarse speckled
pattern of anti-RNP antibody in IIF
coarse speckled
detected in 20% to 30% of patients with SLE, but are also found at a high titer in individuals with mixed connective tissue disease and in lower levels in patients with other autoimmune rheumatic diseases such as systemic sclerosis, Sjögren’s syndrome, and RA
Anti-RNP (ribonucleoproteins) antibody
appears in 24 – 60% of patients with SLE
Anti–SS-A/Ro
closely associated with presence of nephritis, vasculitis, lymphadenopathy, photosensitivity, and hematologic manifestations such as leukopenia
Anti–SS-A/Ro
found in only 9 – 35% of patients with SLE and all of these have anti–SS-A/Ro
Antibodies to SS-B/La
most often found in pt. w/ cutaneous manifestations of SLE, esp. photosensitivity dermatitis
Antibodies to SS-B/La
pattern produced by SS-A/Ro and SS-B/La in IIF
finely speckled
Ab that can cross placenta and associated with neonatal lupus
Antibodies to both SS-A/Ro and SS-B/La
prominent structure within nucleus where transcription, processing of ribosomal RNA and assembly of ribosomes takes place
nucleolus
Ab common in systemic sclerosis (aka scleroderma)
Antibody to fibrillarin
pattern produced by Antibody to fibrillarin in IIF
clumpy nucleolar fluorescence
Antibodies associated with scleroderma
Antibodies to:
RNA polymerase
fibrillarin
PM-1 antigen
pattern produced by Antibodies to RNA polymerase in IIF
speckled nucleolar pattern
Antibodies to the PM-1 antigen is aka
PM/Scl
Ab found in polymyositis and systemic sclerosis
Antibodies to the PM-1 antigen (aka PM/Scl)
bind to proteins in the middle region of a chromosome where sister chromatids are joined
Anticentromere antibodies
directed against 3 centromere antigens of molecular weights 16kDa, 80kDa, and 120kDa
Anticentromere antibodies
found in 50–80% of patients with CREST syndrome, a subset of scleroderma
Anticentromere antibodies
5 major features of CREST syndrome
calcinosis
Raynaud’s phenomenon
esophageal dysmotility
sclerodactyly
telangiectasia
pattern produced by Anticentromere antibodies in IIF
discrete speckled staining in cell nuclei
Methods of ANA Detection
- IIF
- immunoperoxidase staining
- enzyme-linked immunosorbent assay (ELISA)
- microsphere multiplex immunoassays (MIA)
- radioimmunoassay (RIA)
- immunodiffusion
- immunoblotting (Western blot)
- dot blot
- immunoelectrophoresis
- microarray
heterogeneous group of antibodies that bind to phospholipids alone or phospholipids complexed with protein
Antiphospholipid antibodies
associated with deep-vein, arterial thrombosis and recurrent pregnancy loss
Antiphospholipid antibodies
found in up to 60% of patients with lupus
Antiphospholipid antibodies
identified by their ability to cause false-positive results in nontreponemal tests for syphilis, lupus anticoagulant assay, and immunoassays for antibodies to cardiolipin or other phospholipids
Antiphospholipid antibodies
APTT may be prolonged, but is not corrected by mixing with normal plasma; factor assays may also need to be performed to rule out any factor deficiencies or factor-specific inhibitors
Antiphospholipid antibodies
Rheumatoid Arthritis affects ___ of adult population
0.5 – 1.0%
age affected by RA
25 and 55
W:M of RA
3:1
chronic, symmetric, and erosive arthritis of peripheral joints that can also affect multiple organs such as heart and lungs
Rheumatoid Arthritis
Etiology of RA
HLA-DRB1 alleles or PTPN22 gene polymorphisms
cigarette smoking
strongest environmental risk factor of RA
cigarette smoking
caused by inflammatory process that results in bone and cartilage destruction
RA
lesions show an increase in cells lining the synovial membrane and pannus formation
RA
sheet of inflammatory granulation tissue that grows into the joint space and invades the cartilage
pannus
RA occur due to the balance between?
proinflammatory and anti-inflammatory cytokines;
IL-1, IL-6, IL-17, and TNF-α
trigger the release of matrix metalloproteinases from fibroblasts and macrophages; these enzymes degrade important structural proteins in the cartilage.
Proinflammatory cytokines
local bone erosion is found in this condition wherein osteoclasts become overly activated in inflammatory environment of the joints
RA
receptor activator of nuclear factor kappa-B ligand
RANKL
induces the differentiation of osteoclasts and inhibits bone formation in conjunction with other cytokines and RANKL
TNF-α
second major type of antibody associated with RA
antibodies to cyclic citrullinated proteins (anticyclic citrullinated peptide antibody [anti-CCP or ACPA])
modifies amino acid arginine by replacing an NH2 group with a neutral oxygen
citrulline
nonspecific symptoms of RA such as malaise, fatigue, fever, weight loss, and transient joint pain that begin in the small joints of hands and feet (joints are typically affected in a symmetric fashion) are usually present in the
MORNING
RA inflammation left untreated may lead to
permanent joint dysfunction and deformity
extra-articular manifestations of RA
subcutaneous nodules formation
pericarditis
lymphadenopathy
splenomegaly
interstitial lung disease
vasculitis
most common cause of death with RA
CV disease due to acceleration of arteriosclerosis by proinflammatory cytokines
treatment for RA
disease-modifying anti-rheumatic drugs (DMARDs)
methotrexate
inhibits adenosine metabolism and T-cell activation
methotrexate
key therapies for RA that blocks the activity of cytokine, TNF-α is classified into 2 categories
monoclonal antibodies to TNF-α
TNF-α receptors fused to an IgG molecule
treatment: monoclonal antibodies to TNF-α
▪ infliximab
▪ adalimumab
▪ certolizumab
▪ golimumab
treatment: TNF-α receptors fused to an IgG molecule
etanercept
antibody most often tested to make an initial diagnosis for RA
Rheumatoid Factor (RF)
an autoantibody, usually IgM class, that reacts with Fc portion of IgG; 70% to 90% of patients with RA test positive with this
RF
T/F
RF can be found in patients with other connective tissue diseases such as SLE, Sjögren’s syndrome, scleroderma, mixed connective tissue disease, some chronic infections
T
used for many years to detect RF
Manual agglutination tests using charcoal or latex particles coated with IgG
presence of this precedes the onset of RA by several years, making it a better marker for early disease
antibody to cyclic citrullinated peptides (anti-CCP) - ELISA
About __ of RF-negative patients are positive for anti-CCP
20 – 30%
Specificity of anti-CCP + RF testing for RA
98 – 100%
enable more accurate diagnosis of RA by allowing better differentiation from other forms of arthritis
anti-CCP + RF testing
(rheumatologists recommended)
CRP, ESR, and complement component levels in RA
CRP and ESR: elevated
Complement components: normal/elevated (due to increased acute-phase reactivity)
type of hypersensitivity of SLE
3
levels correlate well with RA disease activity because levels reflect the intensity of inflammatory response
CRP
aka Granulomatosis With Polyangiitis
Wegener’s Granulomatosis
rare autoimmune disease involving inflammation of small- to medium-sized blood vessels, or vasculitis
Wegener’s Granulomatosis
begins with localized inflammation of upper and lower respiratory tract
Wegener’s Granulomatosis
majority of patients have renal involvement, which can range from mild glomerulonephritis with little functional impairment to severe glomerulonephritis that can rapidly lead to kidney failure
Wegener’s Granulomatosis
involves pain and arthritis of the large joints, which is usually
symmetric but not deforming; skin lesions; ocular manifestations – potentially lead to vision loss
Wegener’s Granulomatosis
Without treatment of this disease, more than 90% of patients will die within 2 years of diagnosis
Wegener’s Granulomatosis
Etiology of Wegener’s Granulomatosis
HLA-DPB1 *0401 - Caucasian patients
HLA-DRB1 *0901 - Asian
HLA-DRB *1501 - African
chronic nasal infection with Staphylococcus aureus - WG relapse
Risk factors: exposure to silica or certain drugs (hydralazine and penicillamine)
In WG, S. aureus induce molecular mimicry as it contains peptides similar to
proteinase 3 (PR3) autoantigen
most have antibodies to neutrophil cytoplasmic antigens; in 80% of these, antibody is directed against an enzyme found in azurophilic granules of neutrophils called PR3
Wegener’s Granulomatosis
enzyme found in azurophilic granules of neutrophils
PR3
conditions to diagnose WG/GPA if 2 are met
- nasal or oral inflammation with oral ulcers or purulent or bloody nasal discharge
- abnormal chest x-ray, showing presence of nodules, fixed infiltrates, or cavities
- urinary sediment with microhematuria or RBC casts
- granulomatous inflammation on biopsy
Ab where WG/GPA is positive
antineutrophil cytoplasmic antibody (ANCA)
General laboratory findings of WG/GPA
▪ normochromic, normocytic anemia
▪ leukocytosis
▪ eosinophilia
▪ elevated ESR
▪ decreased albumin concentration in blood
▪ mild to severe renal insufficiency
▪ Urinalysis:
– Microhematuria
– Proteinuria
– Cellular casts
Serological findings of WG/GPA
▪ elevated CRP
▪ elevated immunoglobulin levels
▪ positive ANCAs (c-ANCA pattern)
▪ other autoantibodies, such as RF and ANAs
autoantibodies produced against proteins that are present in the neutrophil granules
Antineutrophil Cytoplasmic Antibodies (ANCAs)
ANCA is strongly associated with 3 syndromes involving vascular inflammation:
- GPA or WG
- microscopic polyangiitis (MPA)
- eosinophilic granulomatosis with polyangiitis
(EGPA; formerly known as ChurgStrauss syndrome)
*collectively known as ANCA-associated vasculitides (AAV)
mainly directed against PR3 antigen
GPA
specific for myeloperoxidase (MPO) Fluorescence observed through IIF, using ethanol-fixed leukocytes
MPA & EGPA
As the cellular substrate; 2 patterns of fluorescence of ANCA
cytoplasmic or c-ANCA
perinuclear or p-ANCA
appears as a diffuse, granular staining in the cytoplasm of neutrophils
cytoplasmic or c-ANCA
staining is most intense in the center of the cell between the nuclear lobes and gradually fades at the outer edges of the cytoplasm
cytoplasmic or c-ANCA
fluorescence surrounds the lobes of the nucleus, blending them together so that individual lobes cannot be distinguished
perinuclear or p-ANCA
