ICL 10.0: Autoimmune Diseases Flashcards
what causes autoimmune diseases?
loss of self tolerance
what are the two categories of autoimmune diseases?
- organ specific
2. organ nonspecific
what are organ specific autoimmune diseases?
autoimmunity is directed against a component of a single organ, thus, the resulting clinical symptoms are related to dysfunction of that organ
ex. Hashimoto’s
what are organ nonspecific autoimmne diseases?
autoimmunity directed at antigens that are dispersed in many organs
ex. SLE
what is the pathogenesis of autoimmune diseases?
the pathogenesis involves T cell recognition of specific autoantigen resulting in T and B cell activation and the generation of autoantibodies
autoimmunity in the pancreas causes what?
type I diabetes
autoimmunity in the stomach causes what?
pernicious anemia
autoimmunity in the CNS causes what?
multiple sclerosis
autoimmunity in the thyroid causes what?
Grave’s diseases
Hashimoto’s thyroiditis
autoimmunity in the muscles causes what?
myasthenia gravis
what is pernicious anemia?
results from malabsorption of vitamin B12 that is caused by intrinsic factor deficiency due to one of two mechanisms
B12 has to bind to IF in the stomach in order to be absorbed from the gut into the bloodstream
parietal cells secrete IF
what are the two mechanisms in pernicious anemia that can cause intrinsic factor deficiency?
- progressive autoimmune destruction of parietal cells of the gastric mucosa leading to intrinsic factor deficiency
- the presence of blocking autoantibodies to the intrinsic factor that prevents the formation of vitamin B12-intrinsic factor complex
95% of patients have demonstrable anti-parietal cell antibodies &/or anti-Intrinsic factor antibody
what is the clinical presentation of pernicious anemia?
- low Hb
- unsteady gait, mental changes, confusion, impaired memory, inappropriate behavior
- high MCV
- low B12 levels
what is myesthenia gravis?
an autoimmune disorder that affects the neuromuscular junctions leading to weakness of voluntary muscles with repeated use
the autoantibody involved is anti-ACh receptor antibodies
the autoantibodies target ACh receptors and if ACh can’t bind, then the muscles can’t depolarize and there’s no muscle contraction
which diseases are examples of organ-nonspecific autoimmune diseases?
- Rheumatoid Arthritis (RA)
- Systemic Lupus Erythematosus (SLE)
- Scleroderma, Systemic Sclerosis (SSc)
- Sjögren’s Syndrome (SS)
- Polymyositis/Dermatomyositis (P/DM)
- Vasculitis
- Seronegative spondyloarthropathy
what are constitutional symptoms?
aka systemic symptoms
malaise, low grade fever, and weight loss
what lab results would you see with systemic inflammation?
- elevated RBC sedimentation rate
- elevated C-reactive protein (CRP)
- autoantibodies
what are the two categories of autoantibodies?
- disease nonspecific antibodies
2. disease specific autoantibodies
which autoantibodies are disease non-specific?
antinuclear antibodies (ANA)
rheumatoid factor (RF)
what concentration is a negative titer?
<1:40
what concentration is a low antibody level titer?
1:40 to 1:80
what concentration is an elevated antibody level titer?
> 1:80
what are the 5 titer patterns?
- peripheral/rimmed
- homogenous
- speckled
- centromere
- nucleolar
what antibody and disease is related to a peripheral/rimmed pattern?
antibody: anti-dsDNA
disease: SLE
what antibody and disease is related to a homogenous pattern?
antibody: anti-dsDNA, anti-histone
diseases: RA & SLE
what antibody and disease is related to a speckled pattern?
antibody: SS-A, SS-B, anti-Sm, anti-RNP, anti-Jo-1, anti-Mi-2, anti-Scl-70
diseases: SLE, SSc, PM/DM, Sjogrens
what antibody and disease is related to a centromere pattern?
antibody: anti-centromere
disease: SSc
SSc = Systemic Sclerosis
what is ANA used to test for?
super helpful for diagnosing SLE and systemic sclerosis (SSc)
somewhat useful for diagnosing Sjogren’s syndrome and PM/DM
also helpful with identifying:
- idiopathic arthritis in kids
- distinguishing patients with primary Raynaud’s phenomenon from those with Raynaud’s phenomenon associated with an underlying systemic autoimmune disease
- drug induced lupus
- autoimmune hepatitis
is being ANA positive diagnostic for an autoimmune disease?
no!
ANA positivity is not specific for autoimmune diseases
15% of the healthy population is ANA+!
normal people are ANA+ but at low titer concentrations; as the concentration increases ANA is more indicative of autoimmune disease
what are rheumatoid factors?
disease *nonspecific autoantibodies
RFs are antibodies directed against the Fc fragment of IgGs
RFs are present in 80% of RA patients but they are also present in many other autoimmune diseases and 10% of the healthy population so they are not diagnostic for RA!
what is the serum sickness model?
- an animal (rabbit) is injected intravenously with another animal’s (horse) serum
- recipient animal generates antibodies to donor serum
- at a certain stage, the recipient develops circulating immune complexes that consist of donor antigens combined with recipient antibodies
- IC deposit in the tissues, fixes complement and initiates inflammatory reactions that causes tissue injury
in the one shot serum sickness model surviving animals will have life long immunity to the offending antigen
recurrent serum sickness leads to chronic illness with carditis, nephritis, arthritis and skin rashes
what’s the net result of serum sickness?
immune complexes depositing in tissues and joints
usually in kidney tissue!
what is SLE?
a multi-system autoimmune disease associated with genetic and environmental risk factors
SLE is characterized by inflammation in several organ systems and by the production of autoantibodies that participate in immunologically mediated tissue injury
what population is SLE most common in?
women of childbearing years
specifically non-white ethnic women
African Americans, Asian, Hispanic, and Native Americans are three times more likely to develop SLE than Caucasians and they often have more aggressive form of SLE
what is a major cause of death in SLE patients?
cardiovascular disease
due to widespread inflammation
what are the main symptoms of SLE?
- fatigue
- low grade fever
- anorexia/weight loss
does SLE have a genetic predisposition?
yup
there is a high concordance in monozygotic twins - 25% chance of the second twin getting SLE if the first one has it
5-13% of relatives have disease
which gene encodes for SLE?
trick question, there is no single lupus gene! the disease is polygeneic
there are at least 40 susceptibility genes that have been identified
which genes put people at risk for SLE?
HLADR2
HLADR3
HLADR4
HLADR8
these are present in 75% of SLE patients
theses genes are associated with B and T cell activation, apoptosis induction and removal of apoptotic bodies, and clearance of immune complexes
what are the effects of SLE on the immune system?
- activation of innate immunity
- loss of tolerance via failed elimination of autoreactive T lymphocytes
- polyclonal activation of B cells
- defective function of T regulatory cells
- delayed clearance of apoptotic cells, resulting in autoantigenic stimulation
- defective clearance of circulating immune complexes = tissue damage
- deficiency or dysfunction of the early complement components
what are the specific antibodies involved in SLE?
- anti-dsDNA
- anti-Sm (Smith)
both are highly specific for SLE
**absence of these antibodies does NOT rule out SLE
what changes occur during an SLE flareup?
decreased complement because it’s binding to the accumulating immune complexes
increased anti-dsDNA
what is used to treat SLE?
corticosteroids like prednisone
they help to increase complement levels and decreased anti-dsDNA so that symptoms subside
which organs are commonly involved in SLE?
- CNS
- kidneys** 50% of SLE patients have nephritis
- eyes and mucous membranes
- GI
- heart and lungs
- skin
- hematologic
- musculoskeletal
what are the symptoms of SLE?
- fevers
- swollen joints
- extreme fatigue
- skin rashes
- anemia
most common, in that order
what is the criteria to officially be diagnosed as having SLE?
if you have 4/11 of the following, there is a 86% you have SLE
Malar rash
Discoid rash
Photosensitivity
Oral/nasal ulcers
Serositis
Nephritis
Non-erosive arthritis
Cytopenias
Neuropsychiatric
+ ANA
+ Immunoserology
how do you treat SLE?
there is no cure for SLE, just drugs to modify the course of the disease and alleviate symptoms
Hydroxychloroquine
Methotrexate
Corticosteroids
Mycophenolate mofetil
Cyclophosphamide
Rituximab
Belimumab
IVIG
Plasma exchange
what is the mortality of SLE?
bimodal mortality
early deaths: infection and renal involvement
later deaths: atherosclerotic disease
what is rheumatoid arthritis?
a chronic disabling inflammatory arthritis, which is associated with a significant morbidity and an increased mortality
progressive joint destruction and extra-articular manifestations account for the disability and increased mortality
what population is RA more common in?
3x more common in women than men
what 3 signs would make you suspect RA?
- symptoms lasting for over 6 weeks
- inflammatory synovitis
- symmetrical and polyarticular swelling
which joints are usually not effected by RA?
thoracolumbar spine
DIPs of the fingers and IPs of the toes
what is the specific autoantibody in RA?
anti-CCP
anti-citrullinated cyclic peptide
how is peptide cirtullination related to RA?
Peptide citrullination is post-translational conversion of arginine to citrulline by peptidylarginine deiminase (PAD)
WBC release PAD during inflammation so peptide citrullination can be seen in any chronic inflammatory process
patients with RA react to citrullinated peptide by forming antibodies “rheumatoid signature”
how accurate is anti-CCP in detecting RA?
sensitivity: up to 70% of RA patients
specificity: 98% specific for RA
which autoantibodies are related to RA?
- anti-CPP
2. RF
how is RA categorized?
based on if anti-CPP and/or RF autoantibodies are present
- patient with RA may have positive RF and positive CCP antibodies (60%) = most aggressive
- positive RF and negative CCP
- positive CCP and negative RF
- negative RF and negative CCP
what are the risk factors for RA?
- genetics
- bacterial or viral agents: parovirus, hepatitis, EBV, rubella
- environmental triggers: tobacco,
which gene is associated with an increased risk for RA?
HLA-DRB1 gene
what is the pathology of RA?
the pathology of RA extends throughout the synovium and joint
in contrast to the acellular nature of normal synovial fluid, RA synovial fluid is enriched predominantly with neutrophils; but macrophages, T lymphocytes, and dendritic cells are also present
the increase in cellularity is most obvious in the synovial membrane, which becomes infiltrated by cells recruited from the blood
the most abundant cells of the pannus are macrophages and T lymphocytes, but plasma cells, dendritic cells and activated fibroblasts are also found
inflammation in the synovium will grow into the joint and start eroding the bone and cartilage
what effects does RA have on the body outside of the joints?
- episcleritis
- digital infarct
- rheumatoid nodules
pulmonary fibrosis - pleural effusion/pleurisy/lung nodules
- pericarditis/myocarditis/valvular heart disease
what are the two treatment options for RA?
- disease modifying drugs (DMARDs)
2. immunosuppressive drugs
which DMARDs are used to treat RA?
- hydroxychloroquine
- minocycline
- sulfasalazine, hydroxychloroquine
which immunosuppressive drugs are used to treat RA?
- methotrexate
- azathioprine
- cyclophosphamide
- cyclosporine
what are the newer therapies for RA?
1. Anti-TNF-α: Monoclonal antibody: Infliximab. Adalimumab. Soluble TNF receptor: Etanercept.
- Anti-IL1: IL1-Ra, anakinra.
- Anti-IL6 receptor antibody, tocilizumab.
- Anti-B cells: rituximab.
- Costimulatory molecules inhibitors: abatacept.
what is systemic sclerosis?
SSc is a chronic systemic autoimmune disease that targets skin, lung, heart, GI tract, kidneys, and the musculoskeletal system
the pathology is characterized by immune activation and widespread & progressive vasculopathy and tissue fibrosis
skin isn’t stretchy
which antibodies are related to scleroderma?
centromere
Scl70
RNA pol III
what are the major clinical complications of SSc?
Extensive skin fibrosis and musculoskeletal disorder including myopathy
Interstitial lung disease and pulmonary fibrosis
Pulmonary arterial hypertension
Diastolic cardiac dysfunction (stiff heart)
Digital ischemic ulcers
Malabsorption and GI dysmotility
Renal crisis and renal vascular disease
