15 - Hypersensitivity and Auto Immunity 2 Flashcards
An immune reaction against self antigen is the definition of _. When is this not a bad thing?
Autoimmunity Tumors
What are the 3 criteria for diagnosing autoimmunity?
-presence of autoimmune rxn-evidence that rxn is not secondary to tissue damage-absence of well defined cause of disease
A break down of what process leads to pathologic autoimmunity?
Self tolerance
A state where the individual is incapable of developing an immune response to a specific antigen is _. What are the 2 types?
- Immunological tolerance
- Central and peripheral tolerance
One mechanism of central tolerance is clonal deletion. What happens during clonal deletion?
Deletion of self reactive clones of cytolytic and helper T-lymphocytes
Why is it thought that clonal deletion of B cells is of minor importance?
Because there is a relatively high rate of auto-antibodies documented
Within the thymus, where are each of the following cells found? Lymphoid cells,epithelial cells, dendritic cells, macrophages? Which express MHC1? Which express MHC 2?
Lymphoid cell - Thymus - MHC1
Epithelial cells - Cortex - MHC1
Dendritic cells - Corticomedullary junction - MHC1 and 2 Macrophages - medulla - MHC1 and 2
Regarding central tolerance, the process where thymocytes are selected for their ability to bind self MHC molecules is _
Positive selection
Regarding central tolerance, the process of elimination of clones of thymocytes that bind self antigens is _. This also known as _
Negative selection Clonal deletion
Clonal anergy is a tolerance mechanism important is central or peripheral tolerance?
Peripheral tolerance
What are 2 signals required for maximal stimulation of a T cell?
Recognition of MHC2 on antigen presenting cell (APC)
Costimulators presented by APC
What happens when T cells are presented with antigen in the absence of costimulators?
No activation / immune response, anergy of the T cell, essentially its elimination
Another mechanism for peripheral tolerance is suppression. What cells are characteristically involved with this process? What are the 2 major cytokines involved?
- CD4+/CD25+ cells
- IL-10 and TGF-beta
Another mechanism of peripheral tolerance is activation induced cell death. How does this happen? What receptor / ligand pair is associated with this process?
- High antigen dose + chronic stimulation leads to elimination of T-cells- Fas receptor and fas ligand (FasL)
Which is more highly expressed in the human body, self antigens or foreign antigens? What does this mean for self reactive lymphocytes?
Self antigens Self reactive lymphocytes will be maximally and continually stimulated, leading to their apoptosis and elimination (activation induced cell death)
What is the number 1 cause of acquired immune deficiency globally?
Malnutrition
Another mechanism of peripheral tolerance is sequestration. What does this mean? What are the 3 examples provided in the lecture?
Antigens are kept in immuno-priviledged areas Eye, testis, brain
What disease is associated with defect in Fas/FasL?
ALPS - Autoimmune lymphoproliferative syndrome
What are 2 ways infection can cause breakdown of self tolerance?
- Alteration in levels of co-stimulators (e.g. on fibroblasts and epithelial cells)
- Molecular mimicry
What are the 2 broad categories of autoimmune disease?
- Systemic multi organ disease
- Organ systemm of cell type specific
Regarding lupus, is it more common in men that women? What is thought to underlie this difference in gender prevalence?
- More common in women
- Estrogen - make more tolerant
In what stage of life are people more likely to be affected by lupus?
Child bearing years, mainly women
What are the HLA types associated with lupus? A congenital deficiency in what 2 complement proteins may promote lupus development?
- HLA types DR2 and DR3
- Deficiency of C2 and C4 complement components
A hallmark of SLE is B lymphocyte hyperactivity. What are 3 antibodies that are diagnostic for lupus?
- Anti-nuclear ab
- Anti-native DNA
- Anti-Sm
A hallmark of SLE is B lymphocyte hyperactivity. What are 3 antibodies that are mentioned in our notes that alter the symptomatology of SLE disease?
- Anti-RBC
- anti- lymphocyte
- Anti-phospholipid (e.g. anti cardiolipin)
What is the characteristic skin finding on SLE patients, especially on sun exposed areas? (2)
- Butterfly (malar) rash on face
- erythematous patches
What is a kidney finding on SLE patients?
Destruction of glomeruli (glomerulonephritis)
What is the major determinant of the different manifestation of SLE in different patients?
The variety of auto antibody produced
A SLE subtypes that is associated with skin manifestations only in the skin, especially the face and scalp with rare incidence of systemic manifestation is _. What type of antibody would you NOT see in this case?
- Chronic discoid lupus
- Won’t see DS/native DNA antibodies
A SLE subtype associated with skin localized and mild systemic symptoms is _. What antibody and HLA genotype is associated with this SLE subtype?
- Subacute cutaneous lupus
- Anti-SSA-HLA-DR3
An SLE subtype associated with drugs that induce antinuclear antibody formation is _. What symptoms, compared to normal lupus, is usually not present in these patients?
- Drug induced lupus
- No CNS or renal manifestations
In patients with drug induced lupus, would you expect to find anti-DS-DNA antibodies? What about anti-histone antibodies? What HLA subtype is associated with this type of lupus?
- Anti- DS-DNA antibody negative
- Anti-histone antibody positive
- HLA-DR4
How do you treat patients with drug induced lupus?
Remove the drug
What are behavior modifications that can be suggested to treat lupus?
- Reduce stress
- avoid sun
What are the 3 drugs that were presented as immunosuppresives used to treat the systemic manifestations of lupus?
- Corticosteroids
- Cytoxan
- 6-mercaptopurine
Why is therapy for SLE using rituximab considered “hit or miss”?
Rituximab targets CD20. Plasma cells producing antibodies associated with lupus don’t have CD20 on their surfaces
The 10 year survival for SLE patients is at about 80%. What are the 2 main causes of death in these patients?
- Immunosuppressive toxicity (BM aplasia,secondary neoplasms, infectious diseases)
- Renal failure
Rheumatoid arthritis affect more males or females? What is the age range of most patients?
- More females than males
- 35-50 yrs old
Symmetric symptoms including pain affecting 2-3 joints, stiffness that improves as the day goes along, swelling and inflammation in joints are all characteristic of _.
Rheumatoid arthritis
True or false. RA may be associated with malaise, fever, fatigue, loss of appetite, weight loss, myalgias,weakness
True - In serious cases only
What are joints that are most affected by RA?
Hands and wrists
Is juvenile RA more or less common that adult RA? Is it more or less severe?
Less common, more severe
What happens to the normal cartilage within the joints of patients with RA?
It is destroyed by inflammatory cells and replaced by fibrous tissue
What is the cytokine that is secreted by infiltrating leukocytes and inflamed synovial cells that is thought to underlie the positive feedback loop associated with RA pathogenesis?
TNF-alpha
What are the 3 types of hypersensitivity associated with RA? Which is particularly associated with extrarticular manifestations of RA?
- Types 2, 3 and 4
- Type 3 assoc. with extra-articular manifestations of RA
What is the autoantibody that is detected in serum of 80% of RA patients? Is it specific for RA?
Rheumatoid factor
Not specific
How would the clinical course of RA be described?
Relapsing and remitting
True or false: joint deformities associated with RA are progressive in only 50% of patients
True
What is the classic treatment for RA?
Rest and aspirin
Beyond aspirin, what are 3 types of drugs used to treat RA?
- Corticosteroids
- Cytotoxic drugs
- Biological response modifiers
What are the 3 examples of biological response modifiers used to treat RA?
- TNF-alpha blockers
- Anti-TNF-alpha antibodies
- Rituximab
What is another name for systemic sclerosis? Are males or females more likely to be affected? What are 2 genes associated with this disease?
- Scleroderma
- More females than males
- HLA class 2 and Fibrillin
Majority of the clinical findings associated with systemic sclerosis are because of _
Increased deposition of connective tissue in skin, intestines and blood vessels
What are 2 antibodies used to diagnose systemic sclerosis? Which is specific for the CREST variant of systemic sclerosis?
- Anti Scl-70 antibody
- Anti-centromere antibody (specific of CREST variant)
What lyphocyte type is thought to mediate increased release of cytokines associated with the manifestations of systemic sclerosis? What cells are thought to be hyperreactive to these released cytokines?
- CD4+ cells cause cytokine release
- Fibroblast hyperreactive to the cytokine release
The variant of scleroderma that has widespread skin andvisceral involvement with rapid progression is _
Diffuse scleroderma
The variant of scleroderma that mainly has skin involvement primarily in the face, hands and forearms is called _.
- CREST syndrome
- C alcinosis
- R aynaud Phenomenon,
- E sophageal dysmotility,
- S clerodactyly,
- T elangectasia
What is the result of vascular thickening as seen in systemic sclerosis?
Reduced blood flow
What is the major cause of death in patients with systemic sclerosis?
Malnutrition - Because of replacement of GI submucosa with fibrosis
What is the patient demographic of Sjogren’s syndrome?
50-60 y.o. females
What are the 5 proteins (non-antibody) associated with Sjogrens?
- HLA-B8,
- HLA-DR3,
- HLA-DQA1,
- HLA-DQB1,
- DRW52
What are the 2 auto antibodies associated with Sjogrens?
- Anti - SS-A (ro)
- Anti - SS-B (La)
What are the 2 glands destroyed in patients with Sjogren’s syndrome? What are the 2 likely mediators?
- Lacrimal and salivary glands
- CD4+ cells
- Viruses (EBV, HCV, HTLV-1)
Why do many patients with Sjogren’s go blind?
Loss of lacrimation leads to drying of the cornea
