Section 2: Systemic autoimmunity - Systemic Lupus Erythematosus Flashcards
Autoimmunity
failure of an organism to recognize self antigens, resulting in immune responses to that organism’s tissues
-if affects 5-7% of the population
-a variety of factors result in autoimmune diseases (genetics, environmental exposures, and infections)
-in general all result from the breakdown of self tolerance and the development of an adaptive immune response to self antigens
-more common in women than in men
central tolerance
- In the thymus, T cell progenitors give rise to billions of thymocytes, each with a different T cell receptor
- thymocytes are positively selected by epithelial cells in the cortex of the thymus
- positively selected thymocytes to survive and divide
- Positively selected thymocytes clones are negatively selected in the thymic medulla
- clones surviving negative selection leave the thymus for circulation (less than 1% are selected by pathogens)
Mechanisms that contribute to self-tolerance
-negative selection in bone marrow (B cell) and thymus (T cell)
-expression of tissue-specific proteins in the thymus
-no lymphocytes access to some tissue (brain, eye, testis)
-supression of autoimmune response by regulator T cells
-induction of anergy in autoreactive B+T cell
anergy
-state of programmed functional inactivation following exposure to an antigen. B+ T cells are said to be anergic when they cannot respond to their specific antigen
senescence
(immunosenescence) is the graudal loss of immune function due to natural aging
Autoimmune effector functions
-similar to hypersensitivity reactions, autoimmune diseases can be classified by the effector mechanism causing the disease
-three types: Type II, Type III, and Type IV
-can also be group by organ specific or systemic
autoimmune hemolytic anemia: autoantigen and consequence
-Rh blood group antigens, I antigen
-destruction of RBC by complement and phagocytes anemia
Autoimmune thrombocytopenia purpura: autoantigen and consequence
-platelet integrin
-gpllb:llla
-abnormal bleeding
Goodpasture’s syndrome: autoantigen and consequence
-non collagenous domain of basement membrane collegen type IV
-glomerulonephritis , pulmonary hemorrhage
pemphigus vulgaris: autoantigen and consequence
-epidermal cadherin
- blistering of skin
acute rheumatic fever: autoantigen and consequence
-streptococcal cell wall antigens, antibodies cross-react with cardiac muscle
-arthritis
-myocarditis
-late scarring of heart valves
graves’ disease: autoantigen and consequence
-thyroid stimulating hormone receptor
-hyperthyrodism
myasthenia gravis: autoantigen and consequence
-acetylocholine receptor
-progressive weakness
type 2 diabetes (insulin resistant diabetes): autoantigen and consequence
-insulin receptor (antagonist)
-hyperglycemia
-ketoacidosis
hypoglycemia: autoantigen and consequence
-insuline receptor (agonist)
-hypoglycemia
subacute bacterial endocarditis: autoantigen and consequence
-type III
-bacterial antigen
-glomerulonephritis
mixed essential cryoglobulinemia: autoantigen and consequence
-type III
-rheumatoid factor IgG complexes (with or without hepatitis C antigens)
-systemic vasculitis
systemic lupus erythematosus: autoantigen and consequence
-type III
-DNA, histones, ribosomes, snRNP, scRNP
-glomerulonephritis
-vasculitis
-arthritis
Type I diabetes (insulin-dependent diabetes mellitus): autoantigen and consequence
-type IV
-pancreatic B cell antigen
-B cell destruction
Rheumatoid arthritis: autoantigen and consequence
-unknown synovial joint antigen
-joint inflammation and destruction
multiple sclerosis: autoantigen and consequence
-myelin basic protein, proteolipid protein
-brain degeneration paralysis
Lupus erythematosus
-is a group of similar conditions which IgG antibody is formed to nuclear antigens (DNA histones) that have been released due to cell death
- systemic lupus (most common)
-discoid lupus
-drug induced lupus
-neonatal lupus
SLE Epidemiology
-SLE is 10x more common in women than men
-more prevalent in non-Europeans
-no single genetic factor or cause linked to SLE, though there is a genetic component that is heritable in families (HLA)
-environmental exposure have been suggested to play a role in onset or exacerbation (infection, drugs, hormones, stress)
SLE symptoms
-difficult to diagnosis b/c symptoms mimic a variety of other clinical syndromes
-symptoms caused by immune complex deposition: fever, pain, confusion, proteinuria, loss of appetite
-90% of SLE patients suffer from arthritis
50% of SLE patients suffer from classical butterfly facial rash
-was first described as SLE on the basis of the butterfly shaped rash on the face that gives the patient a wolf-like apperance
-rash is caused by the deposition of immune complexes in the skin (type III)
erythema- meaning
lupus- meaning
red, redness of the skin
-wolf
antinuclear antibodies (ANA)
Ab directed against nuclear antigens
-other contributing factor to the development of ANAs is an abnormality in apoptosis
-body replaces more than 1 million cells every second
-the inefficient clearing of dying cells and the accumulation of cell remnants are considered an intrinsic defect that leads to the development of ANAs and ultimately SLE
-there is also probably a breakdown in T-cell tolerance
-nuclear antigens form immune complexes that travel throughout the body
-antibodies that target “normal” proteins within the nucleus of a cell
-immune complex deposition in: kidneys, joints, blood vessels, skin, lungs, liver, nervous system, heart
diagnosis and testing (SLE)
-test for the presence of ANAs (95% of SLE patients have a positive ANA, but ANA can also be found in other autoimmune disease (sjorgen’s syndrome and rheumatoid arthritis)
indirect immunofluorescence (IFF)
-classic test used to test for ANAs
-test various dilutions of patients serum against a cell substrate to observe presence and pattern of ANA staining
-cell substrate: HEp-2 cells, human laryngeal epithelioma cancer cells
common ANA patters
-homogenous diffuse
-nucleolar
-speckled
-peripheral (rim)
systemic lupus erythematosus
-autoreactive B cells probably exist normally in circulation but without a T-cell that also recognizes the auto antigen… the B cell will not be activated and produce antibodies
1. H1-specific helper T cell activates histone H1-specific B cells that process nucleosomes containing H1 and present H1 peptides
2. Activates B cell differentiates into plasma cells secreting anti-H1 antibody
3. H1-specific helper T cell activates DNA- specific B cells that process nucelosomes and present H1 peptides
4. Activated B cell differentiates into plasma cells secreting anti-DNA antibody
SLE (ANA-IIF)
-have the hept2 cell mobilized onto the cell and incubate the patient serum to see if they have antibodies. Come in with a detection antibody (anti-human IgG) and get it to fix and incubate then wash away. Then set it up with a fluroscent scope
Homogenous staining: antibody/antigen and disease
-deoxyribonucleoprotein
-histones
-dsDNA
-Systamatic lupus
-most important
peripheral staining: antibody/antigen and disease
-dsDNA
-SLE
-most important
speckled staining: antibody/antigen and disease
-saline extractable antigens
-anti smith Ab (Sm)
-SLE
-Anti-Ro (SS-A)
- Anti-La (SS-B)
-sjogren’s syndrome
-Anti-topoisomerase I (Scl-70)
-systemic sclerosis
anti-nuclear ribonucleoprotein (RNP)
-SLE
-Mixed connective tissue disease (MCTD)
Nucleolar staining: antibody/antigen and disease
-nucleolar RNA
-SLE
-systemic scleroderma
Three common ANA type for SLE
-Anti-dsDNA
-Anti-Sm
-Anti-histone
SLE testing and ELISA
-ELISA’s are used to narrow the diagnosis (mostly in the case of speckled stained cells)
-the ELISA can identify what specific antibody is present in the patient serum
-antibodies to dsDNA producing a homogenous or peripheral stain are the most disgnostic for SLE
(70% present in patients with SLE)(<1% in patients without SLE)
-Anti-Sm is also seen predomiately in SLE patients but is rarer 20-30% and produced the speckled pattern
SLE testing and flow cytometry
-each bead has its own fluorescent profile is coated with a different specific antigen
-mix together with patient IgG or patient sample, then come in with anti-human IgG and as long as their is patient antibody to patient antigen you will get production of complex
-you wash away and use flow cytometer to read as a flow cytometry
