I17 Flashcards
1
Q
What is autoimmunity?
A
adaptive immunity that is specific for self-determinants.
2
Q
What is an antagonist in the sense of autoimmunity?
A
An antibody that binds to a cell surface receptor, thereby preventing its function
3
Q
What is an agonist in the sense of autoimmunity?
A
an antibody that binds to a cell surface receptor in a way that mimics the binding of the actual ligand to the receptor
4
Q
How do autoimmune diseases arise?
A
through breakdown of the negative selection processes that remove self-reactive B cells and T cells from the lymphocyte repertoire
5
Q
What are some body functions that help prevent autoimmunity?
A
1) Negative selection in bone marrow and thymus via AIRE2) Restricting lymphocyte accèss from certain sites (e.g. eyes and testes)3) Tregs
6
Q
What are some common Type II autoimmunity disorders?
A
1) Autoimmune hemolytic anemia2) Autoimmune thrombocytopenia purpura3) Goodpasture’s syndrome4) Pemphigus vulgaris5) Graves disease6) Myasthenia graves7) Type 2 diabetes8) Hypoglycemia
7
Q
What is autoimmune hemolytic anemia?
A
a condition that results from priming of an acquired antibody response to surface determinants of RBCs. These responses are mediated primarily by IgG, but some IgM will also be produced and can participate. When this response is made, the antibodies bind to RBCs and become ligands for complement component C1q. Once C1 binds, the classical complement pathway becomes activated, resulting in deposition of C3b on RBCs as well as direct lysis of RBCs by abundant membrane attack complex formation. Opsonized RBCs are taken up and destroyed by phagocytes (via CR1) that recognize complement and IgG opsonins in the spleen.
8
Q
How can autoimmune hemolytic anemia be verified?
A
a direct Coomb’s assay (direct antiglobulin test)
9
Q
How would you treat autoimmune hemolytic anemia?
A
corticosteroids
10
Q
What is Autoimmune (Idiopathic) Thrombocytopenic Purpura?
A
IgG-mediated inhibition of an enzyme responsible for cleavage of von Willdebrand factor (vWF)OR IgG specific for gpII:IIIa on platelet surface
11
Q
What happens when vMF is not cleaved?
A
excessive platelet adhesion occurs, partially occluding small blood vessels. As RBCs pass thru the partially obstructed vessels, they are damaged (microangioplastic hemolytic anemia)
12
Q
What else occurs in Autoimmune Thrombocytopenia Purpura?
A
In addition, excessive platelet adherence results in damage to kidneys, liver, and even the brain, as well as platelet depletion from the circulation.Reduced platelet numbers reduce the ability of the host to produce clots, so these patients also develop purpura (bruising).
13
Q
How is diagnosis of ATP perfomed?Treatment?
A
Diagnosis: observation of microangioplastic hemolytic anemia. Treatment: plasma exchange (plasmapheresis) with plasma from healthy donors.
14
Q
What is Goodpasture’s syndrome?
A
a condition caused by an IgG response to the α-chain of type- IV collagen (lines basement membranes all over the body)
15
Q
What does IgG binding to type IV collagen result in?
A
Once antibodies bind, inflammation mediated by the classical complement cascade (and then the alternative pathway) and phagocytes causes tissue damage.
16
Q
What tissues are most affected by Goodpastures?
A
The most important tissue damage is in the kidneys, resulting in progressive kidney dysfunction and culminating in glomerulonephritis.25% of ALL kidney failure can be attributed to damage caused by the immune system
17
Q
What are some common symptoms of Goodpasture’s disease?
A
loss of appetite, weakness, fatigue, progressive loss of kidney function
18
Q
How do diagnose Goodpasture’s?Treatment?
A
measurement of glomerular basement membrane-specific antibodies (anti-GBM)Treatment: plasma exchange and with anti-inflammatory drugs
19
Q
What is Schleroderma?
A
an IgG-mediated autoimmune disease that results in damage to the vascular endothelium of arteriole and smooth muscle cells that results in replacement of damaged tissue with collagen that results in skin thickening and hardening.
20
Q
What other tissues besides skin are impact by Scleroderma?
A
kidneys, blood vessels, liver, and brain
21
Q
What are the common symptoms of Scleroderma?
A
localized or systemic skin thickening: hard, smooth, ivory colored areas of hardened skin
22
Q
What are the symptoms of Scleroderma mediated by?
A
ANA (anti-nuclear Abs), ATA (anti-topoisomerase Abs), and ACA (anti-centromere Abs), all IgGs.diagnosis is via presence of any of these
23
Q
What is the treatment of Scleroderma?
A
no standard treatment, but most include drugs that increase blood flow to extremities
24
Q
What are the two forms of Scleroderma?
A
1) Limited scleroderma or CREST syndrome2) Diffuse scleroderma
25
What is CREST syndrome characterized by?
Involves production of anti-centromere antibodies. This form is milder, and skin thickening is less widespread, typically confined to fingers, hands, and face and slowly developing
26
What is Acute Rheumatic Fever caused by?
an autoimmune condition that results from molecular mimicry. A normal IgG response to group A Streptococcus pyogenes (GAS) infection cross reacts with normal host tissue. There are streptococcal envelope components that are very similar to determinants that are expressed on cardiac tissue. Typically, several weeks after a GAS infection (in some patients), damage to the heart is mediated by cross-reactive IgG, and the resulting inflammatory response (myocarditis) becomes symptomatic due to scarring of heart valvesnot a memory response
27
What are the symptoms of Acute rheumatic fever?
chest pain, shortness of breath, fever, joint pain
28
What is acute rheumatic fever "acute" in nature?
since T cells do not recognize the streptococcal surface antigens, B cells cannot be fully activated; therefore, no immunological memory results and the autoimmune disease is transientmainly an IgM response, not a memory response
29
What is Pemphigus vulgaris?
autoimmune condition mediated by IgG specific for 2 proteins (desmoglein 1 and 3); results in loss of cohesion inkeratinocytes in the epidermis
30
What are the symptoms of Pemphigus vulgaris?
painful chronic skin blistering
31
How is diagnosis of Pemphigus vulgaris performed?
immunofluorescent staining to identify IgG4 AB bound to tissue from a punch biopsy
32
What is the treatment for Pemphigus vulgaris?
corticosteroids and ritiximab (CD20-specific mAb)
33
What is Grave's disease?
an autoimmune condition in which thyroid stimulating hormone receptor (TSH receptor)-specific IgG antibodies cause over-production of thyroid hormone because they act as receptor agonists of TSH
34
What are some of the symptoms caused by Grave's disease?
bulging eye syndrome (with a characteristic stare) is hallmark; also: enlarged thyroid, heat intolerance, nervousness, irritability, weight loss, and moist skin
35
How does normal thyroid functioning occur?
When thyroid hormone does not need to be produced, thyroglobulin is stored in the thyroid in an iodinated form.When thyroid hormone is needed, the pituitary produces TSH that, in turn, binds to TSH receptors on the thyroid, resulting in secretion of active T3 and T4 thyroid hormones.Grave's disease targets this.
36
Is Grave's disease hereditary?
No, but because Grave’s disease is an IgG-mediated autoimmune disease, a pregnant woman with the condition will pass these IgGs to the developing fetus, and the fetus will also suffer from the condition.Following birth, the treatment for the child is plasma exchange (or plasmaphoresis) to remove the antibodies. Once the mother’s TSH-specific IgGs are removed from the child’s circulation, normal thyroid function will be restored.
37
What is Myasthenia Gravis caused by?
IgG antibodies bind to acetylcholine receptors, causing them to be endocytosed and destroyed (recycled). Over time, this results in depletion of acetylcholine receptors at neuromuscular junctions, making muscles less sensitive to neuronal stimulation. Patients with this condition experience progressive weakness due to muscle atrophy.
38
What are the common symptoms of Myasthenia gravis?
typically begin with facial muscles, and especially muscles of the eyes and eyelids. These patients often present with diplopia (double vision) and ptosis (sagging eyelids). Over time, the condition progresses to generalized muscle weakness (worse in the evenings)Approximately 10% of these patients also develop a thymoma (a tumor of the thymus that is either benign or malignant).
39
What is the treatment of Myasthenia gravis?
With immunosuppressive drugs (to prevent formation of autoantibodies), or a drug called pyridostigmine which inhibits cholinesterase (which degrades acetylcholine); longer-lived acetylcholine can better compete with autoantibodies for binding to acetylcholine receptors.
40
What is subacute bacterial endocarditis?
an autoimmune condition mediated by IgG that is made in response the the normal flora organism Streptococcus viridans that have colonized damaged heart valves. ***(Typically, this organism only colonizes heart valves that have already been damaged (e.g. rheumatic fever, congenital condition, etc.)).****When S. viridans has colonized heart valves, IgG specific for determinants of this bug bind to the bacteria, promoting recognition of the immune complex by phagocytes as well as initiation of the classical complement cascade. The inflammation that results causes further damage to the heart valves and myocardium.This is considered an immune complex “hypersensitivity” or immune complex autoimmune disease because the inflammation results from recognition of immune complexes.
41
What is Mixed essential cryoglobulinemia?
an odd condition that is characterized by production of what are known as cryoglobulins.
42
What are cryoglobulins?
Cryoglobulins are immunoglobulins that become insoluble at reduced temperatures (sometimes they are only composed of light chains) and are similar to rheumatoid factor in that they have specificity for the Fc regions of antibodies and can cause immune complex disease.
43
Cryoglobulins consisting of only light chains are called ______.
Bence-Jones proteins
44
When are cryoglobulins commonly produced?
by patients with a B cell proliferative disorder (Multiple myeloma or Waldenstrom macroglobulinemia)
45
What are the common symptoms of Mixed essential cryoglobulinemia?
Meltzer's triadPurpura, arthralgia, and myalgia
46
What is Systemic lupus erythematosus?
autoimmune disease caused by autoantibodies (antinuclear antibodies or ANA, anti- dsDNA or anti-Smith, and anti-histone) specific for many intracellular macromolecules present in all cells in the body (DNA, histones, ribosomes, etc.)
47
Why is SLE considered an immune complex disease?
Autoantibodies bind to surface determinants of host cells, initiating inflammatory responses that lead to tissue damage and release of autoantigens. Once this occurs, immune complexes are formed in the extracellular spaces and in the circulation and are deposited onto blood vessels, joints, kidneys, etc. Ultimately, this results in an immune complex disease, and it carries all of the problems associated with immune complex hypersensitivity.The disease is progressive because inflammation results in release of auto-antigens that can cause further priming of acquired immune responses (more autoantibodies).
48
What are the common symptoms of immune complex hypersensitivity?
vasculitis, kidney damage progressing to glomerulonephritis, and even neurological dysfunction due to vasculitis in the brain.
49
What are the symptoms of SLE?
butterfly rash, photosensitivity, fever, malaise, joint pain, myalgias, and fatigue, arthritis. Once advanced, progressive kidney dysfunction occurs due to the deposition of immune complexes and resulting inflammation. **Blood in urine and positive direct Coomb's test** and reduced C1 levels, moderate proteinurialupus=wolf like
50
What is the incidence of SLE?
1 in 500 African/Asian women (more common in women than men)severity is highly variable
51
Why is SLE a progressive disease?
As tissue is damaged and inflammatory responses are initiated, additional priming of autoimmune reactions occurs. In effect, the autoimmune responses that cause SLE “mature” over time, and the disease gets progressively worsecommonly, the disease follows a course in which outbreaks of intense inflammation alternate with periods of relative “calm”; this cycling of symptoms is poorly understood
52
What is Antiphospholipid syndrome (APS or APLS)?
an autoimmune disease that is mediated by autoantibodies (IgG) that are specific for host phospholipids
53
What kinds of antibodies are common APS?
anti-cardiolipin or anti-β2- glycoprotein-I antibodies (these are a subset of anti-cardiolipin antibodies)
54
What are the mains symptoms of APS?
These antibodies cause thrombosis in both arteries and veins, and in severe cases, known as catastrophic antiphospholipid syndrome, can result in rapid organ failure and death.
55
What impact does APS have on pregnancy?
This condition is also notable for the difficulties it can cause during pregnancy. The autoantibodies can cause miscarriages or stillbirths, preterm delivery, and preeclampsia.
56
How is APS diagnosed?
requires: (1) at least one clinical event that could be either thrombosis or a complication of pregnancy, and (2) measurement of either lupus coagulant or anti-cardiolipin or anti B2-glycoprotein-1 antibodies in serum samples collected at least 3 months apart.APS can be a primary condition, or it can be secondary to other autoimmune conditions (most notably, SLE).
57
What are some autoimmune diseases that are mediated by T cells?
Type 1 diabetesRheumatoid arthritisMultplie sclerosis
58
What is insulin-dependent Diabetes Mellitus (IDDM) caused by?
autoimmune disease that results in the selective destruction of insulin-producing cells by CTLs that have specificity for some determinant(s) in beta pancreatic cells in the islets of Langerhan
59
T or F. There are a finite number of beta cells in the pancreas?
T. Because the beta cells produce insulin, their destruction has a very negative impact on the host. There are a finite number of beta cells and they are not regenerated after being destroyed.
60
What is the incidence rate of IDDM?
1 in 300 European descent
61
What symptoms are common with IDDM?
symptoms usually manifest in childhood or adolescence; if untreated, can rapidly progress to coma and death
62
What is the treatment for IDDM?
usually consists of daily injections of insulin purified from the pancreas tissue of cattle or pigs.Unfortunately, some patients produce immune responses against the porcine(pig)/bovine insulin (since it is non- self), which results in reduced activity of the insulin and can lead to immune complex disease (Type III hypersensitivity disease) making the patient’s problem much worsePatients that cannot use insulin from other species are forced to use the more expensive human-derived insulin.
63
What is Rheumatoid Arthritis?
autoimmune disease that results in chronic or episodic inflammation of the joints and that has historically been believed to be mediated by autoreactive T cellsThe inflammatory responses in the joints cause damage to the soft tissues (cartilage and ligaments), causing loss of function and disfigurement of the joints.
64
What is the incidence of RA?
RA is the most common rheumatic disease, affected 1-3% of the US population. Women outnumber men 3:1 in incidence of this disease.disease symptoms usually become noticeable between the ages of 20–40
65
What is rheumatoid factor?
80% of patients produce autoantibodies (IgM, IgG, and IgA) that are specific for the Fc regions of human IgG molecules;this antibody is not required for tissue damage as 20% of patients do not produce rheumatoid factor
66
What is another autoantibody commonly seen in RA patients?
anti-CCP (or anti-cyclic citrullinated peptide); this test is considered more specific that rheumatoid factor, but a negative anti-CCP test does not rule out rheumatoid arthritis
67
Joints in patients with RA are all high in what?
characteristic leukocyte infiltrate that includes CD4 and CD8 T cells, B cells, plasma cells,neutrophils, and macrophages; inflammatory responses result in tissue damageneutrophils release lysosomal enzymes causing tissue damage; in addition, CD4 effector cells activate macrophages that accumulate in the synovium, adding to the tissue damageapproximately 35% of patients develop rheumatoid nodules (up to walnut size) that are typically associated with the affected joints (elbow, hands, fingers, knuckles)
68
What is treatment for RA?
There are two treatment that are moderately effective. (1) infliximab (anti-TNF-alpha MAb), It appears that TNF-α is one of the primary mediators of the inflammation observed in rheumatoid arthritis patients and (2) rutiximab (anti CD20 MAb, a B cell surface marker).
69
How does infliximab treat RA?
It reducing the inflammation (as measured by reduced C-reactive protein and joint swelling) and the pain associated with RA. This treatment seems logical because TNF-alpha is an inflammatory cytokine that is produced by TH1 effector cells. If this disease is in fact mediated by T cells, this treatment makes a lot of sense.
70
How does rutiximab treat RA?
Ritiximab treatment also appears to be an effective treatment. This is illogical if the disease is really caused by T cells, because this MAb preparation is specific for the pan B cell marker (a marker that is found on all B cells) CD20, and binding of these IgG antibodies to B cells results in their destruction by NK cells via ADCC. The efficacy of this treatment suggests that Abs may have a significant role in this autoimmune malady.
71
Is RA mediated by T cells alone?
rheumatoid arthritis may not be mediated by T cells alone; a new treatment that is relatively effective is infusion of rituximab that have specificity for a B cell surface marker (CD20); these antibodies bind to B cells and serve as a trigger for ADCC by NK cells; kills B cells. Gives major benefit to 80% of patients and some benefits to 50% of patients.suggests some AB involvement
72
What is Sjogren's syndrome?
an autoimmune condition that is mediated by autoreactive T cells that are specific for determinants expressed in the exocrine glands that produce tears and saliva.
73
Are most people affected by Sjogren's syndrome men or women?
Nine out of ten Sjögren's patients are women and the average age of onset is late 40s. It is estimated to strike as many as 4million people in the United States alone making it the second most common autoimmune rheumatic disease.
74
What are the symptoms of Sjogren's syndrome?
dry eyes, mouth, nose, sometimes skin, and vaginal dryness.may also affect kidneys, blood vessels, lungs, liver, pancreas, peripheral nervous system and brain
75
How is Sjogren's syndrome diagnosed?
1) blood tests for antibodies specific for one or more Ro proteins that are found in the nucleus of host cells (anti-SSA/RO) or antibodies specific for an RNA-binding protein that shuttles between the cytoplasm and nucleus (anti-SSB/LA)2) the Schirmer test measures tear production: a strip of filter paper is held inside the lower eyelid for five minutes, and its wetness is then measured with a ruler. 3) a slit-lamp exam is done to look for dryness on the surface of the eye4) Salivary gland function test: measure saliva produced in 5 minutes 5) lip biopsy can reveal lymphocytes clustered around salivary glands 6) Ultrasound of the salivary glands is the simplest confirmatory test
76
What is the treatment for Sjogren's syndrome?
artificial tears, punctal plugs (to retain tears), and goggles (to increased local humidity). There is no known cure.
77
What is Multiple sclerosis caused by?
is an autoimmune condition that is caused by a break down in tolerance to determinants of the myelin sheath around nerve cells.
78
What happens in MS?
This immune response is mediated by autoreactive TH1 CD4+ effector cells that activate macrophages via IFN-y, enticing them to produce inflammatory cytokines and release proteases. The chronic inflammation causes demyelination of white matter in the CNS resulting in poor transmission of nerve impulses.
79
What are the symptoms of MS?
progressive muscle weakness, impaired vision, loss of coordination and spasticity (muscle hypertonia/stiffness).
80
What are the auto antigens of MS?
structural proteins of myelin (myelin basic protein, proteolipid protein, or myeloidoligodendricyte glycoprotein)
81
What is the treatment for MS?
Immunosuppressive drugs and IFN-β1 (reduces incidence of disease attacks). For unknown reasons, MS (like many autoimmune diseases) has episodes of disease progression followed by periods of relative quiescence with little progression of disease.
82
How is MS diagnosed?
oligoclonal bands of IgG in CSF in very common in MS patients (85%)
83
T or F. Autoimmune disease susceptibility runs in families
T. the most important genetic factors appear to be HLA antigen expression (can be either MHC class I or MHC class II)HOWEVER, unlike some diseases that can be linked to a single mutant gene (i.e. cystic fibrosis), susceptibility to autoimmunediseases is determined by many genetic factors (and environmental) in combination
84
HLA-DR3 (HLA halotype) is associated with what diseases?
production of autoantibodies that interfere with endocrine function as well as with neuronal signaling.(Grave's disease, Myasthenia graves, and Addison's disease) Also type I diabetes and SLE
85
DQ6 (HLA halotype) is associated with what diseases?
Nacrolepsy and MS and Type 1 Diabetes (point mutation that alters the amino acid at position 57)
86
DR4 (HLA halotype) is associated with what diseases?
Rheumatoid arthritis, type I diabetes
87
What are some immunologically privileged sites in the body?
the eyes and testes and the placenta
88
What is a main consequence of immunologically privileged sites?
None of the antigens that are unique to that tissue were available during thymic negative selection.Therefore, no removal of self reactive T cells that recognize those unique determinants has occurred, and there is no antigen available for priming a self-reactive response to those tissues.However, when a traumatic injury to those tissues occurs, the unique antigens are sometimes released into the body and it is possible to prime a T cell response to those unique determinants. Because these tissues are vascularized, effector T cells can enter those tissues and perform their damaging effector mechanism. (sympathetic opthalmia)
89
What is one place in the body that can never be attacked by T effector cells?
One clear exception is the cornea, which is no vascularized and cannot be attacked by effector T cells.
90
How does smoking impact autoimmunity?
only 40% of people that suffer from Goodpasture’s syndrome develop pulmonaryhemorrhage as well. those that develop lung hemorrhages are typically those that are habitual smokers because the basement membrane of alveoli of non-smokers are inaccessible to autoantibodies- smoking damages it.
91
What is molecular mimicry?
a number of organisms produce proteins that are very similar to self-proteins, or contain antigens that closely mimic self components that can elicit an immune response against self-determinants
92
What is Guillain Barrer Syndrome?
a molecular mimicry syndrome that results from production of an IgG response during infection (often with Campylobacter jejuni infection). IgG made in response to the bacterium cross-reacts with gangliosides, resulting in demyelination.
93
What are the symptoms of Guillain barrier syndrome?
symmetrical weakness of lower limbs, rapidly ascending to upper limbs and face with difficulty swallowing and breathing. Partial paralysis often occurs, but in most cases can be reversed with appropriate treatment.
94
What is Granulomatosis with polyangiitis (formerly Wegener’s granulomatosis)?
type II autoimmune disease mediated by anti-neutrophil cytoplasmic antibodies, or ANCAs (IgG).
95
What do ANCAs do?
bind to neutrophils, causing to activate; these cells then up regulate adhesion molecule expression allowing them to bind to vascular endothelial cells and degranulate, causing damage to the vasculature
96
What is the primary determinant in Wegener's granulomatosis?
proteinase-3
97
What are the symptoms of Wegener's?
1st symptom is typically rhinitis and conjunctivitis; lung infiltrates, rapidly progressive kidney dysfunction leading to glomerulonephritis, and usually granulomas are found in all affected tissues.
98
Treatment for Wegener's?
Plasma exchange and anti-inflammatory drug treatment.
99
An HLA-A3 haplotype predisposes people to which diseases?
Hemochromatosis
100
An HLA-B27 haplotype predisposes people to which diseases?
Ankylosing spondylitis, psoriasis, inflammatory bowel disease, Rieter syndrome
101
An HLA-B8 haplotype predisposes people to which diseases?
Grave's disease
102
An HLA-DQ2/DQ8 haplotype predisposes people to which diseases?
Celiac disease
103
An HLA-DR2 haplotype predisposes people to which diseases?
MS, hay fever, SLE, Goodpasture's
104
An HLA-DR5 haplotype predisposes people to which diseases?
Pernicious anemia, Hashimoto's thyroiditis
105
What is Miller-Fisher Syndrome?
a version of Guillian-Barrier disease were symptoms start from the top down (as opposed to GB where symptoms start from the bottom and ascends)can be treated by plasma exchange no memory response for this disease
