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Robbins: Autoimmune Diseases Flashcards

1
Q

Describe the process of central tolerance for B and T cells.

A

B cells: self reactive B cells undergo apoptosis in the bone marrow OR they will undergo a 2nd round of BCR gene rearrangement

T cells: self reactive T cells are deleted in the thymus via apoptosis (negative selection)

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2
Q

Describe the 3 mechanisms of T cell peripheral tolerance.

A
  1. they become ANERGIC when they do not receive co-stimulatory signal from APC or B cell
  2. Treg cells secrete immunosuppresive cytokines (IL-10, TGF-B)
  3. Fas mediated apoptosis
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3
Q

What can mutations in AIRE cause?

A

T cells specific for self proteins escape negative selection in the thymus

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4
Q

What does a FOXP3 mutation cause?

A

IPEX = Treg deficiency = impaired peripheral tolerance

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5
Q

What does mutations is Fas gene cause?

A

ALPS = impaired peripheral tolerance = enlarged lymphnodes and many auto-antibodies produced

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6
Q

How does molecular mimicry lead to autoimmune diseases?

What is an example of a disease that uses molecular mimicry as its MOA?

A

viruses and other microbes may share cross-reacting epitopes that causes the host to attack its own tissues thinking that they are attacking the invading microbe

rheumatic heart disease

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7
Q

Microbial infection causes up-reg of B7 on APCs, potentially leading to a breakdown of peripheral tolerance for ____ cells.

A

T cells

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8
Q

What organs/tissues does SLE primarily effect?

A

skin, kidneys, serosal membranes, joints, and heart

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9
Q

What Ab is classically associated with SLE?

A

anti-nuclear Ab (ANAs)

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10
Q

Diagnosis of SLE is established by demonstration of ___ or more of the 11 criteria for classification.

A

4

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11
Q

What are the 11 criteria for classification of SLE?

A
  1. malar rash
  2. discoid rash (erythematous raised patches with keratoitic scaling and follicular plugging)
  3. photosensitivity
  4. oral ulcers (usually painless)
  5. arthritis (2 or more joints)
  6. serositis– pleuritis and pericarditis
  7. renal disorder
  8. neurologic disorder (seizures and psychosis)
  9. hematologic disorder (leukemia, hemolytic anemia, lymphopenia, thrombocytopenia)
  10. immunnologic disorder (Anti-DNA Ab, Anti-Sm Ab, Anti-phospholipid Ab)
  11. Anti-nuclear Ab
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12
Q

What is the fundamental defect is SLE?

A

failure to maintain self tolerance leading to the production of a large # of auto-Abs that damage tissue with the deposition of immune complexes

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13
Q

What are the genetic risk factors for SLE?

A
  1. one of your 1st degree relatives has SLE
  2. certain HLA haplotypes
  3. classical complement protein deficiencies
  4. polymorphic Fc-gamma-RIIb
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14
Q

What are environmental factors that are involved in the pathogenesis of SLE?

A
  1. UV radiation from sun exposure
  2. cigarette smoking
  3. sex hormones
  4. drugs such as procainamide and hydralazine
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15
Q

What are 3 immunologic abnormalities seen in SLE?

A
  1. abnormally large amts of INF-alpha
  2. TLR signals (TLR9 recognizes DNA and TLR7 recognizes RNA –> both activate B cells specific to nuclear Ags)
  3. Failure of B cell tolerance
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16
Q

Based on the identified genetic, environmental, and immunologic abnormalities seen in pts with SLE, what is the proposed pathogenesis of SLE?

A

UV irradiation or other environmental insults leads to apoptosis of cells. Complement protein deficiencies causes inadequate clearance of the nuclear debris. At the same time, polymorphisms in BCR and TCR genes allows for self reactive B and T cells to remain functional. These self reactive B cells are stimulated by nuclear Ags and Abs are made against them. Nuclear Ag-Ab complexes form and engage TLRs, further activate B cells, and activate DCs. DCs make INF-alpha which causes more apoptosis and the cycle continues…

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17
Q

What test is specific to SLE?

What test is sensitive to SLE?

A

Sp: Abs to dsDNS (Sm Ag) rules in SLE bc they are specific to the disease

Sn: ANA testing by IFA is sensitive (95% of pt with SLE will have these Abs)

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18
Q

Why can pts with SLE have reduced serum levels of C3 and C4 when they have a flare up of the disease?

A

The complement proteins are being consumed faster than it is being made. They are being deposited on the immune complexes that are forming during the flare up.

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19
Q

Why can pts with SLE have cytopenia?

A

Abs against RBCs, WBCs, and platelets cause them to be opsonized and phagocytosed

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20
Q

Why do pts with SLE have inc thrombotic episodes?

A

Abs against phospholipids = anti-phospholipid syndrome

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21
Q

What is an LE body or a hematoxylin body?

A

A neutrophil or macrophage that has engulfed ANAs opsonized nuclear material from damaged cells
*the point is that ANAs cannot permeate intact cells, they can only bind fragments of dead cells

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22
Q

Describe the microscopic morphology of blood vessels in a pt with SLE.

A
  1. acute necrotizing vasculitis
  2. fibrinoid deposits
  3. vessels walls containing Ab, DNA, complement fragments, and fibrinogen
  4. leukocyte infiltrate
  5. in chronic stages, fibrous thickening and luminal narrowing
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23
Q

What is the most common cause of death for pt with SLE?

A

renal failure (also intercurrent infections and CV disease)

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24
Q

In SLE, deposition of DNA-anti-DNA complexes within the glomeruli causes _____

A

glomerulonephritis and an inflammatory response that may cause proliferation of the endothelial, mesangial, and/or epithelial cells –> if severe, necrosis of the glomeruli

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25
There are 6 patterns/classes of glomerular disease in SLE. Which class is this and what characterizes it? Minimal mesangial nephritis
Class I: - immune complexes in the mesangium (area of smooth muscle that control renal blood flow thru capillaries) - no changes visible with might microscopy
26
There are 6 patterns/classes of glomerular disease in SLE. Which class is this and what characterizes it? Mesangial proliferative lupus nephritis
Class II: - mild clinical symptoms - immune complexes in mesangium - mild to moderate inc in mesangial matrix and cellularity
27
There are 6 patterns/classes of glomerular disease in SLE. Which class is this and what characterizes it? Focal lupus nephritis
Class III: - lesions in <1/2 of glomeruli - mild microscopic hematuria and proteinuria to sctive urinary sediment with RBC casts and acute, severe renal insufficiency
28
There are 6 patterns/classes of glomerular disease in SLE. Which class is this and what characterizes it? Diffuse lupus nephritis
CLass IV: - most serious form of renal lesions - lesions in >1/2 of glomeruli - hematuria - moderate to severe proteinuria, hypertension, and renal insufficiency
29
There are 6 patterns/classes of glomerular disease in SLE. Which class is this and what characterizes it? Membranous lupus nephritis
Class V: - widespread thickening of capillary wall - severe proteinuria - nephrotic syndrome
30
There are 6 patterns/classes of glomerular disease in SLE. Which class is this and what characterizes it? Advanced sclerosing lupus nephritis
Class VI: - complete sclerosis of greater than 90% of glomeruli - end stage renal disease
31
What is the involvement of the skin in the presentation of SLE? Also describe histologic findings in the skin.
- butterfly pattern of erythmatous or maculopapular eruption over the malar eminences and bridge of the nose = malar rash - photosensitivity Histo: - liquefactive degeneration if basal layer of the epidermis - edema at the dermoepidermal junction - mononuclear infiltrate
32
What changes can happen to the spleen from SLE?
- enlarged | - onion-skin lesions
33
What affects can SLE have on the heart?
- pericarditis - myocarditis with mononuclear infiltrate - Libman-Sacks endocarditis: non bacterial and causes 1-3 mm warty deposits on valve leaflets - hypertension - accelerated artherosclerosis
34
What effect does SLE have on the joints?
swelling and pain (smilar to RA)
35
What disease is characterized by dry eyes and dry mouth from immune-mediated destruction of lacrimal and salivary glands?
Sjogren Syndrome or sicca syndrome
36
What is thought to be the cause of Sjogren syndrome?
- CD4+ T cell rxn against unknown Ags in ductal epithelial cells of the exocrine glands - systemic hyperactivity of B cells
37
What Ab are typically found in the serum of pt with Sjogren syndrome?
Against ribonuclear protein Ags Ro and La... Anti-SSA (Ro) Anti-SSB (La) *note these are also present in SLE pt and cannot be used for Dx Sjogren syndrome
38
What is the histological findings with Sjogren syndrome?
CD4 T cell and plasma cell infiltrate in the affected glands
39
What immunologic disorder is characterized by excessive fibrosis in multiple tissues, obliterative vascular disease, and the production of multiple auto-Abs?
Systemic sclerosis (scleroderma)
40
What are the 2 classes of SS and what is the difference between them?
Diffuse scleroderma: more severe; initial wisespread skin involvement with rapid and early visceral involvement Limited scleroderma: mild skin involvement (usually skin and face); late visceral involvement
41
Why is limited scleroderma often called CREST syndrome?
Bc it frequently features... - Calcinosis (Ca deposits in soft tissures) - Raynaud phenomenon (vasospastic disorder in fingers and toes) - Esophageal dysmotility - sclerodactyl - Telangiectasia (dilated blood vessels near the surface of skin or mucous membranes)
42
Describe the pathogenesis of systemic sclerosis (scleroderma).
Injury to endothelium causes activation of endothlium and causes recruitment of T cells (mainly Th2). Th2 cells respond to self Ag and secrete cytokines. Macrophages recruited and activated. Th2 and macrophages secrete cytokines (TGF-B, IL-13, PDGF) to activate fibroblasts and stimulate collagen production --> fibrosis Repeated cycles of this along with platelet aggregation causes narrowing of small vessels with eventual ischemic injury
43
What Abs are present in the serum of pts with SS?
Anti-Scl70 (DNA topo I) <--limited SS
44
What organs are most prominently affected by SS?
``` skin musculoskeletal GI Tract Lungs Kidneys Heart ```
45
Describe the morphology (gross and histologic) of skin affected by SS.
Early: edemous with doughy consistency; usually in fingers, and distal regions of upper extremity first; Late: fibrosis of dermis; atrophy of dermal appendages Advanced: fingers become clawed, face takes on "mask-like" appearance; loss of blood supply can lead to cutaneous ulcerations and atrophic changes Histo: - perivascualr infiltration of CD4 T cells - thickening of basal lamina - endothelial damage - later: inc collagen - hyaline thickening of walls of dermal arterioles and capillaries
46
What GI problems do pt with SS have?
- muscularis is replaced with fibrous collagen and this is most severe at the lower 2/3 of esophagus - gasotroesophageal reflux --> barrett metaplasia - loss of villi and microvilli in small intestine --> malabsorption syndrome
47
How are the lungs affected by SS?
- pulmonary hypertension - interstitial fibrosis - pulmonary vasospasm
48
How are the kidneys affected by SS?
thickening of the vessel walls of interlobular arteries
49
What changes to the heart does SS cause?
pathcy myocardial fibrosis along with thickening intramyocardial arterioles
50
What type of heart failure is often seen with SS pts?
right ventricular hypertrophy and failure (cor pulmonale) | *bc of pulmonary hypertension
51
What disease is characterized by a tendency to form tumor-like lesions in several organs, elevated serum IgG4 (or IgG4 producing plasma cells)?
IgG4-Related disease
52
Describe the histopathologic features of IgG4 related disease.
- mixed infiltrate of T and B cells - storiform fibrosis - obliterative phlebitis - tissue eosinophillia
53
Rejection of allografts is a response mainly to _______
MHC molecules
54
What is the direct pathway of recognition and rejection of allografts?
CD8 T cells recognize MHC I on graft --> active CTLs --> destroy graft tissue CD4 T cells recognize MHC II --> Th cells make INF-gamma --> macrophages activated --> destroy graft (similar to DTH)
55
What is the indirect pathway of recognition and rejection of allografts?
No CD8 T cells involved CD4 recognizes MHC II --> Th cells... 1. produce INF-gamma --> macrophage activation 2. activate B cells --> plasma cells make Ab against graft --> a. opsonization of graft for macrophage destruction b. causes vascular injury thru complement activation and leukocytes
56
______ is a special form of rejection occurring if pre-formed anti-donor Abs are present in circulation of the host before transplantation.
hyperacute rejection * can be from transfusions, previous organ transplants * rejection of transplant occurs within minutes to hours
57
When can a hyperacute rejection typically be recognized?
by the surgeon, just after the vascular anastomosis is complete (becomes cyanotic, mottled, and flaccid)
58
When does acute rejection occur?
within a few days to weeks of transplantation
59
T or F: acute rejection is caused by both humoral and cellular immune mechanisms.
True *cellular = mononuclear infiltrate + edema humoral = vasculitis
60
Acute cellular rejection is usually accompanied with _______
clinical signs of renal failure
61
Cyclosporine, an immunosuppressive agent, is nephrotoxic. How is drug toxicity distinguished from acute cellular graft rejection?
cyclosporine induces arteriolar hyaline deposits while rejection has T cell infiltrate
62
Acute humoral rejection is also known as __
rejection vasculitis
63
Describe the histologic lesions seen with acute humoral rejection.
necrotizing vasculitis with endothelial cell necrosis --> fibrosis (older) - neutrophil infiltrate - deposition of Ab, complement, and fibrin - thrombosis
64
When does chronic rejection occur?
months to years after transplant
65
What type of rejection is associated with: T cells destroy graft parenchyma and vessels by cytotoxicity and inflammatory responses
acute cellular rejection
66
What type of rejection is associated with: pre-formed anti-donor Ab that bind to graft endothelium immediately after transplantation, leading to thrombosis, ischemic damage, and rapid graft failure
hyperacute rejection
67
What type of rejection is associated with: Abs damage graft vasculature
acute humoral rejection
68
What type of rejection is associated with: dominated by arteriosclerosis, and is probably caused by T cell secretion of cytokines that induce proliferation of vascular smooth muscle cells, and is associated with parenchymal fibrosis
chronic rejection
69
T or F: HLA matching is critical for heart, lung, liver, and islet transplants.
False: the need by the recipient is usually so urgent that HLA is not of practical importance
70
______ in the recipient is a practical necessity in all organ transplants (except in the case of identical twins).
immunosupression
71
T or F: chronic rejection responds much less effectively than does acute rejection to available immunosupressive agents.
True
72
What is graft vs host disease (GVHD)?
occurs when T cells are transplanted into a recipient who is immunocompromised. The T cells in the donor perceive the recipient's tissue as foreign and begins to react against it --> inflammation and killing of host cells ultimately results
73
What is the difference between acute and chronic GVHD?
Both cause epeithelial cell necrosis in liver, skin and gut but in chronic there are skin lesions that resemble SS
74
What minimizes the chances of a transplant recipient acquiring GVHD?
HLA matching (risk is not eliminated)
75
What are pts with humoral immune deficiencies susceptible to? (in general)
recurrent infections with pyogenic bacteria
76
What are pts with cell mediated immune deficiencies susceptible to? (in general)
viruses, fungi, and intracellular bacteria
77
Name the primary immune deficiency associated with the following characterization: first seen in 6 mo old infants, failure of B cell maturation, low # B cells, no plasma cells, absence of Abs, normal T cells
X-linked agammaglobulinemia: mutated Btk
78
Name the primary immune deficiency associated with the following characterization: hypogammaglobulinemia, impaired Ab response, normal # B cells, NO plasma cella late onset (20-30 yr olds)
Common variable immunodeficiency: cause unknown
79
Name the primary immune deficiency associated with the following characterization: Failure of IgA production; recurrent sinopulmonary infections and diarrhea; normal IgM and IgG levels
isolated IgA deficiency: cause unknown
80
Name the primary immune deficiency associated with the following characterization: Failure of T and B cell maturation
X-SCID: mut common gamma chain (esp IL-7 = responsible for survival and expansion of immature B and T cells)
81
Name the primary immune deficiency associated with the following characterization: T cells are absent
Digeorge Syndrome: caused by lack of mature thymus
82
Name the primary immune deficiency associated with the following characterization: failure of T cell deveopment and secondary defect in Ab responses
Autosomal SCID: mut in ADA which leads to accumulation of toxic metabolites that kill T and B cells
83
Name the primary immune deficiency associated with the following characterization: no IgG, IgA, or IgE in serum, normal or elevated IgM
hyper IgM syndrome: mut CD40L = Th2 cells cannot signal class switching; OR mut AID = no germinal center reaction
84
Name the primary immune deficiency associated with the following characterization: thrombocytopenia, eczema, early death w/o bone marrow transplant
Wiskott-Aldrich Syndrome
85
What autoimmune disorder is characterized by the extracellular depostion of misfolded proteins that aggregate to form insoluble fibrils?
amyloidosis
86
What is AL protein/how is it formed?
produced by plasma cells and is made up of Ig light chains and they accumulate as AL protein bc they are not broken down
87
What is AA fibril/How is it formed?
chronic inflammation --> macrophage activation --> production of IL-1 and IL-6 --> liver cells make SAA protein --> SAA protein not broken down or it has a structural mutation to prevent it from being degraded by macrophages
88
What is AB amyloid? (alpha-beta)
found in the cerebral lesions of Alzheimer's disease
89
What is transthyretin (TTR)/how does it become amyloid?
protein that transports thyroxine and retinol mutations in it prevents it from folding properly or form being degraded so it aggregates as amyloid
90
How does B2-micro-globulin become an amyloid?
in hemodialysis pts, it is not efficiently filtered out by the dialysis membranes so it will accumulates and deposit in synovium, joints, and tendon sheaths

Robbins' Basic Pathology (5 decks)

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