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Tolerance & Autoimmunity Flashcards

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1
Q

what is tolerance induction?
how is tolerance induction conducted by the immune system?

A
  • tolerance induction: induces tolerance to self antigens to prevent autoimmunity. done by two primary methods
    • clonal deletion: central tolerance
      • self reactive T and B lymphocytes are killed by apoptosis in the bone marrow & thymus
    • anergy: peripheral tolerance
      • self reactive lymphocytes are alive but cannot respond to antigen (via Treg)
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2
Q

what is auto-immunity?

A
  • failure of tolerance induction d/t
    • failure to delete T and B cell cells in bone marrow thymus (central tolerance)
    • reactivation of previously anergic T and B cells (peripheral tolerance)
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3
Q
  • what is the means by which central T-cell tolerance in induced?
    • outline the steps of this process
A

central T-cell tolerance = T-cell education: T-cells are selected for in the thymus in four main phases.

  • double negative T-cells
    • cells have neither CD4 nor CD8
    • in subscapular region (outer cortex) of thymus
  • double positive T-cells
    • in the cortex of the thymus:
      • adopt TCR + CD3 + CD4 + CD8
      • undergo-positive selection:
        • exposed to self MHC-I & MCH-II by cortical epithelial cells → those that show moderate affinity advance
    • at the corticomedullary junction
      • undergo 1st round of negative selection
        • exposed to thymic self antigen by IDCS
  • single positive T-cells
    • in the medulla
      • undergo 2nd round of negative selection
        • exposed to non-thymic self antigens by medullary epithelial cells
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4
Q

double negative T-cells

  • found where in the thymus?
  • have what features / undergo what changes
A
  • in subscapular region (outer cortex) of thymus
  • have neither CD4 or CD8
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5
Q

double positive T-cells

  • found where in the thymus?
  • have what features / undergo what changes
A
  • first seen in the cortex of the thymus:
    • adopt TCR + CD3 + CD4 + CD8 markers
    • undergo positive selection (in cortex) → 1st round of negative selection (corticomedullary junction)
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6
Q

positive selection

  • occurs where?
  • involves which cell types?
  • involves what steps?
A
  • in the cortex
  • to DP T-cells, by cortical epithelial cells
    • DP cells exposed to self MHC-I & MCH-II by cortical epithelial cells →
      • those that show MODERATE AFFINITY → advance (“positively selected”
      • those that show too high / too low affinity → apoptosis
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7
Q

negative selection

  • occurs where?
  • to which cell types?
  • involves what steps?
A

occurs in two phases

  • 1st phase
    • in the corticomedullary junction
    • to DP T-cells cells by interdigitating dendritic cells (IDCs)
      • IDCs expose DPs to THYMIC SELF ANTIGENS
  • 2nd phase
    • in the medulla
    • to single positive T-cells by medullary epithelial cells
      • medullary epithelial cells, under regulation of AIRE transcription, expose cells to NON-THYMIC SELF ANTIGEN

cells that do not recognize thymic or non thymic self antigen → leave thymus and populate peripheral lymphoid organs

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8
Q

AIRE transcription regulator- what is its role & clinical significance?

A
  • role: regulates the second round of negative selection, wherein medullary epithelial cells expose single positive cells to non-thymic self antigens
    • clinical significance: a defect in the AIRE gene results in APS (autoimmune polyendocrine syndrome-1)
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9
Q

what is the role of each of these cells in the central tolerance induction of T-cells?

  • cortical epithelial cells
  • interdigitating dendritic cells (IDCs)
  • medullary epithelial cells
A
  • cortical epithelial cells - positive selection: exposes DPs to MHC-I & MCH-II
  • interdigitating dendritic cells (IDCs) - negative selection: expose DPs to thymic self antigen
  • medullary epithelial cells - negative selection: expose SPs to non-thymic self antigen
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10
Q

discuss the mechanism of peripheral T-cell tolerance

A

= anergy: suppression of T-cells that reacted to self antigen but still made it thru T-cell education

  • conducted by T-reg cells
    • that detect self reactive T-cells via detecting T-cells that react with APCs without a B7 receptor - i.e., host cells
    • then release IL-10 & TGF-B → suppression of T-cell
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11
Q

what is the means by which central B-cell tolerance is induced?

A
  • occurs the bone marrow
    • immature B-cells (IgM + and IgD -) are presented with self antigen by stromal cells
    • those that interact with self antigen → deleted
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12
Q

what are the means of peripheral tolerance induction to B-cells?

A
  • anergy: immature B-cells that react to soluble self antigen but made it through negative selection in bone marrow are made unreactive
  • receptor editing: RAG genes reactivated and B-cell antibodies specificity are changed from self → non self reactive
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13
Q

what are the immunologically privileged sites? what does this mean?

A

T-cell x tissue interactions don’t occur in these sites because they are inhibited by a blood-tissue barrier

  • brain
  • anterior chamber of eye
  • placenta / pregnancy uterus
  • testis
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14
Q

T-reg cells

  • have what markers?
  • secrete what cytokines?
  • have what role (s)?
A
  • CD4, CD25, FoxP3
  • secrete IL-10, TGF-B
  • role: conduct peripheral T-cell anergy to → prevent autoimmunity
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15
Q

autoimmune polyendocrine syndrome - 1

  • pathogenesis
  • presentation
A
  • d/t defect in AIRE gene: regulates negative selection (exposure of T-cells to non-thymic self antigens by medullary epithelial cells)
  • clinical presentation
    • mucocutaneous candidasis
    • hypoparathyroidism / thyroiditis
    • type I DM
    • ovarian failure
    • alopecia
    • vitiligo
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16
Q

IPEX

  • pathogenesis
  • presentation
A

= immunodysregulation, polyendocrinopathy, and enteropathy X-linked (autoimmune disease)

  • pathogenesis: mutation of Foxp3 gene (codes for FoxP3 marker on T-reg cell)
  • presentation
    • classic triad = enteropathy + endocrinopathy + dermatitis
      • enteropathy: severe diarrhea
      • endocrinopathy: TIDM, thyroiditis
      • dermatitis - eczema, psoriasis
    • bullous phempigoid
    • high IgE
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17
Q

induction of auto-immunity is influenced by..?

A
  • inheritance of HLA genes (B27, DR2, DR3, DR4)
  • environmental: molecular mimicry
  • physical trauma that breaks immunological privileges
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18
Q

HLA-B27 is associated with development of what autoimmune diseases?

A
  • psoroiasis
  • ankylosing spondylitis
  • IBD: crohns, UC
  • reiter’s syndrome

“PAIR”

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19
Q

HLA-DR2 is associated with development of what auto-immune diseases?

A
  • MS (type IV)
  • SLE (type III)
  • goodpasture (type II)
  • hay fever / allergic rhinitis (type 1)
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20
Q

HLA-DR3 & DR4 are associated with what autoimmune diseases?

A
  • both HLA-DR3/DR4: T1DM
  • HLA-DR4: rheumatoid arthritis
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21
Q

what autoimmune disease is an example of molecular mimicry?

A
  • rheumatic fever following s. pyogenes infection (IgG/IgM made against cardiac myosin that resembles M-protein - Type II hypersensitivity)
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22
Q

what is an example of autoimmunity to trauma?

A
  • sympathetic ophthalmia - antigens released from (anterior chamber of eye) - reacts with T-cells who have never been exposed to them
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23
Q

pernicious anemia

  • molecular target
  • organ target
  • hypersensitivity type
A
  • molecular target: intrinsic factor / parietal cells
  • organ target: stomach
  • hypersensitivity type II
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24
Q

pernicious anemia - mechanism

A
  • Abs made against intrinsic factor / parietal cells (parietal cells produce intrinsic factor). this leads to
    • megoblastic anemia
      • intrinsic factor needed for Vit B12 → Vit B12 malabsorption → dysfunctional RBC production
    • chronic hylicobacter pylori infection
      • parietal cell destruction → achlorhydria → infection
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25
pernicious anemia - clinical presentation
* _class triad_ * **weakness** * **paresthesia** * **tongue - sore, beefy red** * _"megoblastic madness"_ * **delusions / paranoia** * ataxia * chronic H. pylori infections
26
pernicious anemia - diagnosis
* presence of Abs to intrinsic factor * gastric gland atrophy * achlorydia * abnormal RBCs * megoblastic RBCs * oval macrocytic RBCs
27
presence of oval macrocytic RBCs pernicious anemia (autoimmune, type II)
28
megoblastic RBCs pernicious anemia (autoimmune, type II)
29
Abs to parietal cells pernicious anemia (type II,
30
sore tongue * part of **pernicious anemia** triad * weakness * paresthesia * sore tongue
31
pernicious anemia - tx
Vitamin B12 (cobalamin)
32
good-pasture syndrome * molecular target * organ target * hypersensitivity type
* molecular: **type IV collagen** in **basement membrane** * organ: **lungs, kidneys** * hypersensitivity Type II
33
good-pasture syndrome - mechanism
* type II sensitivity → smoking / solvent in the context of HLA-DR → Abs made against **type IV collagen** in the _basement membrane_ of * lungs → pulmonary hemorrhage * kidneys → glomerulonephritis
34
good pasture syndrome - presentation
main manifestations are * **lungs → pulmonary hemorrhage** * dyspnea + cough * chest pain * worse case: respiratory failure → death * **kidneys → glomerulonephritis** * dysfunction of nephron leads to * HTN * edema * hematuria * proteinuria * worst case: ESRD
35
good-pasture syndrome - diagnosis
* CXR: lung consolidations * kidney defects: * **inc BUN & creatinine** * hematuria, proteinuria * immune: * **circulating anti-GDM antibodies** * _form linear bands_ * are “ribbon like”
36
what immunological findings in the blood help dx good-pastures?
* **circulating anti-GBM antibodies** * linear bands → look “ribbon like”
37
what is the m/c cause of death in good-pastures syndrome?
pulmonary hemorrhage → respiratory failure → death
38
39
tx of good-pasture syndrome?
* acute phase tx * intubation / assisted ventilation * hemodialysis * long term tx * pharmaceutical * **plasmapheresis** → removes Abs * **immunosuppression** * corticosteroids * cyclophosphamide
40
Type I DM * molecular target * organ target * hypersensitivity type
* molecular target: **beta cells** * organ target: **pancreas** * hypersensitivity type IV
41
type I DM mechanism
* autoimmune **cell mediated killing** of **beta cells** (Type IV) * viral infection (possibly _Cocksackie virus_) has **“molecular mimicry”** with **GAD45** receptor on B-cell * **Th1 vs Treg** “fight” over **GAD45** on B-cell * If Treg wins: **IL-10/TGF-B** made → anergy of T-cells * if Th1 wins: I**NF-y → Tc** activated → kill host B-cells: * Tc bind: * **IGRP** * **Fas** often occurs in the context of HLA-DR3/DR4
42
T1DM - presentation
* juvenile onset * THIN * hyperglycemia: * **→ polydipsia, polyuria** * **→ ketoacidosis**
43
myasthenia gravis * molecular target * organ target * what type hypersensitivity
* molecular target: **AChR** * organ target: **skeletal muscle** * type II hypersensitivity
44
myasthenia gravis - presentation
* muscle weakness that * _affects one muscle in particular_ * _is worse in the pm_ * results in * **eye defects**: * ptosis * incomplete closure * diplopia * limited adduction * **difficulty chewing / swallowing**
45
neonatal myasthenia * mechanism * presentation
* passively transferred anti-AChR IgG * presenattion - general weakness
46
addison's disease * molecular target * organ target * what type hypersensitivity?
* molecular target**: adrenal cell components** * organ target: **adrenal gland** * type II + type IV hypersensitivity
47
Addison's disease - mechanism
* type II + type IV * auto-Ab against adrenal cell components * cortex atrophy * insufficiency aldosterone * BP drop * ACTH → MSH accumulates
48
addison's disease - presentation
* HYPOTENSION * often orthostatic * MSH ACCUMULATION: * **hyperpigmentation** * **vitiligo** * weight loss + fatigue + abdominal pain
49
bullous pemphigoid * molecular target * organ target * what hypersensitivity type
* molecular target: **hemidesmosome antigens - BPAg1** **&** **BPAg2** at dermal-intradermal junction * organ target: **SKIN** * hypersensitivity type II
50
bullous pemphigoid - mechanism
* type II * IgG antibody made against **hemi-desmosomal antigens** - **BPAg1 & BPAg2** - along basement membrane → * SKIN BLISTERING * rarely involves mucous membranes
51
bullous pemphigoid -presentation
* blisters that are * TENSE * PRECEDED BY URTICARIA
52
bullous pemphigoid- diagnosis
* IgG * in linear band dermal-epidermal junction * on blister roof * circulating, against BPAg2 & BPAg2
53
pemphigous vulgaris * molecular target * organ target * sensitivity type
* molecular target: **keratinocyte desmogleins** * organ target; SKIN + mucous membranes * type II hypersensitivity
54
pemphigous vulgaris mechanism
* type II hypersensitivity * IgG or IgM made against keratinocyte desmogleins * leads to → flaccid blisters
55
pemphigous vulgaris - presentation
* blisters that * are PAINFUL * not pruritic * slough off * penetrate into mucous membranes
56
pemphigous vulgaris diagnosis
* IgG/IgM on the surface of **keratinocytes**, or * circulating IgG that bind the **epidermis** **“fish net appearance”**
57
pemphigous vulgaris - painful (not pruritic) blister that penetrates skin & mcuosa
58
bullous pemphigoid - TENSE, preceded by urticaria
59
**linear band of IgG at dermal-epidermal junction** bullous pemphigoid
60
**salt-split skin: IgG on blister roof** bullous pemphigoid
61
**IgG/IgM on the surface of keratinocytes (on epidermis)** **“fishnet appearance”** pemphigous vulgaris
62
**hyperpigmentation (MSH acculuation)** Addison's disease
63
compare and contrast the two bullous diseases - in terms of mechanism, presentation, dx
both type II diseases bulloid pemphigous * presentation: * tense, preceded by urticaria * ONLY SKIN AFFECTED * dx: IgG that is * in a **linear band** at dermal-epidermal junction * on **blister roof** * circulating, anti-**BPAg1 & BPAg2** pemphigous vulgaris * presentation: * painful (not itchy) * SKIN + MUCOUS MEMBRANES AFFECTED * dx: IgG/IgM * on **keratinocytes** (in epidermis) -"fishnet appearance"
64
Grave's Disease * molecular target * organ target * hypersensitivity type
* molecular target: TSH receptor * organ target: thyroid * hypersensitivity type II
65
Grave's Disease - mechanism
* type II hypersensitivity * auto-Ab made against TSH receptor → is agonistic → hyperthyroidism
66
grave's disease - presentation
* **triad** * goiter * exopthalmos * pretibial myxedema: “orange peel” skin under the knee * hyperthyroidism (hyper-metabolic state) * sweating * heat intolerance * tachycardia * inc GI - diarrhea, weight loss * restless / anxious
67
Grave's disease - dx
* **anti-TSH receptors - diagnostic** * also * TSH LOW * T3, T4 ELEVATED * inc radioactive iodine uptake in thyroid
68
hashimoto thyroiditis * molecular target * organ target * hypersensitivity type
* molecular target: **thyroid globulin & thyroperoxidase** * organ target: **thyroid** * type II hypersensitivity
69
hashimoto thyroiditis - mechanism * molecular target * organ target * what type of hypersensitivity?
* molecular: **thyroglobulin & thyroid peroxidase** (necessary for T3 & T4 synthesis) * organ: thyroid * Type II & Type IV hypersensitivity
70
hashimoto thyroiditis - mechanism
* **Th1 infiltration** of thyroid gland, which triggers * B-cell production of **antibodies** made against **thyroid peroxidase** & **thyroglobulin** * cytotoxic T-cell activation * leads to * formation of lymphoid follicles * lack of T3,T4 → hypothyroidism
71
hashimoto's thyroiditis - presentation
* hypothyroidism (hypo-metabolic state) * cold intolerance * dry scaly skin (no sweating) * bradycardia * dec GI → constipation, weight gain
72
hashimoto thyroiditis - dx
* **antibodies to thyroid peroxidase & thyroglobulin** - diagnostic * also * elevated TSH level * low T3, T4 * decreased uptake of radioactive iodine * _histology:_ lymphoid follicles
73
what is the most common autoimmune disease of the skin?
psoriasis
74
psoriasis - mechanism
Th1 and Th17 cytokines induce keratinocytes
75
psoriasis - presentation
* scaly plaques - **over elbows, knees, scalp, lower back** * _+ blisters that:_ are **filled with STERILE, PUSTILE FLUID** (vs bullous pemphigus & pemphigus vulgaris) * _auspitz sign:_ punctate bleeding
76
psoriasis - presentation
* scaly plaques - **over elbows, knees, scalp, lower back** * _+ blisters that:_ are **filled with STERILE, PUSTILE FLUID** (vs bullous pemphigus & pemphigus vulgaris) * _auspitz sign:_ punctate bleeding
77
psoriasis - scaly plaques on knees/elbows, scalp & back - blisters filled with **sterile, pustule fluid**
78
psoriasis - dx
* **RF negative** * **elevated uric acid** * clinical: scaly plaques, blisters with PUS, auspitz sign
79
rheumatoid arthritis * molecular target * organ target * hypersensitivity type
* molecular target: **synovial components** * organ target: **joints** - synovial membrane / cartilage / ligaments / tendons * type IV hypersensitivity
80
rheumatoid arthritis - mechanism
* type IV hypersensitivity * CD4 T-cells → stimulates synovial cells often in the context of **HLA-DR4 mutation**
81
rheumatoid arthritis - presentation
* **arthritis of 3+ joint areas** * _especially of_ * **HANDS** * **FEET** * also elbows, knees, hips spine, ect.
82
rheumatoid arthritis -diagnosis
* **ESR and CRP elevated** * **+/- circulating RF** * radiographs show: * erosions * decalcifications
83
tx or rheumatoid arthritis?
* rituximab (targets CD20) * anti-TNF-a inhibitors * **infliximab** (same as IBD) * **adalimumab** (same as IBD) * etanercept
84
SLE * molecular target * organ target * hypersensitivity type
* molecular target: **DNA/nucleoproteins** * organ targets: several **- skin + kidneys + joints** * type III hypersensitivity
85
SLE - mechanism
* type III hypersensitivity * **immune complexes** form against DNA/nucleoproteins in the skin + kidney + joints * worsened by _complement deficiency_
86
SLE - presentation
* triad * ERYTHEMA - BUTTERFLY RASH * GLOMERULONEPHRITIS * ARTHRITIS * _sometimes discoid rash_
87
what increases the risk of SLE?
* complement deficiency * increased estrogen
88
butterfly rash SLE
89
discoid rash SLE
90
which autoimmune diseases can cause mouth rashes?
* pemphigus' vulgaris (type II) - painful blisters * SLE - (type III) discoid rash
91
SLE - diagnosis
* **lumpy-bumpy pattern on IF** * antibodies that indicate kidney involvement * **anti-dsDNA antibodies** * **anti-smith antibodies** * +/- RF (less common that RA)
92
SLE - tx
* **avoid sunlight to prevent flares** * NSAIDS * steroids
93
sjogren syndrome (sicca syndrome) * target molecule * target organ * hypersensitivity type
* target molecule: n/a * target organ: exocrine glands - **salivary, lacrimal** * mechanism: type IV hypersensitivity
94
sjogren syndrome - presentation
* **DRY EYES (XEROPHTALMIA) + DRY MOUTH (XEROSTOMIA) - m/c** * can cause dryness of other mucosa - skin, nasal, laryngeal, vaginal * **parotid swelling** (esp. in children)
95
sjogren syndrome - diagnosis
* type IV hypersensitivity * **CD4 cells infiltrate exocrine glands** → impedes secretion
96
sjogren syndrome - dx
* Shirmer test - tear production * salivary / parotid gland biopsy → CD4 cell infiltrate * +/ RF
97
guillane barre syndrome (GBS) * molecular target * organ target * hypersensitivity type
* molecular target: **gangliosides (GM1 & GM1b)** in myelin * organ target: **PNS** * hypersensitivity type IV
98
what is a major complication of Sjogren's syndrome?
non-hodgkins lymphoma
99
GBS - mechanism
* type IV hypersensitivity * molecular mimicry induced - by either _viral infection_ or _previous vaccination_ * viral infection: **c*****ampylobacter -*****m/c** * also VZV/EBV/CMV * causes CD4+ mediated immune response against **myelin gangliosides (GM1 & GMb1)** in **PNS → abnormal nerve conduction**
100
GBS - presentation
* PNS dysfunction → muscle weakness * dysphagia, dysarthria (trouble speaking) * diminished reflexes * ataxia * facial droop / double vision
101
GBS - Dx
* **anti-ganglioside antibodies** * abnormal nerve conduction tests * nerve root enhancement on MRI
102
multiple sclerosis * organ target * molecular target * hyperesensitivity type
* organ target: **CNS** * molecular target: **myelin basic protein** * type IV hypersensitivity
103
MS - mechanism
* type IV hypersensitivity * likely induced by **molecular mimicry** d/t * EBV * HTLV-1 * **TH1/Th17 beat out Treg** * produce cytokines that induce killing of **_oligodrocytes_** → destruction of myelin sheath in white matter of CNS
104
MS - presentation
* _unilateral_ * paresthesia * trunk * one side of face * visual disturbances * **charcot triad** * **dysarthria** * **ataxia** * **tremor** * poor bladder control
105
MS - dx
* **plaques of demyelination on MRI** * **oligoclonal IgG bands** **on agarose electrophoresis** * **+/- myelin basic protein demyelination**
106
MS - tx
* corticosteroids (methylprednisolone), unlike GB * ABC therapy

IMMUNO (4 decks)

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