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MFMII > Autoimmunity > Flashcards

Autoimmunity Flashcards

1
Q

what is epitope spreading

A

as an autoimmune disease progresses, new T and/or B cells are activated against new epitopes from proteins either driving the response or a newly liberated protein from tissue damage aka multiple Ag drive waves of T or B cell responses (makes it a chronic disorder)

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2
Q

what drives autoimmune diseases

A

T and B cell reactivity to select Ags and epitopes (immunodominant) derived from specific organs or tissues

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3
Q

what does immunodominant mean

A

the primary epitope/peptide driving the disease

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4
Q

how is autoimmunity classified?

A

according to the effector mechanisms causing the disease which fall into 3 kinds of hypersensitivity reactions (II, III, IV)

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5
Q

what occurs in autoimmunity corresponding to type II hypersensitivity

A

Ab are directed against Ag of cell surfaces or the extracellular matrix

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6
Q

how does autoimmune hemolytic anemia work?

A

IgG and IgM bind to Ags on RBC surface–>complement fixation–>RBC lysis via MAC or removal via opsonization lead to anemia

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7
Q

what occurs in autoimmunity corresponding to type III hypersensitivity?

A

Ab are directed against SOLUBLE Ag forming immune complexes that deposit in tissues

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8
Q

how does vasculitis from systemic lupus erythematosus work?

A

IgG bind to soluble Ag in blood–>form immune complexes–>lodge in areas of high pressure–>complement fixation–>frustrated phagocytes spew contents–>tissue inflammation and damage = vasculitis

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9
Q

what occurs in autoimmunity corresponding to type IV hypersensitivity?

A

T cells specific to self Ag are activated and produce cytokines and/or produce cytotoxic compounds to destroy tissue cells

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10
Q

how does myelin destruction in MS work?

A

myelin Ags are presented to self reactive CD4 and CD8 cells–>these cells infiltrate the CNS–>Th cells produce IFNgamma to cause direct and indirect damage via macrophages, CTL contribute to damage and some neuron damage = demyelination and sclerotic plaque formation

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11
Q

what causes type I diabetes?

A

damage to Beta cells leads to failure to produce insulin (insulin dependent DM, juvenile onset diabetes)

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12
Q

what type of hypersensitivity is T1D?

A

type IV

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13
Q

what is insulitis

A

when T cell reactivity is initiated early in life with progressive infiltration of islets over time (slow destruction)

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14
Q

why does T1D have slow onset?

A

initial excess of beta cell and the slow rate of beta cell destruction

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15
Q

what occurs in stage 1 of the development of T1D?

A

beta cell autoimmunity and loss is present with the presence of autoantibodies (insulinitis) but there are no symptoms or abnormal glucose

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16
Q

what occurs in stage 2 of the development of T1D?

A

beta cell autoimmunity and loss is present with autoantibodies and hyperglycemia, but no symptoms yet

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17
Q

what occurs in stage 3 of the development of T1D?

A

beta cell autoimmunity and loss is present with autoAb, hyperglycemia, and symptoms of diabetes

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18
Q

what are the steps to generate autoimmunity?

A
  1. generate a pool of self reactive lymphocytes
  2. release and chronic presence of self Ag
  3. activation of self-reactive lymphocytes
  4. destruction of self-Ag expressing target cells
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19
Q

what HLA molecule is present in all individuals?

A

DRB1

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20
Q

what second HLA molecule is carried by some individuals?

A

DRB3, DRB4, DRB5; the Beta chain is highly polymorphic

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21
Q

what chain is most affiliated with autoimmunity and why?

A

beta chain of HLA-DR because the beta chain has the most polymorphic/variable alleles

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22
Q

what haplotypes of HLA are associated with susceptibility and resistance to T1D?

A

HLA-DQ and HLA-DR

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23
Q

why does having 2 allotypes of DQ2 and DQ8 increase susceptibility to T1D?

A

the recombination of components of DQ2 and DQ8 increases susceptibility

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24
Q

what allotype gives 10x more risk of having T1D?

A 
HLA-DQ2 = HLA-DQA1*0501:HLA-DQB1*0201
HLA-DQ8 = HLA-DQA1*03:HLA-DQB*0302
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25
Q

what combination haplotype gives the increased susceptibility to T1D?

A

HLA-DQ8 alpha chain DQA103
and
HLA-DQ2 beta chain DQB10201
= HLA-DQA103:HLA-DQB10201

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26
Q

which other haplotypes have a profound impact upon T1D susceptibility when coexpressed with DQ2, DQ8 or 03:0201?

A

HLA-DRB103 = DR3
HLA-DRB104 = DR4
aka
HLA-DR

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27
Q

what is the HIGHEST disease susceptibility to T1D?

A

DQA103:DQB10201 heterodimer combined with HLA-DR3 or HLA-DR4

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28
Q

why do these haplotypes lead to such susceptibility for disease?

A

MTEC and thymic DC HLA are missing appropriate binding pockets for residues of beta cell Ag, so the HLA poorly presents the self Ag in the thymus during negative selection, and the poor presentation generates a pool of self reactive T cells (because they think the weak TCR signaling is good, but it’s just because it just can’t bind in general)

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29
Q

describe the affinity of self reactive T cells

A

not all self reactive T cells have a higher affinity for self Ag, some have lower avidity (affinity) TCR

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30
Q

what is the impact of weak binding pocket of HLA in the periphery?

A

Ag is presented many many times (chronic presentation) so the T cell is activated slowly

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31
Q

what is the 2nd step of autoimmunity?

A

an unknown trigger (virus or infection?) leads to release of beta cell Ag and maturation of DC, which migrate to the draining lymph node carrying the beta cell Ag – off to display a chronic presence of self Ag

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32
Q

what occurs once the beta cell Ag-carrying DC reach the LN?

A

self-reactive lymphocytes are activated and pools of beta cell Ag-specific T cells migrate to the pancreas

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33
Q

how are self-reactive T cells activated in the lymphoid organs since peripheral tolerance should prevent this?

A

there is a defect in CTLA-4, PD-1, and/or Fas/FasL to get around peripheral tolerance

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34
Q

what do mature DC do when approaching self-reactive lymphocytes?

A

mature DC CD80/86 and PDL1/2 bind to T cell CTLA-4 and PD-1 to activate phosphatases within the activated T cells. These phosphatases inhibit the TCR/CD28 mediated signals. Therefore, the activated T cells are rendered anergic and no longer proliferate.

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35
Q

what specific defects in gene expression, structure and signaling of CTLA-4 and PD-1 are associated with T1D?

A
  1. truncated structure of CTLA-4 (IDDM12)
  2. reduced expression of PD-1 and PDL1
    (this is why anti-PD1/PDL1 can trigger T1D in cancer pt)
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36
Q

what role does Fas play in lymphocyte activation?

A

FasL is expressed by T cells, B cells after activation. Tcell-Tcell interaction through Fas/FasL induces apoptosis to help promote contraction of the T cell response, and is actually an important pathway of cytotoxicity (how cells kill others)

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37
Q

what cytokines increase Fas expression on beta cells?

A

IL-1
IFNgamma
TNFalpha
NO

38
Q

how does T1D utilize Fas?

A

immune cells use Fas to destroy beta cells by cytokine release (increases Fas expression on beta cells), and when Fas expression increases, FasL+ CTL, macs, NK, neuts attack

39
Q

what prevents full assault on beta cells by pancreatic infiltrating cells? (results in insulitis)

A

natural Treg cells upregulate Foxp3 which is a TF that enables nTreg cells to have contact dependent suppressor function

40
Q

how are induced Treg cells effective?

A

TGFbeta mediates suppression activity of iTregs

periphery

41
Q

how are natural Treg cells effective?

A

contact dependent

in the thymus

42
Q

what are nTregs

A

self reactive, high avidity TCR CD4+ T cells in thymus that survive negative selection

43
Q

what do nTregs express

A

always express IL-2Ralpha (CD25) to receive IL-2 survival signals, and upregulate Foxp3

44
Q

what are the functions of Treg cells?

A
  1. deprivation of IL-2
  2. suppress APC maturation and induce IDO
  3. production of suppressive cytokines
  4. direct induction of apoptosis
45
Q

what is the primary action of iTreg cells?

A

to produce suppressive cytokines IL-10, IL-35, and TGFbeta

46
Q

what cytokines suppress T cell activation, proliferation and effector functions?

A

IL-10
IL-35
TGFbeta

47
Q

how to nTregs deprive cells of IL-2?

A

ATP is dephosphorylated to AMP to produce adenosine that can bind A2AR and A2BR to increase cAMP level. more cAMP is transferred by gap junctions to effector cells which blocks IL-2 production = lack of survival
(nTreg suppresses via contact)

48
Q

how do nTregs suppress APC maturation and induce IDP?

A

CTLA-4 expression signals through B7 to suppress APC Ag presentation. The CTLA-4/B7 signaling induces IDO (indoleamine 2,3-dioxygenase) which converts tryptophan to Krn (kynurenines). (decreases availability of Trp)
Environmental Trp is required for T cell proliferation. ALSO krn suppresses signaling (mTOR1) which inhibits effector T cell function and expansion (apoptosis!)

49
Q

what do IL-10, Il-35 and TGFbeta do when secreted by iTreg?

A

suppress T cell activation, proliferation and effector functions

50
Q

how to nTregs directly induce apoptosis?

A
  1. release perforin and granzyme to promote apoptosis of APC and T cell
  2. express FasL to bind Fas on activated B and T cells
  3. express TRAIL (TNFrelated apoptosis inducing ligant) to bind death receptor 4 and 5 and induce apoptosis.
  4. galectin-1 binding to TIM-3
51
Q

which immunoregulation processes are usually deficient in autoimmunity?

A
  1. Treg intrinsic defects
  2. elevated IL-6 (resistant effector T cells)
  3. microbe/damage mediated APC function
52
Q

what aspects of Tregs are defective in autoimmunity?

A

nTregs production, proliferation and function is decreased. (decreased IL-10, IL-35, TGFbeta)

53
Q

how is IL-6 related to resistant effector T cells?

A

Il-6 can render Tregs ineffective. Th17 differentiation opposes iTreg differentiaion because IL-6 overrides TFGbeta mediated Foxp3 expression and can downregulate Foxp3 in Treg cells…
2. overwhelming IL-2, IL-7, IL-15 and IlL-21 production can also block suppression mediated by Treg cells

54
Q

which cytokines are involved in blocking suppression mediated by Tregs?

A

IL-2, IL-7, IL-15, IL-21 block suppression

IL-6 can downregulate Foxp3.

55
Q

how can microbes block Treg mediated suppression of APC?

A

PAMP (TLR ligation) activation of APC leads to IL-6 production, which blocks Treg mediated suppression of APC.

56
Q

how are neutrophils involved in T1D?

A

they are important during initial triggering events leading to beta cell death and Ag release

57
Q

how do macrophages contribute to T1D?

A
  1. IL-12 is involved in NK cell activation
  2. Ag+IL-12 is involved in activation of Th cells
  3. providing O2/hydrogen peroxide for beta cell death
  4. IL-1beta and TNFalpha for beta cell death
  5. FAS/FASL FOR BETA CELL DEATH
58
Q

what does the macrophage contribute for beta cell death?

A
  1. reactive oxygen and hydrogen peroxide
  2. IL-1 beta and TNFalpha
  3. fas/fasL
59
Q

how are NK cells involved in T1D?

A
  1. IFNgamma production increases macrophage function
  2. have Fas/FasL contributing to Beta cell death
  3. defective inhibitory receptor expression may be associated with initial insult leading to beta cell Ag release
60
Q

what could be associated with initial insult leading to beta cell Ag release?

A

NK cell defective inhibitory receptor expression of KIR or NKG2D.

61
Q

how do beta cell specific CD4 and CD8 cells contribute to beta cell death?

A
  1. produce TNFalpha
  2. express Fas/FasL
  3. release perforin/granzyme
62
Q

what is the primary action that helps develop beta cell specific CD4/CD8?

A

Th17 pathway initiates first autoimmune attack whic then propagates into Th1 and autoimmune destruction via IFNgamma activating macrophages. IL-2 also helps support CTL which are the major killers.

63
Q

what are early predictors of T1D onset?

A

anti-insulin and anti-GAD Ab from beta cell specific B cells BUT AB DON’T PLAY A LARGE ROLE IN THE DESTRUCTION

64
Q

how are anergic self reactive B cells activated in the paracortex?

A
  1. anergic self reactive B cells in the T cell zone (bc don’t have CXCR5) engage self Ag.
  2. usually, self Ag engagement results in apoptosis, bc chronic Ag, lack of survival factor, and T cell Fas ligand
    BUT SOMETIMES
  3. activated CD4 can rescue anergic B cells from this fate!
65
Q

how can activated CD4 T cells rescue anergic B cells in the paracortex?

A

bc of chronic Ag presentation/contact of Ag, CD40L is elevated on the T cells. If there is enough CD40L present, it could promote B cell activation rather than apoptosis though Fas/FasL. this reverses anergic conditions and CXCR5 is re-expressed!

66
Q

what does CD40 ligation of T cell with anergic B cell result in?

A

reversal of anergy and induction of CXCR5, cytokine receptors, and AID! now they produce autoAb

67
Q

pathogenesis of Graves’ disease?

A

agonist autoAb bind to TSH receptor and induce overproduction of T3 and T4.
i

68
Q

what to Graves’ disease autoAb stimulate?

A
  1. binding to TSH receptor induces T3, T4

2. production of glycosaminoglycans by TSHR+ fibroblasts and pre-adipocytes around eye orbit (bulging eyes)

69
Q

what causes the bulging eyes in Graves disease?

A

autoAb stimulates production of glycosaminoglycans by TSHR+ fibroblasts and pre-adipocytes around the eye orbit

70
Q

clinical findings of Graves’ disease?

A
  1. goiter
  2. outward bulging eyes
  3. nervousness/tremor
  4. heat intolerance
  5. tachycardia/arrythmia
  6. warm, moist skin
  7. weight loss
71
Q

pathogenesis of Myasthenia Gravis?

A

antagonistic autoAb (IgG) bind to Ach receptors on muscle cells, induces receptor turnover and degradation = reduced density of Ach receptors on muscle cell surface = progressive weakening

72
Q

what is the genetic mutation of Graves disease?

A

defect in HLA-DR3 or CTLA4 leads to increased Th2 response and production of IgG4

73
Q

symptoms of MG?

A
  1. ptosis
  2. double vision
  3. facial muscle weakness
  4. chest muscle weakness and difficulty breathing
74
Q

genetic mutation of MG?

A

CTLA4/HLA-A01, HLA-B08, HLA-DQ2, HLA-DR3 mutants leading to HIGHER SERUM TNFALPHA results in lower Th2 response

75
Q

pathogenesis of hashimoto’s thyroiditis?

A

IgG autoAb bind to thyroid peroxidase and thyroglobulin expressed by thyroid epithelial cells which leads to a loss of thyroid cells, thyroid hormones, and hypothyroidism

76
Q

what does thyroid peroxidase do?

A

catalyzes iodination of TG

77
Q

what can the autoAb in hashimotos activate?

A

activate complement to overwhelm the inhibitor mechanisms for phagocyte recruitment, ADCC via NK and frustrated phagocytosis

78
Q

what do CTL do in hashimotos?

A

CTL lyse Ag-expressing thyroid epithelial cells and Th1 cytokines drive inflammatory response, making ectopic lymphoid tissue in the thyroid

79
Q

clinical findings of Hashimoto’s

A
  1. goiter due to influx of cells
  2. fatigue
  3. muscle ache
  4. wt gain
  5. stiff reflexes
  6. husky voice
  7. dry skin
  8. sensitivity to cold
80
Q

genetic mutation of Hashimotos

A

HLA-DR3/CTLA4 mutants lead to decreased Treg number and function

81
Q

what type of hypersensitivity is hashimoto

A

type II

82
Q

pathogenesis of SLE (systemic lupus erythematosus)

A

IgG autoAb produced against a number of self-Ag that form immune complexes that deposit in blood vessels (vasculitis), kidneys (glomerulonephritis), joints (arthritis) and other tissues causing inflammation and damage

83
Q

how are self-Ag made in SLE?

A

they came from an inability to dispose of apoptotic cells, due to deficiency in pentraxins, C1, C2, C4 (complement)

84
Q

why is SLE so chronic/systemic?

A

epitope spreading maintains a vast supply of self-reactive T and B cells to numerous Ag

85
Q

what defect creates the pool of self reactive T cells in SLE?

A

HLA-DR2 (DRB11501) and HLA-DR3 (DRB10301)

86
Q

what is the Treg presence in SLE?

A

low Treg numbers/loss of function IN ADDITION TO increased IL-6 (diminishes immunosuppression by Treg)

87
Q

what other mutants have been associated with SLE other than HLA, Treg?

A

CTLA4 and Fas/FasL mutants

88
Q

what drives inflammation in SLE?

A

Th1 responses and IgG production

89
Q

what does the complement fixation due to immune complexes lead to?

A

neutrophil, macrophage, and mast cell recruitment and activation, therefore, site of deposition becomes inflamed with structural damage

90
Q

what does the butterfly rash in SLE come from?

A

damaged blood vessels that leak

91
Q

clinical signs of SLE?

A
  1. butterfly rash
  2. proteinuria then hematuria (glomerulonephritis)
  3. lack of movement/swelling/pain in joints (inflamed)

MFMII (29 decks)

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