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Module 3 > Autoimmunity: an overview > Flashcards

Autoimmunity: an overview Flashcards

1
Q

Which genes often confer the highest risk of AI disease?

A

HLA genes

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2
Q

What is thought to be the reason that autoimmunity is increasing in prevalence?

A

hygiene hypothesis

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3
Q

Why are autoimmune diseases thought to be more common in females?

A

sex hormone-determined differences in immune phenotype

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4
Q

What suggests that environment plays a bigger role in most AI diseases than genetics?

A

concordance between monozygotic twins isless than 40%

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5
Q

What are the general environmental risk factors for AI disease?

A

gut microbiota species differences; infectious disease hx and vitamin D levels

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6
Q

What is the molecular mimicry of AI disease?

A

antigenic cross-reactivity between microbial pathogens and self initiates autoimmunity

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7
Q

Give an example of infection-driven autoimmunity?

A

Guillain Barre after campylobacter or reactive arthritis following campylobacter, shigella or salmonella

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8
Q

What is the targeted antigen in Guillain barre?

A

glycolipids eg GA1; GM1

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9
Q

What is the targeted antigen in addisons?

A

steroid 21-hydroxylase

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10
Q

What is the targeted antigen in AI hepatitis?

A

liver-kidney microsome 1

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11
Q

What suggests that tolerance generally operates efficiently

A

for the majority of proteins encoded by the genome have not been seen to occur as target autoantigens

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12
Q

What cells are involved in peripheral tolerance?

A

regulatory T cells

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13
Q

What is the natural FOXP3 mutant mouse called?

A

scurfy

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14
Q

What happens to scurfy mice?

A

spontaneous, multi-organ autoimmunity and wasting diseases

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15
Q

What suggests that NOD diabetes is caused by reduced numbers and function of Tregs?

A

small numbers of expanded Tregs transferred to NODs reverse even ongoing disease

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16
Q

what have been the value of genome-wide association studies?

A

genetic complexity of AI susceptbility; shown some disease-common and some disease-unique genes and pathways; reinforced the immunological aetiology of diseases–hope of predicting highly at risk individuals for screening and early tx

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17
Q

What was the first evidence for the importance of Th12 cells in autoimmunity?

A

when knocking out Th17 pathways, no longer able to induce EAE in mice, demonstrating their role in the disease previously thought to be Th1

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18
Q

Give an example of a monoclonal antibody in studies for MS treatment?

A

secukinumab- antiIL17

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19
Q

What was the first monoclonal antibody to be approved for the tx of MS?

A

natalizumab

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20
Q

What is the function of natiluzimab?

A

prevents leukocyte migration into the CNS

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21
Q

Give an example of a disease driven by a specific gut microbiota species?

A

segmented filamentous bacteria drive AI arthritis via Th17; enhanced susceptbility to RA caused by prevotella copri

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22
Q

What is the function of Clostridia clusters for T cell development?

A

specific species are needed to fully expand Tregs

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23
Q

What disease is related to a lack of clostridia clusters and therefore Tregs?

A

UC

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24
Q

How have stem cells been used in autoimune disease?

A

studies using autologous HSC transplantation to reprogramme immune repertoire in severe AI disease has been successful

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25
Q

what demonstrates the complex relationship between immune-mediated diseases and a shared pathobiology?

A

familial clustering of multiple diseases; epidemiological co-occurence and the efficacy of therapies across diseases

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26
Q

What is the purpose of GWAS studies?

A

locate regions of the genome harbouring disease risk alleles by comparing allel frequencies between cases and controls, from which the effect size can be estimated

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27
Q

What is the effect size?

A

proportion of disease risk attributable to each gene region

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28
Q

What is the general effect size at each genomic locus?

A

small

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29
Q

Why do disease risk variants have larger effects on cellular processes than disease suscepbility?

A

risk variants perturb disease-relevant cellular functions that alter an individuals overall likelihood of disease but are not sufficient to cause disease by themselves

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30
Q

Give an example of where risk variants from GWAS do not currently explain all the genetic component of disease risk?

A

about 50% of the genetic component of MS is explained by currently known association

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31
Q

What may explain the missing heritability from GWAS studies?

A

independent variants modify each otehr to generate greater-than-expected risk effects- epistasis between loci or pathways; rare variants not captured by GWAS or an overestimation of the heritability of idsease

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32
Q

What is the percentage of risk alleles with evidence of association with multiple diseases?

A

44%

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33
Q

What are the implications of discrete, shared mechanisms underlying multiple diseases?

A

1- expansion of current therapies and new treatments based on shared disease pathways, 2- possibility of classifying patients by defects in such patwhays rather than clinical symptoms

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34
Q

What shows that autoimmunty can be provoked by inducing a specific adaptive response to self antigens?

A

autoimmune disease can be induced by injection of self tissues taken from a genetically identical animal and mixed with strong adjuvants

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35
Q

give an example of a disease where autoantigens are cleared from the body?

A

Hashimoto’s thyroiditis

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36
Q

Give examples of autoimmune diseases in which effector T cells seem to be the main destructive agents?

A

T1DM; psoriasis; IBD; MS

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37
Q

What does the ability for a disease to be transferred from a disease individual to a healthy one by transferring antibodies or T cells indicate?

A

that the disease is autoimmune in nature and prooves the involvement of the transferred material in the pathological process

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38
Q

Why are the mechanisms that limit the immune response lost in autoimmune disease?

A

the self-antigen cannot be easily eliminated as it is in vast excess or ubiquitous

39
Q

What is sequestration?

A

the barrier which keeps many self-antigens away from the immune system

40
Q

What is the result of constant presence of autoantigen?

A

chronic infammation which leads to the release of more autoantigens as a reuslt of tissue damage breaking down sequestration

41
Q

What is epitope spreading?

A

the recruitment of new clones of lymphocytes reactive to new epitopes on the initiating autoantigen as well as new autoantigens

42
Q

What are the methods of epitope spreading?

A

self-antigens that are normally present in concentrations too low to activate naive cell processing of hte internalised autoantigen can reveal new, previously hidden peptide epitopes that the B cell can then present to T cells ; B cells internalise molecules closely associated with a antigen specific to their BCR which can then be presented

43
Q

What is the name for the new, previously hidden peptide epitopes involved in epitope spreading?

A

cryptic epitopes

44
Q

Give 2 examples of diseases where epitope spreading is implicated?

A

pemphigus vulgaris and SLE

45
Q

How can a CD4 T cell speicifc for H1 peptide provide help to B cells specific for H1 and DNA?

A

DNA as well as H1 is an epitope on the surface of the nucleosome so B cells specific for the DNA will be able to internalise it and present constiutents of the nucleosome to the T cell, such as H1, then the T cell will then activate the DNA-specific B cell

46
Q

How were the mechanisms of tissue injury in autoimmunity classified?

A

according to a hypersensitivity scheme

47
Q

What is type II hypersensitivity?

A

binding of IgG or IgM to autoantigens located on cell surfaces or ECM

48
Q

What is type III hypersensitivity?

A

tissue localisation of immune copmlexes composed of soluble antigens and their cognate antibodies

49
Q

What is type IV hypersensitivty?

A

Th1 cells and/or cytotoxic T cells directly cause tissue damage

50
Q

Give an example of autoimmune disease caused by a type 3 immune response in which Th17 cells promote inflammmation at a barrier tissue?

A

psoriasis or Crohns

51
Q

What happens in autoimmune haemolytic anaemia?

A

IgG or IgM against RBCs are rapidly cleared by interaction with Fc or complement receptor by macropahges in the spleen or attacked by MAC

52
Q

Why is lysis of nucleated cells by complement less common?

A

cells are better defended by complement-regulatory proteins

53
Q

How are circulating nucleated cells targeted by autoantibodies killed?

A

mononuclear phagocytic system or ADCC

54
Q

How does IvIG work?

A

inhibitis the Fc-mediated uptake of antibody-coated cells and activates inhibitory Fc receptor to suppress production of inflammatory mediators by myeloid cells

55
Q

What happens when sub-lytic amounts of MAC are on the surface of IgG or IgM targeted tissue cells?

A

provides a powerful activating stimulus to produce cytokines; respiratory burst; generation of arachiodonic acid; atttraction of further leukocytes by C5a which are further activated by antibody and C3 on the cell surface —damage due to products of activated leukocytes and ADCC

56
Q

give an example of an autoimmune disease where antibodies against a receptor stimulate the receptor?

A

Grave’s

57
Q

Give an example of an autoimmune disease caused by antibody responses to the ECM?

A

Goodpasture’s

58
Q

Why do immune complexes usually cause little tissue damage?

A

cleared by RBCs that bear complement receptors of phagocytes of the reticuloendothelial system that have complement and Fc receptors

59
Q

What are hte main antigens in SLE?

A

nucleosome subunits of chromatin; spliceosome; small cytoplasmic ribonuceloprotein complex containing 2 proteins Ro and La

60
Q

why are hereditary defieincies of some complelement proteins especially C1q; C2 and C4 assocaited with SLE?

A

they are early components of hte complement pathway and are important in antibody-mediated clearance of apoptotic cells and immune complexes

61
Q

What does the reduced clearance of apoptotic cells and immune complexes mean in SLE?

A

there is a higher chance of activation of low-affinity self-reactive lymphocytes

62
Q

How do nucleic acid:antibody complexes stimulate production of IFNa?

A

bind to FcyIIa receptors on pDCs which are then delivered to endosomes where the ssRNA or dsDNA is recognised by TLR7 and TLR9 to induce IFNa production

63
Q

How does IFNa contribute to increased autoimmune antibody production?

A

stimulates BAFF prodcution by myeloid cells- monocytes and DCs which increases autoreactive B cell survival and increased autoantibody production

64
Q

Why has it been more difficult to demonstrate the existance of autoreactive T cells?

A

cannot transfer disease to experimental animals because T cell recognition is MHC restricted and autoanticodies can be used to stain self-tissues to reveal distribution of autoantigen, which cannot be done with T cells

65
Q

How was the role of T cells discovered in the T1DM?

A

when patients with diabetes were transplanted with half a pancreas from an identical tiwn donor, the beta cells in the grafted tissue were rapidly adn selectively destroyed by the recipients T cells and can be prevented by cyclosporin A which inhibits T cell activation

66
Q

What allows T cells to get through the BBB in the initial stages of MS?

A

inflammation as they can bind VCAMs on activated endothelium and it makes the barrier more leaky

67
Q

What suggested that T cells were important in the pathogenesis of RA?

A

association seen with a particular class of HLA-DR genes

68
Q

What stimulates the differentaition of osteoclast precursors into mature osteoclasts in RA?

A

IL17A stimulates the expression of ligand for receptor activator of NFkB (RANKL) which stimulates osteoclasts

69
Q

What produced by fibroblasts causes tisssue destruction in RA?

A

RANKL and MMP

70
Q

What is the function of peptidyl arginase deiminase in RA?

A

converts arginine residues to citrulline causing a structual alteration in self protein that can cause the immune system to recognise it as non-self

71
Q

What is a lcear demonstration of genetic disposition to autoimmunity?

A

inbred mice very prone to developing autoimmunity- NOD mice that get dibetetes with female mice becoming diabetic faster than males

72
Q

What indicates that environmental influences are important in inbred mice?

A

although most membrers of a colony of NOD mice develop diabetes, they do so at different ages and this differs between different colonies despite being genetically identical

73
Q

What are the mutations in mice that develop autoimmunity likely to be in?

A

cytokines; coreceptors; antigen-signalling casacdes; co-stimulatory molecules; proteins involved in apoptosis; proteins that clear antigen or immune complexes

74
Q

Which autoimmune diseases show association with genetic mutations in CTLA4 locus on chromosome 2?

A

T1DM; Grave’s; Hashimoto’s thyroiditis; RA; MS

75
Q

How do Fas mutations contribute to autoimmunity?

A

cause excessive tissue damage releasing autoantigens

76
Q

How can both a decrease and increase in signalling transudction intensity contribute to autoimmunity?

A

decrease- in the thymus would result in failure of negative selection whilst an increase in periphery would result in greater and prolonged activation with an exaggerated immune response

77
Q

What disease is caused by mutations in Fas?

A

autoimmune lymphoproliferative syndrome

78
Q

What do mutations in Fas result in in mice?

A

a disease that resembles SLE

79
Q

Why are autoimmune diseases caused by single genes important?

A

mutations causing them identify important pathways that normally prevent the development of autoimmune responses

80
Q

What strongly suggests the role for MHC alleles through animal models?

A

development of experimental diabetes or arthritis in transgenic mice expressing specific human HLA antigens

81
Q

What strongly suggests the role for MHC alleles in humans?

A

GWAS; 2 siblings affected with the same autoimmune disease are far more likely than expected to share the same MHC haplotype

82
Q

What explains the relationships of Mhc alleles to autoimmune diseases?

A

susceptibility is determined by differences in the ability of different allelic variants of MHC molecules to present autoantigenic peptides to autoreactive T cells ; the role that MHC alleles have in shaping the T cell repertoire as self-peptides assocaited with certain MHC molecules may drive the postiive selection of developing thymocytes that are specific for particular autoantigens - some may bind too poorly for negative selection but bind strongly enough for positive selction

83
Q

What shows that MHC alleles driving thymocyte repertoire is important in autoimmune disease?

A

the allele in NOD mice binds many peptides very poorly so may be less effective at driving negative selection

84
Q

What is Crohns disease thought to result from?

A

hyperresponsiveness of CD4 T cells to antigens of the commensal gut microbiota rather than to true self antigens

85
Q

What causes the hyperresponsiveness of T cells in Crohns?

A

inability of immune mechanisms to sequester luminal bacteria from the adaptive immune system; T cell intrinsic defects that cause heightened efector responses or failure of Tregs to suppress microbiota reactive Th17/Th1 cells

86
Q

Why would loss of mutations in NOD2 cause Crohns?

A

NOD2 activation in Paneth cells stimulates antimicrobial peptide secretion and helps sequester commensal bacteria

87
Q

Give an example of an immunoregulatory function of vitamin D?

A

suppresses Th17 development

88
Q

What indicates the importance of the commensal microbiota in shaping the immune response?

A

diversity of commensal microbiota having a role in contributing to autoimmune disease

89
Q

What modes may infection play in breaking self-tolerance?

A

breaking down barriers allowing release of sequestered autoantigens- sympathetic opthalmia; moelcular mimicry; increasing activation of selfreactive lymphocytes ; proinflammatory cytokines decrease the suppressive activity of Tregs

90
Q

Give an example of infection affecting autoimmune disease?

A

the severity of T1DM in NOD mice is exacerbated by Coxsackie virus B4 infection

91
Q

Give an example of the role of TLRs in driving disease?

A

anmial model of arthritis where injection of bacterial CpG DNA into the joints of mice induces arthritis

92
Q

Give an example of an animal model of molecular mimicry?

A

transgenic mice who express a viral antigen in the pancreas do not normally respond to this “self” antigen but upon infection with that virus mice develop diabetes

93
Q

What is thought to be the mechanism by which some drugs can cause autoimmunity?

A

may react chemicallly with self proteins and form derivatives that the immune system recognises as foreign

94
Q

give an example of a drug causing autoimmunity?

A

heavy metals e.g gold administered to susceptible strains of mice causes a predictable autoimmune syndrome

Module 3 (33 decks)

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