Autoimmunity: an overview Flashcards
1
Q
Which genes often confer the highest risk of AI disease?
A
HLA genes
2
Q
What is thought to be the reason that autoimmunity is increasing in prevalence?
A
hygiene hypothesis
3
Q
Why are autoimmune diseases thought to be more common in females?
A
sex hormone-determined differences in immune phenotype
4
Q
What suggests that environment plays a bigger role in most AI diseases than genetics?
A
concordance between monozygotic twins isless than 40%
5
Q
What are the general environmental risk factors for AI disease?
A
gut microbiota species differences; infectious disease hx and vitamin D levels
6
Q
What is the molecular mimicry of AI disease?
A
antigenic cross-reactivity between microbial pathogens and self initiates autoimmunity
7
Q
Give an example of infection-driven autoimmunity?
A
Guillain Barre after campylobacter or reactive arthritis following campylobacter, shigella or salmonella
8
Q
What is the targeted antigen in Guillain barre?
A
glycolipids eg GA1; GM1
9
Q
What is the targeted antigen in addisons?
A
steroid 21-hydroxylase
10
Q
What is the targeted antigen in AI hepatitis?
A
liver-kidney microsome 1
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
12
Q
What cells are involved in peripheral tolerance?
A
regulatory T cells
13
Q
What is the natural FOXP3 mutant mouse called?
A
scurfy
14
Q
What happens to scurfy mice?
A
spontaneous, multi-organ autoimmunity and wasting diseases
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
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
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
18
Q
Give an example of a monoclonal antibody in studies for MS treatment?
A
secukinumab- antiIL17
19
Q
What was the first monoclonal antibody to be approved for the tx of MS?
A
natalizumab
20
Q
What is the function of natiluzimab?
A
prevents leukocyte migration into the CNS
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
22
Q
What is the function of Clostridia clusters for T cell development?
A
specific species are needed to fully expand Tregs
23
Q
What disease is related to a lack of clostridia clusters and therefore Tregs?
A
UC
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
25
what demonstrates the complex relationship between immune-mediated diseases and a shared pathobiology?
familial clustering of multiple diseases; epidemiological co-occurence and the efficacy of therapies across diseases
26
What is the purpose of GWAS studies?
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
27
What is the effect size?
proportion of disease risk attributable to each gene region
28
What is the general effect size at each genomic locus?
small
29
Why do disease risk variants have larger effects on cellular processes than disease suscepbility?
risk variants perturb disease-relevant cellular functions that alter an individuals overall likelihood of disease but are not sufficient to cause disease by themselves
30
Give an example of where risk variants from GWAS do not currently explain all the genetic component of disease risk?
about 50% of the genetic component of MS is explained by currently known association
31
What may explain the missing heritability from GWAS studies?
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
32
What is the percentage of risk alleles with evidence of association with multiple diseases?
44%
33
What are the implications of discrete, shared mechanisms underlying multiple diseases?
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
34
What shows that autoimmunty can be provoked by inducing a specific adaptive response to self antigens?
autoimmune disease can be induced by injection of self tissues taken from a genetically identical animal and mixed with strong adjuvants
35
give an example of a disease where autoantigens are cleared from the body?
Hashimoto's thyroiditis
36
Give examples of autoimmune diseases in which effector T cells seem to be the main destructive agents?
T1DM; psoriasis; IBD; MS
37
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?
that the disease is autoimmune in nature and prooves the involvement of the transferred material in the pathological process
38
Why are the mechanisms that limit the immune response lost in autoimmune disease?
the self-antigen cannot be easily eliminated as it is in vast excess or ubiquitous
39
What is sequestration?
the barrier which keeps many self-antigens away from the immune system
40
What is the result of constant presence of autoantigen?
chronic infammation which leads to the release of more autoantigens as a reuslt of tissue damage breaking down sequestration
41
What is epitope spreading?
the recruitment of new clones of lymphocytes reactive to new epitopes on the initiating autoantigen as well as new autoantigens
42
What are the methods of epitope spreading?
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
What is the name for the new, previously hidden peptide epitopes involved in epitope spreading?
cryptic epitopes
44
Give 2 examples of diseases where epitope spreading is implicated?
pemphigus vulgaris and SLE
45
How can a CD4 T cell speicifc for H1 peptide provide help to B cells specific for H1 and DNA?
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
How were the mechanisms of tissue injury in autoimmunity classified?
according to a hypersensitivity scheme
47
What is type II hypersensitivity?
binding of IgG or IgM to autoantigens located on cell surfaces or ECM
48
What is type III hypersensitivity?
tissue localisation of immune copmlexes composed of soluble antigens and their cognate antibodies
49
What is type IV hypersensitivty?
Th1 cells and/or cytotoxic T cells directly cause tissue damage
50
Give an example of autoimmune disease caused by a type 3 immune response in which Th17 cells promote inflammmation at a barrier tissue?
psoriasis or Crohns
51
What happens in autoimmune haemolytic anaemia?
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
Why is lysis of nucleated cells by complement less common?
cells are better defended by complement-regulatory proteins
53
How are circulating nucleated cells targeted by autoantibodies killed?
mononuclear phagocytic system or ADCC
54
How does IvIG work?
inhibitis the Fc-mediated uptake of antibody-coated cells and activates inhibitory Fc receptor to suppress production of inflammatory mediators by myeloid cells
55
What happens when sub-lytic amounts of MAC are on the surface of IgG or IgM targeted tissue cells?
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
give an example of an autoimmune disease where antibodies against a receptor stimulate the receptor?
Grave's
57
Give an example of an autoimmune disease caused by antibody responses to the ECM?
Goodpasture's
58
Why do immune complexes usually cause little tissue damage?
cleared by RBCs that bear complement receptors of phagocytes of the reticuloendothelial system that have complement and Fc receptors
59
What are hte main antigens in SLE?
nucleosome subunits of chromatin; spliceosome; small cytoplasmic ribonuceloprotein complex containing 2 proteins Ro and La
60
why are hereditary defieincies of some complelement proteins especially C1q; C2 and C4 assocaited with SLE?
they are early components of hte complement pathway and are important in antibody-mediated clearance of apoptotic cells and immune complexes
61
What does the reduced clearance of apoptotic cells and immune complexes mean in SLE?
there is a higher chance of activation of low-affinity self-reactive lymphocytes
62
How do nucleic acid:antibody complexes stimulate production of IFNa?
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
How does IFNa contribute to increased autoimmune antibody production?
stimulates BAFF prodcution by myeloid cells- monocytes and DCs which increases autoreactive B cell survival and increased autoantibody production
64
Why has it been more difficult to demonstrate the existance of autoreactive T cells?
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
How was the role of T cells discovered in the T1DM?
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
What allows T cells to get through the BBB in the initial stages of MS?
inflammation as they can bind VCAMs on activated endothelium and it makes the barrier more leaky
67
What suggested that T cells were important in the pathogenesis of RA?
association seen with a particular class of HLA-DR genes
68
What stimulates the differentaition of osteoclast precursors into mature osteoclasts in RA?
IL17A stimulates the expression of ligand for receptor activator of NFkB (RANKL) which stimulates osteoclasts
69
What produced by fibroblasts causes tisssue destruction in RA?
RANKL and MMP
70
What is the function of peptidyl arginase deiminase in RA?
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
What is a lcear demonstration of genetic disposition to autoimmunity?
inbred mice very prone to developing autoimmunity- NOD mice that get dibetetes with female mice becoming diabetic faster than males
72
What indicates that environmental influences are important in inbred mice?
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
What are the mutations in mice that develop autoimmunity likely to be in?
cytokines; coreceptors; antigen-signalling casacdes; co-stimulatory molecules; proteins involved in apoptosis; proteins that clear antigen or immune complexes
74
Which autoimmune diseases show association with genetic mutations in CTLA4 locus on chromosome 2?
T1DM; Grave's; Hashimoto's thyroiditis; RA; MS
75
How do Fas mutations contribute to autoimmunity?
cause excessive tissue damage releasing autoantigens
76
How can both a decrease and increase in signalling transudction intensity contribute to autoimmunity?
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
What disease is caused by mutations in Fas?
autoimmune lymphoproliferative syndrome
78
What do mutations in Fas result in in mice?
a disease that resembles SLE
79
Why are autoimmune diseases caused by single genes important?
mutations causing them identify important pathways that normally prevent the development of autoimmune responses
80
What strongly suggests the role for MHC alleles through animal models?
development of experimental diabetes or arthritis in transgenic mice expressing specific human HLA antigens
81
What strongly suggests the role for MHC alleles in humans?
GWAS; 2 siblings affected with the same autoimmune disease are far more likely than expected to share the same MHC haplotype
82
What explains the relationships of Mhc alleles to autoimmune diseases?
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
What shows that MHC alleles driving thymocyte repertoire is important in autoimmune disease?
the allele in NOD mice binds many peptides very poorly so may be less effective at driving negative selection
84
What is Crohns disease thought to result from?
hyperresponsiveness of CD4 T cells to antigens of the commensal gut microbiota rather than to true self antigens
85
What causes the hyperresponsiveness of T cells in Crohns?
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
Why would loss of mutations in NOD2 cause Crohns?
NOD2 activation in Paneth cells stimulates antimicrobial peptide secretion and helps sequester commensal bacteria
87
Give an example of an immunoregulatory function of vitamin D?
suppresses Th17 development
88
What indicates the importance of the commensal microbiota in shaping the immune response?
diversity of commensal microbiota having a role in contributing to autoimmune disease
89
What modes may infection play in breaking self-tolerance?
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
Give an example of infection affecting autoimmune disease?
the severity of T1DM in NOD mice is exacerbated by Coxsackie virus B4 infection
91
Give an example of the role of TLRs in driving disease?
anmial model of arthritis where injection of bacterial CpG DNA into the joints of mice induces arthritis
92
Give an example of an animal model of molecular mimicry?
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
What is thought to be the mechanism by which some drugs can cause autoimmunity?
may react chemicallly with self proteins and form derivatives that the immune system recognises as foreign
94
give an example of a drug causing autoimmunity?
heavy metals e.g gold administered to susceptible strains of mice causes a predictable autoimmune syndrome
