Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Medicine Unit 9 UoS > Unit 9 - Diseases of the immune system > Flashcards

Unit 9 - Diseases of the immune system Flashcards

1
Q

What is the function of the immune system?

A

Sensing - of pathogens, tolerance to self, ignorance of harmless antigens
Responding - innate and adaptive immunity, memory
Repairing - contraction of immune system, repair of damaged tissue

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What can occur if the balance of the immune system becomes disturbed?

A

Autoimmune disease/autoinflammatory - damage to self
Immunodeficiency - greater susceptibility to infection and cancer

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What are the main categories of immune diseases?

A

Immunodeficiency - poor or no response to pathogens
Hypersensitivity and allergy - inappropriate response to harmless foreign antigens
Autoimmunity - inappropriate response to self antigens

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are lymphocyte antigen receptors?

A

TCR (can recognise 1 epitope) and BCR (can recognise two epitopes at a time)
Antigen receptors have variable and constant parts
New receptors are produced from genes being chopped up and rearranged

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

How are different lymphocyte receptors created?

A

Somatic Recombination
Enzymes cleave DNA in certain locations, where variable antigens regions are encoded in gene segments
Dna is joined back up in different combinations of gene segments
Final combo is gene that can be expressed

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What are RAG genes?

A

RAG 1 and 2 genes encode enzymes that recombine and rearrange antigen receptor and immunoglobulin genes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What is central and peripheral tolerance?

A

Eliminates self-reactive lymphocytes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Where does central and peripheral tolerance occur?

A

Central - where lymphocytes develop - Thymus Tcells, Bone marrow B cells
Peripheral - in peripheral tissues everywhere lese in body

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Where do T cells originate and go to to develop?

A

Originates as common lymphoid progenitor (CLP) in bone marrow
Migrate to thymus to develop

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What is the process of development of T cells from CLP stem cells until they enter cortical epithelial cells?

A

CLP leaves bone marrow enters thymus becomes thymocytes
Thymocytes proliferate and safe cells leave thymus (2-4%) as double negative thymocytes (CD3-4-8-)
Double negative thymocyte rearranges B chain section D-J
Presents pre TCR with B chain and surrogate a chain
If interacts with APC in thymus, receives positive signal, stops rearrangement of B chain, signals to begin expressing CD4 CD8
CD4 CD8 signal to start rearrangement of a chain
Ready for positive or negative selection

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

After developing CD4 and 8 receptors, how do T cells develop?

A

Positive selection: in cortical epithelial cells
- If TCR has higher affinity for MHC 1, receive a positive signal to keep CD8
- If TCR has higher affinity for MHC II, receive positive signal to keep CD4
Negative selection: in medullary epithelial cells
- Gene in thymus expresses in thymus every self antigen
- No binding = released
- If CD8 cell TCR binds to any self antigens, cells is killed or silenced
- If CD4 cell TCR has high affinity for any = apoptosis
- If CD4 cell TCR has low affinity for any = produced T reg cell - CD4+CD25+

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What is AIRE?

A

Auto-Immune Regulator
Transcriptional regulator induces expression of self proteins in thymus
Expressed in nucleus of the thymic medullary stromal cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What is an example of the outcome when there is a mutation in the AIRE gene?

A

APECED
Autoimmune PolyEndocrinopathy Candidiasis Ectodermal Dystrophy
Immune response
The immune system attacks multiple endocrine tissues

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Why is peripheral tolerance needed?

A

Central tolerance doesn’t cover every antigen
T cells are reliant on costimulation by CD28 receptors which only occurs if a PAMP or DAMP is present

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What mechanisms does peripheral tolerance work by?

A

Anergy: no costimulation given by APC -> no response by naive T cell
Ignorance: anatomical barrier between APC and T cell e.g. BBB
Deletion: FasL:Fas cytotoxic mechanism - kills overactivated T cell
Inhibition: CTLA-4 on T reg cells - costimulatory molecule - Inhibits APCs from interacting with dangerous T cell
Suppression: Sufficient IL-10 and TGF-B from T-reg can suppress activation of dangerous T cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

ALPS

A

Autoimmune Lymphoproliferative Syndrome
FasL and Fas are dysfunctional
T cells can’t be killed by deletion

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What are the roles of natural T regulatory cells?

A

Cell killing: release granzyme and perforin to kill self reactive Tcell
Cytokine secretion: release Il-10 and TGF-B to suppress activation of SR Tcell
Competition: uses CTLA-4 to bind with costimulatory molecules on APC, so SR Tcell cannot bind instead
IL-2 depletion: CD-25 on nTreg has high affinity for IL-2 preventing SR Tcell proliferation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Where are Tregs found?

A

In mucosa to promote tolerance to innocuous foreign antigens and so prevent chronic inflammation
Some move between spleen and circulation and recruited to sites of inflammation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What are the stages of B cell development?

A

Common lymphoid progenitor (CLP) stem cell stays in bone marrow
Heavy chain rearrangement D-J
Heavy chain rearrangement Variable region D-J
Pre B cell receptor expressed with surrogate variable regions to check heavy chain rearrangement
If successful, signal causes light chain gene rearrangement V-J until functional receptor formed
IgM expressed on the surface
If successful, class switched for IgD

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What disease is linked to B cell development?

A

X-linked agammaglobulinaemia
Tyrosine kinase dysfunctional
Many immature B cells, non-functional BCRs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

What if B cells have no self reaction?

A

B cells are released to the periphery expressing IgD on the surface

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What happens if a B cell recognises a multivalent self molecule?

A

Multivalent self molecule has many repeating sequences of an epitope
Will bind to many IgD on B cell
Kills B cell by activation induced cell death - overactive signal
Or is released after receptor editing

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What happens if a B cell recognises soluble self molecules?

A

Recognises small soluble self molecules, does not crosslink the IgD
Leaves bone marrow as silent - anergic - and die in periphery quickly.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

What happens if the B cell has low affinity for self molecules and no crosslinking?

A

Migrate to periphery
Affinity for self, but does not react in normal conditions

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

Why is B cell selection not as important as T cell selection?

A

T cells are required to activate B cells, and so self reactive T cells have more of an impact

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

Primary immunodeficiency
Examples
Treatment

A

Genetic
Severe combined immunodeficiency, Agammaglobulinaemia

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

Secondary immunodeficiency
Examples
Treatment

A

Acquired
AIDS, immunosupression from drugs, impaired immunity from starvation
Variable treatment, management with anti-microbials

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

AIDS causing immunodeficiency

A

Infects CD4 T cells and dendritic cells, carried to lymph node, transmits to cells in lymph node
Cytotoxic cells recognise infection in CD4 T cells, kills them, low CD4 levels early on
CD4 cells also killed from virus exiting to infect other cells
= immunodeficient

29
Q

What areas in innate immunity can cause primary immunodeficiency? and what conditions/infections are they related to?

A

TLR signalling - MyD88 gene - pyogenic bacterial infections
Complement - C5-C9 - Recurrent Neisseria infections
ROS-mediated killing (oxygen free radicals) - CYBB gene - recurrent fungal and bacterial infections

30
Q

What areas of adaptive immunity can cause primary immunodeficiency? and what conditions/infections are they related to?

A

Lymphocyte development - IL2RG, RAG gene - SCID
B cell development - BTK gene - Agammaglobulinaemia
Defective cytokine killing - STAT3 gene - recurrent skin and resp infections

31
Q

X linked SCID

A

Adaptive primary immunodeficiency
Loss of function mutation in gene IL2RG on the X chromosome
IL2R common gamma chain is needed for a set of cytokine receptors to signal - expressed by many immune cells
Affects IL 2, 7 and 15 and other IL

32
Q

Chronic Granulomatous Disease

A

CGD
Innate primary immunodeficiency
Simplified NAPH oxidase complex affected - would produce oxidative burst of bacteria
Instead bacteria lives inside APC that has phagocytosed bacteria
Forms granuloma

33
Q

How common are autoimmune diseases?

A

More than 5%

34
Q
A
35
Q

What is autoimmunity?

A

Pathological state where there has been a breach in tolerance to selfand immune system attacks own tissues
Response to self is normal - damaging effector response to self is not

36
Q

What is the positive feedback loop in chronic autoimmune disease?

A

Injury leads to inflammation
Self peptides presented to immune response under conditions to promote immune response
Inability to clear self antigens
Immune response attempts to clear antigen causes more damage
Immune response broadens
More self antigens are released, more cells recruited
-> inflammation

37
Q

Why may autoimmunity develop?

A

Genetic factors:
- MHC (HLA)
- AIRE, FOXP3 - self tolerance genes
- Immune signalling/regulatory genes
Environmental Factors:
- Smoking
- Chemicals
- UV
-Infection
These lead to imbalance in response and breach of tolerance
These lead to autoimmunity

38
Q

What roles do genes have that increase susceptibility to autoimmunity?

A

Disrupt tolerance
Disrupt apoptosis
Promote inflammation
Promote cell activation

39
Q

What is monogenic vs complex susceptibility?

A

Monogenic - predominant genetic risk with minor additional genetic and environmental factors
Complex - multiple genetic and environmental factors

40
Q

What genes are involved in autoimmunity?

A

AIRE
CTLA4
FOXP3
FAS
C1q

41
Q

How may AIRE be involved in autoimmunity? What disease is this linked to?

A

Autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy (APECED)
Decreased expression of self antigens in the thymus -> defective negative selection of self reactive T cells

42
Q

How may CTLA4 be involved in autoimmunity? What disease is this linked to?

A

Grave’s disease, type 1 diabetes
Failure of T cell anergy
Reduced activation threshold of self reactive T cells
Reduced T reg function

43
Q

How may FOXP3 be involved in autoimmunity? What disease may this be linked to?

A

Immune dysregulation, polyendocrinopathy, enteropathy, X linked syndrome
Decreased function of Treg

44
Q

How may FAS be involved in autoimmunity? What disease may this be linked to?

A

Autoimmune lymphoproliferative syndrome
Failure of apoptotic death of self reactive B and T cells

45
Q

How may C1q be involved in autoimmunity? What disease may this be linked to?

A

Systematic lupus erythematosus
Defective clearance

46
Q

Give autoimmune disease examples (7)

A

Type 1 diabetes
Multiple sclerosis
Crohn’s disease
Psoriasis
Grave’s disease
Rheumatoid arthritis
Systematic lupus erthematosus

47
Q

What generally occurs in crohn’s disease?

A

Autoreactive T cells kill intestinal flora
Leads to intestinal inflammation and scarring
Organ specific

48
Q

MHC vs HLA

A

MHC is the gene
HLA is the protein that the gene encodes

49
Q

MHC gene characteristics

A

Polygenic - gene locus contains multiple different MHC class I and II genes, so many kinds of molecules can be expressed on cells with different binding specificities
Polymorphic - multiple alleles of each gene within the population

50
Q

What do polymorphisms do to HLA molecules?

A

Affect recognition of antigen by T cells
Alters peptide binding site of HLA molecule
Alter interaction between TCR and HLA+peptide
Some will be better at binding to self

51
Q

What is HLA association?

A

Some HLA types occur in higher frequency in some diseases
Not a predictor of autoimmunity but contributing factor
Some HLAs are protective - related to negative selection in the thymus

52
Q

Where is there female susceptibility in autoimmunity? Why may this occur?

A

Many autoimmune conditions are more common in women
Women have stronger humoral response than men, producing higher levels of antibodies
Testosterone reduces T cell survival
Oestrogen can enhance B cell responses

53
Q

What are examples of risk alleles in autoimmunity?

A

MHC and CTLA4 in T helper cell activation
PTPN22 in T cell signalling
FAS gene - apoptosis gene
FOXP3 and IL-10 in iTreg cells
CD25 in nTreg cells

54
Q

What environmental factors can increase risk of autoimmunity?

A

Smoking
Viral and bacterial infections: Hep C and EBV infect B cells and may affect cell function

55
Q

What is the adjuvant effect in autoimmunity?

A

Inflammation is induced when autoantibodies are injected WITH microbial products
Shows importance of environmental factors in autoimmunity

56
Q

Name the different mechanisms by which peripheral tolerance can be overcome to cause autoimmunity

A

Cryptic antigens
Molecular mimicry
Bystander activation
Epitope spreading
Antigen is also a DAMP

57
Q

How can cryptic antigens overcome peripheral tolerance to cause auotimmunity?

A
  • Antigens hidden in cells or altered due to environmental conditions e.g. hypoxia
  • Appear differently in bone marrow and thymus, look like non-self in the periphery
    = cryptic anitgens
  • Can activate T and B cells to cause damage and further release anitgens
58
Q

How can molecular mimicry overcome peripheral tolerance to cause auotimmunity? examples and associated infections

A
  • Some pathogen antigens structurally resemble self antigens and may bind BCR/TCR with higher affinity
  • Infections can activate cross reactive responses to self antigens and initiate autoimmunity
    e.g. ankylosing spindylitis - K.pneumonaie
    Guillan barre syndrome - C.jejuni
59
Q

How can bystander activation overcome peripheral tolerance to cause autoimmunity?

A
  • T and B cells with low affinity for self antigens can escape selection and go to periphery
  • Antigen alone cant activate these
  • Inflammation and infection causes co-inflammatory molecules to be expressed by APC
  • APC overcome T cell anergy. T cell activated and attacks self
60
Q

How can epitope spreading overcome peripheral tolerance to cause autoimmunity?

A
  • Immune reactions to infection/self antigens leads to damage of self-cells
  • Leads to release and presentation of cryptic or normal self-antigens at higher concs
  • Can lead to activation of more T cell and B cells of different specificities > immune response spreads
61
Q

How can the antigen as a DAMP as well, overcome peripheral tolerance to cause autoimmunity?

A
  • Some autoantigens are also DAMPs e.g. unmethylated CpG nucleic acid
  • Host unmethylated CpG normally only becomes available during cell death
  • If not cleared quickly, self reactive B cell may be activated by TLR and BCR signals
62
Q

How does the immune system cause damage?

A
  • Cytotoxic T cells > direct cell killing
  • T helper cells > activate myeloid cells (granulocytes and monocytes) > release cytokines and enzymes
  • Antibodies > autoantibodies bind to cell surface receptors > mark them for targeted attack
  • Antibodies > complement activation
  • Antibodies > Fc receptors activation enhanced pahgocytosis
63
Q

What are the most important cells in autoimmunity?

A

Treg cells - if mutation in FOXP3 gene, issue with converting TGFB into Treg - likely to have autoimmunity
Th17 in excess - associated with RA, SLE, MS, psoriasis and IBD

64
Q

How do most therapies work to manage autoimmune diseases?

A

Target IL-6 and TGFB to reduce Th17 production
Target Il-17 which normally promotes release of more pro-inflammatory mediators and MMPs = treat inflammatory diseases
e.g. tocilizumab - anti IL6 receptor antibody which disrupts the pro-inflammatory actions of IL6

65
Q

How is Grave’s disease mediated?Pathophysiology?

A

Antibody mediated
Stimulating overproduction
Autoantibodies to the TSH receptor stimulate thyroid hormone production
High levels of thyroid hormones negatively regulate the thyroid which reduces production of TSH but cant affect the antibody levels

66
Q

How is Myasthenia gravis mediated? Pathophysiology?

A

Antibody mediated
Inhibiting receptor function
Autoantobodies bind to ACh receptors
ACh receptors internalised and degraded
No muscle contraction

67
Q

How is Type I diabetes mediated? Pathophysiology?

A

Cytotoxic T cell mediated
Selective cell destruction
The islets of Langerhans have specialised cells that secrete hormones
They express generalised and specific self antigens on MHCl
CD8+ T cells with receptors for antigens of B pancreatic islets cells target these for killing
Glucagon can still be produced, but no insulin produced

68
Q

Mechanism of rheumatoid arthritis?

A
  • Unknown inflam trigger > attracts leukocytes to tissue including self reactive T cells
    > These stimulate macrophages resulting in sustained inflammation
    > macrophages release pro-inflam cytokines and MMPs
    > Fibroblasts are stimulated to produce MMPs and RANKL
    > Osteoclasts degrade into the bone

Medicine Unit 9 UoS (11 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions