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

Unit 9 - Diseases of the immune system Flashcards

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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

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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

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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

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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

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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

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6
Q

What are RAG genes?

A

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

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7
Q

What is central and peripheral tolerance?

A

Eliminates self-reactive lymphocytes

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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

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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

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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

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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+

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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

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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

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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

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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

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16
Q

ALPS

A

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

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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

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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

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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

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20
Q

What disease is linked to B cell development?

A

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

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21
Q

What if B cells have no self reaction?

A

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

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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

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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.

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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

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25
Why is B cell selection not as important as T cell selection?
T cells are required to activate B cells, and so self reactive T cells have more of an impact
26
Primary immunodeficiency Examples Treatment
Genetic Severe combined immunodeficiency, Agammaglobulinaemia
27
Secondary immunodeficiency Examples Treatment
Acquired AIDS, immunosupression from drugs, impaired immunity from starvation Variable treatment, management with anti-microbials
28
AIDS causing immunodeficiency
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
What areas in innate immunity can cause primary immunodeficiency? and what conditions/infections are they related to?
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
What areas of adaptive immunity can cause primary immunodeficiency? and what conditions/infections are they related to?
Lymphocyte development - IL2RG, RAG gene - SCID B cell development - BTK gene - Agammaglobulinaemia Defective cytokine killing - STAT3 gene - recurrent skin and resp infections
31
X linked SCID
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
Chronic Granulomatous Disease
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
How common are autoimmune diseases?
More than 5%
34
35
What is autoimmunity?
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
What is the positive feedback loop in chronic autoimmune disease?
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
Why may autoimmunity develop?
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
What roles do genes have that increase susceptibility to autoimmunity?
Disrupt tolerance Disrupt apoptosis Promote inflammation Promote cell activation
39
What is monogenic vs complex susceptibility?
Monogenic - predominant genetic risk with minor additional genetic and environmental factors Complex - multiple genetic and environmental factors
40
What genes are involved in autoimmunity?
AIRE CTLA4 FOXP3 FAS C1q
41
How may AIRE be involved in autoimmunity? What disease is this linked to?
Autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy (APECED) Decreased expression of self antigens in the thymus -> defective negative selection of self reactive T cells
42
How may CTLA4 be involved in autoimmunity? What disease is this linked to?
Grave's disease, type 1 diabetes Failure of T cell anergy Reduced activation threshold of self reactive T cells Reduced T reg function
43
How may FOXP3 be involved in autoimmunity? What disease may this be linked to?
Immune dysregulation, polyendocrinopathy, enteropathy, X linked syndrome Decreased function of Treg
44
How may FAS be involved in autoimmunity? What disease may this be linked to?
Autoimmune lymphoproliferative syndrome Failure of apoptotic death of self reactive B and T cells
45
How may C1q be involved in autoimmunity? What disease may this be linked to?
Systematic lupus erythematosus Defective clearance
46
Give autoimmune disease examples (7)
Type 1 diabetes Multiple sclerosis Crohn's disease Psoriasis Grave's disease Rheumatoid arthritis Systematic lupus erthematosus
47
What generally occurs in crohn's disease?
Autoreactive T cells kill intestinal flora Leads to intestinal inflammation and scarring Organ specific
48
MHC vs HLA
MHC is the gene HLA is the protein that the gene encodes
49
MHC gene characteristics
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
What do polymorphisms do to HLA molecules?
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
What is HLA association?
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
Where is there female susceptibility in autoimmunity? Why may this occur?
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
What are examples of risk alleles in autoimmunity?
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
What environmental factors can increase risk of autoimmunity?
Smoking Viral and bacterial infections: Hep C and EBV infect B cells and may affect cell function
55
What is the adjuvant effect in autoimmunity?
Inflammation is induced when autoantibodies are injected WITH microbial products Shows importance of environmental factors in autoimmunity
56
Name the different mechanisms by which peripheral tolerance can be overcome to cause autoimmunity
Cryptic antigens Molecular mimicry Bystander activation Epitope spreading Antigen is also a DAMP
57
How can cryptic antigens overcome peripheral tolerance to cause auotimmunity?
- 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
How can molecular mimicry overcome peripheral tolerance to cause auotimmunity? examples and associated infections
- 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
How can bystander activation overcome peripheral tolerance to cause autoimmunity?
- 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
How can epitope spreading overcome peripheral tolerance to cause autoimmunity?
- 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
How can the antigen as a DAMP as well, overcome peripheral tolerance to cause autoimmunity?
- 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
How does the immune system cause damage?
- 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
What are the most important cells in autoimmunity?
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
How do most therapies work to manage autoimmune diseases?
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
How is Grave's disease mediated?Pathophysiology?
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
How is Myasthenia gravis mediated? Pathophysiology?
Antibody mediated Inhibiting receptor function Autoantobodies bind to ACh receptors ACh receptors internalised and degraded No muscle contraction
67
How is Type I diabetes mediated? Pathophysiology?
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
Mechanism of rheumatoid arthritis?
- 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)

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