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I&I WCII > Infections and auto-immune diseases > Flashcards

Infections and auto-immune diseases Flashcards

1
Q

What happens to antigen-specific T cells during an immune response?

A

Naïve T cells recognizing an antigen undergo clonal expansion to fight the infection. Afterward, most die off (contraction), leaving a small population of memory T cells.

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2
Q

What is the frequency of antigen-specific naive T cells before and after an immune response?

A

Before 1/100k T cells are antigen-specific, after expansion 1/100

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3
Q

How is TCR diversity generated?

A

Through somatic rearrangement of V(D)J segments, with added diversity from random nucleotide insertions or delection by TdT.

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4
Q

How does TCR diversity change with age?

A

Aging reduces thymic output, lowering TCR diversity as existing clones expand

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5
Q

What are the implications of reduced TCR diversity? (3)

A

It weakens immune surveillance, limits responses to new antigens, and increases vulnerability to infections and cancer.

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6
Q

What are T cell receptor excision circles (TRECs) and why are they important?

A

TRECs are byproducts of V(D)J recombination and indicate recent thymic output, marking newly produced T cells

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7
Q

How are TRECs measured and why?

A

qPCR, for applications like SCID screening and post-therapy T cell monitoring

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8
Q

What happens to T cell dynamics after a thymectomy?

A

Thymectomies reduce thymic output, lowering TRECs and TCR diversity. Peripheral proliferation compensates T cell numbers.

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9
Q

How does ageing affect T cell dynamics? (3)

A

Thymic involution reduces naive T cell production, memory T cells dominate, and immune function declines.

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10
Q

How do infections like HIV alter T cell dynamics?

A

HIV depletes CD4+ T cells, disrupting homeostasis in T cell type proportions. CD8+ T cells proliferate to compensate. Immune responses against bacteria are weakened.

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11
Q

What is in vivo labeling, and how is it used to study recent thymic emigrants (RTEs)?

A

Deuterium labeling tracks dividing cells by labeling TRECs which are only produced during V(D)J recombination and not in dividing cells, distinguishing RTEs from peripheral proliferating cells.

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12
Q

Why are RTEs measured? (3)

A

Newborn screening for SCID and monitoring T cell recovery after therapies like bone marrow transplantation or antiretroviral therapy for HIV.

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13
Q

What is the significance of CD45RA+CD31+ expression?

A

It is a unique marker for TREC-rich RTEs with low replicative history in humans.

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14
Q

What are transient altered T cell dynamics? (2)

A

A transitional phase of altered dynamics caused by hematopoietic stem cell transplants and chemotherapy.

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15
Q

What T cells recover faster, CD4+ or CD8+?

A

CD8+ T cells

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16
Q

How does TCR selection work and where? (2 steps)

A

It occurs in the thymus.
Positive selection in the thymic cortex: Thymocytes without a TCR and those with TCRs that recognize non-self die due to neglect, thymocytes that recognize self-MHC are positively selected
Negative selection in the thymic medulla: TCRs with strong recognition of self-MHC and self-peptide undergo apoptosis (clonal deletion), TCR with weak/medium self-MHC and self-peptide recognition survive

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17
Q

Where does lineage commitment of T cells occur?

A

In the bone marrow

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18
Q

What is the difference between the microbioma and microbiota?

A

Microbiome: The collection of all microbes and their genes living on or inside the body
Microbiota: The specific combination of microorganisms in a particular environment, influenced by genetics and environment

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19
Q

What makes the skin a complex and dynamic ecosystem?

A

The skin hosts diverse microbes (bacteria, fungi, viruses) in a unique environment: high salt, low pH (~5), lipid-rich, dry, and nutrient-poor. These factors shape microbial communities and interactions.

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20
Q

What are the roles of ceramides and free fatty acids in the skin?

A

Ceramides maintain the skin barrier, while free fatty acids show antimicrobial activity against microbes and regulate immune responses

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21
Q

How do bioactive molecules from skin microbes contribute to defense?

A

AMPs, PSMs and free fatty acids inhibit pathogen colonization, modulate immune responses and stimulate keratinocytes to produce immune mediators like IL-1.

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22
Q

How does cross-talk work between the skin microbiota and the host?

A

Microbes produce bioactive molecules (AMPs, PSMs, free fatty acids) that modulate immune responses, while host cells release cytokines and AMPs to regulate microbial communities

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23
Q

How is Staphylococcus epidermidis benefitial to the skin microbiome? (2)

A
  1. Promotes AMP production by keratinocytes
  2. Inhibits Staphylococcus aureus biofilm formation, reducing pathogenic potential
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24
Q

How do langerhans cells contribute to the skin immune system?

A

Present microbial antigens to T cells

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25
How do Th17 cells contribute to skin immunity?
Reinforce barrier integrity by stimulating keratinocytes to produce AMPs and recruit neutrophils
26
How do kerastinocytes form a mechanical barrier? (2)
Produce structural proteins that are chemically cross-linked. They secrete ceramides and other lipids, creating a hydrophobic layer that prevents water loss and blocks pathogen entry
27
How do keratinocytes contribute immunologically to the barrier? (3)
1. AMP production 2. Cytokine secretion (IL-1, IL-6, and TNF-a) 3. Complement activation
28
What is the role of IL-17 in skin homeostasis?
Il-17 stimulates keratinocytes to produce AMPs, recruits neutrophils, and enhances barrier integrity
29
What distinguishes pathgenic from non-pathogenic Th17 cells?
Pathogenic Th17 cells lack regulation and cause inflammation and tissue damage, whilel non-pathogenic Th17 cells produce IL-17A/F with regulatory signals (TGF-ß), maintaining balance.
30
What is the role of IL-17A/F in skin inflammation?
It is produced by Th17 cells and stimulates keratinocytes to produce AMPs and pro-inflammatory cytokines. Excessive IL-17A/F leads to chronic inflammation and tissue damage
31
What does IL-22 do in the context of inflammation?
It acts on keratinocytes, promoting hyperproliferation of dermal layers (leading to psoriasis) and increased secretion of pro-inflammatory mediators that worsen immune activation.
32
How does IL-23 amplify Th17-driven inflammation?
It is produced by DCs and macrophages and is critical for maintaining Th17 populations and increasing production of IL-17A/F and IL-22, thus acting as a feedback loop.
33
How do pathogenic Th17 cells drive skin inflammation?
Excess IL-17A/F and IL-22 from pathogenic Th17 cells activate cytokine loops involving IL-23 and TNF-a, causing chronic inflammation in conditions like psoriasis.
34
Why are cytokine loops in psoriasis significant?
Cytokines create a self-sustaining inflammatory environment, persistently activate keratinocyte hyperproliferation, loss of barrier function and immune cell infiltration, leading to visible skin lesions
35
What does IL-22 usually do?
Promote non-hematopoietic cell proliferation, resistance to apoptosis and wound healing, maintaining barrier function
36
What is RA?
A chronic autoimmune disease characterized by persistent inflammation of the synovial joints, leading to joint destruction, pain and disability.
37
What is the initial trigger for RA?
Genetic susceptibility and environmental factors trigger a loss of tolerance to self-antigens, leaing to autoantibody production.
38
What is synovitis?
Inflammation of the synovial membrane, caused by immune cell infiltration, production of pro-inflammatory cytokines and synovial fibroblast activation, leading to pannus formation.
39
What is pannus and how does it cause joint destruction?
A hyperplastic, inflamed synovial tissue that invades cartilage and bone, enriched with fibroblasts (that degrade cartilage) and osteoclasts (that resorb bone)
40
What role do T cells play in the pathogenesis of RA?
Th1 and Th17 secrete TNF-a, IL-17 and RANKL, driving inflammation and osteoclastogenesis
41
How do macrophages contribute to cartilage destruction?
IL-1 stimulates chondrocytes to release enzymes that degrade cartilage
42
What is the role of RANKL in bone erosion?
RANKL, produced by osteoblasts and T cells, binds to RANK on osteoclast precursors, driving their maturation, fusion and activation into bone-resorbing osteoclasts
43
How does the JAK/STAT pathway drive RA progression?
Cytokine receptor binding activates JAK kinases, which phosphorylate STAT proteins. TThese dimerize, enter the nucleus, and drive pro-inflammatory gene expression
44
What are the benefits and risks of JAK inhibitors in RA treatment?
They broadly block cytokine pathways, reducing inflammation efficiently, however they increase risk of infection due to systemic immunosuppression.
45
What are the main biological therapies targeting cytokines in RA?
Anti-TNF, IL-6R inhibitors, IL-17 inhibitors, and JAK inhibitors
46
Why is the RANKL/OPG balance important in RA?
RANKL promotes octeoclast formation and bone erosion, while OPG inhibits RANKL. Imbalance towards RANKL leads to excessive bone destruction.
47
Where does OPG come from?
It is secreted by osteoblasts
48
Where do osteoclasts come from?
They are derived from monocyte/macrophage precursors
49
What is OPG?
It acts as a decoy receptor for RANKL, preventing osteoclast activation
50
How does IL-17 affect bone remodeling?
IL-17 stimulates RANKL production by osteoblasts and T cells, increasing osteoclast activity
51
What inhibits OPG?
Pro-inflammatory cytokines such as TNF-a and IL-17
52
What is the role of IL-6 in RA? (3)
Activates T cells and synovial fibroblasts Promotes B cell activation -> autoantibody production Bone resorption: Enhances RANKL expression and osteoclast activity
53
What do IL-6R inhibitors target?
IL-6 receptor, which stops downstream JAK-STAT signaling
54
What is an autoimmune disease?
A condition where the immune system mistakenly attacks the body'ss own tissues due to a loss of self-tolerance
55
How is immune tolerance maintained?
Through central tolerance (AIRE in the thymus) and peripheral tolerance (such as checkpoint inhibition)
56
What are two key causes of autoimmune disease?
Dysregulation of autoreactive T or B cells and molecular mimicry
57
In what two categories can auto-immune diseases be categorized?
Systemic and organ-specific
58
How is vasculitis categorized and why?
According to vessel size. They have a different clinical presentation, different pathogenic mechanism and different treatment
59
What type of vasculitis is more common?
Small vessel vasculitis
60
What is the pathogenesis of large vessel vasculitis?
DCs become activated but do not migrate to the LNs. Lymphocytes present in the vessel wall will become activated and start a Th1/Th17-driven reaction against the vessel
61
What is the pathogenesis of small vessel vasculitis?
Production of antibodies against antigens in the blood vessels, forming immune complexes that attach to the blood vessel wall, initiating a complement- and phagocyte/granulocyte-driven immune reaction that leads to blood vessel destruction.
62
What are the two types of treatement against auto-immune diseases and what are consequences of each?
1. Suppressing the immune system, which can lead to systemic autoimmune disease 2. Symptomatic relief for specific organs, which can lead to organ-specific AI diseases
63
Whare are the main mechanisms of action of auto-immune therapies? (4)
Influence cytokine production Direct toxicity of immune cells (ex. Rituximab) Influence co-stimulation Influence cell migration
64
What is myositis?
A group of heterogeneous systemic autoimmune diseases characterized by muscle inflammation and variable involvement of skin, joints and lungs
65
What are the three pillars for diagnosis of myositis (subgroups)?
Serology, biopsy and clinical manifestations
66
What is ESR?
Erythrocyte sedimentation rate. It indicates the abundance of positively charged protein (such as antibodies and fibrinogen) in the blood, since they cause erythrocytes to stick together and go to the bottom of the vial faster.
67
What do CK levels indicate?
It is increased when there is muscle damage, such as in myositis
68
How are ANAs used in diagnosis?
Anti-nuclear antibodies in patient serum can bind to cytoplasm and/or nuclear proteins in cells in different patterns in certain diseases. This can be visualized by adding serum of patients to cells and fluorescently labeling them with a secondary antibody.
69
What is special about Jo-1 as an auto-antibody?
It is the only auto-antibody known that is specifically present in a proportion of myositis patients and not other diseases, like many other auto-antibodies, such as MDA5 which can cause severe ILD.
70
What is Jo-1 associated with?
Anti-synthetase syndrome, thickinening of the outer layr of the skin, with a speckled cytoplasmic ANA pattern
71
What are challenges when using auto-antibodies to diagnose myositis?
There is an overlap of auto-antibodies present in different systemic auto-immune diseases
72
What are challenges when using clinical manifestations to diagnose myositis?
Sometimes there is no muscle involvement, and associated ILD can be found in many other disorders.
73
What are possible treatment targets for myositis?
B cells (Rituximab), T cells, IVIg (dilution of auto-antibodies), JAK inhibitors for interferons
74
What is the biggest value of determining auto-antibodies in myositis?
They have prognostic value, especially MDA5 and anti-TIF-1
75
What are the two steps of sarcoidosis?
Inflammatory response, followed by fibrosis (irreversible organ damage)
76
What are the main treatments against sarcoidosis?
Prednisone and anti-TNF
77
How does sarcoidosis differ from other granulotamous disease?
Sarcoidosis is associated with hyperglobulinemia with granulomas, while others are associated with hypogammaglobulinemia with recurrent infections, caused by primary antibody deficiencies.
78
What can cause antibody deficiency in granulotamous disease?
XLA or CVID (common variable immunodeficiency disorder
79
How are granulomas in sarcoidosis formed?
They form due to chronic inflammation driven by Th1 cells, macrophages, and cytokines like IL-12 and IFNy.
80
How are granulomas associated with primary antobody deficiencies?
They result from immune dysregulation and low levels of IgG, IgA and IgM, often affecting the lungs.
81
What is common variable immunodeficiency disorder (CVID)?
A primary antibody deficiency with low IgG, IgG and/or IgM, poor vaccine responses and recurrent infections, autoimmunity and increased risk of hematological malignancies
82
What causes infection susceptibility in sarcoidosis?
The use of steroids
83
What is granulomatous disease in primary antibody deficiencies treated?
Combination immunosuppressive therapies and immunoglobulins
84
Why is early detection of granulomatous disease important?
Delayed diagnosis can lead to irreversible organ damage and worsen prognosis
85
What is the role of BTK in B cell development?
When pre-BCR is successfully expressed on immature B cells, BTK is activated and amplifies the BCR signal, indicating that the heavy chain has been successfully rearranged. This promotes proliferation of pre-B cells and induces light chain rearrangement. It ensures that autoreactive BCRs are eliminated by facilitating signaling pathways that determine whether a B cell progresses or undergoes apoptosis.
86
What does NF-kB do in B cell survival and proliferation?
It is transcribed as a result of BTK activation (as a result of successful BCR heavy chain rearrangement) and activates genes such as Bcl-2 that inhibit apoptosis
87
What disease is associated with BTK deficiency?
X-linked agammaglobulinemia (XLA), characterized by arrested B cell development and low immunoglobulin levels
88
How is BTK involved in autoimmune diseases?
Enhanced BTK activity increases BCR signaling, promoting autoantibody production and B cell hyperactivation, leading to diseases like RA and Sjogrens.
89
What evidence supports a role for BTK in autoimmunity?
Increased BTK phosphorylation is observed in B cells from patients with ACPA+ RA, Sjogrens syndrome and vasculitis
90
What are clinical applications of BTK inhibitors?
B cell malignancies (such as CLL: Chronic lymphocytic leukemia) which has a high efficacy, perhaps also MS, RA and Sjogrens (promising results sofar in clinical trial)
91
What challenges exist in BTK-targeted therapy?
Acquired resistance mechanisms in malignancies (such as mutations in BTK, preventing binding of inhibitors) and potential rewiring or bypassing of BCR signaling pathways
92
What is the impact of BTK inhibition on autoantibodies?
BTK inhibition reduces autoantibody production by blocking B cell activation and downstream signaling
93
How can we overcome BTK inhibitor resistance pathways?
Agents with improved binding profiles and/or combination therapy
94
How does BTK dysregulation contribute to disease?
Autoimmunity: Hyperactive BCR signaling leads to excessive activation and autoantibody production B cell malignancies: Uncontrolled proliferation and survival of malignant B cells

I&I WCII (8 decks)

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