MTA W1 Flashcards
(176 cards)
1
Q
Acción de los mecanismos de tolerancia
A
Eliminan e inactivan los linfocitos con alta afinidad por antígenos propios
2
Q
Riesgo implicado por la recombinación aleatoria en el desarrollo de linfocitos T y B
A
Reacciones contra las células del individuo que provocan daño/enfermedad al mismo
3
Q
La tolerancia es específica del ________ y ocurre por clones individuales de un mismo linfocito
A
Antígeno
4
Q
V/F: la tolerancia solo puede inducirse frente a células extrañas
A
F: los tolerágenos pueden ser proteínas, células extrañas y antígenos
5
Q
¿Qué factores influyen en si un factor es inmunógeno o tolerágeno?
A
- Exposición al antígeno durante la maduración del linfocito
- Reconocimiento por linfocitos específicos en presencia o ausencia de respuestas inmunitarias innatas
6
Q
Tipo de tolerancia inducida en linfocitos autorreactivos inmaduros en los órganos linfáticos generadores
A
Tolerancia central
7
Q
Tipo de tolerancia inducida en linfocitos autorreactivos inmaduros en zonas periféricas
A
Tolerancia periférica
8
Q
Función de la tolerancia central
A
Asegura que linfocitos maduros vírgenes sean incapaces de responder a antígenos propios expresados en los órganos linfáticos generadores
9
Q
Órganos linfáticos centrales o generadores
A
Timo - linfocitos T
MO - linfocitos B
10
Q
Mecanismo que impide la activación de los linfocitos potencialmente lesivos que escaparon de la tolerancia central
A
Tolerancia periférica
11
Q
Los antígenos en el timo y la médula ósea durante la maduración de los linfocitos son…
A
Antígenos propios ubicuos o muy diseminados
12
Q
Mature auto-reactive periferic lymphocytes undergo…
A
- Inactivation after being presented with the self-antigen
- Death by apoptosis
13
Q
A
14
Q
What is the role of Tregs in periferic tolerance?
A
Active suppression of the activation of specific lymphocytes against self-antigens (and others)
15
Q
Treg mediated suppression takes place in…
A
Secondary lymphatic organs and extralymphatic tissue
16
Q
Immunitary response against organisms of the microbiome and the fetus in cases of pregnancy are attributed to the regulation by:
A
Tregs
17
Q
Anatomic barriers (eyes and testicles) and fisical barriers (keratin and mucus) provide ________ to antigens, meaning…
A
- Protection
- They don’t produce a response and are ignored instead
18
Q
Possible uses of the induction of immunitary tolerance
A
- Avoidance of immunitary reactions in autoimmune and allergic diseases
- Transplant rejection
- Genotherapy
- Promotion of stem cell transplant acceptance
- Avoidance of reactions against external proteins
19
Q
Mechanisms of peripheral tolerance affect ____ lymphocytes and consist of these 3 actions:
A
- Mature
- Anergy (functional unresponsiveness)
- Suppression by T regs
- Apoptosis
20
Q
Inactivation upon re-exposure to an antigen in peripheral tissues
A
Anergy
21
Q
Suppresion sites of Tregs
A
- Secondary lymphoid organs
- Non-lymphoid tissues
22
Q
Where does central tolerance of T lymphocytes takes place?
A
Thymus (during T cell maturation)
23
Q
What are the outcomes of high avidity self antigen recognition by T cells?
A
- Apoptotic cell death (deletion or negative selection)
- Development into regulatory T cells (CD4+ lineage)
24
Q
T or F: Negative selection affects only class I MHC-restricted T cells (CD8+)
A
F: it affects both classes of MHC (I and II) (CD8 and CD4)
25
Double positive T cells go through negative selection in the ____, while newly generated single positive T cells go through it in the ______
| Parts of the thymus
* Cortex
* Medulla
26
Cells that express peripheral tissue-specific antigens in the thymus
MTECs (Medullary thymic epithelial cells)
27
What is AIRE and how does it work?
* Autoimmune regulator (transcription level)
* Controls expression of tissue-specific antigens in METEC
28
Consequences of the absence of functional AIRE
1. Antigens are not expressed in thymus
2. Self-reactive CD4 and CD8 escape deletion, leading to maturation and the attack of target tissues
29
Syndrome related to absence of AIRE
APS1 (lymphocyte and antibody mediated injury to the parathyroids, adrenals, pancreatic islets and skin)
30
What molecules do autoantibodies in APS1 target and neutralize?
* IL-17
* IL-22
* IFN-1
31
IL-17 deficiency predisposes to:
Mucocutaneous candidasis due to lack of antifungal defense
32
Transcription regulator involved in elongation and chromatin remodelling that promotes expression of tissue-restricted antigens in the thymus
AIRE
33
In central tolerance, high-affinity TCR signaling in immature T cells triggers:
Mitochondrial pathway of apoptosis
34
How does signal interpretation differ in mature/immature T cells?
* Immature = apoptosis
* Mature = activation
35
What do non-deleted self-reactive CD4 T cells become and what is their action?
* T regs
* Leave the thymus and suppress immune responses to self antigens in peripheral tissues
36
T or F: peripheral tolerance only conduces to tolerance of tissue-specific self antigens, especially those not abundant in the thymus
F: they may also induce unresponsiveness to foreign antigens when presented under tolarogenic conditions
37
State in which mature CD4 T cells become unresponsive to an antigen after prolonged exposure **without coestimulation or innate immunity**
Anergy
| Remember that these self-reactive T cells are not killed, just inactivated
38
T cell activation requirements
* Signal 1 (Antigen recognition by TCR)
* Signal 2 (Co-stimulatory signals mainly via B7-1 and 2 binding to CD28)
39
Fate of anergic cells
* Survival in a quiescent state for days or weeks
* Cell death
40
# T-cell tolerance
Mechanisms of anergy
* TCR-Induced signal blockade
* Activation of ubiquitin ligases
* Engagement of inhibitory receptors
41
# T-cell tolerance
Decreased TCR expression and the recruitment of inhibitory molecules to the TCR complex lead to _____________ and, therefore ___________
TCR-induced signal blockade --> anergy
42
# T-cell tolerance
The recognition of self-antigens without coestimulation activates ubiquitin ligases. What do these molecules do?
Tag TCR associated proteins for proteolytic degradation, leading to loss of signaling moleculaes and defective T cell activation
43
# T-cell tolerance
Important T cell ubiquitin ligase that is essential for mantaining unresponsiveness to self antigens
CBL-b
44
# T-cell tolerance
Key inhibitory receptors with physiological roles in self-tolerance
* CTLA-4
* PD-1
45
# T-cell tolerance
Inhibitory receptor that performs mainly in **secondary lymphoid organs during the induction phase (priming)** and acts constitutively on Tregs
CTLA-4
46
# T-cell tolerance
What is the mechanism of action of CTLA-4?
It outcompetes CD28 for B7, binds B7-1 and 2 and removes B7 from APCs via transendocytosis
47
# T-cell tolerance
While CTLA-4 is expressed constitutively high on Tregs, on recently activated T cells it is ________ expressed
Transiently
48
# T-cell tolerance
This inhibitory receptor works mainly on peripheral tissues in the effector phase of t cells by inhibiting mostly CD8+
PD-1
49
# T-cell tolerance
How does PD-1 work?
It inhibits kinase-dependent signals from CD28 and TCR
50
# T-cell tolerance
What cells express PD-L receptors?
* APCs
* Bone marrow APCs (PD-L2)
51
# T-cell tolerance
After engagement of PD-1 by PD-L1/2, what molecules are phosphorilated and what is their action?
1. ITIM and ITSM
2. ITIM and ITSM bind SHP2 phosphatase, resulting in the inhibition of kinase-dependent signaling from TCR-coreceptor and CD28
52
# T-cell tolerance
Molecules expressed by Tregs
high levels of iL-2 receptor ą chain and FOXP3
53
# T-cell tolerance
Syndrome derived from loss-of-function mutations in FOXP3
IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked)
54
# T-cell tolerance
Why does IPEX syndrome lead to fatal systemic autoimmune disease in children unless treated with HTSC?
It results in deficiency of Tregs, leading to self-tolerance
55
# T-cell tolerance
Regulatory T Cells express these factors in order to control the diverse immune responses:
* CD4+
* **FOXP3+**
* **CD25+**
* **CTLA-4**
* Low CD127 (IL-7 receptor)
56
# T-cell tolerance
T/F: In various immune responses, T regs can be induced to express the same chemokine receptors as effector T cells
True
57
# T-cell tolerance
Sites of Treg generation
* Thymus
* Peripheral tissues (without srong innate immune responses and after inflammatory reactions)
58
# T-cell tolerance
What is the role of IL-2 in Treg maintenance?
It is essential for the generation, survival and functional competence of Tregs
59
# T-cell tolerance
Cytokine that promotes thymic differentiation of Tregs and is essential for their manteinance in the periphery
IL-2
60
# T-cell tolerance
Transcription factor activated by IL-2 to enhance FOXP3 expression, leading to upregulation of Treg function-related genes
STAT5
61
# T-cell tolerance
TGF-B plays a role on Tregs action by:
Stimulating FOXP3 expression
62
# T-cell tolerance
Primary targets of Tregs
* Dendritic cells (inhibits their stimulatory capacity)
* T cells (direct suppression)
* B cell (suppresses their activation)
* NK (supresses cell proliferation and differentiation)
63
# T-cell tolerance
Key suppressive mechanisms of Tregs
1. CTLA-4-mediated inhibition of co-stimulation
2. Production of immunosuppressive cytokines
3. IL-2 consumption (deprives other cells from it = no proliferation or differentiation of immune cells)
64
# T-cell tolerance
Immunosuppresive cytokines produced by Tregs
* IL-10
* TGF-B
65
# T-cell tolerance
How does TGF-B inhibit immune cell activation?
* Suppresses T cell proliferation and effector functions
* Inhibits classical macrophage activation
* Suppresses activation of neutrophils and endothelial cells
66
# T-cell tolerance
Although TGF-B can inhibit the development of TH1 and TH2 it also has a dual role consisting of:
* Promotion of Tregs (anti-inflammatory)
* Promotion of Th17 cells (proinflammatory)
67
# T-cell tolerance
Transcription factor that induces B cell isotype switching to IgA
TGF-B
68
# T-cell tolerance
How does TGF-B promote tissue repair?
Stimulates:
* Collagen synthesis
* Matrix-modifying enzyme production
* Angiogenesis
69
# T-cell tolerance
Because of its tissue repair abilities, TGF-B may have a pathologic role in fibrotic diseases such as:
* Pulmonary fibrosis
* Systemic sclerosis
70
# T-cell tolerance
This interleukin produced by activated macrophages, DCs, Tregs, TH1/2 cells and some B lymphocytes controls innate immune reactions and cell-mediated immunity
IL-10
| Acts as a negative feedback regulator!
71
# T-cell tolerance
IL-10 receptor
Type 2 cytokine receptor family
72
# T-cell tolerance
How does IL-10 regulate immune function?
* Inhibits IL-12 production and secretion by DCs and macrophages
* Inhibits IFN-y (by consequence)
* Inhibits costimulatory and antigen-presenting molecules (MHC II on DCs and macrophages)
73
# T-cell tolerance
Factors that favor immune response
1. Short-lived antigens (persistence)
2. Subcutaneous or intradermal portal of entry
3. Antigens with adjuvants that induce costimulators and cytokines
4. Mature DCs with high levels of costimulators
74
# T-cell tolerance
Factors that favor tolerance to self-antigens
1. Prolonged persistence that leads to antigen receptor engagement
2. Intravenous or mucosal portal of entry
3. Presence in generative lymphoid organs
4. Antigens without adjuvants (low costimulators and cytokines)
5. Immature/resting DCs
75
# T-cell tolerance
Resting DCs that present self-antigens continously, are in an immature state, express low levels of costimulators and travel to secondary lymphoid organs at a steady state tend to induce...
* Anergy
* Treg differentiation
* Non-effector or memory T cells
76
# T-cell tolerance
Therapeutic interest of DCs
Manipulating DCs properties may offer ways to enhance or suppress immune responses
77
# Tolerance
Type of tolerance that occurs during B cell maturation in the bone marrow as the immature B cells express membrane IgM as their antigen receptor
Central tolerance
78
# B Central tolerance
Name the 3 mechanisms of central B cell tolerance
* Receptor editing
* Deletion
* Anergy
79
# B Central tolerance
This mechanism is triggered by strong signaling and recognition of self antigens at high concentration
Receptor editing
80
# B Central tolerance
After strong recognition, immature B cells reactivate ____ and ____ to initiate new ______ recombination at _______ locus
| Receptor editing
* RAG1 and RAG2
* VJ
* Ig k light chain locus
| Results in a new light chain + new BCR specificity
81
# B Central tolerance
What happens if initial Vk to Jk rearrangements fail?
| Receptor editing
* Try rearrangement at k locus on other chromosome
* Then try at λ loci
82
# B Central tolerance
Tolerance mechanism that happens after strong self-antigen recognition by immature or transitional B cells and leads to apoptosis
Deletion
83
# B Central tolerance
Deletion mechanism
* Presumedly similar to mitochondrial apoptosis pathway in T cells
| B cells attempt receptor editing first and die if it fails
84
# B Central tolerance
Tolerance mechanism triggered by **weak recognition ** of self antigens
| Soluble antigens, low affinity interactions or limited BCR cross linking
Anergy
85
# B Central tolerance
Anergy results in...
* Functionally unresponsive B cells that exit the bone marrow in an unresponsive state
86
# B Central tolerance
Anergy mechanisms involve...
* Downregulation of BCR expression
* Block in antigen receptor signaling
87
# B peripheral tolerance
Requisit for B peripheral tolerance
That mature B cells in the periphery recognize tissue self antigens without specific helper T cells
| Because of elimination or anergt
88
# B peripheral tolerance
Antigen recognition without additional stimuli results in B cell tolerance. Why is that?
* T cells are not sufficient or inactive
* Self antigens are not protein antigens
* Self antigens do not activate complement or pattern recognition receptors
89
# B peripheral tolerance
Name 4 mechanisms of peripheral B cell tolerance
* Anergy
* Deletion
* Signaling by inhibitory receptors
* Regulation by regulatory T cells (Tregs)
90
# B peripheral tolerance
Anergic B cells require higher than normal levels of ____/ for survival. Since they can't compete effectively with normal B cells, this inactivated cells have ________ lifespan and are ________ more rapidly.
* BAFF/BLyS
* Shorter
* Eliminated
91
# B peripheral tolerance
In this tolerance mechanism, high avidity recognition of self antigens leads to **apoptotic death via the mitochondrial pathway**
Deletion
92
# B peripheral tolerance
Deletion occurs in ________ B cells outside the bone marrow.
| Many are autoreactive; most are deleted before maturation
Transitional
93
# B peripheral tolerance
What is the role of inhibitory receptors in B cell activation?
Inhibitory receptors prevent B cell activation by setting an activation treshold. They are engaged primarily by self antigens whereas foreign antigens provide signals through multiple pathways.
94
# B peripheral tolerance
The inhibitory receptors **CD22 (Siglec-2)** and **FcyRIIB** help regulate B cell activation by recruiting the enzyme ________, which dampens BCR signaling.
SHP1 (tyrosine phosphatase)
95
# B peripheral tolerance
CD22 (Siglec-2) binds to...
| Receptor inhibition
Sialic acid-decorated proteins on B cell surface
96
# B peripheral tolerance
Defects in SHP1, LYN, FcyRIIB, or CD22 lead to...
Autoimmunity
97
# B peripheral tolerance
What happens when CD22 (Siglec-2) binds sialic acid–decorated proteins on the B cell surface?
CD22 dampens BCR signaling by recruiting SHP1 after its ITIMS are phosphorylated by LYN
98
# B peripheral tolerance
In this mechanism, Tfr enter the lymphoid follicles and limit T cell help to germinal center b cells
Regulation by follicular regulatory T cells
99
# B peripheral tolerance
Factors involved in the regulation by Tregs
* Follicular T regs
* Tregs
* Control of Tfh cell number and activity
* Prevention of promiscuous B cell activation
100
# B peripheral tolerance
Treg deficiency is associated with...
Autoantibody production
101
# Tolerance to commensal microbes and other foreign antigens
Why do commensal microbes not elicit immune respones despite beign foreign?
* They do not invade epithelial barriers
* Induce and activate Tregs (inhibit effector and memory T cell development)
102
# Tolerance to commensal microbes and other foreign antigens
Protein antigens + adjuvants favor __________
Immunity
| Adjuvants stimulate innate immune responses + costimulator expression
103
# Tolerance to commensal microbes and other foreign antigens
Repeated antigen doses without adjuvants favor ______
Tolerance
| Adjuvants stimulate innate immune responses and costimulator expression
104
# Oral tolerance
Oral tolerance consists of:
Oral administration of protein antigen + suppression of systemic humoral and cell mediated responses to that antigen
105
# Therapeutic tolerance induction
Possible applications of autoimmune diseases & their antigens
* Type 1 diabetes (antigen: insulin)
* Multiple sclerosis (antigen: myelin basic protein)
* Rheumatoid arthritis (citrullinated peptides)
* Allergies
106
# Therapeutic tolerance induction
This strategy includes small doses of self antigen-derived peptides in their aqueous form without adjuvants, leadig to T cell anergy or deletion and activation of Tregs
| Strategies
Repeated administration of immunodominant peptides
| Desensitization/peptide immunotherapy effective in allergic patients
107
# Therapeutic tolerance induction
Strategy of peptide linkage to immunogenic substrates such as nanoparticles or erythrocyte membranes; similar to aqueous peptide administration
Antigen coupled delivery systems
108
# Therapeutic tolerance induction
Strategy where B7 molecules are blocked using CTLA4-Ig (inhibits immune responses but may not induce long-lived tolerance)
Costimulatory blockade
109
# Mechanisms of autoimmunity
Contributing factors to autoimmunity
* Genetic susceptibility
* Environmental triggers (infections/local tissue injury)
* Emerging factors
110
# Mechanisms of autoimmunity
What are the most important ways that environmental triggers induce autoimmunity?
* Promote influx and activation if autoreactive lymphocytes
* Tissue injury
* Pro-inflammatory cytokine production
* Activation of self-reactive tolerance
111
# General features of autoimmune disorders
Antigen distribution of systemic autoimmune diseases
Triggered by circulating self antigens forming immune complexes
| Systemic lupus erythematosus SLE
112
# General features of autoimmune disorders
Antigen distribution of organ-specific autoimmune diseases
Caused by autoantibody or T cell responses against tissue-restricted self antigens
| Myasthenia gravis, Type 1 diabetes, Multiple sclerosis
113
# General features of autoimmune disorders
Factors that contribute to chronicity, progressiveness and self perpetuating autoimmune diseases
* Persistence of self-antigens
* Activation of immune amplification mechanisms
* Epitope spreading
| ES --> tissue injury --> self antigens --> activation of autoreactive LC
## Footnote
Explains prolonged and worsening disease progression
113
# General features of autoimmune disorders
Effector mechanisms of tissue injury
* Immune complexes
* Circulating autoantibodies
* Autoreactive T lymphocytes
* Disease features depend on the dominant effector mechanism
114
115
# Immunologic abnormalities leading to autoimmmunity
Autoimmunity underlying causes
Imbalance between lymphocyte activation and control mechanisms
116
# Immunologic abnormalities leading to autoimmmunity
Failure of negative selection, receptor editing in B cells, apoptosis, inhibitory receptor function and Tregs contribute to...
Inadequate deletion or regulation of T or B cells
117
# Immunologic abnormalities leading to autoimmmunity
All individuals have self-reactive lymphocytes and, although tolerance is mantained by central selection processes + peripheral mechanisms, loss of tolerance can occur if...
* Self-reactive lymphocytes mature and are not inactivated
* APCs present self antigens in an immunogenic context
118
# Abnormal display of self antigens
Enzymatic modifications and cellular stress or injury lead to the presentation of ____, to which the immune system is not tolerant
| Structural changes
Neoantigens
| Not previously recognized by the immune system
## Footnote
Ex. citrullination or post-translational modifications
119
# Inflammation or initial innate immune response
Infections or tissue injury trigger local (...) immune reactions. Name the effects of it.
* Innate
* Activation of APCs
* Increased expression of costimulators
* Overcome of regulatory mechanisms + excessive T cell activation
120
# T cells in autoimmunity
Why are T cells a major focus on recent research?
1. Helper T cells regulate both cell-mediated + humoral responses to proteins
2. Many autoimmune diseases are associated with specific MHC alleles
121
# T cells in autoimmunity
Failure of T cell self-tolerance results in
* Tissue damage
* Cell-mediated autoimmune diseases
* Autoantibody production
122
# Genetic basis of autoimmunity
Types of genetic associations
* Shared polymorfisms (general immune mechanisms)
* Disease specific-loci (organ-specific damage or autoreactive lymphocytes)
123
# Genetic basis of autoimmunity
Genetics hypothesis
Disease develops when multiple susceptibility polymorphisms are coinherited in 1 individual
124
# Association of MHC alleles with autoimmunity
Genes with strongest associations with autoimmunity
MHC genes (HLA in humans)
125
# Association of MHC alleles with autoimmunity
Class (...) HLA, specifically HLA-(...) and HLA-(...) alleles are most commonly associated with autoimmune diseases.
* Class II
* DR
* DQ
126
Allele HLA-B27 (Class 1) is associated with
Ankylosing spondilitis
127
RA, Type 1 diabetes, multiple sclerosis and systemic lupus erythematosus are associated with this class 2 allele
HLA-DRB1
128
Celiac disease is associated with these class 2 alleles
HLA-DQA1, HLA-DQB1
129
# Association of MHC alleles with autoimmunity
Linkage disequilibrium
Inheritance of alleles together more often than by chance
130
# Association of MHC alleles with autoimmunity
Disease-associated nucleotide polymorphisms encode polymorphic residues on MHC molecules. Name their influence:
* Antigen presentation
* T cell recognition
131
# Association of MHC alleles with autoimmunity
T/F: HLA expression is sufficient to cause disease
False, it is present in many healthy individuals
132
# Association of MHC alleles with autoimmunity
T/F: some alleles may be protective against autoimmune diseases
True
| As in type 1 diabetes and rheumatoid arthritis
133
# Select non-HLA genes associated with autoimmune diseases
Gene associated with rheumatoid arthritis, type 1 diabetes, autoimmune thyroiditis and others.
It alters signaling in immune cells.
PTPN22
134
# Select non-HLA genes associated with autoimmune diseases
Gene associated with Crohn's disease.
Works as a cytoplasmic sensor of bacterial peptidoglycans in intestinal epithelial cells
NOD2
* Reduced NOD2 fx. = inadequate control of intestinal microbes = chronic intestinal inflammation
135
# Select non-HLA genes associated with autoimmune diseases
Alterations in complement proteins (C1q, C2, C4) are associated with this autoimmune disease
Systemic lupus erythematosus
136
# Select non-HLA genes associated with autoimmune diseases
Polymorphisms in IL-23 receptor are associated with
Increased risk for IBD and psoriasis
| Other variables may be protective
137
# Select non-HLA genes associated with autoimmune diseases
Polymorphisms that affect expression or function of IL-2 receptor a chain (CD25) are associated with...
Multiple sclerosis, Type 1 diabetes
| Impair Treg development or function
138
# Select non-HLA genes associated with autoimmune diseases
Polymorphisms in FcyRIIB are associated with (...) by impairing inhibitory signaling + reducing feedback inhibition of B cells
Systemic Lupus Erythematous
139
# Select non-HLA genes associated with autoimmune diseases
Polymorphisms in ATG16L1 (component of autophagy machinery) are associated with
Crohn's disease
140
# Select non-HLA genes associated with autoimmune diseases
Polymorphic repeat sequences with the insulin gene are associated with Type 1 diabetes as they...
Reduce thymic expression of insulin = incomplete negative selection of insulin-specific T cells
| Self-reactive T cells survive and attack B cells in pancreas
141
# Main mechanisms by which infections promote autoimmunity
Consequence of the infection of tissues and triggering of local innate immunity (leukocyte recruitment + activation of APCs)
| Induction of local innate immune responses
* Expression of costimulators
* Secrete T cell activating cytokines
* Breakdown of T cell tolerance
* Activation of T cell specific for cell antigens
142
# Main mechanisms by which infections promote autoimmunity
Mechanisms by which microbial antigens cross-react with self antigens and produce a cross reactive response against self
Molecular mimicry
143
Molecular mimicry involved in rheumatic fever
**Rheumatic fever**
Anti-strepto antibodies cross react with myocardial proteins, resulting in myocarditis
| Streptococcal infections
144
# Microbiome and autoimmunity
The intestinal and cutaneous microbiome influence autoimmunity by...
Affecting maturation + activation of the immune system
| Microbiome alterations change incidence and severity of autoimmune dis.
145
146
What are the three essential mechanisms by which self-tolerance is maintained?
(1) Central tolerance (deletion of self-reactive T/B cells), (2) Peripheral tolerance (anergy, apoptosis, Treg suppression), (3) Immune privilege (restricted antigen presentation in certain tissues).
147
What are the two major inhibitory receptors involved in peripheral tolerance, and how do they work?
CTLA-4 outcompetes CD28 for B7 binding, preventing T cell activation. PD-1 recruits phosphatases to suppress TCR signaling, reducing immune response intensity.
148
How does defective apoptosis contribute to autoimmunity?
Accumulation of apoptotic debris leads to aberrant antigen presentation, activating autoreactive lymphocytes (e.g., defective Fas-FasL signaling in ALPS).
149
What is molecular mimicry, and how does it lead to autoimmune disease?
Pathogens express antigens similar to self-proteins, leading to cross-reactivity (e.g., Group A Streptococcus M protein triggering rheumatic fever).
150
What is bystander activation, and how does it promote autoimmunity?
Infection-induced inflammation activates nearby autoreactive lymphocytes without specific antigen engagement, breaking tolerance.
151
What is the hallmark pathogenic mechanism in systemic lupus erythematosus (SLE)?
Autoantibodies against nuclear antigens form immune complexes, depositing in tissues and activating complement, causing inflammation.
152
What are the key diagnostic autoantibodies in SLE?
Anti-dsDNA (specific, associated with nephritis), Anti-Smith (anti-Sm) (specific), and ANA (sensitive but nonspecific).
153
Why is Type I IFN (e.g., IFN-α) central to SLE pathogenesis?
IFN-α enhances antigen presentation, stimulates autoreactive B cells, and skews T cell responses towards inflammation.
154
How do TLRs contribute to SLE pathogenesis?
TLR-7 and TLR-9 recognize self-RNA/DNA from apoptotic cells, activating B cells and dendritic cells, promoting autoimmunity.
155
How does hydroxychloroquine work in SLE?
Blocks endosomal acidification, preventing TLR activation by self-DNA/RNA, reducing B cell activation.
156
What is the key autoantigen in Type 1 Diabetes (T1D), and how do CTLs contribute to β-cell destruction?
Glutamic acid decarboxylase (GAD65); CD8⁺ T cells kill pancreatic β-cells via perforin/granzyme and Fas-FasL pathways.
157
What is the key cytokine driving Th1-mediated autoimmunity in T1D and multiple sclerosis (MS)?
IFN-γ enhances antigen presentation and activates macrophages, promoting tissue destruction.
158
What is the main immunopathogenic mechanism in multiple sclerosis (MS)?
Myelin-specific CD4⁺ Th1 and Th17 cells infiltrate the CNS, causing demyelination and axonal damage.
159
How does natalizumab treat MS?
Blocks α4-integrin, preventing T cell migration into the CNS.
160
What autoantibodies define myasthenia gravis, and what is their effect?
Anti-ACh receptor antibodies block neuromuscular transmission, causing muscle weakness.
161
What is the role of TSH receptor autoantibodies in Graves' disease?
They stimulate thyroid hormone production, causing hyperthyroidism.
162
How does Hashimoto’s thyroiditis differ from Graves’ disease at the immunopathogenic level?
Hashimoto’s involves CD8⁺ T cell-mediated thyroid destruction, while Graves’ involves stimulatory autoantibodies.
163
What is the role of Th17 cells in autoimmune diseases like psoriasis and rheumatoid arthritis (RA)?
IL-17 and IL-22 recruit neutrophils, enhance inflammation, and promote tissue damage.
164
How does TNF-α drive inflammation in RA?
TNF-α upregulates MMPs, increases leukocyte recruitment, and promotes synovial hyperplasia (pannus formation).
165
How do TNF inhibitors (e.g., infliximab) treat RA, and what is a major side effect?
Block TNF-α signaling, reducing inflammation; risk of reactivating latent TB.
166
What cytokine is the main therapeutic target in Giant Cell Arteritis (GCA)?
IL-6 (targeted by tocilizumab).
167
How does rituximab (anti-CD20) work in autoimmune diseases like RA?
Depletes B cells, reducing autoantibody production.
168
What is the most specific antibody for RA?
Anti-CCP (anti-citrullinated peptide antibodies).
169
How does the failure of immune checkpoints contribute to autoimmune disease?
Loss of CTLA-4 or PD-1 function leads to unchecked T cell activation against self-antigens.
170
What is IPEX syndrome, and what is its immunological defect?
FOXP3 mutation → defective Tregs → severe multi-organ autoimmunity.
171
What is ALPS (Autoimmune Lymphoproliferative Syndrome), and what causes it?
Fas/FasL mutation, preventing T cell apoptosis, leading to lymphoproliferation and autoimmunity.
172
What is the link between CTLA-4 blockade (e.g., ipilimumab) and autoimmunity?
Loss of peripheral tolerance, leading to immune-related adverse effects (colitis, dermatitis, hepatitis).
173
Why do JAK inhibitors (e.g., tofacitinib) help in autoimmune diseases?
Block cytokine signaling (IL-6, IFN-γ, IL-23), reducing immune activation.
174
How do B cell-depleting therapies like belimumab (anti-BAFF) work in SLE?
Reduce B cell survival, decreasing autoantibody production.
175
What is the significance of immune complex deposition in SLE nephritis?
Triggers complement activation, leading to kidney inflammation and damage.
