Autoimmunity Mechanisms and Rhematic Dzs Flashcards
(109 cards)
1
Q
Rheum means
A
bodily fluids
2
Q
How does the NIH define rhematic disease?
A
Umbrella term for arthritis and other conditions that affect the joints, tendons, muscles, ligaments, bones, connective tissues and skin
3
Q
What are examples of non-inflammatory rheumatic diseases?
A
- Osteoarthritis
- Fibromyalgia
- Osteoporosis
- Charcot joint
4
Q
What is osteoarthritis?
A
Wear and tear, the cartilage break down and the underlying bone changes
5
Q
What is fibromyalgia?
A
Nervous system amplified pain widespread all over the body
6
Q
What are inflammatory rheumatic diseases?
A
- Rheumatoid arthritis
- Gout
- Systemic lupus erythematosus
- Spondyloarthritis
- Systemic sclerosis
- Sjogren syndrome
- Bullous pemphigoid
7
Q
What are autoinflammatory examples?
A
- Bechet’s vasculitis
- Periodic fever syndromes
- IBD
- Familial Mediterranean fever
- Tumor necrosis factor receptor associated periodic syndrome
8
Q
What are autoimmune diseases?
A
- Rheumatoid arthritis
- Systemic lupus
- Bullous pemphigoid
- Systemic sclerosis
- Sjoren syndrome
9
Q
How is Behcet’s disease characterized?
A
by mucocutaneous manifestations
10
Q
What is Behcet’s disease?
A
Auto-inflammatory systemic vasculitis
11
Q
Patients with Behcet’s disease typically develop
A
recurrent, large, painful oral and genital ulcerations
12
Q
Children with periodic fever develop
A
recurrent febrile episodes, apthous stomatitis, pharyngitis and adenitis
13
Q
Describe what Periodic Fever Syndromes are
A
NLRP3 associated auto inflammatory disease, where the NLRP3 inflammasone mediates caspase-1 activation and the secretion of proinflammatory cytokines IL-1B/IL-18
14
Q
What is NLRP3?
A
critical component of the innate immune system
15
Q
What are the cardinal signs of inflammation?
A
Redness, heat, swelling, pain, loss of function
16
Q
What are 2 common inflammatory markers?
A
- Eryhtrocyte sedimentation rate (ESR)
- C-Reactive protein (CRP)
17
Q
Why are ESR and CRP not diagnostic tests?
A
They are nonspecific and high on many diseases
18
Q
ESR and CRP levels correlate with
A
disease activity. They help see how well a pt is responding to treatment
19
Q
Describe Erythrocyte sedimentation rate
A
- Blood test for the current presence of inflammation
- Small amt of blood is put in an upright tube and the rate that your RBCs settle toward the bottom of the tube is followed in an hour
20
Q
Describe C-Reactive Protein Test
A
- Measures CRP in blood
- Interleukin 6 from macrophages and T cells induces the liver to produce CRP in response to inflammation
21
Q
How is autoimmunity defined?
A
Breakdown of the mechanism responsible for self-tolerance and the induction of an immune response against components of the self.
Mistaken attacks on self
-Targeting normal cells, tissues, and organs of a persons own body
22
Q
What are mechanisms to prevent immune attack against self structures?
A
- Sequestration of molecules
- Central tolerance
- Peripheral tolerance
23
Q
Certain tissues possess specific antigens that are isolated from
A
interaction with immune cells
24
Q
The lack of lymphatic drainage protects the
A
self-antigens from attack
25
What are the immunologically privileged sites?
-Brain, eye, testis, uterus
26
Central tolerance takes place in
primary lymphoid organs, thymus and bone marrow
27
Central tolerance: B and T cell precursors occasionally generate
BCR or TCR receptors that can bind to self-molecules
28
Central tolerance: Self reactive B cells are
edited, or they are eliminated in the bone marrow
29
Central tolerance: In the thymuc, T cell receptors are tested against
Self antigens presented on MHC I and II to limit the development of autoreactive T cells
30
Outside bone marrow and thymus, active __________ render self-reactive lymphocytes non-responseive and anergic
inhibitions
31
Anergy =
functionally inactive
32
What are mechanisms to maintain tolerance in the peripheral?
- Missing co-stimulatory signals for antigen presentation
- Engaging inhibitory receptors whose function is to terminate or turn off T cell responses. WHen T helper cells are unavailable to activate, B cells stay anergic
- T regulatory cells suppress autoreactivity
33
Peripheral tolerance
deletion, anergy or induction of regulatory function in T cells recognizing self antigen
34
Clonal selection
activation and differentiation of effector T cells that recognize foregin antigen
35
Lack of CD80/86-CD28 interaction in T macrophage interactions induces
anergy in T cells
36
Inhibitory receptors: CD80/86 binds to what to shut down signaling pathways?
PD-1 or CTLA-4
37
Tregulatory cells inhibit or turn down
T cell responses
38
What are the 3 important factors towards developing autoimmune diseases?
- Genes
- Environment
- Sex hormones
39
Some autoimmune dz occur more frequently in specific populations, linked to
specific MHC alleles
40
Environmental factors such as what may trigger autoimmune diseases in people with susceptible genetics?
Cigarette smoke, microbiome imbalance, and microbial infection
41
What does the hygiene hypothesis state?
Lack of early childhood exposure to microbial agents may explain the rise in susceptibility to autoimmune and allergic diseases in developed countries
42
When the diversity of the intestinal microbiota decreases, the immune system becomes
more prone to activation because up-regulators dominate over down-regulators. Then, mucosal tolerance decreases and autoimmunity increases
43
How are tissues damaged?
By - auto antibodies
- Immune compelxes
- Cell mediated responses
- Combinations of antibodies and cell-mediated reactions
44
What is molecular mimicry?
Cross reactivity between microbial and self determinants as a principal cause or mechanism to enhance autoimmunity
45
Describe bystander activation?
APCs and autoreactive lymphocytes will become activated indirectly by cytokines and PAMPS
46
Describe epitope spreading
Microbial induced determinant spreading, like a runway train, leading to the presentation of previously cryptic autoantigens by microbe activated APCs
47
What are examples of autoimmune diseases that are influenced by intermolecular and intramolecular B cell epitope spreading?
Systemic lupus erythematosus, MS and many others
48
Molecular mimicry: Microbe's antigens activate autoreactivity because they are
similar to self peptides
49
What is bystander activation?
Cytokines, microbial products, chemicals can non-antigen specifically activate autoreactive B cell clones
50
What is an example of bystander activation?
LPS binds to a receptor ont he surface of the auto-antigen specific B cells and delivers an activating signal to the clone
51
What is epitope spreading?
Diversification of the immune response induced y an antigen to new T cell and antibody specificities in autoimmune disease
52
Describe the "First hit"
Initial break of tolerance, which leads to the production of autoantibodies. Patients may have low activity for many years before developing symptoms
53
Describe the "second hit"
- Progressively autoantibody accumulates and diversifies in the antigen specificity
- Additional triggers enhanced T cell help and autoreactive B cells, inducing an inflammatory autoimmune response
- Response matures and onsets the clinical disease
54
Epitope spreading represents the process of
diversification of B and/or T cell response from the initial dominant epitope to a secondary epitope over time
55
Epitope spreading that occurs within a single antigen or involves different antigens is termed
intramolecular and intermolecular ES, respectively
56
Intramolecular ES consists of the diversification of immune response in
the same autoantigen
57
Intermolecular ES commonly involves
different antigens of a single macromolecular complex or that colocalize the same anatomical site
58
Before they mature, the immune system avoids self damage by deleting self reactive T cells in
the thymus
59
Self reactive B cells are modified or deleted in the
bone marrow
60
Some self reactive T and B cells persist and enter the periphery, what keeps them under control?
Down-regulatory mechanisms such as Treg, checkpoint inhibition
61
How can peripheral tolerance to self molecules be broken?
When an infecting microbe bears a structure mimicking those of self molecules (molecular mimicry)
62
What are the 2 autoantibodies produced in rheumatoid arthritis?
1. Anti-CCP antibody (ACPA)
2. Rheumatoid factor
63
What is anti-CCP antibody?
Family of antibodies that recognize a range of citrullinated proteins. THe antibodies is highly specific for RA
64
What does RF targer?
The Fc portion of immunoglobulin G
65
Neutrophils and macrophages release
peptide-arginine deaminase (PAD)
66
What is peptide-arginine deiminase?
Enzyme tha tpost-translationally modifies proteins, converting arginine to citrulline (citrullination)
67
The extracellular fiber networks called neutrophil extracellular traps (NETs) in response to cell damage and extracellular pathogens contain
citrullinated vimentin and alpha-enolase
68
What are the proteins that usually are citrullinated?
Type II collagen, vimentin, alpha-enolase, fibrinogen, filaggrin and histones
69
What is the primary genetic risk factor of RA?
HLA DRB1 alleles
70
The genetic background of MHC molecules is directly linked to the
antigenicity of specific peptides
71
Where do HLA-DRB1 molecules bind citrullinated peptides?
In the groove
72
Presentation of the citrullinated peptides promote
antigen specific T cells
73
T helper cells promote B cell maturation and activation, leading to the production of
anti-CCP antibodies
74
Smoking, silica exposure, and some air pollutants can lead to molecular changes in the lung and bronchoalveolar lavage fluid, resulting in increased expression of
citrullinated proteins and peptides
75
Porphyromonas gingivalis, a pathogen found in deep periodontal pockets associated with advanced periodontal disease, has what citrullinating enzyme?
Prophyromonas peptidyl arginine deiminase (PPAD)
76
In the gut mucosal microbiome, accumulation of Prevotella copra was correlated with what?
Citrulline in feces and RA onset
77
Estrogen receptors are present on cells involved in immune responses, including
thymocytes, macrophages and endothelial cells
78
The complements activate cells of the innate immune system, such as
monocytes, macrophages, granulocytes and dendritic cells
79
Where doe synovial dendritic cells migrate to?
Lymph nodes and prime T cells
80
Il-17 stimulates the production of
pro-inflammatory cytokines, chemokines and MMPS
81
IL-17 also enhances the production of vascular endothelial growth factor-A (VEGF-A), IL-6, IL-8, MMP-1, and MMP-3 in RA synovial fibroblasts, contributing to
pannus growth, osetoclastognesis and synovial neoangiogenesis
82
Osteocytes, chondrocytes and immune cells in the articular cavity initiate an
inflammatory reaction
83
T cells activate macrophages and fibroblasts and transform them into
tissue-destructive osteoclasts and RA fibroblast like synoviocytes
84
Pannus
synovium thickens due to an increase of cells, prod of proteins, and other factors in the joint which can lead to pain, redness and warmth.
Thickened synovium pushes into the joint
85
What contributes to lupus?
A key enzyme's DNase1 failure to dispose of dying cells
86
Systemic lupus: patients have auto-antibodies that are directed against DNA structures within cells. These antibodies include
- Antinucelar antibodies (nuclei)
- Anti-cardiolipic antibody (mitochondria)
87
Systemic lupus erythematosus can present with many signs and symptoms in multiple organs. Some include
- Joints (arthritis), muscles (myositis), BVs(vasculitis), Lungs (pleuritis), heart (pericarditis), kidney, brain (psychosis), poor circulation
88
SLE: Self-antigens, DAMPS, TLR ligands, BAFF/APRIL and T-cell-derived cytokines promote
the formation of germinal centers and the production of autoantibodies
89
SLE: Loss of adaptive immune tolerance leads to an increase in
autoreactive B cells
90
SLE: autoantiboides from immune complexes activate
downstream pathways and drive organ inflammation
91
SLE: Recruited inflammatory cells release cytokines and IC to
Induce complement activation and tissue damage is caused by mediators
92
SLE: Apoptotic debris and reduced phagocytosis lead to
impaired clearance
93
What is the most distinctive feature of SLE patients?
Presence of polyreactive B cells which produce a range of autoantibodies
94
Describe drug induced lupus
Only skin is involved, usually resolves when the medications are discontinues, causes permanent hair loss, may develop into systemic lupus
95
What are the autoantibodies of bullous pemphigoid?
- BP180- Type XVII colalgen
- BP230- plakin of skins basement membrane
96
Genetic factor of Bullous pemphigoid
- Primary risk factor is HLA-D
- Genetic background of MHC molecules is directly linked to the antigenecity of specific peptides
97
WHat are enviornmental factors of bullous pemphigoid?
UV radiation, traumas, and drugs
98
Immunological reactions leading to BP
- Imbalance between Th and Treg
- T cell independent activation of TLR system induce B cell stimulation, with consequent BP autoantibody secretion
- Th17 pathway activate the inflammatory cascade started by humoral hyper activation
- complement cascade in BP blister formation
99
What is scleroderma?
Autoimmune disease involving endothelial cell damage and fibroblast overproduction of ECM, causing interstitial lung disease, pulmonary arterial hypertensiona nd heart failure
100
What are the autoantibodies of scleroderma?
- Anti-centromere
- Anti-scl-70
101
What are oral manifestations of scleroderma?
- Limited jaw opening
- Gum disease
- Tooth loss
- Difficulty eating and drinking
- Changes to the mouth
102
What are the environmental factors for scleroderma?
Exposure to silica and organic solvents
103
Describe immunological reactions leading to SLE (scleroderma)
- Antigen drives activation of Th2 and IL-4/13 (induce fibrosis)
- B cells activate. Autoantibodies cause fibroblasts to adopt a profibrotic phenotype
- Macrophages activated and produce chemokines, transforming GP beta and platelet derived growth factor, promotes fibrosis
104
What are the autoantibodies for Sjogren syndrome?
- Anti-Ro (SS-A)
- Anti-La (SS-B)
105
primary Sjogren syndrome occurs in the
absence of another underlying rheumatic disorder
106
Secondary sjogren syndrome is associated with
another rheumatic disease such as SLE, RA or scleroderma
107
What is Sjogren syndrome?
Chronic, systemic autoimmune disease that attacks the secretory glands
108
What are environemental factors for primary sjogrens?
Infections (EBV), air pollutants, smoking, solvent
109
What ist he most distinctive feature of SLE patients?
Presence of polyreactive B cells which produce a range of autoantibodies
