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Induced innate immune response and lymphoid tissue Flashcards

1
Q

Increase in vascular permeability has what affect on BP?

A

Decrease BP - in severe cases (coupled with vasodilation) can cause ischemic tissue injury

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2
Q

TLR3, TLR4, and NOD activavtion

Diagram

A
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3
Q

Signaling PRRs

A

Can be external (to detect extracellular PAMPs) or internal (to detect intracellular PAMPs)

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4
Q

TLR4

A

The prototype extracellular TLR that detects bacterial LPS

LPS binding protein (LBP) in serum facilitates TLR4 activation by binding to and transporting LPS to the TLR4 receptor complex

LPS/TLR4 binding activates the transcription factor NF-κβ

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5
Q

TLR3

A

Intracellular TLR and binds to dsRNA (viral PAMP) and utilizes a signalling pathway leading to production of type I interferons (IFN-α or IFN-β)

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6
Q

PAMP induction of inflammation

A
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7
Q

NOD-like receptors

A

NODR or nucleotide oligomerization domain-like receptors

Family of intracellular signaling PRRs that detect PPG subunits inside of cell

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8
Q

NF-κβ

A

Upregulates many host cell genes (like pro-inflammatory cytokines) that ultimately activate induced innate and adaptive immune functions

Including NADPH oxidase and iNOS

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9
Q

Activation of inflammatory cytokines

A
  1. Signaling PRRs activate NF-κβ which increases cytokine gene transcription
  2. Inflammasome activation - contains proteases that cleave cytokine pro-forms (like pro-IL1β) into mature active cytokines (like IL-1β)

Inflammasome activation also induces cell death by pyroptosis which is very pro-inflammatory due to DAMP release

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10
Q

Tumor necrosis
factor alpha
(TNF-α) and
Interleukin-1β
(IL-1β):

A

Increase vasodilation, vascular permability, and vascular endothelial adhesion molecule expression (E-selectin and VCAM-1)

Bind receptors on the endothelium and vascular smooth muscle - particularly TNF-alpha

Increase body temperature (these cytokine are endogenous pyrogens that act directly on the hypothalamus) - particularly IL-1beta

Increase tissue factor (TF) release from macrophages and endothelial cells this promotes local clotting by the extrinsic clotting pathway - or if systemic promotes disseminated intravascular coagulation (DIC) - particaularly IL-1beta

Both act on mucosal goblet cells and increase mucus secretion

TNF-alpha is the major mediator of vascular effects in SIRs and sepsis

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11
Q

IL-6

A

Increases liver release of actue phase proteins (like CRP, MBL, and fibrinogen)

Because IL-6 increases clotting factor production, it also involved in pathophysiology of DIC

Increases body temp (major endogenous pyrogen acting directly on hypothalamus)

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12
Q

IL-12

A

Activates NK cells to better kill target cell and produce the cytokine IFN-gamma

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13
Q

IL-8

A

Chemokine that increases recruitment of neutrophils to the site of infection or injury - bacterial PAMPs and DAMPs are strong inducers of IL-8 production and induce a strong neutrophil response

Binding of IL-8 to neutrophil receptors activates “inside out” signaling that increases the affinity of neutrophil LFA-1 for ICAM-1 on the endothelium

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14
Q

iNOS

A

Inducible nitric oxide synthase enzyme

Potent vasodilator

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15
Q

Pro-inflammatory cytokines

A

Tumor necrosis factor alpha (TNF-α) and Interleukin-1β (IL-1β) and IL-6

Produced in infected/damgaged peripheral tissues can enter circulation, CNS, and act on specific regions of the brain

Allows peripheral inflammatory responses to evoke sickness behaviors - appetite loss, fatigue, and sleepiness, increased pain sensitivity, social withdrawal, and anhedonia

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16
Q

TLR3

A

Binds viral dsRNA initiates IFN-α or IFN-β secretion

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17
Q

Type I IFN binding to IFN receptors on uninfected host cells

A

Activates transcription of genes that encode the enzymes ribonuclease L (RNase L) and protein kinase R (PKR)

These enyzmes are inactive unless host cell is subsequently virus infected

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18
Q

RNase L

A

Degrades viral and cellular mRNA - inhibiting translation of viral and host proteins

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19
Q

PKR

A

Inactivates a host ribosomal sub-unit (protein synthesis initiation factor elF-2) -turning off host cell ribosomes and preventing translation of viral and host mRNAs

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20
Q

IFN-α/β Therapy

A

Increases NK cell killing activity

Antiviral effects of type I IFNs are short lived and reversible:

Used in HPV and Hep C infections

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21
Q

What happens when an iDC binds a PAMP to its PRR?

A

This stimulates the iDC carrying pathogen antigen to migrate to nearby secondary lymphoid tissues and mature

Increase expression of B7 co-stimulatory molecule

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22
Q

Local vs. systemic inflammatory responses

A
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23
Q

Molecular basis of sepsis-induced organ failure

A
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24
Q

Compensatory anti-inflammatory response syndrome

A

Neuroinflammatory signals inhibit pro-inflammtory cytokine production, immune cells undergo apoptosis, anti-inflammatory immune cell populations (reg T cells and myeloid suppressor cells) expand and anti-inflammatory cytokines are produced

Can lead to lasting immunosuppression

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25
SIRS
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Sepsis
The presence of SIRS in response to a suspected or culture confirmed infection
27
Two most common types of infection associated w/ sepsis
Pneumonia and UTIs
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Septic shock
BP<90 mmHG or a reduction >40 mmHg from baseline in the absence of other causes for hypotension
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MODS
Multiple organ dysfunction syndrome i.e. adult respiratory distress syndrome (ARDS), central nervous system dysfunction, CV, renal, and liver failure
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Electron micrograph of plasma cells "clock face" nucleus and golgi halo (asterisk)
31
IgA secretion in the mammory gland
1. Plasma cells produce IgA dimers 2. Membrane-bound Fc receptors on the basal surface of mammary epithelial cells recognize these IgA dimers 3. IgA is internalized via receptor-mediated endocytosis 4. IgA is transported in membrane-bound vesicles to the apical epithelial surface 5. IgA is released into the mammary secretions
32
Areas of the body that lack lymphatics
CNS - immunoligically priviledged site Cartilage (lymph and blood vessels) Bone/teeth despite high metabolic activity Placenta Thymic parenchyma (functional tissue of thymus)
33
Lymphatic capillaries
Originate as **blind-ended vessels** Single layer of endothelial cells - are not associated with pericytes (pericytes provied structural support and regulate endothelial permeability in blood capillaries) Not fenestrated - lack small pores No tight junctions between cells
34
Lacteals
Lymphatic capillaries that **transport chylomicrons (lipids) to the liver** Chylomicrons are synthesized by intestinal epithelial cells and are exocytosed into lacteals ## Footnote Smaller image - plica circularis
35
Lymphoreticular organs
1. Thymus 2. Lymph nodes 3. Spleen Characterized by internal structure consisting of network of reticular or stromal cells that surround and support parenchymal cells
36
Lymphoepithelial organs
1. GALT (Gut) 2. BALT (Bronchiolar) 3. MALT (Mucosal)
37
What embryological structures does the thymus originate from?
The third (and sometimes fourth) oropharyngeal pouch ## Footnote Thymus is the first organ to acquire lymphoid functions - seeded by stem cells from yolk sac, then the liver and finally from the bone marrow
38
Cortex of the thymus
Composed principally of T lymphocytes at various stages of development ## Footnote Largest immature lymphocytes are towards periphery, mitotic figures often visible Most T cells at center of cortex and in medulla are degenerating (clonal deletion) Macrophages and APCs also in cortex
39
Tonofibrils
Exhibited by thymic stromal cells - keratin cytoskeletal elements
40
What keeps developing T lymphocytes in the thymus from being exposed to circulating antigens prematurely?
The stromal cells that form a blood-thymus barrier
41
What cells seed the thymus?
Common lymphoid progenitor cells from the bone marrow
42
What developing T lymphocytes first undergo positive selection in the thymus?
Developing T lymphocytes that can recognize foreign and self-antigen ## Footnote After passing this positive selection - migrate to the medulla where negative selection occurs such that self-recognition T cells are eliminated
43
Individuals with what syndrome lack a thymus?
DiGeorge syndrome - T-cell immunodeficiency
44
What thymic stromal cells form boundaries within the thymus?
Types III and IV
45
Hassal's corpuscles
Fx not known Dx feature of the thymus: Concentric rings of reticular cells (type VI) seem to possess keratohyalin granules that calcify and die
46
What thymic stromal reticular cells are critical for T selection?
Types II (+ selection) and V (- selection)
47
Why does the thymus' medulla stain lighter than the cortex?
There are fewer synthetically active lymphocytes in the medulla ## Footnote Lymphocytes w/ abudant rER to synthesize surface proteins are involved in negative/positive selection and are located in the thymic cortex
48
Characteristic features of all lymph nodes
A subscapsular sinus, trabecular or intermediate sinus and medullary sinus
49
Reticular cells of the lymph nodes
Fibroblast-like cells - **synthesize and secrete collagen III** and ground substance that forms the surrounding stroma Also express suface molecules and produces chemokines that attract lymphocytes and DCs
50
What MHC do dendritic cells express?
MHC I and MHC II
51
Follicular DCs
Have thin branching processes that **interdigitate between B-lymphocytes in germinal centers**; antigen-Ab complexes adhere to these processes and can be held for very long periods (sometimes years)
52
High endothelial cells
Allow naive lymphocytes to home-in to the lymph node cortex Naive lymphocytes express L-selectins and integrins - endothelial cells express E and P selectins and chemokines that attract lymphocytes
53
54
How do lymphocytes enter lymph nodes?
1. Afferent lymphatic vessels, for primarily B-lymphocytes w/i lymph fluid 2. Post capillary venules for immunologic surveillance by T-lymphocytes in the blood
55
70-80% of circulating lymphocytes in the blood are ______ ?
T-lymphocytes
56
What cells compose the capsule of the spleen?
**Myoepithelial cells** - form dense CT capsule of spleen and sends trabecula inward to incompletely divide the organ into compartments
57
White pulp of the spleen
Splenic nodules (aka Majphigian bodies) Equivalent to lymphatic tissue Cyclidrical masses of lymphocytes arranged around a central artery that constitutes the **periarterial sheath (PALS)**
58
Red pulp of the spleen
aka the splenic cords (aka cords of Billroth) - lie between the splenic sinusoids Contains reticular fibers, RBCs, WBCs, macrophages, and lymphocytes
59
Open circulation of the spleen
Endothelial cells that line the splenic sinuses are extremely long and arranged in a parallel fashion to the direction of the vessel Unlike typical endothelial cells, there are few contact points between these endothelial cells, thus there are **prominent intercellular spaces - allows blood cells to readily pass out of the sinuses**
60
Circulation in the spleen
Since open circulation predominate - erythrocytes in the red pulp cords must "reverse diapedesis" into sinusoids - serious complication in severe trauma or sickle cell disease Open circulation is highly efficient as a **blood filtering** mechanism - blood is exposed to macrophages in the pulp cords Open circulation also provides a mechanism for **serveillance** T and B cells to monitor foreign antigens in the blood **NO HEV in spleen** (entry is unregulation)
61
GALT and BALT
Are nodular lymphatic tissue Peyer's patches in the ileu - example of lymphatic nodules not surrounded by CT capsules (similar nodules are abundant in the appendix) - otherwise are simialr to nodules w/i the cortex of lyph nodes Nodules consist primarily of B-lymphocytes and plasma cells Specialized M cells (or microfold cells) are APCs in the epithelium above Peyer's patches
62
Tonsils
1. Palantine tonsils 2. Pharyngeal tonsil 3. Lingual tonsils
63
ID
Palatine tonsil -Stratified squamous epithelium on oral surface -numerous lymphatic nodules (L) and diffuse lymphoid tissue -tonsillar crypts are common (TC) -mucus-secreting glands (MG) are near base of crypts
64
ID
Pharyngeal Tonsil (adenoid) Single organ in the roof of nasal pharynx -ciliated, pseudostratified columnar epithelium -deep aspects w/ thin CT capsule
65
ID
Lingual Tonsil There are many lingual tonsils on the dorsal surface of the tongue -stratified squamous epithelium -deep aspects with flimsy CT capsule
66
ID
Lymphatic nodules of **ileum**
67
ID
Lymphatic nodules of **bronchus**
68
ID
Lymphatic nodules of **appendix**
69
ID
Lymphatic nodules of **colon**
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Septic shock
Evidence of SIRS (≥2 criteria), hypotension that is unresponsive to fluid resuscitation and organ dysfunction in response to an infection
81
This effector protein promotes MAC-mediated lysis of bacteria and is produced by the liver in response to IL-6 stimulation
Mannose-binding lectin
82
Which is produced by the NADPH oxidase enzyme?
Superoxide
83
Which IL is specifically required for the tight binding of circulating neutrophils to the endothelium at sites of tissue inflammation?
IL-8 ## Footnote IL-8 and receptor FLA-1 on neutrophil and ICAM-1 on endothelium
84
Which inflammatory mediator increases E-selectin expression, promotes clotting, and contributes to the fever, appetite loss, and fatigue that accompany many infections?
IL-1𝝱
85
Lymph node
86
Thymus tissue
87
Palantine tonsil
88
A. Deep cortex

MI Immuno/Heme (35 decks)

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