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Immunology > GI Immunology > Flashcards

GI Immunology Flashcards

1
Q

LO

A

Describe IBD (Crohns disease and ulcerative colitis) as an inappropriate and exaggerated mucosal immunity to normal microflora)

Outline the differential diagnosis of Crohn’s disease and ulcerative colitis

Define the role of environmental factors in IBD

Define the role of genetic factors (IBD1, also called NOD2 or CARD15) in IBD

Provide evidence for the role of bacterial factors in the pathogenesis of IBD

Explain the role of commensalism anti inflammatory microflora (bactericides) int he GI tract homeostasis

Describe the role of TH1 type (IFN-gamma, TNF, and IL2/IL23) and TH17 type (IL17) of immune responses in pathogenic mechanisms of crohns diseae

Define the involvement of th2 type immune responses (IL4 and IL13 ) in pathogenic mechanisms of ulcerative colitis

Explain functional role of T regulatory cells in active suppression of immune responses in the intestinal tract

Describe current immunotherapeutic approaches in treatment of IBD

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2
Q

Inflammatory bowel disease

A

Chronic relapsing idiopathic inflammation of the GI tract

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3
Q

What does IBD cause

A

Irreversible impairment of GI structure and function

Increased intestinal permeability

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4
Q

Causes of IBD

A

Unclear
Hygiene hypothesis-Increased incidence of IBD

Abnormality in epithelial layer or in restitution following epithelial damage

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5
Q

Current hypothesis of IBD

A

Inappropriate and exaggerated mucosal immunity to normal microflora which, in part, controlled by genetic factors plats an important role in the pathogenic mechanisms of IBD

Also-persistent specific infection, dysbiosis (abnormal ratio of beneficial and detrimental commensalism microbial agents), defective microbial clearance , or aberrant immunoregulation

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6
Q

IBD is associated with __ permeability of the pithelial of the gut

A

Increased

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7
Q

Changes in the permeability is considered as the __ abnormality in IBD

A

Primary

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8
Q

Intestinal microbes increase further inflammatory reactions leading to __

A

SELF SUSTAINED MUCOSAL INFLAMMATION

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9
Q

Due to increased permeability , bacterial components cross the mucosal barrier, come into direct contact with immune cells and induce __ __ __-

A

ADAPTIVE IMMUNE RESPONSE

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10
Q

__ and __ immune responses to a variety of antigens have been described in IBD

A

Cellular

Humoral

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11
Q

It is __ whenther immune regulatory defect is a primary cause of IBD or a response to increased mucosal permeability and inflammation

A

Unclear

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12
Q

Microbiota

A

Collective term for allot he microscopic organisms that reside on or in the human body

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13
Q

Microbiome

A

Combined genomes of all the organisms that constitute the microbiota

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14
Q

Mycobiota

A

The subset of the microbiota that includes fungi alone

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15
Q

Virome

A

Collection of all viruses, including viruses integrated into the human genome, found in or on humans

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16
Q

Dysbiosis

A

A condition in which there is disequilibrium of the microbial communities that constitute the microbiota at a given body site

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17
Q

Germ free

A

Experimental animals birthed and raised ina. Sterile environment, devoid of microbes

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18
Q

Gnotobiotic

A

Describes animals in which the full complement of colonizing microbes is known

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19
Q

Where does IBD develop

A

In areas of high bacterial concentration (terminal ileum and the colon)

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20
Q

What does diversion of the fecal stream do

A

Prevents intestinal inflammation, reestablishment of flow leads to recurrence

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21
Q

Antibiotics and probiotics

A

Beneficial effects on IBD

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22
Q

Abs against bacteria bacterial components

A

Detected in IBD

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23
Q

Lymphocytes from patients with IBD

A

Show reactivity against fecal ags

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24
Q

Ulcerative colitis

A

Only colon involved

Continuous inflammation extending proximally from rectum

Inflammation in mucosa and submucosa only

No granulomas
PANCA-positive (perinuclear anti-neutrophil cytoplasmic antibodies)

Bleeding (common)

Fistulae (rare)

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25
Q

Crohn’s disease

A

Pan intestinal

Skip lesions with intervening normal mucosa

Transmural infalmmation

Noncaseating granulomase

ASCA positive (anti saccharomyces cerevisiae antibodies)

Bleeding uncommon
Fistulae common

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26
Q

Positive ASCA test and negative pANCA

A

Crohns

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27
Q

Various factors contribute to chronicintestinal inflammation of CBD

A

Genetic, environmental, luminal microbial antigens and adjuvants, immune response

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28
Q

Genetic susceptibility to IBD is influenced by the __ ___

A

Luminal microbiota

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29
Q

Microbial ags ac as __ that stimulate either pathogenic or protective immune responses

A

Adjuvants

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30
Q

Environmental triggers are __ to initiate or deactivate disease expression

A

Necessary

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31
Q

How do we know environmental factors are important for IBD

A

Low concordance rate in identical twins

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32
Q

__ affects systemic and mucosal immunity, altering a wide range of both innate and adaptive immune functions

A

Smoking

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33
Q

Effects of smoking

A

May alter ration of T elder to T regulatory cells

May inhibit T cell proliferation

May modulate apoptosis

May decrease serum and mucosal immunoglobulin levels

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34
Q

Smoking reduces mucosal __ ___ and promotes ___ of leukocytes to endothelial cells

A

Cytokines production

Adhesion

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35
Q

Smoking enhances small bowel __ and colonic __ production

A

Permeability

Mucus

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36
Q

Nicotine has __ effects in patients with ulcerative colitis. How

A

Beneficial

Not sure….the risk of someone who smokes of developing UC is half

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37
Q

Diet and IBD

A

Immunologic mechanisms have been postulated to link sensitization to some dietary antigens and the development of intestinal inflammation

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38
Q

Evidence of diet and IBD

A

only indirect

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39
Q

Refined sugar might be a risk factor for _ but not _

A

CD UC

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40
Q

Fat intake has been linked to _

A

UC

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41
Q

Fiber consumption seems to decrease the risk of __

A

IBD

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42
Q

Early __ is associated with a reduced incidence of UC

A

Appendectomy

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43
Q

Diets high in __ are beneficial to both UC and CD and indecency of the disease

A

Fiber

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44
Q

What are the two categories of dietary fiber

A

Fermentable and nonfermentable

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45
Q

Fermentable fibers

A

Pectins, beta Glucans, betafructans, gums, inulins, oligosaccharides, and dextrin are fermented by the gut microbiota, producing lactate, SCFAs and gas

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46
Q

Nonfermentable fibers

A

INSOLUBLE
Polysaccharide CELLULOSE present inmost vegetables and fruits, has been found to serve as a tropical factor for colonocytes (epithelial cells of the colon)

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47
Q

Fermentable and nonfermentable fibers have ____ effects in chemically induced colitis rates

A

Anti inflammatory

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48
Q

Oral contraceptives

A

Increase risk x2

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49
Q

NSAID

A

Cause relapse

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50
Q

IL10 knockout mice

A

Spontaneously develop colitis upon treatment with NSAIDS

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51
Q

There is an established - gradient in IBD incidence in both Europe and North America

A

North south????

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52
Q

IBD is more preventing amount ____ socioeconomic groups

A

Higher

White!

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53
Q

__ workers are at higher risk for IBD

A

Sedentary

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54
Q

How do we know stress exacerbates clinical manifestation of IBD

A

Non human primary develop UC type colitis only when kept in captivity

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55
Q

Age of onset for UC and CD

A

Early adults 20-40

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56
Q

CD and CU more common in women or men

A

Women

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57
Q

UC is 10 fold less in __ and ___ populations

A

Asian and african

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58
Q

CD seems very uncommon in _ and __

A

Asia and africa

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59
Q

Genetics to IBD

A

Increased risk amount first degree relatives

Greater concordance among monozygotic than dizygotic

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60
Q

IBD-1 gene

A

Susceptibility locus found in chromosome 16

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61
Q

IBD-1 locus contains ____ genes

A

CARD15/NOD2 (caspase recruitment domain family member 12 formerly known as NOD2-nucleotide binding oligomerization domain 2 gene)

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62
Q

Defects in CARD15/NOD2 are found in 17-27% of cases of _

A

CD

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63
Q

Homozygous CARD15

A

More than 20 fold increased risk of developing CD

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64
Q

What is CARD15

A

Intracellular pathogen recognition receptor PPR

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65
Q

CARD15 what recognize

A

Recognizes molecules containing the specific structure called murayl dipeptide MDP

66
Q

What does activation of CARD15 cause

A

Activation of NF-KB

67
Q

What is CARD15 expressed in

A

Monocytes/macrophages

68
Q

CARD15 gene activated NFKB which induces inflammation. Shouldn’t a defect int his be protective against IBD

A

Initial abnormality in the innate immune response (NFKB mediated) causes the following induction of adaptive immune response

CARD15 mutation may increase susceptibility to chronic intracellular infection or prevent the development of tolerance to commensalism microflora

Disruption of mucosal homeostasis via CARD15 mediated effects on APC in generation of effector T cells and/or regulatory T cells

69
Q

A defect in NFKB activation causes an abnormal activation of __ immune responses

A

Adaptive

70
Q

IBD may occur as a result of acute infection. What finding supports this

A

Increased number of surface adherent and intracellular bacteria is found in the colonic epithelium of patients with IBD

71
Q

Any specific microorganism for IBD

A

No but maybe
M paratuberculosis
Persistent measles virus (paramyxovirus)
Listeria monocytogenes

72
Q

How do we know that normal intestinal microflora may be important in the pathogenesis of CD

A

Spontaneous colitis does not occur in mutant mouse strains when they are maintained in a germ free environment

It develops rapidly when these mice are colonized by commensalism bacteria

73
Q

We have evolved to depend on ___ for several functions, including the degradation of components of our diet that our own cells cannot digest

A

Commensals

74
Q

Microflora

A

Dynamic bacterial community

Number of microbiota exceed 10 times the total number of body cells

75
Q

Collective genome

A

More than 400 species of microbiota

Which contain 100 times more genes than the human genome

76
Q

Why are the microflora a part of an extremely complex and highly regulated system

A

In intestine they are in permanent contact and RECIPROCAL INTERACTION with the host cells and with nutrients

77
Q

Protective function of gut microflora

A

Maintaining a physical barrier against colonization or invasion by pathogens

Facilitation nutrient digestion and assimilation

Providing immunological surveillance signals at the gut mucosa lumen interface

78
Q

The numbers a types of bacterial communities, as well as physiological factors vary along the length of the GI tract

A

Ok

79
Q

Proximal GI tract

A

Aerobic and facultative anaerobic bacteria

80
Q

Distal small intestine (ileum) and colon

A

Obligate anaerobic bacteria

81
Q

Proximal GI tract environment (stomach , duodenum, jejunum)

A

Oxygen, bile acid, intestinal motility antimicrobial peptides (AMP), luminal pH

82
Q

Distal GI environment

A

Hypoxic, physiological pH, reduced bile acids and AMPE, gut motility

83
Q

What do oxygen sensitive microbes produce

A

Short chain fatty acids (acetate, propionate, butyrate) from complex carbohydrates (fiber) to be sued for important colonic and immunological processes

84
Q

During homeostasis, the gut microbiota has an important role in the development of __ ___

A

Intestinal immunity

85
Q

___ are microorganisms associated with chronic inflammatory conditions

A

Pathobionts

86
Q

Beneficial subsets of commensal bacteria tend to have _____ activities

A

Anti-inflammatory

87
Q

Basal activation of _ and _ cells provide cytokines that maintain the integrity of the GI

A

TH17, TH1

88
Q

Pathobionts

A

Directly suppressed by beneficial commensal bacteria partly through the induction of regulatory immune responses involving Treg, IL10 and regenerating islet derived protein 3 y

REGIIy-ONLY FYI

89
Q

What does microbiota help develop

A

GALT
TH1, 17
Barrier

90
Q

Dysbiosis

A

Get disruption of the microbial community structure from a combination of genetic and environmental factors

91
Q

Dysbiosis results in a loss of __ bacteria and/or in the accumulation of pathobionts, which leads to chronic inflammation

A

Protective

92
Q

Chronic inflammation involves hyperactivation of _ and _

A

TH1 and TH17

93
Q

COMPARE BASAL (HOMEOSTASIS) VS HYPERACTIVATION (PATHOLOGY)

A

A type of dose effect relationship

94
Q

Mucus

A

Primary barrier limiting contact between the microbiota and host tissue preventing microbial translocation

95
Q

Epithelial cells produce __ ___ that also play a significant role in limiting exposure to the commensal microbiota

A

Animicrobial peptides

96
Q

Translocating commensals are rapidly eliminated by what

A

Tissue resident macrophages

97
Q

Commensal Ag can be captured by _ that reaffirm to the mesenteric LN from the lamina propria

A

DC

98
Q

Presentation of commensal Ag by these DC leads to the differentiation of commensal specific _ Calls, __ cells and ___ B cells

A

Treg
TH17
IgA producing B cells

99
Q

Commensal specific lymphocytes traffic to the lamina proporia and Peters patches. Int he Peters patches, treg can further promote class switching and _ generation against commensals

A

IgA

100
Q

The combination of the epithelial barrier, mucus layer, igA and DC and T cells comprise the __ __

A

Mucus firewall,

101
Q

Purpose of mucosal firewall

A

Limits the passage and exposure of commensals to the gut associated lymphoid tissue, preventing untoward activation and pathology

102
Q

The symbiotic relationship between host and bacteria involves __ __ process

A

Microbial fermentation

103
Q

The predominent end products of bacterial fermentation in the gut are ___, such as acetate, propionate, ad butyrate

A

Short chain fatty acids

104
Q

The intestinal microflora are contributes to __ __

A

Aminoacid synthesis (high concentrations off urea are found in the colon of germ free rates, indicating the role of bacteria in intestinal nitrogen recycling)

105
Q

Microbiota metabolize ___, reduce ___, and degrade __ ___ produced by the intestinal epithelium goblet cells

A

Bilirubin
Cholesterol
Mucus glycoproteins

106
Q

The microbiota induces host immune tolerance to commensal bacteria directly via:

A

A microbe associates molecular pattern MAMP

Polysaccharide PSA signaling

Indirectly through the production of short chain fatty acids

Potentially through expression of epithelial intestinal alkaline phosphatase IAP which detoxifies luminal LPS

107
Q

Segmented filamentous bacteria (SFB) promote immune development of __ cells through epithelial cytokine production and Ag presentation by DC

A

TH17

108
Q

SCFA also induce _ and _ secretion into the lumen, promote epithelial barrier integrity, and prevent pathogen colonization

A

IgA

Mucus

109
Q

Microbiota as a whole is required for proper ___ development. The microbiota also participate in the formation of the active , secondary forms of bile acids

A

GALT

110
Q

There is a __ relationship between host and commensal microflora

A

Symbiotic

111
Q

Microflora regulates inflammatory immune response to what

A

Food, antigens, microbes

112
Q

Commensal microflora suppress ___

A

NFKB

113
Q

The tolerance is related to _ which do not sense the presence of microflora and thus do not secrete pro inflammatory cytokines

A

Macrophages

114
Q

In IBD tolerance is __

A

Lost

115
Q

Consequently, a chronic immune-inflammatory response is triggered int he mucosa;

A

Epithelial Ags and altered aerobic bacteria trigger UC

Anaerobic bacteria trigger CD

116
Q

In the absence of commensal bacteriodes

A

Salmonella flagellin binds to TLR5 intestinal epithelial cells

Activates IKB kinase _>activation and nuclear translocation NFKB

NFKB mediated transcription of proinflammatory genes

117
Q

In the presence of commensal bacteriodes

A

Proinflammatory response caused by s enteritidis is attenuated

Induction of peroxisome proliferation activated receptor (PPAR)
Which exports the activated of NFKB from nucleus

118
Q

Crohn’s disease is characterized as what

A

TH1 and TH17 type disease driven by the production TNF/IFN-y (th1) and il17

119
Q

Ulcerative colitis is often viewed as ___ disease because of increased mucosal expression of the TH2 cytokine IL5 and IL13 produced by natural killer cells

A

TH2

120
Q

T cell activation and differentiation is modulated by _____ signals between ___ and ____

A

Co-stimulatory signals

BAPC and naive T cells

121
Q

How does an activated T cell become TH1

A

Il12

122
Q

How does an activated T cell become a TH2 cell

A

IL4

123
Q

How does an activated T cell become a TH17 cell

A

IL6, 23, TGFb

124
Q

What do TH1 cells secrete

A

IFNy

125
Q

What does IFNy do

A

Antigen presentation and cellular immunity

126
Q

What does TH2 secrete

A

IL4, 5, 13

127
Q

What does IL4, 5, 13 do

A

Humoral immunity and allergy

128
Q

What do TH17 secrete

A

IL17

129
Q

What does IL17 do

A

Tissue inflammation

130
Q

IL6 and IL23 are produced by __

A

APC

131
Q

IL23

A

Closely related to IL12 and regulates TH1 response

Regulates macrophages and DC

Stimulates T cells to produce IL17(TH17_ but not IFNy(TH1) or il4 (TH2)

132
Q

Mice deficient in IL23

A

Do NOT have type IV delayed hypersensitivity

133
Q

CD is characterized by the generation of TH1 ad TH17 polarized T cell responses driven by the production of IL12 (TH1) and IL6 and IL23 (TH17) by _ and _

A

DC and macrophages

134
Q

TH1 polarized cells secrete

A

Il2, IFNy, and TNF

135
Q

TH17 secrete

A

IL17 and IL22

136
Q

UC Is characterized by an atypical what

A

TH2 polarized T cell, and natural killer T cells response mediated by IL5 (TH2) and IL13 (NKT cells)

137
Q

Polarized T cell responses initiate an ___ cascade that involves ___ activation , ___production, and recruitment of __ cells and ____

A 
Inflammatory 
Endothelial
Chemokine
B cells
WBC
138
Q

The balance between proinflammatory and antiinflammatory cytokines in the mucosa regulates the development and potential perpetuation of mucosal inflammation in patients IBD

A

Ok

139
Q

WHAT LEADS TO CD

A

Il12 th1->IFNy cytokines
Il23 th17->il17 cytokines
Il23 macrophages, dendrites->TNF cytokines

Causes gut inflammation

140
Q

Commensals have been part of human micro ecology for millennia, however these good bugs are now less frequent or even absent in the microbial environment of out____ societies

A

Industrial

141
Q

There is a link between the increasing incidence of allergies (TH2 driven_ and what

A

Modern hygienic lifestyle

142
Q

Hygiene hypothesis

A

Dysregulation in the T helper (TH1.TH2 balance

143
Q

What does the hygiene hypothesis not explain

A

The increased incidence of several other immunological disorders such as IBD, MS, type I diabetes, and obesity, which are all primarily driven by TH1 cells

144
Q

Induction of ___ cells by certain microorganisms can prevent or alleviate such diseases

A

Regulatory T

145
Q

Defects in immunoregulatory processes, such as tolerance against the commensal microflora, have been shown to be associated to the pathogenesis of __

A

IBD

146
Q

Limited expression of pro inflammatory cytokines by APCs and an excess of tgfb result in differentiation of naive T cells into Treg cells which suppress TH1, TH2, and TH17 responses

A

Up to 10% of T cells in GALT are Treg cells

147
Q

T cell differentiation

A

TGFB and other polarizing cytokines

148
Q

Immune responses int he intestinal lumen GI are tightly regulated

A

Tolerance to resident commensal bacteria and dietary antigens present

Rapid immune response against pathogenic microbes

Active suppression by Treg cells

149
Q

IBD is believed to be the result of a breakdown of tolerance to resident enteric bacteria

A

Ok

150
Q

Properties of Treg cells

A

Act locally in tissues ad draining lymph nodes

Become activated by local APC presenting auto Ag

Suppress APC directly through cell to cell interactions or indirectly via cytokines or chemokine

Might act directly on T cell effectors

151
Q

Look at picture

A

Yup

152
Q

TH27 cells are protective CNS and not protective (pancreas)

A

Ok

153
Q

MS

A

Broad spectrum antibiotics are given orally to mice reduce the symptoms of experimental autoimmune encephalomyelitis

Segmented filamentous bacteria colonization induces TH17 cell development in the intestine. These TH17 cells might migrate to the periphery to affect systemic and central nervous system immunity

By contract , beneficial commensal bacteria can attenuate CNS inflammation through the induction of FOXP3+Treg cells

154
Q

Arthritis

A

Microbiota-induced IL-Ib participates in the development of RA through the induction of TH17 cells

The IL-1R antagonist blocks IL-1B signaling and abrogates joint inflammation

155
Q

Type 1 diabetes

A

A decreased firmicutes/bacteriodes ration is associated with an attenuated risk of type 1 diabetes
SFB induced TH17 cells protect the host against type 1 diabetes development by an unknown mechanism

156
Q

Allergic inflammation

A

Under germ free conditions, host immune response are TH2 biased. Restoration of the gut microbiota in germ free mice results in an increase in TH1 and TH17 cells and a reduction of TH2 type responses

Exposure to microorganisms in neonatal, but not adults, life decreases the accumulation of invariant in the lungs

Mice treated with antibiotics have an expansion of basophils in the peripheral blood as well as increased IgE serum levels

157
Q

Treatment

A

Aminosalicylates

Corticosteroids

Antibiotics

Immunosuppressants

158
Q

TNF blockers

A

These agents are humanized monoclonal Ab that bind TNFa

Generally reserved for moderate to severe UC and CD

Administered as an IV infusion or subcutaneously

The risk for worsening of heart failure, reactivation of infections and malignancy

159
Q

Leukocyte adhesion inhibitors

A

These agents are humanized monoclonal Ab that inhibits the adhesion of integrins to receptors on the endothelial cells of the gut

The risk of life threatening progressice multifocal leukoencephalopathy

Recommended for patients who failed previous therapy, including TNF blockers

160
Q

Precision medicine and the microbiome

A

Use of advanced genomic techniques for detailed assessment microbiota functions in health and specific diseases

Application of host genome and microbiome data to predict disease susceptibility and responses to therapy

Identification and targeted eradication and replacement of deleterious organisms

Assembly of limited designer microbiotas to initiate therapeutic reconstruction of dysbiosis patient microbiota

Immunology (14 decks)

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