GI Immunology Flashcards
LO
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
Inflammatory bowel disease
Chronic relapsing idiopathic inflammation of the GI tract
What does IBD cause
Irreversible impairment of GI structure and function
Increased intestinal permeability
Causes of IBD
Unclear
Hygiene hypothesis-Increased incidence of IBD
Abnormality in epithelial layer or in restitution following epithelial damage
Current hypothesis of IBD
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
IBD is associated with __ permeability of the pithelial of the gut
Increased
Changes in the permeability is considered as the __ abnormality in IBD
Primary
Intestinal microbes increase further inflammatory reactions leading to __
SELF SUSTAINED MUCOSAL INFLAMMATION
Due to increased permeability , bacterial components cross the mucosal barrier, come into direct contact with immune cells and induce __ __ __-
ADAPTIVE IMMUNE RESPONSE
__ and __ immune responses to a variety of antigens have been described in IBD
Cellular
Humoral
It is __ whenther immune regulatory defect is a primary cause of IBD or a response to increased mucosal permeability and inflammation
Unclear
Microbiota
Collective term for allot he microscopic organisms that reside on or in the human body
Microbiome
Combined genomes of all the organisms that constitute the microbiota
Mycobiota
The subset of the microbiota that includes fungi alone
Virome
Collection of all viruses, including viruses integrated into the human genome, found in or on humans
Dysbiosis
A condition in which there is disequilibrium of the microbial communities that constitute the microbiota at a given body site
Germ free
Experimental animals birthed and raised ina. Sterile environment, devoid of microbes
Gnotobiotic
Describes animals in which the full complement of colonizing microbes is known
Where does IBD develop
In areas of high bacterial concentration (terminal ileum and the colon)
What does diversion of the fecal stream do
Prevents intestinal inflammation, reestablishment of flow leads to recurrence
Antibiotics and probiotics
Beneficial effects on IBD
Abs against bacteria bacterial components
Detected in IBD
Lymphocytes from patients with IBD
Show reactivity against fecal ags
Ulcerative colitis
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)
Crohn’s disease
Pan intestinal
Skip lesions with intervening normal mucosa
Transmural infalmmation
Noncaseating granulomase
ASCA positive (anti saccharomyces cerevisiae antibodies)
Bleeding uncommon
Fistulae common
Positive ASCA test and negative pANCA
Crohns
Various factors contribute to chronicintestinal inflammation of CBD
Genetic, environmental, luminal microbial antigens and adjuvants, immune response
Genetic susceptibility to IBD is influenced by the __ ___
Luminal microbiota
Microbial ags ac as __ that stimulate either pathogenic or protective immune responses
Adjuvants
Environmental triggers are __ to initiate or deactivate disease expression
Necessary
How do we know environmental factors are important for IBD
Low concordance rate in identical twins
__ affects systemic and mucosal immunity, altering a wide range of both innate and adaptive immune functions
Smoking
Effects of smoking
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
Smoking reduces mucosal __ ___ and promotes ___ of leukocytes to endothelial cells
Cytokines production
Adhesion
Smoking enhances small bowel __ and colonic __ production
Permeability
Mucus
Nicotine has __ effects in patients with ulcerative colitis. How
Beneficial
Not sure….the risk of someone who smokes of developing UC is half
Diet and IBD
Immunologic mechanisms have been postulated to link sensitization to some dietary antigens and the development of intestinal inflammation
Evidence of diet and IBD
only indirect
Refined sugar might be a risk factor for _ but not _
CD UC
Fat intake has been linked to _
UC
Fiber consumption seems to decrease the risk of __
IBD
Early __ is associated with a reduced incidence of UC
Appendectomy
Diets high in __ are beneficial to both UC and CD and indecency of the disease
Fiber
What are the two categories of dietary fiber
Fermentable and nonfermentable
Fermentable fibers
Pectins, beta Glucans, betafructans, gums, inulins, oligosaccharides, and dextrin are fermented by the gut microbiota, producing lactate, SCFAs and gas
Nonfermentable fibers
INSOLUBLE
Polysaccharide CELLULOSE present inmost vegetables and fruits, has been found to serve as a tropical factor for colonocytes (epithelial cells of the colon)
Fermentable and nonfermentable fibers have ____ effects in chemically induced colitis rates
Anti inflammatory
Oral contraceptives
Increase risk x2
NSAID
Cause relapse
IL10 knockout mice
Spontaneously develop colitis upon treatment with NSAIDS
There is an established - gradient in IBD incidence in both Europe and North America
North south????
IBD is more preventing amount ____ socioeconomic groups
Higher
White!
__ workers are at higher risk for IBD
Sedentary
How do we know stress exacerbates clinical manifestation of IBD
Non human primary develop UC type colitis only when kept in captivity
Age of onset for UC and CD
Early adults 20-40
CD and CU more common in women or men
Women
UC is 10 fold less in __ and ___ populations
Asian and african
CD seems very uncommon in _ and __
Asia and africa
Genetics to IBD
Increased risk amount first degree relatives
Greater concordance among monozygotic than dizygotic
IBD-1 gene
Susceptibility locus found in chromosome 16
IBD-1 locus contains ____ genes
CARD15/NOD2 (caspase recruitment domain family member 12 formerly known as NOD2-nucleotide binding oligomerization domain 2 gene)
Defects in CARD15/NOD2 are found in 17-27% of cases of _
CD
Homozygous CARD15
More than 20 fold increased risk of developing CD
What is CARD15
Intracellular pathogen recognition receptor PPR
CARD15 what recognize
Recognizes molecules containing the specific structure called murayl dipeptide MDP
What does activation of CARD15 cause
Activation of NF-KB
What is CARD15 expressed in
Monocytes/macrophages
CARD15 gene activated NFKB which induces inflammation. Shouldn’t a defect int his be protective against IBD
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
A defect in NFKB activation causes an abnormal activation of __ immune responses
Adaptive
IBD may occur as a result of acute infection. What finding supports this
Increased number of surface adherent and intracellular bacteria is found in the colonic epithelium of patients with IBD
Any specific microorganism for IBD
No but maybe
M paratuberculosis
Persistent measles virus (paramyxovirus)
Listeria monocytogenes
How do we know that normal intestinal microflora may be important in the pathogenesis of CD
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
We have evolved to depend on ___ for several functions, including the degradation of components of our diet that our own cells cannot digest
Commensals
Microflora
Dynamic bacterial community
Number of microbiota exceed 10 times the total number of body cells
Collective genome
More than 400 species of microbiota
Which contain 100 times more genes than the human genome
Why are the microflora a part of an extremely complex and highly regulated system
In intestine they are in permanent contact and RECIPROCAL INTERACTION with the host cells and with nutrients
Protective function of gut microflora
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
The numbers a types of bacterial communities, as well as physiological factors vary along the length of the GI tract
Ok
Proximal GI tract
Aerobic and facultative anaerobic bacteria
Distal small intestine (ileum) and colon
Obligate anaerobic bacteria
Proximal GI tract environment (stomach , duodenum, jejunum)
Oxygen, bile acid, intestinal motility antimicrobial peptides (AMP), luminal pH
Distal GI environment
Hypoxic, physiological pH, reduced bile acids and AMPE, gut motility
What do oxygen sensitive microbes produce
Short chain fatty acids (acetate, propionate, butyrate) from complex carbohydrates (fiber) to be sued for important colonic and immunological processes
During homeostasis, the gut microbiota has an important role in the development of __ ___
Intestinal immunity
___ are microorganisms associated with chronic inflammatory conditions
Pathobionts
Beneficial subsets of commensal bacteria tend to have _____ activities
Anti-inflammatory
Basal activation of _ and _ cells provide cytokines that maintain the integrity of the GI
TH17, TH1
Pathobionts
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
What does microbiota help develop
GALT
TH1, 17
Barrier
Dysbiosis
Get disruption of the microbial community structure from a combination of genetic and environmental factors
Dysbiosis results in a loss of __ bacteria and/or in the accumulation of pathobionts, which leads to chronic inflammation
Protective
Chronic inflammation involves hyperactivation of _ and _
TH1 and TH17
COMPARE BASAL (HOMEOSTASIS) VS HYPERACTIVATION (PATHOLOGY)
A type of dose effect relationship
Mucus
Primary barrier limiting contact between the microbiota and host tissue preventing microbial translocation
Epithelial cells produce __ ___ that also play a significant role in limiting exposure to the commensal microbiota
Animicrobial peptides
Translocating commensals are rapidly eliminated by what
Tissue resident macrophages
Commensal Ag can be captured by _ that reaffirm to the mesenteric LN from the lamina propria
DC
Presentation of commensal Ag by these DC leads to the differentiation of commensal specific _ Calls, __ cells and ___ B cells
Treg
TH17
IgA producing B cells
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
IgA
The combination of the epithelial barrier, mucus layer, igA and DC and T cells comprise the __ __
Mucus firewall,
Purpose of mucosal firewall
Limits the passage and exposure of commensals to the gut associated lymphoid tissue, preventing untoward activation and pathology
The symbiotic relationship between host and bacteria involves __ __ process
Microbial fermentation
The predominent end products of bacterial fermentation in the gut are ___, such as acetate, propionate, ad butyrate
Short chain fatty acids
The intestinal microflora are contributes to __ __
Aminoacid synthesis (high concentrations off urea are found in the colon of germ free rates, indicating the role of bacteria in intestinal nitrogen recycling)
Microbiota metabolize ___, reduce ___, and degrade __ ___ produced by the intestinal epithelium goblet cells
Bilirubin
Cholesterol
Mucus glycoproteins
The microbiota induces host immune tolerance to commensal bacteria directly via:
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
Segmented filamentous bacteria (SFB) promote immune development of __ cells through epithelial cytokine production and Ag presentation by DC
TH17
SCFA also induce _ and _ secretion into the lumen, promote epithelial barrier integrity, and prevent pathogen colonization
IgA
Mucus
Microbiota as a whole is required for proper ___ development. The microbiota also participate in the formation of the active , secondary forms of bile acids
GALT
There is a __ relationship between host and commensal microflora
Symbiotic
Microflora regulates inflammatory immune response to what
Food, antigens, microbes
Commensal microflora suppress ___
NFKB
The tolerance is related to _ which do not sense the presence of microflora and thus do not secrete pro inflammatory cytokines
Macrophages
In IBD tolerance is __
Lost
Consequently, a chronic immune-inflammatory response is triggered int he mucosa;
Epithelial Ags and altered aerobic bacteria trigger UC
Anaerobic bacteria trigger CD
In the absence of commensal bacteriodes
Salmonella flagellin binds to TLR5 intestinal epithelial cells
Activates IKB kinase _>activation and nuclear translocation NFKB
NFKB mediated transcription of proinflammatory genes
In the presence of commensal bacteriodes
Proinflammatory response caused by s enteritidis is attenuated
Induction of peroxisome proliferation activated receptor (PPAR)
Which exports the activated of NFKB from nucleus
Crohn’s disease is characterized as what
TH1 and TH17 type disease driven by the production TNF/IFN-y (th1) and il17
Ulcerative colitis is often viewed as ___ disease because of increased mucosal expression of the TH2 cytokine IL5 and IL13 produced by natural killer cells
TH2
T cell activation and differentiation is modulated by _____ signals between ___ and ____
Co-stimulatory signals
BAPC and naive T cells
How does an activated T cell become TH1
Il12
How does an activated T cell become a TH2 cell
IL4
How does an activated T cell become a TH17 cell
IL6, 23, TGFb
What do TH1 cells secrete
IFNy
What does IFNy do
Antigen presentation and cellular immunity
What does TH2 secrete
IL4, 5, 13
What does IL4, 5, 13 do
Humoral immunity and allergy
What do TH17 secrete
IL17
What does IL17 do
Tissue inflammation
IL6 and IL23 are produced by __
APC
IL23
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)
Mice deficient in IL23
Do NOT have type IV delayed hypersensitivity
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 _
DC and macrophages
TH1 polarized cells secrete
Il2, IFNy, and TNF
TH17 secrete
IL17 and IL22
UC Is characterized by an atypical what
TH2 polarized T cell, and natural killer T cells response mediated by IL5 (TH2) and IL13 (NKT cells)
Polarized T cell responses initiate an ___ cascade that involves ___ activation , ___production, and recruitment of __ cells and ____
Inflammatory Endothelial Chemokine B cells WBC
The balance between proinflammatory and antiinflammatory cytokines in the mucosa regulates the development and potential perpetuation of mucosal inflammation in patients IBD
Ok
WHAT LEADS TO CD
Il12 th1->IFNy cytokines
Il23 th17->il17 cytokines
Il23 macrophages, dendrites->TNF cytokines
Causes gut inflammation
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
Industrial
There is a link between the increasing incidence of allergies (TH2 driven_ and what
Modern hygienic lifestyle
Hygiene hypothesis
Dysregulation in the T helper (TH1.TH2 balance
What does the hygiene hypothesis not explain
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
Induction of ___ cells by certain microorganisms can prevent or alleviate such diseases
Regulatory T
Defects in immunoregulatory processes, such as tolerance against the commensal microflora, have been shown to be associated to the pathogenesis of __
IBD
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
Up to 10% of T cells in GALT are Treg cells
T cell differentiation
TGFB and other polarizing cytokines
Immune responses int he intestinal lumen GI are tightly regulated
Tolerance to resident commensal bacteria and dietary antigens present
Rapid immune response against pathogenic microbes
Active suppression by Treg cells
IBD is believed to be the result of a breakdown of tolerance to resident enteric bacteria
Ok
Properties of Treg cells
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
Look at picture
Yup
TH27 cells are protective CNS and not protective (pancreas)
Ok
MS
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
Arthritis
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
Type 1 diabetes
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
Allergic inflammation
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
Treatment
Aminosalicylates
Corticosteroids
Antibiotics
Immunosuppressants
TNF blockers
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
Leukocyte adhesion inhibitors
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
Precision medicine and the microbiome
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
