8. Gut Immunology

Question 1

The gut flora or microbiota is influenced by early-life exposures such as maternal microbes, infant diet, antibiotics, probiotics and the physical environment. What does the gut microbiota lead to?

Answer 1

It contributes to the development of the immune system, intestinal homeostasis and host metabolism. (disruption of the gut flora can lead to diseases)

Question 2

Microflora is needed in order for GALT and matured mucosa to form. MAMps sensed by PRRs on epithelial cells and DCs recruit T and B cells cause cryptopatches to turn into?

Answer 2

mature ILFs (isolated lymphoid tissue), which act as a site for IgA production

Question 3

Microbes can also enter into peyers patches through M cells. Ag loaded DCs induce T cell and B cell maturation Which induce what?

Answer 3

IgA producing plasma cells

Question 4

Commensal bacteria are present in high density. They are usually outside the mucus layer that covers the epithelium. If the do penetrate the epithelial layer they are killed by?

Answer 4

macrophages in the lamina propria

Question 5

Some of the commensal bacteria gets into peyers patches and DCs uptake for a while and induct IgA producing B and T cells. these lymphocytes leave the mesenteric LNs enter the blood stream at the thoracic duct and go back to the?

Answer 5

intestinal mucosa

Question 6

Mucus and epithelial AMPs (antimicrobial peptides) prevent microbes from going into the intestines. When they do get past the epithelium, they are rapidly elimnated by macrophages which induce which cytokine?

Answer 6

IL10

Question 7

Commensal flora can also be uptaken by DCs which produce IL6/TGFB which go to the lamina propria. Presentation by these DCs lead to Treg cell differentiation. What is another thing that DCs can activate?

Answer 7

Th17 cells which upregulate the secretion of AMPs and control gut microbiota

Question 8

Symbiosis (or two organisms benefiting from eachother) occurs when there is a balanced microbial composition, maintaining homeostasis. Dysbiosis occurs d/t environment factors which would lead to?

Answer 8

dysregulation (lack of homeostasis) of the immunt system and lead to inflammation in susceptible host (genetics)

Question 9

Microbiota and immune system co-evolve. Malnutrition affects both, which can sometimes disrupt the microbiota which act as a barrier to enteropathogen infection. What would reccurent enteric infections lead to?

Answer 9

nutrient deficiencies as well as impaired instestinal mucosal barrier function… increasing the susceptibility to infections

Question 10

Undigested dietary carbohydrates are femented by gut commensal bacteria to produce short chain fatty acids (SCFAs: acetate propionate, butyrate). Administration of acetate in drinking water results in accumulation of IL 10 Tregs. What do SCFAs help to support?

Answer 10

an effective IgA-mediated response to the gut pathogens and stimulate production of mucus.

(along with butyrate: induce T reg production for better protection)

Question 11

Immune tolerance is sustained immune unresponsiveness to self-Ags, beneficial Ags and commensal bacteria. Oral tolerance is suppression of immune responses to Ags that have been administered by oral route. What occurs when there is failure to induce tolerance to food protein?

Answer 11

food allergy and celiac disease ( because the body sees it as foreign)

Question 12

Peripheral tolerance is when there are mature self reactive lymphocytes in peripheral tissues which are either inactivated, killed, or supressed. In the intestines, what is needed?

Answer 12

additional layers of peripheral tolerance are needed to ensure tolerance to Ags such as food and commensal organisms

Question 13

Oral tolerance is lead by mø, DCs, and Treg cells in the lamina propria and mesenteric LNs. Mø grab Abs from lumen and bring to DCs in LP via gap junctions. What happens next?

Answer 13

Ag loaded DCs move from LP to mLN and the DCs stimulate naive CD4T cells.

Question 14

Once the Naive T cells are stimulated, they are made into FoxP3 T reg cells via the release of RETINOIC ACID (RA), TGF-B and indoleamine23dioxygenase (IDO)*. Why?

Answer 14

RA makes CD4 t cells, IDO drives FoxP3 t reg development and it’s expression is determined by TGFB

Question 15

There are two main types of adverse food reactions, toxic and non-toxic. Non toxic comprises pathogenic mechanisms that are both immune mediated and non immume mediated. Nonimmune mediate mechanisms include?

Answer 15

pharmacological, enzymatic, irritants, psychosomatic

Question 16

Immune mediated include IgE mediated, a type 1 hypersensitivity while non-IgE mediated reaction are what type?

Answer 16

type III (IgG/IgM related) or IV (delayed/cell-mediated)

Question 17

Food allergy is when an immunological mechanism has been defined, either IgE or non-IgE. IgE are divided into immediate and late-phase while nonIgE reactions are belived to be?

Answer 17

T cell mediated, 4-48 hours post digestion

Question 18

In genetically predisposed people, allergens contact the GI, respiratory and skin, causing an allergic/primary sensitization which induces IgE production. What would happen if the person is exposed to the allergen a second time?

Answer 18

Activates T cells and induces IgE responses, inflammation in the intestines, skin and respiratory tract occurs soon after

Question 19

In food allergy, activation of mast cells is central. This activation causes the release of proteases, histamine and cytokines such as IL1 and TNFa which increases?

Answer 19

epithelial permeability

Question 20

When mast cells release histamine it also causes increase in vascular permeability, resulting in C3 and C5. When tryptase is released from mast cells, what occurs to the C3 and C5?

Answer 20

generates C3a and C5a which further activates mast cells and increases symptoms such as inflammation

Question 21

Vitamins D, A and folate suppress inflammation while high-fat diet promotes inflammation. microbiota can suppress allergic response via induction of Treg cells. what do they do?

Answer 21

Tregs supress Th2 cells which generate IgE and allergic effector cells.

Question 22

You have a lesser chance of food allergy if you have high vitamin D,A and long chain FA, inc. in T reg and dec. in basophils and IgE. What puts you at a high risk of food allergy?

Answer 22

high fat diet, medium chain triglycerides, increased Th2

Question 23

What are the most common food allergies in the US?

Answer 23

milks (MOST COMMON 2% infants have), eggs peanut, soy, wheat

Question 24

Peanuts are eat, taken up by dendritic cells, and T cells are made. Th2 activate B cells to make peanut IgE specific Abs. So when peanuts are eaten what happens?

Answer 24

Histamines, leukotrienes, cytokines, and prostaglandins are released and there is itching, swelling, airway obstruction, hives.

Question 25

Peanuts and nuts in general can contribute to shock by causing production of C3a. C3a stimulates macrophages, basophils and mast cells to produce PAF and histamine. What do they do?

Answer 25

They increase vascular permeability and smooth muscle contractility

Question 26

It is important to take a detailed history when diagnosing IgE mediated allergy. Along with this, blood tests and skin prick tests need to be ordered. What may be completed which is considered to be the gold standard?

Answer 26

oral food challange

Question 27

Mast cells are central to both local and systemic manifestations of food allergy. Ag disseminated systemically can trigger distal reactions through mechanisms dependent on?

Answer 27

histamine and platelet activating factor (PAF)

** systemic

Question 28

GI manifestations of food allergy are dependent on Th2 cytokines like IL4 IL13 and IL9. Mastocytosis is necessary for the local symptoms. What mediates local acute GI response (diarrhea)?

Answer 28

PAF and serotonin

Question 29

Anaphylactic reactions in the GI induces increased fluid secretion, increased peristalsis leading to diarrhea/vomiting. Mast cell activation and granule release in the airways (anaphylaxis) causes decreased diameter and increased mucus secretion leading to phlegm and coughing. What about blood vessels?

Answer 29

increased blood flow and permeability leading to edema, inflammation, lymph flow increased

Question 30

Anaphylaxis is a reaction d/t sudden release of multiple chemical mediators d/t IgE antibodies. The effects of the mediators are?

Answer 30

itching, hives, swelling of throat, bronchoconstruction, low BP, and death

Question 31

Non-IgE mediated food allergy (Type IV hypersensitivity) are commonly triggered by autoimmunity and?

Answer 31

exaggerated or persisitent responses to environment Ags and microbial Ags.

Question 32

Cow’s milk allergy in patient has showns no IgE specific for CM protein, meaning that it is a delayed hypersensitivitiy type IV. Nut induced allergy is activated by IgE, PAF and histamine. There is also a IgG induced activation of…?

Answer 32

macrophages and neutrophils which produce PAF which causes smooth muscle contractility

Question 33

B cells and the allergen can either activate IgG or IgE for food allergy and anaphylaxis. IgE directly activates mast cells while IgG?

Answer 33

activates mø and PAF and the complement and C3a and C5a which activates mast cells as well

Question 34

Food intolerance.. lack of an enzyme needed to fully digest food (lactose intolerant). Irritable bowel syndrome is a chronic condition that can cause cramping/constipation. What is food poisoning?

Answer 34

toxins such as bacteria in spoiled food can cause severe digestive symptoms

Question 35

Food intolerance ranges from sensistivity to additives such as sulfites to recurring stress/psychological factors about eating food can make you sick. What is celiac disease?

Answer 35

chronic digestive condition triggered by eating gluten. Symptoms are mainly gastrointestinal, not at risk of anaphylaxis

Question 36

What are some signs of the systemic immune disorder caused by permanent sensitivity to gluten, celiac disease?

Answer 36

Failure to thrive
Delayed puberty
autoimmune disorders
inflammation
Neurological/metabolic disorders

Question 37

95% of CD goes undiagnosed because they show no symptoms, those with CD are found to test positive for which antibodies?

Answer 37

anti-tTG2 (tissue transglutaminase 2)

Question 38

HLA-DQ2 and HLA-DQ8 are the main genetic disposing factors, these play a key role in making an adaptive immune response against gluten peptides. What is the hallmark of CD?

Answer 38

immune mediated enteropathy that involves both innate and adaptive immune system

Question 39

Class II MHC molecules are found on professional APCs. Microbial Ags are taken up via phagocytosis or endocytosis. The Ags undergo degredation into peptides which are loaded into class II MHC and presented to CD4 T helper cells. What does this represent?

Answer 39

This is how gluten is taken up and presented to T cells, which causes CD

Question 40

Gluten is proline rich usually poorly digested in SI d/t lack of prolyl. It is also rich in glutamine, usually 10-50 AAs. Some of these glutamines are deaminated by TG2 resulting in?

Answer 40

negatively charged glutamic acid residues

Question 41

Peptides with proline and glutamic acid bind to HLA class II on APCs. The majority of CD patients express the HLADQ2.5 heterodimer (or HLADQ8) and generate?

Answer 41

gluten specific Th1 cells

Question 42

Tissue damage occurs in a type IV hypersensitivity which leads to release of auto-ags such as tTG2. B cell response leads to anti-tTG2 antibodies which results in?

Answer 42

chronic inflammatory response

Question 43

Anti-tTG2 are found as IgA and IgG isotypes. Assaying for TG2specific IgA is most commonly used. This has the best specificity and sensitivity than any other test. What was used in the past?

Answer 43

intestinal biopsies

Question 44

Gluten peptides that are highly resisitant to intestinal proteases reach the lamina propria where crosslinkning and demaination of gluten by TG1 creates epitopes that are presents via HLADQ2/8 on APCs. Activated T cells secrete mainly Th1 cyotkines such as IFN-G whcih induces the release of?

Answer 44

MMPs by myofibroblasts resulting in mucosal remodeling and villus atrophy

Question 45

Additionally Th2 cyotkines are produced driving the production of auto-Abs to gluten and TG2. IL18, IFN-g, and IL21 play a role in maintaining the Th1 repsonse. What does IL 15 do?

Answer 45

links adaptive immune system to innate immune responses

Question 46

What are some signs/symptoms used to know if one should be tested for CD or not?

Answer 46

failure to thrive
persistent diarrhea
abdominal pain
constipation/vomiting
dermatitis
osteoporosis
iron deficiency

Question 47

Again, to test for CD, measure IgA antibody to human tissue transglutaminase TTG, what is recommended to confirm diagnosis in all cases?

Answer 47

intestinal biopsy

Question 48

ALL PATIENTS with CD have HLA DQ2 or DQ8. 95% have DQ2, 5% have DQ8…

Answer 48

HLADQ2/8 can be tested for and if the patient has neither allele then CD can be excluded from the ddx