Final Exam- Week 3 Flashcards by Danielle Meyer

mucosal barrier

External environment interface: lots of immune cells

neutrophils, MPs, T cells (h and c), eosinophils, mast cells, DCs, B cells, plasma cells

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GALT

Gut-ass lymphoid tissue
Microvillar extensions: actin-rich
Epithelial cells: tight junctions
Secreted mucins-> glycocalyx
Paneth cells-> antimicrobial peptides
M cells: over Peyer's patches/follicles for luminal microbe sampling (reduced mucin secretion)
SED: pro-APCs
DCs: extend dendrites b/w tight junctions for luminal microbe sampling

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glycocalyx

part of GALT

formed by attached and secreted mucins on apical side of epithelial cells

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Paneth cells

secrete antimicrobial peptides in crypts

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M cells

microfold cells over Peyer’s patches and follicles in GALT
help sample luminal microbes
reduced mucin secretion and modified apical/basolateral surfaces to inc uptake/transport of luminal contents

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SED

Sub-epithelial dome of Peyer’s patches and lymphoid follicles
contains dendritic cells

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dendritic cells (GALT)

can extend dendrites between tight junctions to sample luminal contents (microbes)

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Th cells (Ag recognition in gut)

Ag enters through M cells -> DCs
DCs -> T cells (Peyer’s Patch) or -> mesenteric LN
activated T cells disperse through peripheral imm sys (efferent lymph vessel-> thoracic duct-> bloodstream-> lamina propria)

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Anti-inflammatory mechanisms (gut)

Immune Exclusion: limit pathogen colonization (IgA)

2. Oral Tolerance: food proteins/microbiota suppress Th1 (IgG), Th2 (IgE), Th17 (IL-17)

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Immune Exclusion

anti-inflammatory mechanism in the gut (few days)
limits pathogen colonization by IgA secretion (some IgM)
Mechanism:
1. Ag recognition at inductive site (PP)
2. Stimulation of T (CD4/8) and B (IgA/M) cells at effector site (mucosa)

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Oral Tolerance

anti-inflammatory mechanism in the gut

food proteins/microbiota (TGFb)-> Treg diff-> suppress inflammatory rxns from Th1 (IgG), Th2 (IgE and DTH), Th17 (IL-17)

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Treg cells (GALT)

up to 10%

suppress Th1, Th2, and Th17 cells in oral tolerance

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Th17 cells

accumulate in intestine, possibly due to segmented filamentous bacteria (SFB)
autoimmune disease: produce IL-17 and IL-22 (pro-inflam)

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Treg cells

subset of CD4+ cells, CD25+ (have IL-2 receptor)
Transcr factor: FOXP3
accumulate in intestine (number likely controlled by microflora), prevent self-reactive imm resp against microflora
depletion-> Th cell expansion (removes suppression)-> intestinal inflammation

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IgA

secreted as SIgA due to J subunit
promotes intestinal barrier function
maintains commensal mutualism
coats bacteria (commensal AND pathogenic) to inhibit binding to host epithelium/penetration of lamina propria
regulates composition/function of gut microflora

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flagellin

microflora-derived

promotes synthesis of retinoic acid-> facilitates differentiation of IgA B cells

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microflora

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maintain homeostasis in GI
maintain Treg cells and IgA production
develop GALT
prevent pathogenic colonization
polarize imm responses (regulate own composition)
digest/ferment carbs
conjugate bile acids
produce vitamins

IgA deficiency

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most common immunodeficiency
compensated for by other Ig’s
usually not discovered until genetic testing

environmental signals

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control balance b/w tolerance and proinflammatory responses

Functional medicine

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studies how commensal microflora affects different aspects of health (ex- asthma)
treat ex- clean out microflora, replace w/healthy colonization

germ-free mice

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show decreased mucus thickness
longer/thinner villi
less complex vascular network
shallower crypts w/less proliferative stem cells
few lymphoid follicles, immature PPs/MLNs
low IgA and antimicrobial peptides

microflora protection

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GALT development
inc Th17/Th1
inc barrier fxn
inc anti-microbial peptides
Beneficial bacteria: inc Treg, inc IL-10, inc anti-microbial peptides

REGIIIg

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anti-microbial peptides

inc by commensal microflora

Chronic inflammation

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due to environment and genetics -> dysbiosis
very high Th17/Th1
dec Treg/IL-10/anti-microbial peptides

microflora and NFkB

commensal microflora SUPPRESS NFkB (so anti-inflam)

Macrophage microflora tolerance

don't sense microflora -> don't secrete pro-inflam CKs prevents chronic inflammation in mucosa (microflora suppress NFkB)

commensal Bacteroides

Prevents inflammation by creating complex w/NFkB Increases proinflam response caused by S. Enteritidis Induces PPAR-> exports activated NFkB from nuc

Absence of commensal bacteroides

1. Salmonella flagellin binds TLR5 on intestinal epithelial cells 2. Activates IkB kinase (IKK)-> activ/nuc translocation of NFkB 3. NFkB transcribes pro-inflam genes

Hyperimmunity

Over production of pro-inflam mediators (IL-6, IL-12, TNF)

Immunodeficiency

Mutations in immuno-regulatory proteins such as NOD2 or IL-10 influence gut microbiota composition

NOD2

Nucleotide-binding oligomerization domain protein 2 Involved in immuno-regulation Mutated in immunodeficiency

Factors shaping intestinal microbial composition

Lifestyle (exercise, diet- bacteria like FIBER) Hygiene Abx Hyperimmunity/Immunodeficiency

Can prescribe w/Abx

Probiotic (yogurt) Every 6-12 hrs AFTER abx NOT AT SAME TIME

Dysbiosis

Altered intestinal microbiota | Linked to chronic inflammation and metabolic dysfunction

Chronic inflammatory diseases

IBS Asthma Arthritis, Obesity, CV disease

Central tolerance

Induced in IMMATURE self-reactive lymphocytes Location: bone marrow & thymus Fxn: Prevents MATURATION of self-reactive lymphocytes Not perfect-> peripheral tolerance as back up to prevent activation

Peripheral tolerance

Induced in MATURE self-reactive lymphocytes Location: peripheral sites Fxn: prevents ACTIVATION of self-reactive lymphocytes (Treg cells watch over)

Central T cell Tolerance

1. Thymus: Thymic Epithelial Cells present self Ag to Immature T cells 2. Cells w/TCRs w/no affinity for self Ag-self MHC -> no survival signal-> spontaneous apoptosis in thymus Cells w/TCRs w/high affinity for self Ag-MHC -> death signal -> apoptosis Cells w/TCRs w/INTERMED affinity for self Ag-MHC -> MATURE in thymus-> MIGRATE to periphery-> activated

AIRE

AutoImmune REgulator gene (possibly a transcr factor) Expressed in thymic epith cells Exposes imm cells to complete set of self-Ags

AIRE mutation

Mutation-> decreased expression of self-Ags in thymus-> imm cells not exposed to complete set of self-Ags-> breaks central tolerance-> Autoimmune Polyendocrine Syndrome (APS): Abs/lymphocytes destroy endocrine organs

Thymic epithelial cells

Self-APCs Express large number of self-Ags, present to developing T cells AIRE (TF) enables them to activate tissue-restricted Ags (TRAs) Mutation-> dec expression of self-Ags

TRAs

Tissue-restricted Ags Genes activated in thymus by AIRE in thymic epith cells-> peptides displayed on Medullary Thymic Epithelial Cells Self-reaction w/TRA by T cell-> neg selection (deletion) AIRE mutation-> TRA-reactive T cells not tested-> not eliminated (failure of neg selection)-> enter periphery-> autoimmunity (like APS)

Final Exam- Week 3 Flashcards

(42 cards)