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Mucosal Immunity (Innate (GALT (stratification (lamina propria (population…

- - - - O-linked oligosaccharides
      - secreted & membrane-bound forms (glycocalyx)
      - form barrier & help trap bacteria
  - - - minimize direct contact b/w bacteria & epi
      - barriers: mucins, anti-bacterial proteins, IgA, tight epi cells, large number of immune cells
      - lamina propria
        
        population dynamic & depends on Ag environment
        
        germ-free: few cells
        
        highly infectious: greatly expanded pop
    - - confine bacteria to limit systemic exposure
      - phagocytic cells in LP
      - homing of activated lymphocytes to mucosal surface
    - - Peyer's Patches
        
        5-200 B cell follicles w/ GCs
        
        only in SI
        
        act like LN but w/o encapsulation
        
        immune response
        
        (+) naive lymphocytes >> effector cells proliferate >> LN >> circulation >> LP of mucosal tissue
        
        in nursing mothers, plasma cells move from mucosal sites to mammary glands >> IgA thru breast milk to baby
    - - single follicle, mostly B cells
      - in SI & LI
  - - - expressed in basolateral membrane
      - DCs in LP express lower levels
      - biased toward anti-inflammatory response
    - - expressed in cytoplasm
- - - - most prevalent in young children
      - food-specific
      - response:
        
        vomiting
        
        diarrhea
        
        pruritis
        
        urticaria
        
        anaphylaxis
      - sensitization (priming)
      - immediate hypersensitivity
        
        IgE:FceR1 on mast cells
        
        early phase rxn w/in minutes:
        vasoactive amines (histamine), lipid mediators
        
        late phase rxn (6-24 hrs): cytokines
        
        IgE binds allergens >> activation of mast cell
    - - Th2-cell mediated
      - chronic skin &/or GI symptoms
      - eosinophilic disorders
    - - IgE & non-IgE
    - - inappropriate digestion
        
        NL: di & tri-peptides, non-immunogenic
        
        ABNL: longer peptides; some immunogenic
        
        d/t genetics, diet, drugs, toxins, age(?)
      - hygiene
        
        lack of early childhood exposures
        
        inc. susceptibility to allergic disease
      - microflora
        
        western lifestyle alters gut microflora
        
        leads to allergies & other inflammatory diseases
    - - very common (milk, eggs, etc.); most "outgrown"
      - theory: mucosal barrier not complete until ~4y/o
      - symptoms: GI, skin
      - anaphylactic responses are not outgrown
  - - - affects entire thickness of bowel wall
      - most often in terminal ileum
      - may share genetic risk loci w/ celiac disease
    - - restricted to colonic mucosa
    - - defective Treg cells
        (FoxP3 & IL-2/IL-2R deficiencies)
      - autoreactive T cells in LP (overactive Th17; granulomatous inflmmation by IFN-g-producing Th1 cells)
      - dysregulated innate response
        (def. defensin; inadeq. commensals)
      - defective autophagy
    - - transfer of CD4 CD25 Treg cells >> home to mesenteric LN in colon >> proliferate & inhibit autoreactive T cells
      - after inflammation resolves >> Tregs remain in clusters w/ DCs & autoreactive T cells
  - - - autoimmune disease of gut mucosa mediated by T cells
      - genetic factors
        
        75% monozygotic twins
        
        all have HLA-DQ2 or -DQ8
        
        30% caucasian pop has DQ2
        
        3-5% of DQ2/DQ8 develop celiac
      - assoc w/ other autoimmune (DM1, autoimmune thyroid)
      - & environmental factors
    - - abdominal pain, diarrhea, growth failure, anemia, osteoporosis, or even asymptomatic
    - - endomysium (IgA)
      - gliadin (IgA & IgG)
      - deamidated gliadin
      - tissue transglutaminase (tTG)
        
        IgA (sensitive & specific)
        
        IgG (check if IgA def.)
        
        10% of DM1 develop these Ab
        
        glutamine >> glutamic acid >> fits DQ pocket better
    - - lifelong gluten-free diet
        
        difficult d/t:
        
        hidden: protein filler in sausage, soups, soy sauce, ice cream
        
        cross-contamination during milling & storage
        
        50 mg/day for 3 mo >> intestinal changes
        
        completely reverses clinical & histo findings
      - novel therapies
        
        enzyme therapy
        
        bacterial prolyl endopeptidase
        
        pretreatment of gluten containing food
        
        zonulin antagonists (AT-1001)
        
        normally inc. intestinal permeability
        
        small clinical trials >>
        no inc. permeability after gluten challenge
        
        inhibition of DQ2/DQ8 Ag-presentation
        
        small molecules block binding pockets
    - - gluten degraded in gut
        
        gliadin
        
        alpha, gamma, omega
        
        alcohol soluble
        
        enters gut tissue
        
        (alcohol insoluble) glutenins
      - naive CD4 T cells respond >> inflammatory effector T cells >> villous atrophy, malabsorption & diarrhea
      - gluten reactive T cells found in blood of both healthy & celiac pts; only found in guts of celiacs
      - gliadin + tTG >> deamidated gliadin >> binds to APCs w/ HLA-DQ2/DQ8
  - - - most common primary immunodeficiency
      - majority asymptomatic; relatively healthy
      - compensated w/ inc. IgM, IgG
      - could reflect developed countries w/ few parasitic infections
    - - Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked disease
      - mutation in FoxP3 >> no functional Treg cells >> widespread autoimmunity
      - symptoms:
        
        intractable watery diarrhea
        
        failure to thrive
        
        dermatitis
        
        autoimmune diabetes
      - Ig levels normal except inc. IgE