• immunologic ignorance
• anergy
• negative co-stimulatory molecules
• regulatory cells and cytokines
• cell death
• clearance of immune complexes

Name some immunologically priveleged site. What is responsible for this?

• brain
• eye
• testis
• uterus/fetus

Due to anatomical barriers and environment bein intrinsically toleragenic due to production of immunoregulatory cytokines like TGF β

1. trauma to one eye cause released of sequestered intraocular protein Ag
2. release intraocular Ag carried to lymph nodes and activates T cells
3. effector T cells return via blood stream and encounter antigen in BOTH eyes

• CD28 (T cell) interacts with B7 (on APC)
• CD40 (B cell) interact with CD40L (T cell)

inactivation of T cell (anergy)

• activate PI3K path
• cell survival/protection from apoptosis
• promote IL-2 production
• cytoskeletal rearrangements/shape change

Effect of lack of T cell help for B cells

• peripheral tolerance
  • block Ag-receptor induced signal (anergy)
  • exclude B cells from lymphoid follicles

Role of CD40L of T cells in B cell activation

• only expressed after T cell activation (critical for T and B cell responses)
• required for:
  • germinal center formation
  • isotype switching
  • memory cell formation

CTLA-4

PD-1

Fcγ receptors

• phosphorylation of inhibitory receptor
• leads to recruitment of inhibitory phosphatases (ex: SHP-1, SHP-2, SHIP)

1. competes with CD28 for binding with B7 molecule
   • has 100x higher affinity for B7 than CD28
2. transmit a negative signal that block CD28 signaling pathway
3. transmit signal to dendritic cell via B7 to induce indoleamine 2,3 dioxygenase (promote Trp metabolism); block T cell activation

Effect of polymorphisms associated with reduced expression of CTLA-4 in humans and mice

• humans- associated with increase risk for autoimmune disease (ex: SLE, Hashimotos thyroiditis)
• mice- have lethal autoimmune lymphoproliferative syndrome

Effect of pharmaceutical agents that block CD28/B7 interaction

• induce transplant tolerance
• treat autoimmune disease

• may compete with CD28 for B7 OR
• activate protein phosphatase and block PI-3 kinase activity

• enhance T cell immune function in chronic viral infection
• improve vaccine efficacy

• genetic disease due to lack of FoxP3
  • TF needed for development/function of CD4+CD25+ regulatory T cells

Mechanism of action of Treg cells

• contact dependent inhibition of T cell response
• secrete cytokines that inhibit T cell responses (contact independent)(IL-10, TGF-β)

Also remember it can inhibit the activation or effector functions of T cells.

• deletional tolerance- self reactive T cells deleted in thymus or if they escape to periphery, these self reactive T cells could be activated
• regulatory tolerance- when T cell specific for a self antigen can become regulatory T cell, leading to this regulatory T cell producing cytokines that will inhibit other self reactive T cells

• cause- pathogenic T cells in lamina propria
• treatment
  • transfer CD4+CD25+ T regulatory cells that home to mesenteric lymph node and colon
  • they will proliferate and inhibit pathogenic effector T cells
  • after inflamm. resolve, T reg cells remain in clusters with dendritic cell and pathogenic effector T cells

• inhibit Th1 and Th2 effector function/dev.
• promote dev./function of Treg cells
• promote dev. of Th17 cells in conjunction with IL-6

APC's have the potential to be regulatory cells. What types of environments and conditions would regulatory function of APC's be associated with?

• specific microenvironments
  • tumor
  • placenta
  • mucosal surfaces
• ingestion of apoptotic cells
• parasitic infections (ex: Leishmania, Schisto)

• acquire/present Ag to Ag-specific T cell
• low constitutive expression of surface MHC molecules
• low net expression of co-stimulatory molecules
• low production of IL-12
• high IL-10, IDO production
• resist maturation in response to danger signals (exL CD40L, TLR ligands)
• generate, select, expand alloAg specific, naturally occuring or adaptive regulatory T cells
• promote apoptotic death of effector T cells
• respond to Treg cells by upregulating expression of inhibitory molecules (ex: IL-10, IDO) to provide inhibitory feedback loop

• cause- genetic deficiency involving FAS or FASL genes
• clinical signs
  • lymphadenopathy
  • lymphocytic infiltrates in non-lymphoid organs
  • auto-Ab production

• passive- remove cytokines that promote survival
• active- Fas binds to FasL, activating caspase-8

Process of passive cell death

1. remove cytokines that promote survival
2. increase mitochondrial permeability, release cyc c
3. cyc c and Apaf-1 induced activation of caspase 9
4. activate effector caspases
5. apoptosis

Deficiencies in what complement proteins are associated with lupus like symptoms? Why?

Different types of phenomenon involved in the spread of autoimmune disease

• molecular mimicry
• bystander activation
• epitope spreading
• MHC regulation

• Ag receptor has cross reactivity btw microbial peptide and self peptide
• ex: S. pyogenes Ab could cross react with epitopes in heart, muscle, kidney, joints in rheumatic fever

• APC activated by inflammatory/pathogen product, but then proceeds to activate an autoreactive cell
• Forms 
  • T independent Ag's could stimulate autoreactive cells
  • IFN γ produced during inflammation induce MHC II on non-professional APCs (ex: tyroid epithelial cells) and present autoAg to activated T cells

Role of C3b in its interaction with the RBC

1. B cells with specificity for DNA bind soluble fragments of DNA, sending signal through BCR
2. cross linked BCR internalized with bound DNA molecule
3. GC rich fragments from internalized DNA bind to TLR-9 in endosomal compartment
4. this will send a co-stimulatory signal that activates the B cell

• immune response to self-Ag expands to additional self-Ag's as autoimmune pathology develops over time

• disrupt cell/tissue barrier
• infect APC
• binding of pathogen to self protein
• molecular mimicry
• superAg

• if dysregulated, could have autoimmune disease
• ex: IL-17 overexpression implicated in rheumatoid arthritis, IBD

How does MHC II active site structure influence development of IDDM

• Asp at position 57 promotes stability of DQ molecule
• if you substitute Asp with an uncharged AA
  • alter stability
  • decrease efficiency of peptide presentation
  • this all can lead to defect in negative selection