• CD40 L (on CD4+  T cell surface)

• CD40 (receptor on APC surface)

• this interaction also ensures that the APC activated is the one that will respond most efficiently

how does T cell activation enhance macrophage function?

• upregulation of MHC and costimulatory molecules (B7): improves Ag presenting function of these cells leading to amplification of T cell response
• secretion of cytokines: TNF-a, IL1, IL12 that may stimulate T cells
• killing of phagocytosed microbes via ROI, NO

• Th2 secretion of IL4, IL5, IL10, IL13 can inhibit the activation of macrophages and Th1 cells, thereby limiting DTH rxn
• IL 10, IL4, IL 13 block the activity of IFN-g (macrophage activation) and TNF-a (inflammation)
  

• secrete pro inflammatory cytokine, IL 17
• generated from stimulation of naive T cells in presence of IL 6/IL10 and TGF b
• important role in mediating inflammation of the skin, GI tract; immunity against extracellular bacteria
• serve effector T cell functions in autoimmune diseases, like RA and MS

• increased susceptibility to infections by viruses and intracellular bacteria
• potential impairments could be:
  • defective IL 12 receptor
  • defective IFN-g receptor
  • defective CD40 L

CD4+ effector T cell binds its CD40 ligand to APCs CD40

also, CD4+ cell secreted IFN-g that binds to APCs IFN-g receptor

• Ag challenge to skin
• leukocyte migration out of bvs into perivascular tissue close to site (via chemokines, cytokines, and adhesion moles)
  • "mononuclear cell infiltration"
• effector T cell migration out of bvs to tissue; these Ag-specific CD4+ T cells get re-activated at the site
• CD4+ T cells secrete IFN-g (macrophage activation), TNFa (endothelial cell stimulation)
• result: vasodilation, leukocyte extravasation
• if microbe assault is chronic, macrophages unable to clear it and begin to accumulate in the area--> GRANULOMA formation
  • may form multi-nucleated Giant cells
• at the same time, macrophage microbicidal agents disperse, causing more tissue damage
• fibrosis is end result of chronic inflammation

• activated macrophages
• activated lymphocytes
• activated endothelial cells

every immune cell type has its own associated adhesion molecules.  what are they for PMNs, monocytes, and Tcells?

• Neutrophils: E selectin
• Monocytes: ICAM-1
• T cells: VCAM-1

what is the time course of leukocyte infiltration during antigen challenge?

•  PMNs respond first and quickly (expression of E selectin shoots UP fast)
• Monocytes then increase in number more gradually over first 12-18 hours and have a relatively sustained presence (ICAM-1 expression maintains...)
• after 18 hours, T cell proliferation occurs, peaking around 36 hours...its VCAM expression started much earlier, but as it begins to peak, we see more T cell infiltration to site

agent: Mycobacterium tuberculosis

damage caused by chronic granulomatous inflammation

Tb granulomas have this *unique* feature:

central area of caseating necrosis

what CD4+ T cell subset is associated with lepromatous leprosy?

more dispersed infection resulting from inability to control the intracellular assault. Th1 (CMI) would handle this type of response, but impaired/inadequate in the case of lepromatous leprosy

so:

TH2 (humoral mediated) response predominates in lepromatous leprosy

what CD4+ T cell subset is associated with tuberculoid leprosy?

TH1 (CMI) response predominates in tuberculoid leprosy

Th1 cytokines are lacking:

• IFN-γ
• TNF
• IL 2

Th2 cytokines are lacking in tuberculoid lep:

• IL 4
• IL 5
• IL 10

what are some of the pathologies seen in schistosomiasis?

• formation of granulomas around schistosome eggs in liver
• extensive hepatic fibrosis and tissue damage resulting from chronic DTH response, mediated by CD4+ T cells

in schistosomiasis there is a strong Th2 response. what cytokines are implicated and what do they stimulate?

the granulomas formed around the schistosome include: macrophages, lymphocytes, neutrophils, and eosinophils

Th2 cells (that secrete IL-4, 5, and 3)  are responsible for eosinophilia (IL-5- growth factor for eosinophils), mastocytosis (IL-3 and 4), and high serum IgE (IL-4).

self antigenic targets:

heat shock proteins

collagen type II

insulin

GAD65

self antigens involved:

myelin basic protein

proteolipid protein

immune damage is also possible w/or w/o CD4+ mediated DTH, and primarily resulting from CD8+ activity.  what are some examples of these conditions?

• graft rejection
• contact dermatitis (poison ivy)
• viral hepatitis (by hep B)
• myocarditis (following coxsackie virus B infection)

etanercept is a recombinant soluble TNFa receptor antagonist that binds TNFa

this has beneficial results for RA pts, but not for those with latent Tb infection

TNFa is crucial in maintaining the mycobacterium dormancy

• block cytokine action via neutralization or by interference w/ receptor binding
  • anti-TNFa Ab/ anti-IL 6 Ab/ anti-IL1 Ab
  • soluble TNFa receptor (etanercept!)
• inhibition of T cell activation
  • block costimulation by anti-CD40L Ab
  • CTLA-4-Ig (binds to APC B7, only transmits inhibitory signals, not stimulatory ones)
  • anti-CD3 Ab
• immune deviation (ie: Th1 -> Th2)
  
  • use of altered peptide ligands
• induction of regulatory T cells
  • priming of Treg cells (that secrete TGFβ, IL10) with nasal/oral Ag admin 
  • in vitro expansion of CD25+CD4+ T cells (ie: FoxP3 expressing T reg cells) for use in vivo