Antigen-presenting cells, defects

Litlierland SA, XieXT, Hutson AD, Wasserfall C, Wliittaker DS, She JX, Hofig A, Dermis MA, Fuller K, Cook R, Schatz D, Moldawer LL, Clare-Salzler MJ (1999) Aberrant prostaglandin synthase 2 expression defines an antigen-presenting cell defect for insulin-dependent diabetes mellitus. J Clin Invest 104 515—523. 

Muraille E, De Smedt T, Andris F, Pajak B, Armant M, Urbain J, Moser M, Leo O Staphylococcal enterotoxin B induces an early and transient state of immunosuppression characterized by V beta-unrestricted T cell unresponsiveness and defective antigen-presenting cell functions. J Immunol 1997 158 2638-2647. 

Noonan, F. R, De Fabo, E. C., and Morrison, H., Cis-urocanic acid, a product formed by UVB irradiation of the skin, initiates an antigen presentation defect in splenic cells in vivo, J. Invest. Dermatol. 90, 92-99, 1988. 

Finally, in this brief overview of lymphocyte defects, mention should be made of mutations affecting major histocompatibility-complex (MHC) Class II molecules. These mutations affect a multiprotein transcription factor complex that regulates the expression of MHC Class II molecules (121). Affected patients have undetectable levels of MHC Class II antigens HLA-DP, DQ, and DR on the surface of monocytes and B cells. Lack of these antigen-presenting molecules leads to impaired immune response. Affected individuals have moderate lymphopenia with a severely reduced number of CD4+ T cells and normal or increased numbers of CD8+ T cells. Since MHC molecules in the thymic epithelium play a key role in positive and negative selection of primitive T cells, selection of competent T cells is also affected in the absence of MHC Class II antigens. 

Synthesis of immunoglobulins is not impaired in most patients with malnutrition. The majority of children above 7 months of age have normal serum immunoglobulin values. About 10% have elevated or low-values, which are now not alw-ays related to the severity of the nutritional defect, but also to whether infection is present or not. Production of specific antibody to many antigens, as well as cell-mediated immunity, are depressed, however, in malnutrition. 

Ubiquitin-dependent proteolysis is as important for the regulation of cellular processes as for the elimination of defective proteins. Many proteins required at only one stage of the eukaryotic cell cycle are rapidly degraded by the ubiquitin-dependent pathway after completing their function. The same pathway also processes and presents class I MHC antigens (see Fig. 5-22). Ubiquitin-dependent destruction of cyclinis critical to cell-cycle regulation (see Fig. 12-44). The E2 and E3 components of the ubiquitination cascade pathway... 

One approach has been to develop strains of many of the viruses listed above as replication-defective or replication-incompetent . These viruses are cultured initially in conditions that provide some nutrient or element of the replicating machinery exogenously. Spontaneous mutations then create strains of virus that cannot replicate unless the crucial element is provided, and it is assumed that after human administration this will be the case. There is always the concern that, after injection, the virus will find some way to overcome its incompetency, e.g. by recruitment of the host cell machinery for this purpose. Similarly, non-viral vectors may offer an advantage by presenting the patient with less foreign antigen. 

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